Grand Rounds at the New England Eye Center

Woman presents with progressive loss of vision

Priti Batta, MD
Priti Batta
Namrata Nandakumar, MD
Namrata Nandakumar

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 patient’s 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.”

Examination

On examination, the patient’s 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

Figure 1. Optic disc photos of the right and left 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 TR

Figure 2. Humphrey 30-2 visual fields

Figure 2. Humphrey 30-2 visual fields

Figure 2. Humphrey 30-2 visual fields suggested centrocecal scotomas in both eyes.

Figure 3. OCT of the peripapillary nerve fiber layer
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 Leber’s 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.

Discussion

Autosomal dominant optic atrophy (ADOA), or Kjer’s 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 inconsistent.

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 patient’s 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 nutrition.

References:

  • Fournier AV, Damji KF, Epstein DL, Pollock SC. Disc excavation in dominant optic atrophy: differentiation from normal tension glaucoma. Ophthalmology. 2001;108(9):1595-1602.
  • Ito Y, Nakamura M, Yamakoshi T, Lin J, Yatsuya H, Terasaki H. Reduction of inner retinal thickness in patients with autosomal dominant optic atrophy associated with OPA1 mutations. Invest Ophthalmol Vis Sci. 2007;48(9):4079-86.
  • Kim TW, Hwang JM. Stratus OCT in dominant optic atrophy: features differentiating it from glaucoma. J Glaucoma. 2007;16(8):655-658.
  • Vortruba M, Moore AT, Bhattacharya SS. Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy. J Med Genet. 1998;35(10):793-800.
  • Vortruba M, Thiselton D, Bhattacharya SS. Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy. Br J Ophthalmol. 2003;87(1):48-53.
  • Yu-Wai-Man P, Griffiths PG, Burke A, et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. 2010;117(8):1538-1546.

  • 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: www.neec.com.

  • 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: www.neec.com.
Priti Batta, MD
Priti Batta
Namrata Nandakumar, MD
Namrata Nandakumar

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 patient’s 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.”

Examination

On examination, the patient’s 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

Figure 1. Optic disc photos of the right and left 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 TR

Figure 2. Humphrey 30-2 visual fields

Figure 2. Humphrey 30-2 visual fields

Figure 2. Humphrey 30-2 visual fields suggested centrocecal scotomas in both eyes.

Figure 3. OCT of the peripapillary nerve fiber layer
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 Leber’s 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.

Discussion

Autosomal dominant optic atrophy (ADOA), or Kjer’s 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 inconsistent.

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 patient’s 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 nutrition.

References:

  • Fournier AV, Damji KF, Epstein DL, Pollock SC. Disc excavation in dominant optic atrophy: differentiation from normal tension glaucoma. Ophthalmology. 2001;108(9):1595-1602.
  • Ito Y, Nakamura M, Yamakoshi T, Lin J, Yatsuya H, Terasaki H. Reduction of inner retinal thickness in patients with autosomal dominant optic atrophy associated with OPA1 mutations. Invest Ophthalmol Vis Sci. 2007;48(9):4079-86.
  • Kim TW, Hwang JM. Stratus OCT in dominant optic atrophy: features differentiating it from glaucoma. J Glaucoma. 2007;16(8):655-658.
  • Vortruba M, Moore AT, Bhattacharya SS. Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy. J Med Genet. 1998;35(10):793-800.
  • Vortruba M, Thiselton D, Bhattacharya SS. Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy. Br J Ophthalmol. 2003;87(1):48-53.
  • Yu-Wai-Man P, Griffiths PG, Burke A, et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. 2010;117(8):1538-1546.

  • 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: www.neec.com.

  • 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: www.neec.com.