A Diagnostic Odyssey
Diagnostic testing, including imaging and blood work, can often complement your clinical examination. In fact, many times, ophthalmic imaging can help make a diagnosis much easier. Other times, however, imaging is not enough and can even lead you down a much longer road toward an accurate diagnosis than expected. In this article, I detail a pediatric case in which a battery of imaging and testing was required before arriving at the proper diagnosis.
INITIAL PRESENTATION
A 9-year-old female was referred to my clinic by her regular optometrist due to an unexplained decrease in vision. The patient was brought in by her mother, who reported that she had undergone many eye examinations since she was 5 years of age. However, the patient always had trouble reading the acuity chart, and for the past few years in her daily life, she would often have to get very close to objects. The only explanation given was that she needed to wear glasses all the time, which her mother strictly enforced. There was also concern about the patient’s academic performance (she was failing all subjects in school).
There was no history of ocular trauma or surgeries, and the patient’s general health was good. There was no known family history of ocular disease. Her mother and a younger sister wore glasses, but neither of them had problems seeing with their glasses.
The patient’s BCVA was severely decreased at 20/200 OD and 20/200 OS through a low symmetric myopic prescription. Pupil reflexes were normal without an afferent pupillary defect. IOP was also normal. Color vision testing revealed an inability to discern even the test plate. Anterior segment examination was unremarkable. Dilated eye examination revealed bilateral optic atrophy, which accounted for her severe vision loss (Figure). Due to the patient’s decreased visual acuity, it was prudent to obtain an OCT of the retinal nerve fiber layer (RNFL) to quantify the degree of nerve fiber layer loss and damage to the macula. The OCT of the RNFL was clearly abnormal, which confirmed the presence of an optic neuropathy and not overexposed nerve photographs or pseudopallor. The macula OCT ruled out the presence of maculopathy that could be responsible for the decreased vision. Visual field testing was deferred due to the patient’s young age.
ADDITIONAL IMAGING
The highest yield test for unexplained optic atrophy is an MRI. In fact, during workup, an MRI will identify a compressive lesion 20% of the time.1 My typical MRI order for optic atrophy looks like this: “MRI of the brain and orbits with and without contrast focusing on the intraorbital, intracanalicular, and intracranial portions of the optic nerve, including the chiasm and visual pathways in the brain.” Because of the patient’s age, I decided to coordinate with radiology to administer sedation during the MRI.
The MRI came back negative for compression, ruling out a tumor, the most sinister etiology. However, there was still no explanation for the bilateral optic atrophy. Other differentials included infectious, inflammatory, toxic, nutritional, and congenital disorders. Unlikely differentials included vascular and traumatic etiologies. Vascular was unlikely, given the patient’s young age and lack of risk factors. Traumatic optic neuropathy was also unlikely, given bilaterality, symmetry, and lack of ocular or head trauma.
BLOOD WORK
At this point, I obtained a more detailed history and found no evidence of significant illness or infection. The patient had traveled to Mexico once when she was 9 months old. Her only other travel has been within California. She was born full-term without complications, has a normal diet with a variety of foods, and the family owns a cat. I ordered labs, including complete blood count with differential; syphilis antibodies; Lyme antibodies; QuantiFeron-TB Gold Plus (Qiagen) for tuberculosis; Bartonella species antibodies; antinuclear antibody; angiotensin-converting enzyme; antineutrophil cytoplasmic antibodies; vitamins B1, B2, B6, folate, and B12; toxicology screen; and lead.
Each of the labs came back normal, so common infectious, inflammatory, toxic, and nutritional etiologies were ruled out. Because a congenital etiology was still possible, I was concerned about dominant optic atrophy (DOA), the most common inherited optic neuropathy (see DOA FAQs for details about this condition).2 Leber hereditary optic neuropathy (LHON)2 is another less common inherited optic neuropathy that is less likely here because the patient is not in the typical demographic of young adult male, and there was no episode of acute bilateral sequential vision loss.
DOA FAQs
1. DOA, also known as Kjer optic neuropathy, named after the Danish ophthalmologist Poul Kjer, is typically caused by a mutation of the OPA1 gene that encodes a dysfunctional mitochondrial enzyme, which then causes mitochondrial dysfunction, membrane instability, and increased oxidative stress.
2. In children, DOA presents with mild to moderately decreased VA (20/50 to 20/200) and bilateral optic nerve pallor.1
3. DOA can have catastrophic visual consequences, including retinal ganglion cell apoptosis and vision loss.
4. In some cases, one can be a carrier of the pathogenic OPA1 mutation but be asymptomatic due to not expressing the full phenotypic trait (known as variable penetrance).1
5. Without a known positive family history, the only way to definitively diagnose DOA is with genetic testing.
6. There is no FDA-approved treatment for DOA. Researchers have hypothesized that supplementation with specific antioxidants can help,2 but there is a dearth of high-quality randomized control trials on supplementation for DOA.
1. Lenaers G, Hamel C, Delettre C, et al. Dominant optic atrophy. Orphanet J Rare Dis. 2012;7:46.
2. Amore G, Romagnoli M, Carbonelli M, Barboni P, Carelli V, Morgia CL. Therapeutic options in hereditary optic neuropathies. Drugs. 2021;81:57-86.
CONFIRMING THE DIAGNOSIS
I referred the patient to a geneticist with a recommendation to test for an OPA1 mutation, the type of mutation implicated in most patients with DOA. It is of paramount importance to involve a genetics team so that genetic counseling can be initiated with patients and their families, if necessary. Genetics obtained a detailed family history, drew a three-generation pedigree, and performed a physical examination.
Recall that there was no known family history of DOA in this case. Genetics agreed with my recommendation to test for an OPA1 mutation, along with other possible pathologic genetic mutations. After several weeks of waiting for results, genetic testing revealed a pathogenic OPA1 mutation.
ADDITIONAL REFERRALS
After discussing the genetic test results with the patient’s mother, I made a referral for the patient to see a low vision specialist who recommended a large video magnifier, one-on-one instruction at school, and other lifestyle interventions. Additionally, an individualized education plan is being pursued. Due to legal blindness status, I have connected the family with a social worker in case they need assistance with programs and services. I also made a referral to a mitochondrial geneticist, who recommended a specific cocktail of mitochondria-friendly supplements (coenzyme Q10, alpha-lipoic acid, and B-complex vitamins).3
Because DOA is inherited in an autosomal dominant manner, the patient’s mother recently completed genetic testing herself per recommendations from the genetics clinic. The testing revealed that she has the same pathogenic OPA1 mutation as her daughter. Interestingly, the mother’s VA is 20/20 in both eyes, and her optic nerve examination revealed only moderate cupping and temporal tilted discs. The patient’s two younger siblings have been recommended to see me for a complete eye examination.
DON’T SETTLE FOR UNEXPLAINABLE
For many years, this child’s inability to obtain normal visual acuity was brushed off by multiple providers as her not knowing letters, being shy, or malingering. Her poor academic performance was previously unexplained. After sufficient diagnostic testing, I was able to reassure the family that there is a legitimate medical reason behind their child’s symptoms, and we have begun accommodating her accordingly. With a thorough examination and the right knowledge and technology, the medically minded modern optometrist can diagnose and manage even the rarest conditions.
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