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Young man presents with vertical diplopia and unilateral ptosis
Examination showed a large left hypotropia and left upper eyelid ptosis.
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A 26-year-old man was referred to the neuro-ophthalmology clinic at the New England Eye Center for evaluation of diplopia and ptosis of the left upper eyelid. For 1 month, he had persistent binocular vertical diplopia. The diplopia resolved when either eye was closed or when he looked down. As such, he found himself tilting his chin upward to see clearly. Upgaze seemed to worsen the diplopia. In addition, he had persistent left upper lid ptosis. Neither the eyelid position nor the double vision had changed over the month. Furthermore, these symptoms did not seem to worsen over the course of the day. Otherwise, he felt well with no recent illnesses, headaches, weakness, numbness, fevers, chills, sweating, palpitations, nausea or vomiting.
His medical and ocular histories were unremarkable, and he took no medications. His family history included thyroid disease. Although an active rugby player, he had not experienced any recent head trauma. He did not smoke, drink alcohol or use any recreational drugs.
Examination
On initial examination, the patient was a healthy-appearing young man. His vision without correction was 20/20 bilaterally. Pupils were equal and reactive to light without an afferent pupillary defect in either eye. IOPs were equal at 13 mm Hg.
Motility in the right eye was full. The left eye showed severe limitation of elevation, with full abduction and adduction (Figure 1). Maddox rod testing revealed an 18 D left hypotropia in primary gaze as well as in left and right horizontal gaze. The left hypotropia increased to 40 D in upgaze, and the eyes were orthophoric in downgaze. In right head tilt, there was a 20 D left hypotropia. In left head tilt, the left hypotropia was 16 D. Forced duction testing was negative.
Source: Adam T. Chin, MD, Laurel N. Vuong, MD, and Thomas R. Hedges III, MD
The left upper lid was ptotic with a marginal reflex distance-1 of 1.5 mm on the left compared with 4.5 mm on the right. Levator function was normal bilaterally. No proptosis or enophthalmos was appreciated. The remainder of the anterior and posterior exam was unremarkable.
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Binocular vertical diplopia
The differential diagnosis of binocular vertical diplopia with ptosis can be organized broadly into neurogenic and myogenic etiologies.
Neurogenic causes of ptosis and vertical diplopia include oculomotor nerve palsy and myasthenia gravis. While a complete third cranial nerve (CN III) palsy leads to ptosis and limitation of elevation, depression and adduction of the eye, damage to a subdivision of CN III can lead to partial CN III palsies. Specifically, dysfunction of the superior division of CN III, which innervates the levator palpebrae superioris and superior rectus, may present as isolated ptosis and limitation of elevation. Therefore, in this patient, a lesion affecting CN III must be considered. Myasthenia gravis (MG), which is an autoimmune disorder resulting in poor signal transmission across the neuromuscular junction of skeletal muscles, must also be considered. MG may present with ptosis and/or any combination of oculomotor findings and frequently demonstrates motor findings that mimic the patterns seen in cranial nerve palsies.
Myogenic and mechanical etiologies include thyroid orbitopathy, an upper lid or orbital mass, restriction after trauma, silent sinus syndrome, monocular elevation deficiency (double elevator palsy), oculopharyngeal muscular dystrophy (OPMD), chronic progressive external ophthalmoplegia (CPEO) and myotonic dystrophy. Thyroid eye disease is common and may cause restricted motility due to infiltration and thickening of the extraocular muscles. Further, lid retraction often results in contralateral pseudoptosis due to Hering’s law. Upper lid masses, such as neurofibromas, may lead to mechanical ptosis and restrict elevation of the eye. These, however, are more commonly seen in pediatric patients. Given this patient’s history of rugby, old trauma should be considered. A floor fracture or subsequent repair can cause tethering of the inferior rectus. These patients should have true restriction as demonstrated by positive forced duction testing. Another mechanical etiology that may lead to the patient’s diplopia and apparent ptosis is silent sinus syndrome, which typically affects people in their 30s and 40s. In these patients, chronic obstruction and hypoventilation of the maxillary sinus leads to negative pressure, chronic inflammation and weakening of the orbital floor. Eventually, the patient may develop hypoglobus and enophthalmos, resulting in apparent ptosis and diplopia. Monocular elevation deficiency can present as ptosis and poor elevation, but it would not present primarily in a patient in his 20s. Likewise, OPMD and myotonic dystrophy are unlikely given the unilateral findings and lack of involvement of other muscle groups. CPEO is isolated to the extraocular muscles; however, it also typically presents with bilateral involvement.
Workup and management
The patient underwent workup based on the above differential. TSH, free T4, ACE and lysozyme were normal. Testing for acetylcholine receptor (binding, blocking, modulating) antibodies and muscle-specific kinase (MUSK) antibodies was negative.
MRI of the head and orbits revealed asymmetric tortuosity of the left internal carotid artery as it passed through the cavernous sinus. Otherwise, there were no orbital masses or enhancing lesions. There was no displacement of the globe, and the extraocular muscles were normal appearing (Figure 2a). MRA and cerebral angiogram confirmed a significant lateral bend of the left internal carotid artery toward the oculomotor nerve in the cavernous sinus (Figure 2b). No aneurysms were found.
After the angiogram, the patient returned for a follow-up with neuro-ophthalmology. While he continued to have a left hypotropia and ptosis, the ptosis appeared fatigable, and the left upper lid overshot when looking up after sustained downgaze. In an effort to make a definitive diagnosis, Tensilon (edrophonium) was administered in the clinic. Within minutes, his ptosis and diplopia resolved completely (Figure 3). A diagnosis of MG was made.
Discussion
MG is an autoimmune condition characterized by skeletal muscle weakness due to autoantibody inhibition of signal transmission across the neuromuscular junction. While antibodies against acetylcholine receptors (AChR) are classically thought of as the drivers of myasthenia pathophysiology, an array of other post-synaptic targets have been identified as clinically important autoantigens. In normally functioning neuromuscular junctions, acetylcholine receptors cluster on the muscle cell membrane. This clustering of receptors and proper orientation of the neuromuscular junction is mediated, in part, by a complex of molecules that include MUSK and low-density lipoprotein receptor-related protein 4 (LRP4). Disruption of these molecules leads to reduced AChR concentration and function.
While MG only affects skeletal muscles, the extent of involvement can range from mild, localized ocular muscle weakness to generalized weakness and profound respiratory depression. Because generalized MG often presents initially as ptosis and/or diplopia, it is essential for ophthalmologists to be aware of the condition. Further, it is important to screen for symptoms of bulbar and respiratory weakness if myasthenia is suspected.
Ocular involvement is limited to the extraocular muscles, levator palpebrae superioris and orbicularis oculi. Clinically, it presents as any combination of unilateral or bilateral pupil-sparing ophthalmoplegia, ptosis, ectropion or orbicularis weakness. The ophthalmoplegia is highly variable and may mimic any neurogenic pattern. A detailed history may elicit a pattern of weakness worse at the end of the day or with prolonged effort. Some patients demonstrate a characteristic overshoot of the upper lid upon upgaze after sustained downgaze, known as Cogan’s lid twitch.
The diagnosis of MG is a clinical one, based on isolated skeletal muscle weakness and supported by laboratory, EMG and radiologic testing. Autoantibody testing is a central component of MG diagnosis. AChR antibodies are found in 70% to 90% of patients with generalized MG and are nearly 100% specific to the diagnosis of MG. Interestingly, in isolated ocular MG, AChR antibodies may only be found in approximately 50% of patients. Of the other postsynaptic ligands, MUSK and low-density LRP4 are detected in only 1% to 10% and 1% to 5% of generalized MG patients, respectively. While anti-LRP4 antibodies may be seen in isolated ocular MG, anti-MUSK antibodies are almost never detected.
If high clinical suspicion exists in the setting of a seronegative patient, supervised administration of the short-acting acetylcholinesterase inhibitor edrophonium can help establish a diagnosis. Other tests such as the application of ice to the ptotic lid may also elicit improvement of ptosis in MG patients. While electromyography testing by neurology may also be used to support a diagnosis of myasthenia, repetitive nerve stimulation has relatively poor sensitivity, and single fiber EMG of the orbicularis oculi may be required in isolated ocular myasthenia.
The mainstay of treatment is the oral acetylcholinesterase inhibitor pyridostigmine, which increases the amount of available acetylcholine in the synaptic cleft. The drug, thereby, enhances the stimulus to the affected muscle and alleviates symptoms. In patients with generalized disease or at high risk for progression (positive for AChR antibodies, enlarged thymus and/or positive neuromuscular testing), systemic corticosteroids and azathioprine and/or other immunosuppressive medications are often used.
In this patient’s case, the initial ocular motility exam mapped to a partial CN III palsy. However, MG can mimic any neurogenic pattern. The presence of an ipsilateral anomalous internal carotid artery presented a further diagnostic challenge. Aneurysms of the posterior communicating artery, intracavernous internal carotid, basilar, posterior cerebral, superior cerebellar and even anterior communicating arteries have been described causing third nerve palsies. At least one case of an intracavernous internal carotid aneurysm resulted in a partial third nerve palsy isolated to the superior division. However, to the knowledge of the authors, a tortuous internal carotid artery leading to third nerve palsy has not been well described. Therefore, in the presence of clinically suspicious features of myasthenia (Cogan’s lid twitch and fatigability), edrophonium was administered, leading to the diagnosis of MG. At the initial follow-up visit after starting oral pyridostigmine, the patient had resolution of ptosis and improving ocular motility.
- References:
- Gilhus NE. N Eng J Med. 2016;doi:10.1056/NEJMra1602678.
- Gilhus NE, et al. Nat Rev Neurol. 2016;doi:10.1038/nrneurol.2016.44.
- Kupersmith MJ, et al. Br J Ophthalmol. 2005;doi:10.1136/bjo.2004.063404.
- Pascuzzi RM. Semin Neurol. 2003;doi:10.1055/s-2003-40755.
- Smith SV, et al. Neurol Clin. 2017;doi:10.1016/j.ncl.2016.08.008.
- For more information:
- Adam T. Chin, MD, Laurel N. Vuong, MD, and Thomas R. Hedges III, MD, can be reached at New England Eye Center, Tufts University School of Medicine. 800 Washington Street, Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Aubrey R. Tirpack, MD, and Astrid C. Werner, MD. They can be reached at the New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.