Diplopia and nystagmus present in patient with complex neuropsychiatric history
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A 45-year-old woman was admitted to the neurology service at Lahey Hospital and Medical Center with symptoms of double vision, gait disturbance secondary to lower extremity weakness and subjective memory loss.
Her medical history was significant for alcohol use disorder, a recent fall with head strike while intoxicated and withdrawal seizures, for which she required a 2-day hospital admission 6 weeks before this hospitalization. Her medical conditions also included bipolar disorder, anxiety, depression, polysubstance use, asthma and other unspecified seizure disorder. Home medications included albuterol inhaler, buspirone, gabapentin, naltrexone, ondansetron, oxcarbazepine, pantoprazole, paroxetine, quetiapine, vitamin D, calcium, vitamin B12, magnesium, multivitamin, potassium chloride and thiamine. Notably, she had been taking thiamine for more than 18 months before presentation.
The patient stated that after her previous hospitalization, she was involuntarily admitted to a psychiatric facility, where, within the first few days of inpatient treatment, she first began to notice horizontal binocular double vision, worse at distance, as well as “shaking eyes,” with subjective difficulty fixating on objects, particularly in the periphery. She reported that the diplopia had worsened over the course of weeks. She delayed seeking care due to her involuntary inpatient status. Her symptoms fluctuated and progressively worsened over the course of the day. Around the time of symptom onset, she was also noted to have gait disturbance and lower extremity weakness with several falls at the psychiatric facility.
The patient’s ocular history was notable for amblyopia in the left eye. There was no history of ocular trauma. Two weeks before this presentation, she had been seen by an outside ophthalmologist for evaluation of her symptoms. Records indicated a diagnosis of traumatic left cranial fourth nerve palsy as well as suspected medication-induced nystagmus. She was prescribed prism lenses but at the time of this evaluation had not yet received her glasses. She had been wearing an eye patch to alleviate her symptoms.
The ophthalmology service was consulted for evaluation of diplopia and nystagmus after MRI of the brain obtained on admission revealed a 0.33 cm cyst within the cavernous sinus that was noted by radiology to be displacing the right oculomotor nerve (Figure 1).
Source: Erin Lanzo, MD, and Geetha Athappilly, MD
Examination
Vision was noted to be 20/20 in the right eye and 20/70 in the left eye at near with a +2.00 lens. Color vision was full in both eyes by Ishihara color plates. Pupil exam was normal without a relative afferent pupillary defect. IOP was 15 mm Hg in the right eye and 14 mm Hg in the left eye by iCare tonometry. Confrontational visual fields were full bilaterally. Motility exam showed mild adduction and abduction deficits in both eyes with abducting nystagmus in both right and left gaze, suggestive of bilateral internuclear ophthalmoplegia (INO). Alignment measurements on the same day at two different times (morning and afternoon) are shown in Figure 2, with a variable degree of esotropia and variable vertical misalignment on those two occasions.
External exam was normal with no evidence of ptosis or proptosis. Anterior segment exam was unremarkable, except for trace nuclear sclerosis in the right eye and 1+ nuclear sclerosis in the left eye. Optic nerves appeared pink and sharp bilaterally, with a small cup-to-disc ratio in both eyes.
What is your diagnosis?
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Diplopia and nystagmus
In evaluating this patient, it was important to consider her respective symptoms of diplopia and nystagmus and whether they were related to the same pathophysiology or separate entities. The differential diagnosis for concurrent diplopia and nystagmus includes posterior fossa lesions from vascular etiologies, demyelinating causes, malignancy/paraneoplastic etiologies, toxicity, thiamine deficiency and myasthenia gravis.
If the diplopia and nystagmus were felt to be separate entities, the causes of diplopia include single or multiple cranial nerve palsies, which could be secondary to vascular etiologies, demyelinating disease, compressive lesions, traumatic, ischemic or inflammatory etiologies, thyroid eye disease, thiamine deficiency, myasthenia gravis or a paraneoplastic process. The pattern of her alignment measurements and her normal pupil exam did not suggest a compressive third cranial nerve palsy, despite MRI findings. Regarding her alternating, abducting nystagmus, this was suggestive of bilateral internuclear ophthalmoplegia that can be caused by a vascular or demyelinating lesion, as well as myasthenia gravis. The causes of nystagmus in general include sedatives, anticonvulsants, alcohol, illicit drug use, trauma, stroke, INO, demyelination, Meniere’s disease, paraneoplastic syndrome, Chiari malformation and tumor.
Further workup
Complete blood count with differential and comprehensive metabolic panel were within normal limits. Vitamin B12 was low-normal, with elevated homocysteine levels, suggesting vitamin B12 deficiency despite the patient’s daily supplementation. Thyroid stimulating hormone level, HbA1c and thiamine (vitamin B1) level were all normal. Toxicology screen was positive for barbiturates and benzodiazepines.
Based on the patient’s clinical exam, which was notable for normal pupil exam, variable alignment testing and bilateral INOs, there was a high suspicion of myasthenia gravis as the cause. The myasthenia gravis panel was negative. Even so, given our high suspicion, a trial of pyridostigmine was commenced, and the patient’s symptoms of diplopia and nystagmus resolved within a day.
Of note, the patient later reported that she had an uncle with myasthenia gravis.
Discussion
Myasthenia gravis (MG) is a disease that results from autoimmune antibodies directed against acetylcholine receptors (AChRs) at the post-synaptic cleft of the neuromuscular junction. Acetylcholine (ACh) under normal conditions is released from vesicles at the neuronal axon terminal onto receptors at the postsynaptic membrane on skeletal muscle, thereby stimulating an action potential. In patients with MG, antibodies directed against the AChRs block ACh, leading to downregulation of AChRs and complement-mediated damage of the postsynaptic membrane, resulting in lower end-plate potentials. With insufficient end-plate potential, action potentials within skeletal muscles cannot be achieved, leading to muscle weakness and fatigability, exacerbated by use. ACh remaining in the cleft is rapidly degraded by acetylcholinesterase.
Ocular symptoms of MG include unilateral or bilateral ptosis, diplopia and a “pseudo-INO.” Ptosis and diplopia are the heralding signs in more than 50% of cases of MG. About 50% to 80% of those who present with isolated eye symptoms will go on to develop systemic MG symptoms, usually within 2 years. Symptoms classically fluctuate throughout the day and improve with rest. A single clinical exam may not capture this variability, so taking a good history is essential.
Our patient’s bilateral abducting nystagmus was suggestive of bilateral INO. According to Hering’s law, with a weak muscle in one eye, there is a compensatory increase in innervation; concurrently, there is a proportional increase in innervation to the yoke muscle in the other eye, causing a gaze-evoked abduction nystagmus as an adaptive response in cases of INO. INO is usually a sign of a lesion within the medial longitudinal fasciculus (MLF), causing impaired adduction of the eye ipsilateral to the lesion, as well as contralateral abduction nystagmus. This sign can be found in patients with MG without the classic MLF lesion and thus is referred to as a “pseudo-INO.” Extraocular muscle weakness, rather, leads to the adduction deficit, and the compensatory contralateral nystagmus gives a picture similar to an INO.
Acute thiamine deficiency was also in the differential for our patient’s presentation. This can be seen in Wernicke’s encephalopathy. It can also cause neuro-ophthalmic findings, such as gaze-evoked upbeat nystagmus or downbeat nystagmus, bilateral sixth nerve palsies and conjugate gaze palsies. Unilateral INO has been reported in one case. Vision loss, optic disc edema and retinal hemorrhages have also been observed but are uncommon. Isolated reports also suggest that pupil abnormalities may be observed, as well as impaired convergence, spasm of near reflex and ptosis. Our patient, however, lacked the encephalopathy that is often seen with diplopia/ophthalmoplegia and gait abnormalities secondary to Wernicke’s encephalopathy. Her brain MRI was also not revealing of Wernicke’s-related lesions of the mammillary bodies, medial thalamus or periaqueductal gray matter, and furthermore, her thiamine levels were normal. Her variable alignment along with her diurnal symptoms led us to conclude that MG was more likely her clinical diagnosis.
The diagnosis of MG can be made by clinical exam, serology and pharmacologic testing. The motility pattern may or may not fit a specific cranial nerve palsy; further, the measurements will often vary depending on the time of the day. Ptosis may or may not also be observed at the time of the exam and can be evaluated via the lid fatiguability test with sustained upgaze, weak orbicularis oculi and Cogan’s lid twitch. Lid retraction with contralateral ptosis may be noted and can confuse the presentation for thyroid eye disease or may, in fact, indicate coexistent thyroid eye disease. Pupil exam is normal and can distinguish the diagnosis from Horner’s syndrome or compressive third nerve palsy. Other clinical diagnostic tests include the sleep test, ice test (particularly if ptosis is present), edrophonium test (an inhibitor of acetylcholinesterase), single fiber electromyography (EMG) testing and repetitive nerve stimulation testing.
Serology testing includes anti-acetylcholine receptor antibody testing. This result is positive in 80% to 99% of patients with systemic MG and 30% to 77% of patients with ocular MG. If negative, serum anti-muscle specific kinase (anti-MUSK) antibodies can be tested if there is strong clinical suspicion. Negative antibody testing does not exclude the diagnosis, as 10% to 15% of patients with systemic MG and 30% to 50% of patients with ocular MG will test negative, as in our patient’s case.
Patients should always be screened for difficulty chewing, swallowing and breathing, as complications from systemic MG can lead to fatal respiratory failure. They should also have a CT of the chest, as 70% of patients will have thymic hyperplasia and 10% to 15% may have a thymoma. Thyroid function testing is also indicated, as there is a 5% rate of coexisting thyroid disease.
Treatment is medical and includes acetylcholinesterase inhibitors such as pyridostigmine to modulate symptoms. There is no curative therapy. Oral corticosteroids may be indicated if acetylcholinesterase inhibitors are contraindicated, ineffective or not well tolerated. Immunomodulatory therapy with azathioprine, cyclosporine, mycophenolate mofetil and plasmapheresis with intravenous immunoglobulin are used in treatment of refractory cases and in myasthenic crisis. New treatments for refractory cases are in the pipeline.
If a thymoma is present, surgical removal may be warranted to prevent possible thymic tumor development. Thymectomy has been shown to also mitigate symptoms in 60% to 70% of patients, with 35% who undergo the procedure achieving remission.
Patients should be counseled on risk factors for myasthenic crises, which include pregnancy, stress, systemic infection, alcohol use disorder, concurrent thyroid disease, exposure to temperature extremes and some medications.
Patient course continued
Two weeks after discharge on pyridostigmine therapy, the patient reported continued resolution of symptoms with no need for patching. The patient was maintained on 60 mg of pyridostigmine three times daily. She had resolution of diplopia, no longer required patching and had no evidence of nystagmus on repeat exam. Her gait improved with pyridostigmine, which suggested her gait difficulties were secondary to extremity weakness from possible systemic MG. CT of the chest without contrast did not show evidence of a thymoma. Outpatient neuromuscular neurology follow-up and EMG testing are pending.
Regarding her cavernous sinus cyst seen on MRI, it was determined to be an incidental finding. Neurosurgery recommended no intervention.
- References:
- Isen DR, et al. Eye Brain. 2020;doi:10.2147/EB.S234078.
- Nair AG, et al. Indian J Ophthalmol. 2014;doi:10.4103/0301-4738.145987.
- Nijsse B, et al. BMJ Case Rep. 2014;doi:10.1136/bcr-2013-203234.
- Wendell LC, et al. Neurohospitalist. 2011;doi:10.1177/1941875210382918.
- Zee DS, et al. Ann Neurol. 1987;doi:10.1002/ana.410210411.
- For more information:
- Erin Lanzo, MD, and Geetha Athappilly, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Christine Benador-Shen, MD, and Malgorzata Dymerska Peterson, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.