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Woman presents with binocular diplopia
Extraocular motility was restricted in both eyes.
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A 69-year-old woman presented to Tufts Medical Center 2 weeks after developing upper respiratory symptoms. During that time, she also had mild headaches, episodes of nausea and difficulty walking. She later developed acute-onset persistent binocular diplopia.
Her medical history was significant for hypertension and breast cancer, for which she underwent a lumpectomy and chemoradiation. She developed biliary cirrhosis as a side effect of her chemotherapy. Her medications included amlodipine, Arimidex (anastrozole, AstraZeneca), Actigall (ursodiol, Actavis), calcium, fish oil and vitamin B12. Her ocular history was significant only for cataract surgery in the right eye.
Examination
In the office, the patient’s visual acuity was 20/25 in the right eye and 20/30 in the left. On external exam, she had mild anisocoria, with her right pupil at 3.5 mm in dim light constricting to 3 mm in bright light and her left pupil at 4 mm in dim light and 3 mm in bright light. There was no relative afferent pupillary defect. Extraocular motility was markedly restricted in both eyes, with only bare movement of the right eye on attempted abduction (Figure 1). There was no proptosis, and IOPs were within normal limits.
Figure 1. Color photos of ocular motility.
Image: Sitko K, Hedges TR
Slit lamp exam was significant for only a posterior chamber IOL in the right eye and a moderate nuclear sclerotic cataract in the left. Dilated fundus exam was unremarkable, without retinal or optic disc pathology. Notably, the patient had an ataxic gait and required assistance when moving around the clinic and transferring between seats.
What is your diagnosis?
Acute bilateral ophthalmoplegia
The differential diagnosis of acute bilateral ophthalmoplegia includes bilateral cavernous sinus disease such as pituitary apoplexy or a large pontine hemorrhage. Other possible etiologies include medication toxicity from drugs such as phenytoin, infectious or inflammatory vasculitis, neuromuscular diseases such as myasthenia gravis or botulism, and Miller Fisher variant of Guillain-Barré syndrome.
Our patient was admitted to the hospital and found to have decreased deep tendon reflexes on neurologic exam. She underwent an unremarkable brain MRI and subsequently had a lumbar puncture showing normal cerebrospinal fluid (CSF) composition and negative bacterial cultures. CSF PCR testing was negative for herpes simplex 1 and 2, herpes zoster and Epstein-Barr virus. CSF Lyme antibody testing was similarly negative.
On further evaluation, the patient had no risk factors for other causes of ophthalmoplegia, including phenytoin use or eating home-canned or home-jarred foods. Based on her recent upper respiratory symptoms, new-onset ataxia, and negative imaging and CSF studies, she was diagnosed with Miller Fisher syndrome. Subsequent serum GQ1b antibody testing returned positive.
Discussion
C. Miller Fisher first reported three cases of acute-onset extraocular and intraocular ophthalmoplegia, ataxia and areflexia in 1956 and described them as a variant of Guillain-Barré syndrome. The syndrome that has taken his name has since been determined to have a high association with ganglioside GQ1b, an antibody against a glycolipid found in neurons.
GQ1b was first identified as a possible inciting epitope by Chiba et al in 1993. They compared the serum of 24 individuals with clinically suspected Miller Fisher syndrome or Guillain-Barré syndrome with and without ophthalmoplegia to normal controls and patients with other neurologic or immune diseases. While the sera from all but one of the patients with Miller Fisher syndrome or Guillain-Barré syndrome with ophthalmoplegia demonstrated immune reactivity against the ganglioside GQ1b, none of the control sera did. They also showed that most of the binding of the GQ1b antibody occurred in the areas surrounding the nodes of Ranvier of the ocular motor nerves. The same study looked at immunohistochemistry of the ocular motor nerves and determined that there was a higher concentration of GQ1b when compared with other peripheral nerves or central nervous tissue. This serves as a possible explanation for the isolated nature of the ophthalmoplegia in this syndrome as compared with Guillain-Barré syndrome. The location of the pathology has long been hypothesized to be in the peripheral cranial nerves, although some have pointed to features of Miller Fisher syndrome, such as the ataxia that has cerebellar features and the sometimes preserved Bell’s reflex, which suggest a central nervous system location of the pathology.
The majority of patients with Miller Fisher syndrome can identify a preceding upper respiratory illness, as in our patient, or gastrointestinal illness. Epidemiologic studies have shown a higher incidence of antibodies against Campylobacter jejuni and Haemophilus influenzae in Miller Fisher syndrome patients than in controls, and these same organisms have been shown to have cell surface lipopolysaccharides that interact with GQ1b antibodies. This suggests an infection-induced, molecular mimicry-related autoimmune etiology in the pathogenesis of this disease. Given this presumed pathogenesis, treatment strategies have been focused on eliminating the offending antibodies from the bloodstream, through both intravenous immunoglobulin and plasmapheresis. Both treatment strategies have proven effective to hasten recovery, although the natural course is one of recovery.
Clinical course
After her diagnosis was made, our patient was treated with six rounds of plasmapheresis. She had rapid improvement in her extraocular motility in her first week of treatment and will continue to be followed throughout her recovery.