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Two-year-old girl presents with poor vision, nystagmus and bilateral optic nerve pallor
The patient was a healthy child who exhibited a visual acuity of approximately 20/400 in each eye.
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A 2-year-old girl presented to the New England Eye Center because her parents were concerned about her eyesight. Her parents noticed that she was holding her toys close to her face and that she seemed to have trouble tracking objects. They observed that she did not seem to make direct eye contact with people speaking to her although she did look in their general direction. She also seemed to be fearful of other children. The aforementioned behavior prompted the parents to seek an evaluation for possible autism, which revealed normal social behavior.
She was otherwise a healthy little girl. She was born full-term by Caesarean section because the umbilical cord was wrapped around her neck, but her birth history was otherwise uneventful. Her mother had no reported harmful exposures during pregnancy, and all of the patient’s immunizations were up to date. Her ocular history was significant for a left nasolacrimal duct obstruction that was probed at 1 year of age. The patient’s mother denied any personal family history of ophthalmic disease. The patient’s father had a mild exotropia when he was younger.
Examination
The patient was fair-skinned with blonde hair and blue eyes. Obtaining a visual acuity was difficult even with Lea symbols, but she was able to fix and follow with either eye. Pupils were slightly sluggish on constriction, but they were equally round and reactive to light with no afferent pupillary defect. She appeared orthophoric in primary gaze with full extraocular movements. However, she did have an intermittent horizontal nystagmus of small amplitude in primary gaze. On retinoscopy she had a mild refractive error of –1.50 + 1.50 × 90 in both eyes.
Anterior segment was remarkable only for subtle iris transillumination defects in both eyes. Dilated fundus exam revealed temporal pallor of both optic nerve heads but was otherwise unremarkable (Figure 1). For a more accurate assessment of visual acuity, a visual evoked potential was done and demonstrated a visual acuity of approximately 20/400 in each eye, although the reliability of the test was limited by poor fixation (Figure 2).
What is your diagnosis?
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Poor vision, nystagmus
The differential diagnosis for poor vision and nystagmus in a young child with bilateral temporal optic nerve head pallor can be categorized into hereditary optic neuropathy, compressive optic neuropathy, toxic/nutritional optic neuropathy and developmental optic nerve hypoplasia.
Hereditary causes of optic neuropathy include Leber’s hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). LHON typically presents at a later age than that of our patient and more acutely with bilateral, often sequential, vision loss. DOA, on the other hand, tends to present earlier in life and with temporal pallor of the optic nerve heads.
Compressive causes were also fairly high on the differential. Pituitary lesions such as a pituitary adenoma or craniopharyngioma can cause bilateral vision loss with sectoral optic nerve pallor. Craniopharyngiomas, in particular, are commonly seen in younger patients.
Exposure to a toxin or nutritional deficiency causing a toxic/nutritional optic neuropathy was also considered but thought to be lower on the differential. There was no history of toxic exposure, and the patient was a well-nourished child with a good appetite and social situation.
Developmental optic nerve hypoplasia was also considered because this can be seen early in life with severe vision loss and nystagmus. As with our patient, the optic nerve heads in developmental optic nerve hypoplasia may be pallid. However, the optic nerve pallor is not typically sectoral. Rather, the optic nerves themselves appear characteristically small, and the optic disc can be surrounded by a yellow or white ring, a finding that has been coined the “double ring sign.”
Diagnosis and management
Before the initial eye appointment, the family had seen a neurologist because the parents were concerned about their daughter’s gait. The neurologist did not see any abnormalities in the child’s gait, but she did notice nystagmus, which prompted her to send the girl for an MRI, which did not reveal any compressive lesions and was overall unremarkable. In retrospect, it was thought that the issues with gait were more likely related to the patient’s visual impairment.
During the child’s appointment in our clinic, the parents were also examined at the slit lamp and sent for testing in case there was a subclinical hereditary component. The mother’s fundus exam and OCT of the retinal nerve fiber layer (RNFL) were both normal. The father’s best corrected visual acuity was about 20/30, and he had good color vision. Like his daughter, he also had temporal optic nerve pallor of his optic nerve heads. His OCT RNFL analysis was notable for thinning of the temporal optic nerves (Figure 3). Despite his lack of symptoms, the father’s eye exam was suspicious for a hereditary component.
Given these findings, the family was referred to a geneticist. The girl was found to be heterozygous for the OPA1 gene, and the father also had the OPA1 gene. She was diagnosed with DOA. Since her diagnosis, she has been registered with the Massachusetts Commission for the Blind and set up with the Perkins School for the Blind. She was also enrolled in the individualized education program at her school. She is now 4 years old and doing well. Her most recent visual acuity was 20/1600 in the right eye and 20/1200 in the left eye at distance and 20/400 in both eyes at near.
Discussion
DOA is the most common hereditary optic neuropathy. It is inherited in an autosomal dominant fashion with most cases occurring due to mutations in the OPA1 gene. However, there may be no family history due to incomplete penetrance and variable expressivity. Ordinarily the onset of vision loss begins during the first or second decade of life and is typically bilateral, symmetric and slowly progressive. The classic clinical finding is sectoral, wedge-shaped temporal optic nerve head atrophy. Central or cecocentral visual field and color vision deficits are common.
There is no known treatment for DOA. However, there are novel therapies currently under investigation. One such therapy is the use of coenzyme Q/ubiquinone, which bypasses the faulty complex I in the electron transport chain and also has antioxidant properties. It has been used in the treatment of LHON, and one study has investigated its utility in DOA. Another open-label pilot study conducted in Italy investigated the utility of idebenone in DOA patients. In this study, a daily dose of idebenone was administered to seven patients who were then examined 7 months and 1 year following initiation of treatment. Five of the seven patients had either subjective or objective improvement in their visual acuities, color vision or visual field deficits. The two patients who did not demonstrate improvement were older in age and had worse baseline visual acuities.
There have also been studies that explore gene therapy. In one such study, mice with DOA were given intravitreal injections of a gene vector to deliver wild type OPA1 gene to their remaining retinal ganglion cells. Follow-up OCT of the RNFL and ganglion cell complex (GCC) of these mice seemed to indicate that the injections may have halted progression of RNFL and GCC atrophy. While the aforementioned research is still somewhat preliminary, it may have interesting implications for a blinding optic neuropathy without an effective treatment.
- References:
- Barboni P, et al. Brain. 2013;doi:10.1093/brain/aws280.
- Bouaita A, et al. Brain. 2012;doi:10.1093/brain/awr290.
- Kline LB, et al. Arch Ophthalmol. 1979;doi:10.1001/archopht.1979.01020020248013.
- La Morgia C, et al. Front Neurol. 2014;doi:10.3389/fneur.2014.00141.
- Yu-Wai-Man P, et al. Eye (Lond). 2014;doi:10.1038/eye.2014.37.
- For more information:
- Jessica Moon, MD, and Mitchell B. Strominger, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Jessica Moon, MD, and Emily C. Wright, MD. They can be reached at the New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.