Man develops binocular diplopia, ophthalmoplegia, areflexia
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A 54-year-old man developed constant binocular diagonal diplopia. He was initially diagnosed with a fourth nerve palsy.
The evening before symptom onset, he had gone out with friends for dinner and drinks. When he awoke briefly in the middle of the night, he noted blurred vision but returned to sleep. Upon awakening the next morning, he noted new diplopia with obliquely oriented images and presented to an outside hospital for evaluation. His initial ophthalmology exam was notable for a slight abduction deficit in both eyes as well as a right hypertropia and esotropia worse in left gaze but similar with both left and right head tilt. Pupils were equal, round and reactive to light bilaterally with no afferent pupillary defect. He had no orbicularis weakness and no fatigability of his eyelids. His ocular examination was otherwise unremarkable.
His medical history included hypertension, prediabetes, restless leg syndrome and obesity with a recent intentional weight loss of 90 pounds with diet and exercise. He endorsed moderate alcohol use and smoked cigarettes daily. Basic metabolic panel, complete blood count, thyroid-stimulating hormone, vitamin B12, and Lyme and COVID-19 testing were all unremarkable. An MRI of the brain with and without contrast showed no acute findings. The patient was diagnosed with a right fourth nerve palsy and discharged with outpatient neuro-ophthalmology follow-up in 6 weeks.
One day later, the patient presented to the Lahey Hospital emergency department (ED) with new onset of dizziness and disequilibrium. He reported feeling unsteady on his feet and required support to ambulate; after evaluation by physical therapy, a recommendation was made for short-term rehab given the severity of his gait instability. His diplopia persisted, but he denied any new or worsening ocular symptoms. He was evaluated by neurology with a plan for repeat imaging and monitoring; non-contrast MRI of the brain again showed no acute findings.
While awaiting rehab placement, the patient was monitored with serial neurologic exams. On day 2 of his admission in the ED, he was noted to have worsening exam findings with new onset ophthalmoplegia and areflexia.
Examination
Ophthalmology evaluation noted a near visual acuity of 20/20-1 in the right eye and 20/25-2 in the left eye with correction. The patient’s pupils were round and minimally reactive to light and did not constrict with accommodation. There was no afferent pupillary defect. He was noted to have bilateral ptosis greater on the left side with orbicularis weakness. Motility was markedly abnormal, with almost complete ophthalmoplegia in all gaze directions. IOPs were normal. Color vision was intact and full in both eyes. Anterior and posterior segment examinations were unremarkable.
What is your diagnosis?
See answer below.
Ophthalmoplegia
The Miller Fisher variant of Guillain-Barré syndrome, also known as Miller Fisher syndrome, presents with a classic triad of ataxia, areflexia and ophthalmoplegia. A similar entity, Bickerstaff brainstem encephalitis, presents with these findings in addition to encephalopathy.
In any patient with diplopia, ptosis and weakness, a diagnosis of myasthenia gravis (MG) must be considered. MG is an immunologic disorder characterized by variable and fatigable weakness resulting from autoantibodies against nicotinic acetylcholine receptor sites at the post-synaptic neuromuscular junction. Symptoms often worsen throughout the day and improve with rest. Deep tendon reflexes are rarely diminished, and pupil involvement is never seen with MG, as the acetylcholine receptors present in the pupil are muscarinic rather than nicotinic. In patients who present with pupil abnormalities, as in this case, alternative etiologies should be pursued.
Lambert-Eaton myasthenic syndrome is a similar neuromuscular junction disorder involving autoantibodies against presynaptic voltage-gated calcium channels. Typically, it occurs in the setting of malignancy as a paraneoplastic syndrome. While this condition can present with ataxia/extremity weakness, hyporeflexia, diplopia and ptosis, it usually progresses over weeks to months, with ocular signs typically occurring late in the disease course. This patient’s sudden development of diplopia followed by ataxia and then ophthalmoplegia makes this an unlikely diagnosis.
Chronic progressive external ophthalmoplegia is an inherited mitochondrial myopathy that can present with ophthalmoplegia with or without ptosis, but diplopia is typically not seen. Progressive supranuclear palsy, a neurodegenerative disorder affecting the brainstem, causes mostly vertical gaze limitations with gait instability and ophthalmoplegia. Cognitive symptoms and other neurologic signs are likely but notably absent in this patient. Both chronic progressive external ophthalmoplegia and progressive supranuclear palsy are slowly progressive, do not occur acutely and do not affect the pupils, features that were inconsistent with this patient’s presentation.
Workup and management
Miller Fisher syndrome (MFS) is a clinical diagnosis. The patient underwent a lumbar puncture with normal opening pressure of 13 cm H2O. Cerebrospinal fluid (CSF) studies demonstrated an elevated protein count of 62 mg/dL (normal range, 15-45) with normal white blood cell count of 6 cells/µL (normal range < 10). Electromyography was also done, showing a prolonged peak latency of the right dural sensory neural action potential, mild slowing of the right median motor nerve conduction velocity, and absent stretch reflexes, findings noted to be consistent with a demyelinating polyneuropathy such as Guillain-Barré syndrome (GBS). Anti-GQ1b antibody testing returned positive with a 1:400 titer, indicative of MFS. Testing for MG (anti-acetylcholine receptor antibodies) was negative.
Discussion
GBS is an acute inflammatory, immune-mediated demyelinating polyneuropathy characterized by ascending motor weakness and areflexia. A subacute progression of numbness and weakness begins in the lower extremities and usually peaks within 4 weeks, leading to ataxia. The incidence is one to two per 1 million individuals with a slight male predominance. Typically, it is preceded by systemic infection days to weeks prior. Upper respiratory and gastrointestinal illnesses are most common, with the pathogens Campylobacter jejuni, Haemophilus influenzae, Mycoplasma pneumoniae, cytomegalovirus and Epstein-Barr virus most frequently implicated. Autoimmune, neoplastic and medication- or vaccination-related cases have also been reported, including those related to COVID-19. Up to one-third of patients may develop respiratory failure related to phrenic nerve involvement; rarely, intubation and mechanical ventilation are required. Other reported features include headache, facial palsy, divergence insufficiency and dysgeusia.
MFS is a variant of GBS. Although the classic triad of ataxia, areflexia and ophthalmoplegia has been described, many patients may present with only one or two of these features. Diplopia due to bilateral ophthalmoplegia is the most common presenting symptom. A study by Ryu and colleagues found that the lateral rectus is most frequently involved, followed by the superior, inferior and medial rectus muscles, respectively. Pupil involvement and blepharoptosis occur in approximately 40% of patients. Occasionally patients may report eye pain or pain with eye movement.
The pathogenic mechanism of disease is thought to involve molecular mimicry, in which antigenic molecules expressed by pathogens exhibit structural similarity to axonal gangliosides located at neuromuscular junctions, such as GQ1b. Antibodies against these molecular mimics form during infection and cross-react to these gangliosides, leading to activation of the complement cascade and ultimately neuronal and glial injury. Testing for GQ1b antibodies can be helpful, with a positive result occurring in 90% of patients with MFS.
CSF testing can also help, demonstrating albuminocytologic dissociation (elevated total protein concentration with normal white blood cell count) in 64% of patients, although results may depend on timing. Forty-nine percent of patients are found to have an elevation within 1 day of weakness onset and 88% within 2 weeks of onset. CSF studies are also helpful in excluding other diagnoses, including infectious etiologies. Nerve conduction studies can show features of demyelination (decreased or absent sensory responses without slowing of sensory conduction). Nerve ultrasound (demonstrating mild, segmental enlargement of the spinal nerve roots and proximal nerve segments) and spinal MRI (demonstrating thickening/enhancement of spinal nerve roots and cauda equina) are rarely performed.
MFS is generally self-limited, with an excellent prognosis compared with many other neurologic diseases. Most patients show improvement in their symptoms within 1 to 2 months. Eighty-seven percent of patients will experience a full recovery, although a small percentage may have residual foot drop, pain, numbness, weakness and/or fatigue. Recurrence occurs in 5% to 10%.
While limited data exist regarding treatment specifically for MFS, several Cochrane reviews have examined the efficacy of intravenous immunoglobulin (IVIG) and plasma exchange (plasmapheresis) for GBS. Compared with supportive care alone, patients treated with plasma exchange were found to have shorter time to motor recovery on the scale of days for mild disease and on the scale of weeks for severe disease. Patients were also more likely to experience full recovery of muscle strength and less likely to have severe residual weakness when treated with plasma exchange over supportive care. Further systematic analysis suggests that IVIG started within 2 weeks from symptom onset hastens recovery as much as plasma exchange in patients with severe disease. In one Japanese study on IVIG for MFS, the authors noted that IVIG shortened the time to symptom resolution but did not affect the overall outcome, with 96% of patients completely symptom-free at 1 year regardless of their treatment group.
Clinical course continued
The patient was treated with 5 days of IVIG, with a good recovery leading to early discharge home from rehab. He was seen by neurology 2 weeks after hospitalization for follow-up and was noted to have resolution of his gait instability and incoordination, although he still experienced persistent diplopia and fatigue. At neuro-ophthalmology follow-up 4 weeks later, he reported dramatic improvement in his diplopia, extraocular motility and resolution of his ptosis. A small residual esotropia worse in left gaze was noted and expected to continue to improve over time.
- References:
- Al Othman B, et al. Curr Opin Ophthalmol. 2019;doi:10.1097/ICU.0000000000000611.
- Chevret S, et al. Cochrane Database Syst Rev. 2017;doi:10.1002/14651858.CD001798.pub3.
- Hughes RA, et al. Cochrane Database Syst Rev. 2014;doi:10.1002/14651858.CD002063.pub6.
- Inatomi Y, et al. Neuroophthalmology. 2010;doi:10.3109/01658100903470553.
- Mori M, et al. Neurology. 2007;doi:10.1212/01.wnl.0000258673.31824.61.
- Overell JR, et al. Cochrane Database Syst Rev. 2007;doi:10.1002/14651858.CD004761.pub2.
- Rocha Cabrero F, et al. Miller Fisher Syndrome. 2021. StatPearls Publishing.
- Ryu WY, et al. J Clin Neurol. 2019;doi:10.3988/jcn.2019.15.3.308.
- van den Berg B, et al. Nat Rev Neurol. 2014;doi:10.1038/nrneurol.2014.121.
- For more information:
- Angell Shi, 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. Geetha Athappilly, MD, can be reached at Atrius Health; website: www.atriushealth.org.
- Edited by Allison V. Coombs, DO, MS, and Nisha S. Dhawlikar, MD, MPH. 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.