Why Was The Little Girl Going Blind?
by Maryann Brinley

The line between interpreting a patient’s symptoms and rendering a correct diagnosis is not always straight. With this issue, we introduce a new series that will focus on dramatic stories from the patient files of UMDNJ physicians.

Our first narrative was provided by Larry Frohman, MD, UMDNJ - New Jersey Medical School (NJMS) Director of Neuro-ophthalmology and Associate Professor of Ophthalmology and Visual Science as well as Neurology and Neurosciences.

The first time she went blind, she was 4 and recovering from a respiratory infection she had a few weeks earlier. According to Frohman, this type of visual loss in both eyes can be related to an inflammation of the optic nerve and could be the result of hundreds of causes: “Post viral and post-vaccination optic neuritis are common in kids. Multiple sclerosis is the most common source in adults, but infections, sinusitis, collagen vascular disease or vasculitis, as well as some other inflammatory process, can also initiate these neurological episodes.” Yet, Frohman points out that a respiratory infection typically instigates a single bout of optic neuritis, not recurrent attacks as this girl had experienced.

For the original episode, our patient was treated by a pediatric ophthalmologist who indicated that she had become legally blind in both eyes. Yet, he could see no
visible abnormalities in the eyes themselves and surmised that her symptoms might be the result of a neurological problem or maybe a case of hysterical blindness. “The process of vision,” Frohman explains, “is akin to having a video camera hooked up to a TV. The video camera is the eye, which captures the light, processes the images, and sends them via a cable — the optic nerve — back to the brain where they become recognizable images.” This first specialist on the case sent our patient on to a pediatric neurologist for further tests where she was observed to have a clumsy gait and difficulty trying to walk a straight line. An MRI scan showed brain abnormalities, “bilateral cerebral and cerebellar white matter changes,” according to the reports.

Meanwhile, an extensive battery of blood testing could not reveal the source of the neurologic and optic nerve abnormalities. A spinal tap, ordered specifically to detect multiple sclerosis, wasn’t revealing either. “The spinal fluid was normal.” Back then, her physicians decided that she had suffered acute disseminated encephalomyelitis (ADEMS), a typically monophasic neurologic illness, and they ordered treatment with corticosteroids for several weeks. She improved. She could see again.

The next year, at age 5, she suffered another neurological occurrence with symptoms of balance problems, hand tremors and bilateral vision loss. A new spinal tap was normal. So she was treated with corticosteroids and she improved.
The following year, new neurological symptoms surfaced during another bout of blindness. Dizzy and unable to walk or balance, she started dragging her right foot. More corticosteroids were ordered and once again she recovered. This was still a case without a clear diagnosis. Meanwhile, multiple attacks of optic nerve inflammation can have a cumulative effect. It was unlikely that she could experience many more and hope to have a good visual recovery.

A few months later, she was seen by the next pediatric neurologist at another medical school who diagnosed multiple sclerosis (MS). Results of a third spinal tap were unremarkable and another MRI confirmed bilateral multi-focal changes in the white matter in her brain, indicating that whatever was happening to this little girl was still an active disease process. Extensive serological testing by these academic experts still could not yield a definitive diagnosis. And so, despite the lack of typical spinal fluid findings, it was decided that she had atypical multiple sclerosis, which probably began with those first symptoms at age 4. In fact, there is no really definitive test for MS, according to Frohman.

Our patient was finally admitted to University Hospital (UH) when she was 81/2 after an additional spell of vision loss and urinary frequency, both of which were felt to be consistent with her diagnosis of multiple sclerosis. Now at UH, she became the patient of Stuart D. Cook, MD, NJMS professor of neurosciences and one of the top multiple sclerosis specialists in the country. This is when Cook consulted with Frohman because of his expertise in optic nerve inflammations. Frohman, suspecting an immunologic cause of the multiple episodes of blindness, conferred with Leonard J. Bielory, MD, NJMS professor, and director of the Division of Allergy, Immunology and Rheumatology, Department of Medicine. “The three of us have worked together on several complex patients with neurologic visual loss, shared many unusual cases and published results together.

“My initial neuro-ophthalmic exam showed her vision to be 20/200, the
cut-off for legal blindness, and that she had lost most of her color perception. Both optic nerve heads, when viewed through an ophthalmoscope, revealed permanent loss of optic nerve tissue.” She was treated with intravenous corticosteroids. Immuno-modulatory agents to prevent further attacks of multiple sclerosis were about to be started. “I called Dr. Cook and asked him to hold off on those drugs while we did more evaluation. Because of the unusual nature of the multiple attacks and recurrent bilateral optic neuritis at such a young age, I started looking for an alternate
diagnosis to the multiple sclerosis. What condition might possibly allow for this
history of recurrent neurologic episodes, especially bilateral optic nerve inflammation, in such a little girl? Though the original respiratory infection could have caused a single episode of blindness, there are cases where a virus can set up an immune reaction. Viral proteins resemble nervous system proteins so the next time the virus is seen in the body, there can be cross-reactivity where the nervous system is attacked as if it were a virus. This is a principal of molecular mimicry.”

Meanwhile, Frohman asked himself, “What tests could I order?” An antinuclear antibody (ANA), a lupus anticoagulant (LA), and a test for anticardiolipin antibodies (ACA) were requested. Her ANA and LA came back negative but the ACA was markedly elevated at 23. Repeat testing the following week verified this result. She didn’t have lupus but she did have anticardiolipin antibodies, which have been associated with blood clots, platelet abnormalities and recurrent early term miscarriages. Bielory and Frohman had previously published on the association of these antibodies with recurrent attacks of optic nerve disease. “This little girl was too young to have been pregnant and didn’t have any other features associated with anticardiolipin antibodies.

“What further testing could I do? I wanted a tissue diagnosis that would be able to give us a specific targeted therapy.” Frohman states, “Using the Willie Sutton theory of going where the money is, the optic nerve might seem to be the ideal place to go to retrieve that tissue sample, but doing a biopsy on an optic nerve causes irreversible vision loss and what we wanted to do was prevent her from losing her sight.”

Because the team now suspected an autoimmune optic neuropathy, an alternative route for the tissue diagnosis was taken. Though she had no history of rashes or any skin problems, Frohman worked with Bielory and ordered a biopsy of normal skin to be taken from an area on her body that wasn’t exposed to sun. This is a simple outpatient procedure and not terribly different from having a routine TB test. Finding abnormal granular deposits at the epidermal level was the proof: they could see a systemic immune reaction within her skin, which was a diagnostic sign of autoimmune optic neuropathy (AON). “Exceedingly rare in a child,” Frohman says. “We had our evidence of this self-directed immune reactivity. If she had it in her skin, we presumed that she also had it in her optic nerves. This was causing her visual problems.”

Treatment for AON in an adult would include immune-suppressive drugs but they carry the risk of triggering malignancy later in life as well as sterility. Because of her age, these suggested drug regimens weren’t going to be appropriate for a little girl. So, Frohman explains, “We started her on a daily baby aspirin to prevent blood clots and devised a new therapy — monthly treatments with intravenous gamma globulin. Gamma globulin can be used to block the circulating antibodies, which are being directed at the body’s own tissue, from reaching their target site of inflammation. This had never been used before in this rare disease. On the treatment, she recovered her vision to 20/25 in both eyes. While she’s subsequently had some very minor flares of symptoms, there has been nothing as severe as what she experienced before.”

That was seven years ago. “We’ve all followed her progress but she’s seen by me as an outpatient most frequently because her visual problems were her most serious issue.”

Not all AON victims are as lucky. “This rare diagnosis, which required a high index of suspicion, can be made so late in the course of the disease that people are permanently blind,” Frohman says. “The key to preserving vision is to get the patient into the hands of a neuro-ophthalmologist who has access to this kind of multidisciplinary team.”

Larry P. Frohman, MD, attended the University of Pennsylvania School of Medicine and did his residency in ophthalmology and then his fellowship in neuro-ophthalmology at New York University-Bellevue Medical Center. He has been on the NJMS faculty since 1985. His clinical and research interests include ocular manifestations of autoimmune diseases, unexplained visual loss, sarcoidosis as it affects the visual system, vasculitis and the eye, and innovation in ophthalmic education. President of the NJMS Faculty Practice Plan, the NJMS faculty and the North American Neuro-ophthalmology Society, Frohman has received the American Academy of Ophthalmology’s Senior Honor Award and was recognized twice with its Secretariat Award for educational contributions. He can be reached at frohman@umdnj.edu.