July 20, 2018
5 min read
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Man presents with bilateral blurred vision

Exam showed bilateral optic disc hyperemia with tortuous retinal arterioles.

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A 42-year-old man was referred from an outside provider with complaints of bilateral blurry vision. Approximately 1 month before presentation, the patient was grocery shopping and noted new difficulties with reading the food labels at near. He purchased over-the-counter reading glasses at the time that helped, but over the next few weeks, his vision continued to worsen both at distance and near. He also complained of a “fog” overlying the vision in both eyes. In addition to the decreasing quality of his vision, he also noted a new-onset light sensitivity. He did not complain of any specific areas of field loss, had no headaches and did not notice any acute changes in hearing.

The patient was referred to the neuro-ophthalmology clinic at the New England Eye Center for further evaluation and management. He was a daily smoker and prior heavy drinker. His medical history was significant for hypertension and asthma. His only systemic medications were lisinopril and an albuterol inhaler. To his knowledge, he had no known family history of eye disease.

Examination

On initial examination, best corrected visual acuity was 20/100 in the right eye and 20/50 in the left eye. Both pupils were briskly responsive to light, and no afferent pupillary defect was appreciated. Confrontation visual fields were full bilaterally. Color vision testing was slightly decreased with 8/10 Ishihara plates correctly identified in both eyes.

Figure 1. Fundus photographs of the right and left eyes. There is hyperemia of both optic discs, as well as tortuosity of the retinal arterioles.

Source: Omar Dajani, MD, and Thomas R. Hedges III, MD

Figure 2. OCT of the retinal nerve fiber layer of the right and left eyes showed possible thickening of the right optic nerve superiorly and inferiorly.
Figure 3. Ganglion cell analysis of both eyes demonstrating bilateral nasal thinning.

Anterior segment exam was significant only for mild nuclear sclerotic cataracts bilaterally. Fundus exam demonstrated bilateral hyperemia of the optic discs as well as tortuosity of the retinal arterioles (Figure 1). The optic nerve did not demonstrate any flame hemorrhages, and the macula had no visible exudates. OCT revealed possible retinal nerve fiber layer thickening of the right optic nerve superiorly and inferiorly (Figure 2). Ganglion cell analysis demonstrated thinning nasally in both eyes (Figure 3).

What is your diagnosis?

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Subacute vision loss

Our patient was found to have bilateral optic nerve hyperemia with retinal arteriolar tortuosity. A differential diagnosis for subacute-onset bilateral blurry vision with possible optic nerve swelling includes infectious causes such as syphilis, Lyme and tuberculosis, as well as inflammatory disease including giant cell arteritis and sarcoidosis. However, these causes would likely present with additional findings such as a periphlebitis, seen in many cases of sarcoidosis. Giant cell arteritis is likely to demonstrate other systemic symptoms including headaches, jaw pain or weight loss. Vascular insults must also be considered in such a setting; nonarteritic anterior ischemic optic neuropathy and malignant hypertension should be on a differential, but these would likely present with additional signs such as hemorrhages or cotton wool spots in malignant hypertension.

Optic neuritis is a consideration but is less likely given an absence of pain. Compressive mass lesions should also be considered as increased intracranial pressure can lead to papilledema. Acute papilledema that causes such severe vision loss would often show other signs on exam, including retinal venous tortuosity, papillary or peripapillary retinal hemorrhages, and loss of venous pulsations. In light of our patient’s smoking and alcohol use, nutritional issues such as vitamin B12 or folate deficiency should be considered. Additionally, his extensive smoking history raises the potential for paraneoplastic disease stemming from undiagnosed lung cancer, which should be explored. Finally, in a young man with such significant vision loss and retinal arteriolar tortuosity, one must think of Leber hereditary optic neuropathy (LHON).

For an initial workup, an MRI of the brain and orbits was ordered, which demonstrated possible hyperintensity in the intraforaminal and intracranial portion of the optic nerves bilaterally and the optic chiasm. On 3-week follow-up exam, our patient had experienced continued vision loss and was now only able to count fingers at 3 feet bilaterally. His pupils were also now sluggishly reactive to light bilaterally. Additionally, after his initial visit, the patient learned that a maternal uncle and maternal second male cousin both have poor vision. One of his relatives had been tested in the past, and it was revealed that our patient had a strong family history of LHON. A lab workup was then sent, including vitamin B12 level and genetic testing for LHON, which revealed a positive mutation of the nucleotide position 3460.

Discussion

LHON is an inherited mitochondrial disease that affects males generally between the ages of 10 and 30 years old. It results from point mutations in mitochondrial DNA that cause degeneration of retinal ganglion cells. These point mutations result in dysfunction of NADH:ubiquinone oxidoreductase subunit 4. This leads to impairment of glutamate transport, causing an increase in oxygen radicals and apoptosis of retinal ganglion cells. It most often presents as a unilateral, painless, progressive optic neuropathy with subacute vision loss. Over months to years, the fellow eye becomes involved. While vision loss is initially mild, it usually progresses to worse than 20/200. Examination may reveal an afferent pupillary defect if the patient presents during the asymmetric phase of the disease. Peripheral field testing tends to be intact, but there is often a central or cecocentral scotoma. Dilated fundus examination is likely to show hyperemic optic nerves, and there are usually peripapillary telangiectasias present. As in our patient, tortuosity of retinal arterioles often occurs. Despite the hyperemic appearance of the nerves, they do not display leakage on fluorescein angiography. Thus, LHON is considered to demonstrate “pseudo-edematous” optic nerves because while they may appear swollen, there is no actual leakage.

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Diagnostically, if there is no known family history of LHON, other causes of optic neuropathy should be ruled out before a diagnosis of LHON. As mentioned in the differential above, this should include testing for syphilis with an RPR and FTA-ABS and a PPD or QuantiFERON if tuberculosis is suspected. Inflammatory disease, such as sarcoidosis, should be ruled out with an ACE, lysozyme and chest X-ray. As in our patient, nutritional disease must be considered with vitamin B12 and folate levels if clinically appropriate. Indeed, LHON may be associated with nutritional deficiency. MRI of the brain can be useful to eliminate concerns of a compressive lesion, and although this is not considered diagnostic, LHON often demonstrates increased T2 signal in the optic nerves, chiasm and tracts. An orbital fat-suppressed contrast-enhanced MRI may show optic nerve enhancement similar to optic neuritis. Once other causes have been excluded, gene testing is used to confirm the diagnosis. The three most common mutations (11778, 14484, 3460) comprise 90% of all LHON patients.

There is currently no treatment available for LHON. Management is essentially supportive, with a focus on low vision aids and therapy aimed to improve the patient’s daily functions. Gene therapy is currently being explored as a way to possibly improve vision in those with LHON. Separate trials have been researching the use of virus vectors expressing normal mitochondrial genes as a means of introducing oxidoreductase subunit 4 intravitreally. These studies are still in their early phases but, if successful, could lead to improved vision for those patients with LHON.

Clinical course continued

The patient was registered with the commission for the blind in order to help set up support in terms of visual aids and assistance going forward. He was also told to stop smoking and drinking as both have been hypothesized to potentially stress mitochondrial function. He is scheduled to follow up in 3 months from the date of his last appointment.