Many groups around the world have been working tirelessly towards pushing the diagnostic and therapeutic boundaries of diseases that lead to irreversible vision loss. Here, we provide a short primer on some of the advances made in the neuro-ophthalmology community during the past decade.

ACUTE OPTIC NEURITIS

Although the Optic Neuritis Treatment Trial (ONTT), a seminal study published more than 20 years ago, defined the presentation, natural evolution and associated risk of developing multiple sclerosis (MS) in patients presenting with typical optic neuritis, clinical observations over the past decade have expanded our understanding of the range of inflammatory demyelinating diseases that can affect the optic nerve.

Initially, reports of patients who developed severe, often bilateral, optic neuritis and spinal cord inflammation were thought to represent an anatomically isolated form of MS. The discovery that most of these patients had detectable antibodies against the aquaporin-4 (AQP-4) protein led to the distinction of these patients from those who developed MS into the clinical syndrome now known as neuromyelitis optica spectrum disease (NMOSD).

As NMOSD patients tend to present with bilateral simultaneous optic neuritis, they would have been excluded from the original ONTT study. Thus, the teachings from the ONTT have limited application to NMOSD patients. For example, although patients in the ONTT had similar visual outcomes whether they were treated with intravenous (IV) steroids or placebo, studies have shown that patients with NMOSD have worse visual outcomes if immunosuppressive therapy is delayed. Given that serologic testing for anti-AQP4 antibody can take weeks to result, the distinction between patients with MS-related optic neuritis, who can be observed without urgent immunosuppression, vs NMOSD-related optic neuritis, who need urgent treatment, is challenging. In fact, treatment of NMOSD patients with certain MS-approved drugs, namely interferons and natalizumab, can lead to worsening of NMOSD symptoms, making the distinction even more critical.

The following vision-related clinical characteristics have been described to help distinguish adults with NMOSD from typical optic neuritis: NMOSD patients tend to present with more severe loss of vision (eg, hand motions to no light perception), more frequently develop bilateral simultaneous optic neuritis, have longer segments of contrast enhancement of the optic nerve on magnetic resonance imaging (MRI) and more frequently present with optic disc edema. This is not to say that these findings are never associated with typical optic neuritis. Rather, this presentation should alert the general practitioner to the possibility of NMOSD and the need for urgent treatment. Additionally, in patients who show minimal improvement in visual acuity after 5 days of IV methylprednisolone, plasmapheresis can be considered.

Longitudinal studies of patients who satisfy the diagnostic criteria for NMOSD revealed a cohort of patients whose vision responded more rapidly to immunosuppression in the acute phase and who had better visual outcomes in the chronic phase. Serological studies demonstrated an association with anti-myelin oligodendrocyte protein (MOG) antibodies, leading to the classification of these patients into a separate entity: MOG-associated disease (MOGAD).

Similar to NMOSD, MOGAD patients present with severe vision loss from optic neuritis and spinal cord inflammation. The optic neuritis in MOGAD, however, is more commonly associated with optic disc swelling and hemorrhages and macular microcysts than either NMOSD or MS. While contrast enhancement of the optic nerve on MRI in MOGAD patients tends to be long, similar to NMOSD, imaging often uniquely demonstrates concurrent enhancement of the optic nerve sheath. Given the severe vision loss with which MOGAD patients present, IV steroids are commonly considered by practitioners in the acute phase.

ACUTE RETINAL ARTERY OCCLUSION

Many of us are familiar with the American Stroke Association’s FAST (Face, Arms, Speech, Time) campaign to increase public awareness of stroke symptoms. These campaigns were needed when life-changing thrombolysis therapy became available, to get patients to the emergency room fast enough to be eligible for thrombolysis therapy. Recently, the ASA expanded its campaign to include vision loss (BEFAST or Balance, Eyes, Face, Arms, Speech, Time), recognizing that monocular transient visual obscurations that are vascular in etiology are equivalent to cerebral transient ischemic attacks and that retinal artery occlusions are equivalent to cerebral infarctions.

In concert, the AAO and the North American Neuro-Ophthalmology Society put forth recommendations that patients presenting with acute retinal artery occlusions should be sent urgently and directly to emergency rooms that are equipped to handle acute stroke. The two major reasons for this are to recover vision and to evaluate for cerebral infarction.

The premise for the first goal comes from animal studies showing that irreversible retinal ganglion cell damage occurs after more than 100 minutes of ischemia, suggesting that there is a critical window within which, if re-perfused, visual function could be restored. Thrombolysis therapy for retinal artery occlusions could be delivered systemically to patients who present within the 4.5-hour symptom-onset-to-treatment window.

Alternatively, for those institutions that are able to perform intra-arterial, ophthalmic artery thrombolysis, patients who present within the 6-hour symptom-onset-to-treatment window are eligible for treatment.

Although there seems to be significant controversy in the literature regarding the efficacy and safety of thrombolysis for retinal artery occlusions, a recent meta-analysis put forth by Dr. Valerie Biouse’s group showed that studies demonstrating no benefit or harm enrolled patients who were treated outside the recommended treatment window, while those studies that strictly adhered to the treatment window guidelines demonstrated potential benefit. To assess the true potential of thrombolysis therapy to restore vision, two things are needed:

1. Public campaigns to increase awareness of vision loss as a sign of stroke
2. Rapid screening and referral of patients with transient visual obscurations or artery occlusions by community eye providers directly to the emergency room (ie, not to a retina or neuro-ophthalmology specialist).

Another important reason to refer patients with acute retinal artery occlusion to the emergency room is to evaluate for the presence of current cerebral infarction. In the EAGLE study, 78% of patients with central retinal artery occlusions were found to have a previously unknown cardiovascular risk factor. Another group found that 25% of patients with central retinal artery occlusions have “silent” infarcts on MRI. Given this, patients with transient visual obscurations of vascular etiology or retinal artery occlusions presenting within 2 weeks of symptom onset should be sent directly to the emergency room.

LEBERS HEREDITARY OPTIC NEUROPATHY

Lebers Hereditary Optic Neuropathy (LHON) is a maternally inherited, bilateral optic neuropathy that typically blinds young men. Patients with LHON have a mitochondrial genetic mutation that cripples their body’s ability to efficiently harness energy from glucose. As retinal ganglion cells are one of the most metabolically demanding cells in the body, patients develop vision loss from insufficient availability of ATP, a deficiency that is not too infrequently precipitated by recent consumption of metabolic toxins (eg, alcohol).

Herculean collaborative efforts during the past decade have led to the development of gene therapy for the treatment of LHON: adeno-associated viral vector is used to deliver the wild-type form of the mitochondrial ND4 protein, which is defective in patients with the 11778 mutation. Results from the Phase 3 randomized, double-masked, sham controlled clinical trials RESCUE and REVERSE and the follow-up RESTORE study for LHON have been recently reported. In these studies, patients were randomized to receive a single, unilateral injection of carrier virus.

The major difference between the RESCUE and REVERSE trial are that patients had to be enrolled within 6 months of symptomatic vision loss in the former, while patients were enrolled if they presented between 6-12 months of symptomatic vision loss in the latter. The RESTORE trial presented long-term follow-up results of both the RESCUE and REVERSE trials. Unfortunately, in the RESCUE trial, patients achieved comparable visual outcomes in injected and uninjected eyes.

In the REVERSE trial, although treated patients gained on average +15 ETDRS letters from baseline, sham-treated eyes showed a similar improvement (+13 ETDRS letters), contrary to the expected natural history of the disease. RESTORE found that the BCVA and vision-related quality of life improvements observed in treated patients continued to be improved at year 3 when compared to the onset of vision loss.

As gene therapy continues to undergo development for improved clinical application, in the interim many practitioners recommend 900 mg/day of idebenone, a safe and well tolerated co-enzyme Q10 derivative, to their LHON patients.

IDIOPATHIC INTRACRANIAL HYPERTENSION

Idiopathic intracranial hypertension (IIH) is a disease in which elevated intracranial pressure (ICP) leads to symptoms stereotypic of elevation in ICP without radiologic or clinical signs, with the exception of cranial nerve six palsies, of an alternative diagnosis. Although IIH has been shown to have a high association with rapid weight gain and obesity, the exact etiology of IIH is still unknown. Elevation in ICP in IIH, similar to glaucoma, results from decreased drainage of cerebral spinal fluid (CSF) rather than increased production.

How is CSF drained from the brain? Three inter-related pathways are thought to exist:

1. Avascular arachnoid granulations directly from the subarachnoid space into the dural sinuses;
2. The glymphatic system from the periarterial space, through the brain parenchyma, into the perivenular space into dural sinus via vascular arachnoid granulations; and
3. Dural meningeal lymphatics.

The finding that drainage through the glymphatic system is sensitive to metabolic hormones produced in fatty tissue is believed to explain, in part, the association of obesity with IIH. Many groups are working on developing targeted drug therapies to block the effects of these metabolic hormones as a potential new treatment modality for IIH.

Treatment options for IIH begin with weight loss followed by diuretics such as acetazolamide, shunts (eg, ventriculoperitoneal or lumboperitoneal) and optic nerve sheath fenestrations (ONSFs), depending on disease severity and symptoms. Because decrement in central visual acuity is an end-stage finding in IIH, all patients should be monitored with serial visual field testing. The IIH Treatment Trial demonstrated the superiority of acetazolamide combined with weight loss in improving visual field loss overweight loss alone in patients with mild visual field changes.

Of note, the target dose of acetazolamide in the IIH Treatment Trial was 4g/day indicating that effective treatment may require high doses. Although the Surgical IIH Treatment Trial was designed to compare the efficacy of ONSFs vs shunting for the treatment of IIH patients with moderate visual field loss, failure to enroll patients led to the closing of the study.

Dural sinus stenting is becoming more widely accepted as a treatment option for patients with IIH given that over 90% of patients with IIH have stenosis of their dural sinuses, primarily at the transverse-sigmoid sinus junction. Patients with >8 mm Hg transstenotic gradient are likely to benefit from stenting, which is generally performed by an endovascular neurosurgeon or interventional radiologist or neurologist. Advantages associated with dural venous stenting include improvements in visual fields (72.7%), visual acuity (64.6%), headache (71.2%) and papilledema (87.1%). Treatment of IIH requires a multi-disciplinary approach.

CONCLUSION

Although not meant to be an exhaustive list, we hope this primer whets the palate regarding developments in neuro-ophthalmology during the last decade. OM

Kimberly Kinga Gokoffski, MD, PhD, is a board-certified neuro-ophthalmologist at the Roski Eye Institute at University of Southern California in Los Angeles.
Dr. Gokoffski revelaed no relevant disclosures.