High school boy presents with worsening ptosis
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A 15-year-old high school student presented to the pediatric ophthalmology clinic for ptosis.
He initially developed drooping of the left upper eyelid around 5 to 6 years old, and he subsequently developed ptosis of the right upper eyelid around the age of 13 years.
The ptosis had become noticeably worse in the last few years in both eyes. He also had “vision drift” over the last year when he tried to concentrate while reading but denied diplopia otherwise. He had no significant ocular, medical or surgical history. He had a normal birth. His family history was notable for diabetes, hypertension, heart disease and thyroid disease. He had no known drug allergies. He did not smoke or drink alcohol.
Examination
On examination, visual acuity without correction was 20/20 in both eyes. The patient's pupils were 6 mm in dim light, decreasing to 4 mm in bright light without a relative afferent pupillary defect. Confrontation visual fields were full. Color vision was normal in both eyes by pseudoisochromatic plate testing. He saw all four dots on Worth’s Four Dot test at distance and near and had 40 seconds of arc on stereopsis testing. IOPs were 14 mm Hg in both eyes.
External examination was notable for bilateral upper lid ptosis (Figure 1), absence of lid creases and a chin-up position. In both eyes, levator function was 10 mm, palpebral fissures were 7 mm, and midcorneal reflex distances were 1 mm. There was no fatigability or Cogan’s lid twitch. Extraocular motility testing showed limitation of abduction, adduction, supraduction and infraduction. In primary gaze, he had a 25 D exotropia at distance and near that worsened in upgaze. Slit lamp examination of both eyes was unremarkable. Dilated examination demonstrated clear vitreous, pink and healthy optic nerves with a cup-to-disc ratio of 0.1, flat maculae, normal vessels, and pigmentary clumping/dusting throughout the periphery in both eyes (Figure 2).
Source: Teresa P. Horan, MD, and Thomas R. Hedges III, MD
What is your diagnosis?
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Progressive ptosis
The differential diagnosis for this patient with progressive ptosis and ophthalmoplegia included chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, juvenile myasthenia gravis, congenital fibrosis syndrome, myotonic dystrophy and oculopharyngeal muscular dystrophy.
Given the patient’s findings of progressive ptosis and limitation in extraocular movements, chronic progressive external ophthalmoplegia (CPEO) was high on the differential. “CPEO plus,” or Kearns-Sayre syndrome, was more likely given the pigmentary clumping in the peripheral retina. The patient’s age of onset was also consistent with CPEO and Kearns-Sayre clinical presentations.
Juvenile myasthenia gravis, which is estimated to account for 10% to 15% of all cases of myasthenia gravis, can cause ptosis and extraocular muscle involvement in up to 85% of patients. However, myasthenia gravis is usually associated with variable ptosis as well as fatigability and Cogan’s lid twitch on exam. Myotonic dystrophy is characterized by bilateral symmetrical ptosis occurring in the second to fourth decade of life. However, it is associated with temporal wasting, Christmas tree cataracts, frontal alopecia and distal limb weakness. Congenital fibrosis of the extraocular muscles may present similarly to this patient. However, this rare congenital syndrome is usually characterized by nonprogressive unilateral or bilateral restrictive strabismus with or without blepharoptosis. Oculopharyngeal muscular dystrophy was less likely in this patient as it usually presents in the fifth and sixth decades of life. Affected patients experience progressive bilateral ptosis and external ophthalmoplegia followed by dysphagia and proximal muscle weakness.
Workup and management
The patient underwent a Tensilon test in the office for evaluation of myasthenia gravis; no effect on the eyelids or eye movements was noted after 8 mg of Tensilon. He also had two negative screening blood work panels. The first, a progressive external ophthalmoplegia panel, was negative for mutations in the SLC25A4, OPA1, POLG and TWNK genes and for mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). A mitochondrial DNA disease screening panel was negative for MELAS; myoclonic epilepsy with ragged red fibers; neuropathy, ataxia and retinitis pigmentosa; Leber hereditary optic neuropathy; Kearns-Sayre; and CPEO. He then had a muscle biopsy that confirmed the diagnosis of Kearns-Sayre with a m.9214_14753del5540 heteroplasmic deletion in the mitochondrial DNA.
Because patients with Kearns-Sayre can develop third-degree atrioventricular block, he was referred to cardiology and had an unremarkable electrocardiogram, Holter monitor and echocardiogram. He had no evidence of ataxia, short stature, cardiac conduction delay or endocrine problems, which some patients with Kearns-Sayre develop.
He continues to be followed closely by the genetics clinic. He has since developed intermittent horizontal diplopia at near and worsening ptosis but is opting for observation at this time. He takes coenzyme Q10 daily.
Discussion
This case demonstrates many findings typical of Kearns-Sayre syndrome, including ptosis, chronic progressive external ophthalmoplegia and retinal pigmentary changes. This inherited mitochondrial myopathy, first described by Kearns and Sayre in 1958, includes CPEO, pigmentary retinopathy and potentially fatal cardiac conduction abnormalities. About 90% of Kearns-Sayre cases are due to sporadic deletions of mitochondrial DNA, as in this patient with no family history. Onset is usually before age 20 years, and patients initially present with bilateral progressive ptosis with subsequent development of external ophthalmoplegia. The myogenic ptosis associated with Kearns-Sayre is characterized by decreased levator function and is usually one of the earliest signs. The onset of ophthalmoplegia is typically gradual and symmetrical, so many patients do not initially develop diplopia until late in the disease course. The characteristic pigmentary retinopathy due to diffuse depigmentation of the retinal pigment epithelium rarely causes significant vision loss; however, it can lead to progressive peripheral and night vision loss in up to 40% of patients.
Systemically, patients with Kearns-Sayre should be monitored for cardiac complications including heart block and mitral valve regurgitation. Other systemic manifestations include hearing loss, peripheral muscle weakness, cerebellar ataxia and endocrine dysfunction. Associated endocrinopathies include hypoparathyroidism, hypogonadism, diabetes and hypopituitarism.
The clinical diagnosis of Kearns-Sayre requires CPEO and pigmentary retinopathy before the age of 20 years and at least one of the following: complete heart block, elevated CSF protein (more than 1 mg/mL), cerebellar ataxia or endocrine disturbances. Skeletal muscle biopsy can be helpful to establish the diagnosis, and the presence of ragged red fibers can support the diagnosis of a mitochondrial myopathy. Genetic testing can also be used, although there are many genetic defects associated with Kearns-Sayre so extensive panels may be required. In addition, older individuals may have negative blood testing so muscle biopsy may be necessary.
There is no definitive treatment for Kearns-Sayre syndrome. Recent clinical trials have shown beneficial results with coenzyme Q10 supplementation. Symptomatic treatments include ptosis surgery, typically with frontalis suspension, as well as strabismus surgery or prisms for diplopia. Unfortunately, ptosis often recurs or progresses after surgery, requiring additional eyelid surgery.
- References:
- Burnstine MA, et al. 31 progressive myogenic ptosis: evaluation and management. In: Ophthalmic Plastic Surgery of the Upper Face: Eyelid Ptosis, Dermatochalasis, and Eyebrow Ptosis. Thieme; 2019.
- Doroslovaki P, et al. Neuro-ophthalmic considerations in pediatric orbital and oculoplastic disease. In: Katowitz JA, et al (eds). Pediatric Oculoplastic Surgery. Springer; 2018.
- Eagle RC Jr, et al. Ophthalmology. 1982;doi:10.1016/s0161-6420(82)34619-9.
- Goldstein A, et al. Mitochondrial DNA deletion syndromes. 2003. GeneReviews.
- Kearns TP, et al. AMA Arch Ophthalmol. 1958;doi:10.1001/archopht.1958.00940080296016.
- Rubin RM, et al. Ocular myopathies. In: Yanoff M, et al (eds). Ophthalmology. 3rd ed. Mosby; 2008.
- Shemesh A, et al. Kearns Sayre syndrome. 2021. StatPearls Publishing.
- Tarnopolsky MA. Adv Drug Deliv Rev. 2008;doi:10.1016/j.addr.2008.05.001.
- For more information:
- Teresa P. Horan, MD, and Thomas R. Hedges III, 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 Yi Ling Dai, MD, and Teresa P. Horan, 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.