A 47-year-old woman presented to the New England Eye Center for
evaluation of chronic vision loss in both eyes. The patient reported that her
vision has never been correctable to 20/20 in either eye. Her first eye exam
was at age 15, when she was found to have a vision of 20/25 in the right eye
and 20/40 in the left eye. The reduced vision was thought to be secondary to
amblyopia in the left eye. Her vision had gradually decreased to the point that
she was recently unable to pass her driving license exam.
Ocular history was significant only for a presumptive diagnosis of
amblyopia in the left eye. Medical history and review of systems were
unremarkable. She denied tobacco use and drank alcohol occasionally. The
patients family history was significant for a mother with low-tension
glaucoma. She has a brother who is legally blind for unknown reasons, and two
other siblings who have been told they have pale optic nerves.
On examination, the patients best corrected distance visual acuity
was 20/80 in the right eye and 20/60 in the left eye. Her IOPs were 16 mm Hg
and 14 mm Hg, respectively. Her pupils were equal and reactive to light
bilaterally, with no afferent pupillary defect present. Her extraocular
motility was full. She missed all AOHRR color plates in both eyes. Slit lamp
examination of the anterior segment was significant for mild nuclear sclerosis
in both eyes.
Figure 1. Optic disc photos of the right and
left eyes, notable for temporal pallor, increased cup-to-disc ratio, mild
peripapillary atrophy and gray pigmentation.
Images: Carmody JN, Hedges
Figure 2. Humphrey 30-2 visual fields
suggested centrocecal scotomas in both eyes.
Figure 3. OCT
of the peripapillary nerve fiber layer showed diffuse thinning with relative
preservation of the nasal region.
Dilated fundus examination was notable for temporal pallor of both optic
nerves and a cup-to-disc ratio of 0.5 in the right eye and 0.4 in the left.
There was mild peripapillary atrophy and gray pigmentation along the temporal
aspect of the nerves (Figure 1). The remainder of the posterior segment
examination was unremarkable.
Humphrey 30-2 visual fields suggested centrocecal scotomas in both eyes
(Figure 2). Optical coherence tomography revealed diffuse thinning of the nerve
fiber layer with distinctive preservation of the nasal region (Figure 3).
What is your diagnosis?
Bilateral optic atrophy
The differential diagnosis of bilateral optic atrophy includes
hereditary, nutritional and toxin-mediated causes, as well as compressive
chiasmal lesions, bilateral demyelinating disease, and inflammatory or
infiltrative lesions. Hereditary conditions include Lebers hereditary
optic neuropathy, congenital recessive optic atrophy, autosomal dominant optic
atrophy and Wolfram syndrome. The most common nutritional conditions leading to
optic neuropathy involve deficiencies of vitamin B and folate. Toxin-mediated
optic neuropathies include tobacco-alcohol amblyopia as well as ethambutol and
methanol toxicity. In addition to the above diagnoses, normal-tension glaucoma
can also lead to bilateral optic atrophy, with or without cupping.
Autosomal dominant optic atrophy (ADOA), or Kjers optic
neuropathy, is the most common hereditary optic neuropathy, with a prevalence
of one in 50,000 people. It has an autosomal dominant inheritance pattern with
98% penetrance, but variable phenotypic expression can make family history
The most common causative gene has been linked to OPA1 on chromosome 3q
and accounts for about 60% of cases. Several other loci resulting in similar
phenotypes have been identified, including OPA3, OPA4 and OPA5. The OPA1
protein is abundant in the retina and encodes a dynamin-related GTPase anchored
to mitochondrial membranes. Mutations result in loss of mitochondrial membrane
integrity and function, which leads to retinal ganglion cell degeneration and
ascending optic atrophy.
ADOA usually presents in the first 2 decades of life with insidious,
bilateral, symmetric visual loss. At detection, vision is often 20/50 to 20/70
and patients have a tritanopia, red-green or mixed color deficit.
The classic optic nerve appearance of ADOA patients is a temporal
wedge-shaped excavation. Temporal pallor is seen in about half of patients, and
the other half have total disc pallor. Pallor of the neuroretinal rim is seen
universally, in contrast to glaucoma where pallor of the rim is not usually
seen until late stages. Other optic nerve findings suggestive of ADOA include
an increased cup-to-disc ratio (48%), temporal gray crescent (31%) and
peripapillary atrophy (69%).
Visual field testing reveals a central scotoma, a cecocentral scotoma or
an enlarged blind spot. There may be extension of the scotoma to the superior
temporal field in late stages. OCT shows thinning of the nerve fiber layer.
This is especially evident in the papillomacular bundle and often spares the
nasal fibers. Visual evoked potentials have an absent or delayed waveform.
Genetic testing for OPA1 is clinically available. Patients should undergo MRI
testing to rule out other causes of optic neuropathy, unless they have a
classic presentation including a positive family history.
Diagnosis and management
Based on the slowly progressive nature of this patients symptoms,
her family history and otherwise good health, autosomal dominant optic atrophy
was thought to be the most likely diagnosis. Genetic testing was performed, and
the results were positive for OPA1 mutation.
The clinical course of ADOA is stable or slowly progressive. Up to
two-thirds of patients progress, losing about one line of acuity per decade.
Forty percent of patients retain vision better or equal to 20/60, and 15%
progress to worse than 20/200. There is no treatment for the disease, and
patients should be referred for low-vision and genetic counseling. Our patient
was referred to a low-vision specialist and encouraged to maintain optimal
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- Jill N. Carmody, MD, and Thomas R. Hedges III, MD, can be reached
at New England Eye Center, Tufts University School of Medicine, 750 Washington
St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; website:
- Edited by Priti Batta, MD, and Namrata Nandakumar, MD. Drs. Batta
and Nandakumar can be reached at New England Eye Center, Tufts University
School of Medicine, 750 Washington St., Box 450, Boston, MA 02111;
617-636-4219; fax: 617-636-4866; website: