Woman presents with binocular double vision
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A 38-year-old woman presented to neuro-ophthalmology for evaluation of worsening binocular double vision.
Two weeks prior, she developed an upper respiratory infection with associated ear infection and was started on oral antibiotics by her primary care provider.
Source: Kate V. Hughes, MD, and Kevin Sitko, MD
She subsequently developed diarrhea, which resolved after several days. She first noticed double vision upon awakening several days before presentation. She described the images as horizontal, present in all gaze directions including primary gaze but worse when looking left or right, resolving with occlusion of either eye. She denied any other ocular symptoms including pain and decrease in vision. She denied any head or ocular trauma, headaches, pulsatile tinnitus or other systemic symptoms such as weakness and/or tingling of the extremities. She presented to an outside ophthalmologist and was found to have left abducens nerve palsy, so she was urgently referred for head imaging and neuro-ophthalmic evaluation.
The patient’s ocular history was notable for myopia, as well as positive for a mutation in the retinitis pigmentosa GTPase regulator (RPGR) gene and a heterozygous mutation in the oculocutaneous albinism type II (OCA2) gene. She previously underwent genetic testing due to her family history, which was significant for oculocutaneous albinism in her mother and retinitis pigmentosa in her father and paternal uncle. Her mother and father had first met each other at a low-vision school. The patient was not on any ophthalmic medications and had no prior ophthalmic surgeries. Her medical and surgical history was significant for alcoholic cirrhosis status post liver transplant 5 years prior and hypertension. Her medications included tacrolimus, amlodipine, aspirin and ferrous sulfate. She was a middle school teacher, never smoked and had prior alcohol dependency but with no recent alcohol ingestion. She was allergic to amoxicillin, which caused a rash. Her review of systems was unremarkable except as noted previously.
Examination
Visual acuity with correction was 20/20 in both eyes. Pupils were equal in size and reactive to light, with no afferent pupillary defect. IOP was 10 mm Hg in both eyes, with full confrontation visual fields and color plates. Both eyes had abnormal extraocular motility, with roughly 75% deficit of supraduction, infraduction and adduction bilaterally and 100% abduction deficit bilaterally (Figure 1). External exam showed normal adnexa without proptosis. There was slight ptosis of the right eye compared with the left eye (margin reflex distance 1 of 3 mm vs. 4 mm, respectively). Anterior segment exam of both eyes was unremarkable except for mild 2 clock hours loss of iris sphincter tone superiorly in the right eye. Posterior segment exam of both eyes was unremarkable, and both optic nerves were pink and healthy with a cup-to-disc ratio of 0.3. OCT of the nerve fiber layer showed normal thickness in both eyes.
What is your diagnosis?
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Bilateral ophthalmoplegia
The broad differential diagnosis for bilateral ophthalmoplegia can be categorized into several etiologies, including infectious, ischemic, structural, inflammatory and genetic.
From an infectious standpoint, septic cavernous sinus thrombosis, which is the formation of a blood clot within the cavernous sinus secondary to an infection of the sinuses or ears (which the patient had before presentation) can cause acute or subacute cranial nerve palsies. However, cavernous sinus thrombosis is most often unilateral with exophthalmos, periorbital edema and ocular pain, in addition to associated systemic symptoms of fever and headache, which the patient did not have.
A brainstem stroke leading to ischemia of the midbrain or pons could result in gaze palsies including the horizontal gaze pathway, but the patient’s lack of other ocular (including more severe ptosis and pupil abnormalities) and systemic stroke findings makes this less likely.
Structurally, an intracranial or intraorbital neoplasm involving the cranial nerve pathway could cause bilateral ophthalmoplegia, but this would likely have a more chronic onset than the acute onset seen in the patient. As well, additional ocular symptoms such as proptosis or optic nerve involvement (decreased vision, afferent pupillary defect, etc) would likely be present.
An inflammatory etiology of the patient’s presentation is mainly concerning for myasthenia gravis and Miller Fisher syndrome, both of which can present acutely with bilateral ophthalmoplegia and ptosis, often with systemic symptoms such as extremity weakness. Interestingly, the patient did not have obvious ptosis, just very mild ptosis of the right eye, or eyelid fatigability, and she denied any issues with walking or extremity weakness, breathing and swallowing.
Lastly, the patient’s family history of retinitis pigmentosa and known ocular history of genetic mutations in the RPGR gene (associated with X-linked retinitis pigmentosa and cone-rod dystrophy) and OCA2 gene (associated with oculocutaneous albinism type 2) could conceivably increase the concern for a genetic etiology, such as chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome or myotonic dystrophy. However, the acuteness of her symptoms excludes a genetic cause, as these have a gradual, chronic onset (to the point where patients may not even notice their ophthalmoplegia).
Further evaluation
The patient was admitted to the hospital under the neurology service for further evaluation. She underwent head imaging including MRI (Figure 2) and MRV of the brain/orbits, without evidence of pathology including mass, stroke or thrombosis. She also had a normal CTA and CTV of the head/neck and EKG that demonstrated normal sinus rhythm. Neurologic examination was normal except for subtle bilateral areflexia of the Achilles tendons bilaterally. She underwent a lumbar puncture with normal opening pressure of 15 cm H2O. Cerebrospinal fluid (CSF) demonstrated normal protein, glucose and white blood cell levels and was negative for serology (including syphilis, varicella zoster and herpes simplex) and culture. CSF also demonstrated normal neuromyelitis optica IgG levels and was negative for oligoclonal bands. Laboratory serologic testing demonstrated normal CBC, ESR, CRP, RF, ANA, ACE and ANCA. Acetylcholine receptor (binding, blocking and modulating) antibodies and anti-muscle-specific kinase (anti-MuSK) antibodies were normal. However, anti-GQ1b antibodies were markedly elevated at 305 IV, normal being less than 50 IV. Therefore, the patient was formally diagnosed with Miller Fisher syndrome.
Discussion
Miller Fisher syndrome (MFS) is a monophasic antibody-mediated peripheral neuropathy with acute onset that customarily involves the cranial nerves. It is classified as one of the anti-GQ1b syndromes, which include Guillain-Barré syndrome (GBS), Bickerstaff brainstem encephalitis and pharyngeal-cervical-brachial weakness. Like GBS, MFS typically develops after an infection, but it has been associated with several other etiologies such as neoplastic (including Burkitt lymphoma and Hodgkin disease) and medications/vaccines (including TNF-alpha inhibitors and the influenza vaccine). From an infectious etiology, it is most commonly associated with Campylobacter jejuni and Haemophilus influenzae, with an average onset of approximately 7 to 10 days after infection.
The clinical features of MFS are ophthalmoplegia, ataxia, areflexia/hyporeflexia and no extremity weakness. It can often be difficult to distinguish clinically between MFS and myasthenia gravis. However, unlike myasthenia gravis, MFS can present with internal ophthalmoplegia with pupillary areflexia, which can range from sluggish to a completely absent response. On exam, the described patient was found to have a very mild loss of iris sphincter tone superiorly in the right eye, which would not be present in myasthenia gravis. In addition, myasthenia gravis has fatigability of the eyelids and fluctuating extremity weakness, which are absent in MFS.
The pathophysiology behind the development of MFS is molecular mimicry. GQ1b is a ganglioside antigen found in the plasma membranes of Schwann cells of the ocular cranial nerves and presynaptic neuromuscular junctions. Antecedent infection or another inciting etiology causes the production of antibodies that cross-react against these antigens, leading to immune activation of the complement pathway and macrophage infiltration of axonal membranes. The diagnosis of MFS is clinical, but patients most often are found to be positive for these anti-GQ1b antibodies. As well, the level of antibodies has been found to correlate with the severity of disease. Additionally, in terms of diagnosis, CSF studies may show an albuminocytological dissociation (high protein with low WBC levels), but this is not diagnostic. For instance, the described patient had normal CSF protein and WBC levels.
The disease is self-limiting with a good prognosis, with typical recovery around 10 to 12 weeks after symptom onset. However, studies have found up to a third of patients may continue to have residual symptoms. While there have been no randomized trials regarding the management of MFS, intravenous immunoglobulin (IVIG) or plasmapheresis is often used to quicken the onset of recovery. Neither of these treatments have been found to have a major impact on overall outcomes.
Course continued
The patient received 5 days of IVIG, with mild improvement in symptoms, particularly adduction bilaterally. Her exam at the 1-month follow-up clinic appointment demonstrated resolution of adduction deficit, with overall improvement in the other gaze deficits (Figure 3). At her most recent appointment, approximately 6 months since presentation, her motility had completely normalized, but a residual, stable mild esotropia was present, which has been well controlled with prism correction.
- References:
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- For more information:
- Edited by Yi Ling Dai, MD, and Teresa P. Horan, MD, of New England Eye Center, Tufts University School of Medicine. They can be reached at ydai@tuftsmedicalcenter.org and thoran@tuftsmedicalcenter.org.