Unlocking Leber’s Hereditary Optic Neuropathy

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Promising new research offers a glimmer of hope for an otherwise intractable disease.

By Jerome Sherman, O.D., and Jinyoung Choe, B.A.

EXPIRATION DATE: NOVEMBER 1, 2015

GOAL STATEMENT:

Leber’s hereditary optic neuropathy is an uncommon presentation in the optometrist’s office, but its quickly advancing effects will devastate a patient’s vision. While the condition was identified more than a century ago, there are no effective or approved treatments for it. However, at least one promising treatment is in the offing. This course reviews the characteristic ocular signs of Leber’s hereditary optic neuropathy and its typical progression, and also offers some new information on the potential treatment for this devastating condition.

FACULTY/EDITORIAL BOARD:

Jerome Sherman, O.D., and Jinyoung Choe, B.A. He is the past president of the Optometric Retina Society and one of the founding members of the International Foundation of Optic Nerve Disease (IFOND).

CREDIT STATEMENT:

This course is COPE approved for 2 hours of CE credit. COPE ID 36331-NO. Check with your local state licensing board to see if this counts toward your CE requirements for relicensure.

JOINT-SPONSORSHIP STATEMENT:

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

DISCLOSURE STATEMENT:

Dr. Sherman is on the Speakers Bureau for Carl Zeiss Meditec. Ms. Choe has no relationships to disclose. Dr. Sherman lectures and consults for Zeiss, Optovue, and Diopsys.

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A century and a half ago, ophthalmologist Theodor Leber discovered an acute onset optic neuropathy that typically affects males in their 20s and invariably leads to bilateral optic atrophy and irreversible blindness.

This disorder, now known as Leber's hereditary optic neuropathy (LHON), usually occurs in young men aged 15 to 30 years and less commonly in women of the same age.¹ It presents as an acute or subacute disease resulting in characteristic sudden, painless, sequential, bilateral loss of central vision, and ultimately in the formation of centrocecal scotomas.

During the acute phase, the optic disc appears swollen and peripapillary retinal telangiectasias (corkscrew-appearing vessels) are typical. However, there is no disc leakage observed on fluorescein angiography (figure 1).

In the vast majority of cases, vision loss is sequential—involvement of the second eye occurs weeks to months after the first. Visual deterioration is extreme, with acuity often plummeting to worse than 20/200 in each eye; vision reduced to bare light perception is common. Reports of LHON have usually described its course as a rapid visual deterioration (with the exception of one study that reported cases of slow and insidious visual loss).⁵

In addition to LHON, Dr. Leber also described a congenital retinal disorder similar to retinitis pigmen-tosa but present at birth. This outer retinal disorder, termed Leber's congenital amaurosis (LCA), affects the photoreceptors and RPE but has no relationship to the optic nerve disorder LHON.

Electroretinograpy (ERG), the best overall objective test of the retinal function of photoreceptors, is often extinguished or dramatically reduced in LCA. The outer retina (containing the photoreceptors) is normal in patients with LHON; hence, the ERG will be normal. Because LHON is an optic nerve disorder, the visual evoked potential (VEP) will be abnormal. Of interest, the VEP can demonstrate transmission delays even prior to vision loss in LHON.

Another inherited optic neuropathy is Kjer's or auto-somal dominant optic atrophy. It can be transmitted by either parent and can be present in every generation. It is now believed that Kjer's is a mitochondrial optic neuropathy with involvement of the OPA1 gene.⁶ These patients have a slowly progressive bilateral loss of visual acuity, color vision and central visual fields.

CURRENT AND EMERGING TREATMENTS

Although the disease was identified in 1871, there are no effective or approved treatments for LHON or other related mitochondrial optic neuropathies.⁷ Attempts to treat LHON have been largely unsuccessful, but early identification of LHON and avoidance of trigger mechanisms—such as smoking and alcohol—are now stressed to those with the genetic predisposition.

Recently, a small open-label trial of an experimental therapeutic, EPI-743, which is being developed for life-threatening inherited respiratory chain diseases of the mitochondria, has demonstrated preliminary success in treating patients in the acute conversion phase of LHON.⁷ EPI-743 arrested LHON progression and reversed vision loss in four out of five treated patients. Hopefully, the results of this pilot study will be validated through upcoming multicenter randomized controlled studies.

EPI-743 may be the first effective treatment for LHON—which has a well-known history of irreversible vision loss in patients (save for those cases with the 14484 mutation)—as well as other diseases with mitochondria-based pathophysiologic conditions. Edison Pharmaceuticals, the developer of the drug, announced in September 2012 that all subjects with Leigh syndrome—a severe neurological disorder in children with mitochondrial inheritance and with no approved treatments—treated with EPI-743 exhibited reversal of disease progression.⁸ This is remarkable because Leigh syndrome is considered to be 100% progressive and 100% fatal.

Gene therapy also is emerging as a possible, attractive option. A team at Bascom Palmer Eye Institute has reported the use of mitochondria-targeted adeno-associated virus (AAV)-based gene vector in experimental models of LHON.⁹ These experiments suggest that this safe virus vector may act as a vehicle for the introduction of almost any mitochondrial gene into the adult organelle. The researchers have used this intervention to restore functional ND4 levels in LHON; hopefully, more promising research advances are on the horizon.⁹

CASE PRESENTATIONS

Because Leber's is a relatively uncommon presentation in the optometrist's office, and because diagnosis and treatment of LHON are experiencing revolutionary changes, let's take a closer look at this condition through three different clinical case studies.

Case 1: Left Eye Follows Right
A 15-year-old Filipino male with an established family history of LHON mt 11778 was followed closely prior to and during the acute phase of LHON. Vision loss began in his right eye and was followed by similar changes in his left eye several months later. His progression to blindness was well documented with GDx scanning laser polarimetry (Carl Zeiss Meditec), Stratus OCT (Carl Zeiss Meditec), Humphrey automated perimetry (Carl Zeiss Meditec), visual evoked potentials and fundus photography.

Both OCT and scanning laser polarimetry have shown that retinal nerve fiber layer (RNFL) thickening can precede vision loss, and that it occurs in a specific temporal sequence typically starting in the inferior temporal quadrant.¹⁰ Temporal pallor several months after the acute onset correlates with the attenuation of the RNFL in the papillo-macular bundle, which was well documented in the patient's right eye. At the same time, thickening of the remaining RNFL was well revealed with the GDx.

Several months after the RNFL thickened in the right eye—most likely as a result of both axoplasmic stasis and upregulation of mitochondria—it began thinning and resulted in optic atrophy.

Although the patient had no symptoms from age nine to 12 and had 20/20 best-corrected visual acuity (BCVA) in each eye during this period, both discs were not normal and displayed the characteristic findings of LHON carriers who are at risk of converting. Symptoms and VA reduction began in the right eye in May 2007 (at age 15). By August of that year, VA was reduced below 20/400 and serial fundus photos revealed progression to marked temporal pallor.

Advanced serial analysis, using the September 2004 GDx as a baseline, first revealed thickening and then thinning of the RNFL. Similar RNFL findings on OCT have been reported in other LHON patients.¹¹

The patient's VA was 20/20 in September 2004, but the right disc revealed the characteristic peripapillary telangiectatic microangiopathy. In April 2007, slight worsening of the disc, and increased RNFL thickness on GDx, was documented at the time of conversion. By May 2007, we observed temporal disc pallor and the VA had dropped to 20/400 O.D. By August 2007, the entire disc appeared pale and BCVA was now reduced to counting fingers (figure 2).

The left disc and surrounding structures were nearly normal back in September 2004, except for slight disc hyperemia and subtle relative opacity of the RNFL. During the April 2007 visit, the disc and surrounding retina appeared relatively unchanged. BCVA in the left eye at this time was 20/20. Perhaps there was a slight increase in the relative opacity of the RNFL in the left eye in May 2007. BCVA was still 20/20 O.S.

But by August 2007, progression of disc and changes in the surrounding retina were appreciable in the left eye. There was observable increase in disc hyperemia, increased thickness of the RNFL and the presence of some telangiectatic (corkscrew) vessels on and surrounding the optic disc in the left eye. BCVA had dropped to 20/40 O.S.

Likewise, GDx Advanced Serial Analysis did not reveal any major change in the left eye until August 2007. During this visit, GDx revealed marked increased thickness inferior temporally in the left eye. Meanwhile, VA had dropped to 20/40 O.S., and the disc and surrounding RNFL had visibly worsened.

Between September 2004 and April 2007, increased RNFL thickness was visualized in the right eye but not as marked in the left eye.

Since the right eye converted first, we expected that increased disc pallor (representing optic atrophy) would be more evident in the right eye from May 2007 to August 2007 (figure 3).

On the same day that the RNFL was attenuated in the right eye (as revealed on the August 2007 visit), the RNFL in the left eye was increased in thickness. The RNFL was markedly reduced inferiorly in the right eye but increased in the left eye (figures 4 and 5). Within the next year, both RNFLs were profoundly and equally reduced in thickness and both discs were equally pale

By April 2007, there was an obvious central sco-toma in the right eye. Most of the visual field was lost during the next five months. By the August 2007 visit, a central-cecal scotoma was documented in the left eye. The field loss was far more dramatic in the right eye during this period.

About a year later, the field was profoundly reduced and equal in each eye. Currently, the patient has visual acuity of counting fingers O.U.

Case 2: A Trial Treatment
The mother of a 27-year-old white male called and reported that her son began experiencing blurred vision in his right eye several weeks earlier. The patient has a family history of optic atrophy, and genetic testing nearly two decades earlier revealed a mitochondrial mutation at 11778, confirming Leber's hereditary optic neuropathy.

We suspected acute or sub-acute conversion from a carrier state to affected state, so we evaluated the patient that evening. With a low myopic correction, BCVA was a slow 20/25- O.D. and 20/20 O.S. Pupils were normal with no relative afferent pupillary defect (RAPD). (Of interest, the pupil is often spared in LHON due to the preservation of the melanopsin retinal ganglion cells.⁹) OCT fundus images revealed the characteristic signs of disc hyperemia and telangi-ectatic vessels (figure 6).

A Macular Integrity Assessment (MAIA, Ellex) central field was obtained in each eye. This device uses a near infrared scanning laser ophthalmoscope to provide high-resolution retinal images; it is designed to evaluate the patient's macula threshold, fixation stability and change over time. The MAIA monitors eye position 25 times each second and then adjusts the placement of each stimulus onto the intended location regardless of fixation errors.

For the patient's MAIA sensitivity map and threshold histogram O.D., sensitivity values depicted in green are normal, those in yellow are borderline and those in red are reduced significantly (figure 7). The patient's fixation was determined to be quite stable in the right eye. The pattern of sensitivity reduction corresponded to the papillo-macular bundle.

In the traditional 30-2 visual field, the defect is located primarily in the central superior field. In the MAIA field, the defect is projected back onto the corresponding retina.

In the right eye as in the left eye, fixation was stable, and four points had a mildly reduced sensitivity to 23dB.

Virtually all patients with the LHON mt 11778 progress to profound vision loss within weeks to months following initial vision loss. The second eye becomes affected within just several months, and final VA is typically the same in each eye. Visual fields are far better than VA to assess any change over time. When VA drops, many patients with various optic nerve and macula disorders change fixation to a more sensitive retinal location. With standard fields, the visual field loss "moves" when fixation is altered. Unlike standard fields, MAIA monitors eye position, corrects for changes in fixation (25 times per second) and tests the same points on any future MAIA visual field.

Although the BCVA was 20/25-O.D. and 20/20 O.S., the MAIA visual field (figure 7) demonstrates a dramatic difference in the central visual field sensitivity between the two eyes.

The ganglion cell complex, or GCC (which is composed of the RNFL, the ganglion cell layer and the inner plexiform layer), appeared normal and equal in each eye. Very minor differences between all GCC measurements suggest that the central field loss at this point is reversible because the ganglion cells and corresponding axons and dendrites are still intact.

All the findings supported the diagnosis of acute-onset LHON. Accordingly, we recommended that the patient take the first plane the next morning to Los Angeles for possible treatment with Edison Pharmaceutical's new drug EPI-743. All the data, including the previous genetic confirmation of LHON mt 11778, was shared with the group at Doheney Eye Institute, USC Keck School of Medicine. Within a week, treatment was initiated once the FDA approval was obtained.⁷ As mentioned previously, favorable results in four other patients with LHON will perhaps lead to an FDA clinical trial in the near future.

The MAIA was repeated 24 days after the initial visit (two weeks after the initiation of treatment). The sensitivity of many points decreased significantly in the right eye. But in the left eye, sensitivity of various points tested improved slightly, although none reached statistical significance. Take note that the drug has only been tested on a small number of people with LHON, so we have only limited information about how long the drug takes to work. The consensus among researchers involved with EPI-743 is that the drug does not demonstrate a significant effect until six to eight months after initiation of treatment.¹²

Because the patient in this case was treated very early in the course of the disease, improvement in visual field sensitivity is still possible because the ganglion cell complex has yet revealed no loss of cells.

Case 3: Atypical, Early LHON 
A 7-year-old hyperactive white male was evaluated because of possible reduction of VA and possible disc pallor. He was previously diagnosed with attention deficit hyperactivity disorder (ADHD), which likely explained the difficulty in examining the patient. A female resident who spent considerable time with him was able to correct his VA to 20/20 O.D. and O.S. Although ophthalmoscopy revealed temporal pallor, it was unclear whether this was physiologic or pathologic (figure 8). Digital tonometry revealed soft globes.

Optovue iWellness Exam revealed normal sections through the retina (not shown) in the posterior pole but a profound reduction of the thickness of the GCC in both eyes (figure 9). Note the comparison to a normal patient below.

Diopsys VEPs were obtained under NOVA-DN conditions (figure 10). The amplitudes of the VEP under both high contrast and low contrast conditions were normal in both eyes. However, the latency was abnormal under all conditions tested. The amplitudes are consistent with the normal VA, but the large latency increases clearly indicate a bilateral optic neuropathy. Automated visual fields were attempted but were not possible on either of two visits due to the boy's ADHD.

The dramatic reduction in ganglion cell complex and the VEP delays in both eyes confirm an optic nerve disorder. So what could the etiology of this optic neuropa-thy possibly be?

Because our 7-year-old appears to have pale discs without cupping and soft globes, glaucoma is effectively ruled out. But other non-glaucomatous optic neuropa-thies need to be considered, which can be done using the VITAMINES mnemonic (below).

MRIs were obtained, which were within normal limits. However, a detailed family history revealed an optic neuropathy, specifically LHON with a point mutation at mt 4360. Hence, our VITAMINES mnemonic was helpful in guiding the differential diagnosis and workup.

Although LHON is considered to be an acute-onset disorder at an average age of 25, it can occur in the first decade of life with a subacute presentation.¹⁰ The entire family is in the process of being evaluated. A confirmed diagnosis of LHON is more important than ever because treatment may soon be available.

This was an unusual case in that the patient had normal VA but showed dramatic reduction in the ganglion cell complex and delayed VEPs. Currently, this patient (and his older brother and sister) are being followed very carefully for any change.

In summary, acute-onset LHON typically begins in one eye followed within several months by the other eye. Disc hyperemia and peripapillary telangiectasia correspond to an increased RNFL thickness, as revealed with fundus photography, GDx and OCT. As the first eye begins to experience RNFL loss and disc pallor, the second eye may begin the same sequence. Within a year or so after the initial acute presentation in one eye, both eyes appear very similar.

One goal in the treatment of LHON is to prevent the second eye from converting. For the first time in the 150 years since Dr. Leber reported this progressive optic neuropathy, an effective treatment to meet this goal may be on the horizon. It may be instituted at the time of initial vision loss in the first eye. If successful, perhaps the second eye can be protected from converting and a large difference between the two eyes will still exist a year or so following the initiation of treatment.

Dr. Sherman is a distinguished teaching professor at State University of New York College of Optometry and the Schnurmacher Institute of Vision Research. He also practices at The Eye Institute and Laser Center, New York City, and is the current president of the Optometric Retina Society.

Ms. Choe graduated from University of Califor-nia-Berkeley with a B.A. in Integrative Biology. She is now a pre-optometry student at SUNY College of Optometry and working for Dr. Sherman as a volunteer research assistant. 

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