A Case of Late-Onset Leber's Hereditary Optic Neuropathy

By By Carol Aune, B.S., O.D., and James Walters Ph.D., O.D.

Goal Statement:

This article reviews the case of a 51-year-old man with Leber’s Hereditary Optic Neuroparthy (LHON). In addition, it discusses the role of genetic testing in LHON patients, where the diagnosis may be difficult to confirm.

Faculty/Editorial Board:

Carol Aune, B.S., O.D., and James Walters, Ph.D., O.D.

Credit Statement:

This course is COPE-approved for 1 hour of CE credit. COPE ID is 33939-PS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Drs. Aune and Walters have no relationships to disclose.

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LEBER'S HEREDITARY OPTIC NEUROPATHY (LHON) is a maternally inherited mitochondrial disorder that is characterized by painless, subacute, bilateral vision loss. The condition occurs primarily in young, adult males. The average age of onset ranges between 18 and 35 years; however, delayed onset has been reported in patients as old as 73 years of age.

When examining a patient with LHON, the fundus examination may appear normal at the onset of vision loss although the clinician may observe optic nerve and nerve fiber layer (NFL) swelling on optical coherence tomography; vascular tortuosity; arteriolar dilation; and peripapillary telangiectasias.

The atrophic phase demonstrates bilateral, temporal optic pallor that often progresses to complete optic atrophy. Cell death is limited to the retinal ganglion cells and is hypothesized to be a result of apoptosis secondary to oxidative stress caused by mitochondrial mutations.

LHON is largely a diagnosis of exclusion, and other causes of optic neuropathy (i.e., toxic/ nutritional, compressive, ischemic, etc.) must be ruled out. Regardless of age, genetic testing in any individual suspected of LHON should be performed to confirm the diagnosis.

There is no available treatment for LHON, but low vision aids and counseling should be recommended. Also, you should advise LHON carriers to moderate their smoking and alcohol intake.

Here, we will examine the case of a 51-year-old man with LHON. Additionally, we will discuss the role of genetic testing in LHON patients who present with unex plained bilateral vision loss, where the diagnosis remains in doubt.

Patient History

A 51-year-old black male was referred for electrodiagnostic testing by his ophthalmologist as a result of unexplained bilateral vision loss. His chief complaint included loss of central vision in both eyes (O.S. > O.D.) and decreased color vision O.U.

The patient stated that the vision in his right eye became blurred three months earlier, followed by pronounced vision loss in his left eye one month later. He informed us that his vision gradually worsened over a two-month period and then stabilized. His blurred vision was constant, and affected all viewing distances. The patient denied pain while chewing, scalp tenderness or joint ache. He also denied any family history of vision loss.

Recently, the patient was diagnosed with type 2 diabetes mellitus and hypertension. His current medications included metformin, quinapril and verapamil.

At the most recent visit to his ophthalmologist one month earlier, he was diagnosed with unexplained vision loss O.U.; complete color blindness O.U.; mild, non-proliferative diabetic retinopathy with no clinically significant macular edema O.S.; and temporal pallor of the optic nerve heads O.U.

The patient was referred for MRI scans of the brain and orbits (with and without contrast), which were unremarkable. The patient reported discontinuing all alcohol intake four months prior, but he used to consume three to four beers per day. He denied any tobacco and/or illicit drug use. The patient was a truck driver for 27 years, but was on medical leave because of his reduced vision.

Diagnostic Data

The patient's uncorrected entering visual acuity measured 20/400 O.D and 10/400 O.S., with no improvement upon pinhole testing or refraction. Confrontation fields revealed defects in the inferior quadrants of the right eye and all regions of the left eye except the superior temporal quadrant. Other preliminary testing, including pupillary response, ocular motility and bio-microscopy, were unremarkable.

His intraocular pressure measured 22mm Hg O.D. and 17mm Hg O.S. Fundus photography indicated thinning of the temporal rim of the right optic nerve and superior rim of the left optic nerve. We observed a wedge defect in the inferior NFL of the left eye as well as mild temporal optic nerve pallor in both eyes. We performed visually evoked response (VER) and documented no significant pattern. However, a flash VER at 2Hz and 8Hz showed a moderately strong outcome in the right eye and a severely compromised outcome in the left eye.

Initial presentation of our patient indicated mild temporal optic nerve pallor in both eyes.

Nine months later: Increased temporal optic nerve pallor in both eyes.

 

We believed that the patient had bilateral optic atrophy, with a suspected hereditary component. We told him to return to his ophthalmologist, and recommended genetic testing for LHON.

The patient returned nine months later for a low vision evaluation. He stated that his vision remained unchanged and reported that he had not returned to the original referring ophthalmologist for additional testing.

Instead, he went to a different ophthalmologist who diagnosed him with bilateral primary open-angle glaucoma; prescribed topical bimatoprost; and referred him to a neuro-ophthalmologist.

A review of the patient's records indicated that the neuro-ophthalmologist suspected nutritional amblyopia and ordered a complete blood count. The results revealed a slight decrease in hematocrit, hemoglobin, red blood cells and B₁ levels (for which the patient was started on B₁ oral supplements). However, routine chemistries, liver function studies, protein electrophoresis, lead, B₁₂ and folate levels were all normal ruling out nutritional amblyopia. At that time, the neuro-ophthalmologist suggested that LHON was the top differential diagnosis.

Humphrey 24-2 visual field threshold testing revealed a significant secocentral scotoma (O.D. > O.S.) and arcuate defects in both eyes.

 

At the low vision evaluation, the patient's uncorrected entering visual acuity measured 10/80 O.D. and 10/60 O.S., with no improvement upon pinhole testing or refraction. Preliminary testing included pupillary response, ocular motility and biomicroscopy, which were unremarkable. Humphrey 24-2 visual field threshold testing revealed a significant secocentral scotoma in both eyes (O.D. > O.S.). We also documented an inferior arcuate defect of the right eye and a superior arcuate defect of the left eye.

NFL analysis on optical coherence tomography revealed thinning of the inferior and superior temporal quadrants O.U. A high-definition scan of the macula showed loss of the papillomacular NFL bundle O.U., with no other macular pathology.

The pattern VER remained severely depressed, and the 2Hz and 8Hz flash VERs were repeated. The results indicated that the left eye was now more responsive than the right eye. Fundus photography documented increased temporal optic nerve pallor in both eyes as well as increased thinning of the superior temporal rim of the left optic nerve. The patient refused optical aids, although we observed a positive response to magnification. The patient was counseled on a probable diagnosis of LHON, because the genetic testing results for the three primary mutations were still pending.

Two months later, the genetic testing results revealed a G>A nucleotide substitution at mitochondrial position 11778 in the patient's DNA. This finding was consistent with a definitive diagnosis of LHON.

Discussion

LHON is one of the most common hereditary optic neuropathies.¹ Vision loss usually occurs in one eye first, and may occur either suddenly or progressively over two to three months.³ Vision loss in the fellow eye typically occurs nine months later, with two months being the mean interval between vision loss in each eye.³ Simultaneous onset may present in approximately 25% to 50% of occurences.^2,3 Patients often have no family history of vision loss, with 40% of cases occurring in just one family member.² Males are four times more likely to be affected than females.² The worldwide prevalence of LHON is estimated to be one in 50,000.³

LHON carriers typically are asymptomatic until the onset of the acute phase, which causes central vision blurring as well as a central or secocentral scotoma on field testing.^2,7 During the pre-symptomatic phase, carriers may present with temporal NFL swelling and peripapillary telangi-ectasic vessels.^2,8 During the acute phase, fundus examination may be normal in 20% of patients.²

A high-definition optical coherence tomography (OCT) scan of the macula documented loss of the papillomacular nerve fiber layer bundle in both eyes, with no other macular pathology.

 

The atrophic phase demonstrates bilateral, symmetrical, temporal optic pallor that often progresses to complete optic atrophy.^2,7,8,10 Optical coherence tomography frequently reveals preferential involvement of the papillomacular bundle and/or early involvement of the inferior NFL.⁸

Final visual acuities usually are worse than 20/200; however, reports of mild, spontaneous recovery have been documented.^2,3 As with all optic neuropathies, color vision defects, especially red/green anomalies, may be observed. VER amplitudes often are found to be reduced or flat. Vision loss usually is the only symptom of LHON; but, associated neurological complications, such as peripheral neuropathy, postural tremor, movement disorders, multiple sclerosis and cardiac anomalies, have been reported.^2,4

LHON was the first mitochondrial disease to be discovered, and three primary mutations of the mitochondrial DNA (m.3460G>A, m.11778G>A, m.14484T>C) have been found in 90% of all LHON patients.^1-3,8,11,12 These mutations affect the first site of the mitochondrial respiratory chain.^2,11 It is important to note that these primary mutations are more common in patients with a family history of multigenerational vision loss, whereas patients with no known family history often do not have a primary mutation.¹¹

In recent years, 45 other mutations in mtDNA also have been associated with LHON.¹³ Just 50% of males and 10% of females with the genetic defect develop optic neuropathy.^4,12 Due to this incomplete penetrance, it is likely that other factors are involved in disease expression. Smoking and high alcohol intake have been identified as triggers for visual loss in individuals carrying a known Leber's mutation.¹² Other factors, such as poor nutrition, stress, exposure to toxins and trauma, have been reported in clinical practice.¹²

Nerve fiber layer analysis on OCT revealed thinning of the inferior and superior temporal quadrants O.U.

 

The optic nerve is rich in mitochondria, and neurons are dependent on mitochondria for survival. Defects in the respiratory chain of the mitochondria lead to increased free radical proliferation and decreased ATP production, which cause oxidative stress.⁴ It is theorized that neuronal degeneration is a result of oxidative damage caused by associated oxidation.⁴

Cell death is limited to the retinal ganglion cells, and is hypothesized to be a result of apoptosis secondary to oxidative stress (although it is unknown why only the ganglion cell layer is affected or why healthy individuals suddenly develop symptoms).^2,13 The preferential involvement of the papillomacular bundle is thought to occur because of its small axons.⁸

As previously mentioned, there are no known treatments for LHON. The LHON Treatment Trial attempted to use topical brimonidine prophylatically to prevent vision loss in patients' unaffected eyes.⁷ Brimonidine was used because of its antiapoptic properties; however, it was unsuccessful. Other studies have shown that idebenone, minocycline, infrared light and multivitamin supplementation, were ineffective in improving vision or preventing vision loss.^2,3,7,14 Currently, antioxidant gene therapy is under investigation.¹³

Fundus photography of our patient’s left eye at initial presentation. We located a wedge defect in the inferior nerve fiber layer. The posterior pole of the right eye was unremarkable.

The wedge defect in the inferior nerve fiber layer was more evident on red-free photography.

 

LHON is largely a diagnosis of exclusion, and diagnostic confusion may occur with compressive, toxic, nutritional, ischemic or other hereditary optic neuropathies. All patients suspected of LHON should undergo MRI, VER and complete blood testing to rule out other etiologies.

Ultimately, all LHON suspects should be considered for genetic testing to confirm the diagnosis. Remember, however, absence of the mutation does not rule out LHON, because all the mutations attributed to the disease have not yet been identified.

Dr. Aune is an optometrist practicing in Raleigh and Eastern N.C., where she focuses on ocular pathology, low vision and specialty contact lenses. Dr. Walters is an associate professor at the University of Houston College of Optometry and clinical director of the Ocular Diagnostic and Medical Clinic at the University Eye Institute. He has a background in clinical electrophysiology and a special interest in retinal pathology.

References

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