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Show Original Contribution Chronic Progressive External Ophthalmoplegia in the Absence of Ptosis Robert C. Bucelli, MD, PhD, Michael S. Lee, MD, Collin M. McClelland, MD Abstract: Classically defined as bilateral, symmetric, and progressive ophthalmoparesis with myopathic ptosis, chronic progressive external ophthalmoplegia (CPEO) rarely has been reported in the absence of ptosis. We describe 2 patients with CPEO and without ptosis who presented with binocular diplopia related to small-angle esodeviations, poor fusional amplitudes, and slow saccades. In both cases, hematological studies and neuroimaging ruled out alternative etiologies, whereas muscle biopsy showed findings of mitochondrial myopathy. Journal of Neuro-Ophthalmology 2016;36:270-274 doi: 10.1097/WNO.0000000000000384 © 2016 by North American Neuro-Ophthalmology Society P rogressive external ophthalmoplegia is a clinical manifestation of various disorders sharing a common pathophysiology of mitochondrial dysfunction leading to progressive extraocular myopathy. It may occur in isolation during adulthood, termed chronic progressive external ophthalmoplegia (CPEO), or it may occur as one feature of a systemic mitochondrial cytopathic disorder with multiorgan sequelae. Ptosis from levator palpebrae superioris (LPS) weakness, usually presenting simultaneously with or preceding ophthalmoplegia, often represents the earliest clinical feature of CPEO. We present 2 patients with biopsy-confirmed CPEO presenting with diffuse bilateral ophthalmoparesis and binocular diplopia in the absence of ptosis. Department of Neurology (RB), Washington University School of Medicine, St. Louis, Missouri; and Departments of Ophthalmology and Visual Neurosciences (ML, CMM), Neurology (ML), and Neurosurgery (ML), University of Minnesota, Minneapolis, Minnesota. Supported in part by Unrestricted Grant from Research to Prevent Blindness, New York, NY. The authors report no conflicts of interest. Address correspondence to Collin M. McClelland, MD, Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Phillips-Wangensteen Building, 9th floor, 420 Delaware St. SE/ MMC 493, Minneapolis, MN 55455; E-mail: cmc@umn.edu 270 CASE 1 A 64-year-old woman with a medical history of hypertension and migraine headaches presented with intermittent binocular diplopia for 5 years. This was worse at distance and omnidirectional. She denied ptosis, shortness of breath, dysphagia, or systemic weakness except for bilateral, painful hip weakness attributed to bursitis. She reported a distant cousin with congenital strabismus, but there was no family history of ptosis or abnormal eye movements. Afferent visual function, pupillary testing, and structural eye examination were unremarkable in both eyes. Efferent neuroophthalmic testing revealed mild-to-moderate diffuse ophthalmoplegia in both eyes with relative sparing of downgaze (Fig. 1). Ocular motility did not improve with vestibulo-ocular reflex (VOR) maneuvers. Alternate cover testing showed a slightly incomitant, intermittent esotropia measuring 1-4 prism diopters depending on gaze position. There was no ptosis with superior eyelid margin-to-reflex distance (MRD1) measurements of 5 mm in both eyes (Fig. 1). Ocular saccades were markedly slow without dysmetria. There was orbicularis oculi weakness bilaterally. Single binocular vision was achieved with a 3 base-out Fresnel prism that was subsequently ground into her glasses after a stable 2-month follow-up examination. Thyroid stimulating hormone (TSH), thyroid stimulating immunoglobulins (TSI), complete metabolic profile (CMP), and acetylcholine receptor binding/modulating antibodies were normal. Magnetic resonance imaging (MRI) of the orbits showed atrophic extraocular muscles bilaterally (Fig. 2). Quadriceps muscle biopsy showed scattered cytochrome oxidase (COX)-negative fibers (Figs. 3A, B), and mitochondrial enzymatic activities showed a moderate reduction in Complex I and III activity (25% and 27% of normal, respectively). The patient was referred to cardiology for intermittent palpitations. Electrocardiogram and Holter monitoring were unremarkable. Transthoracic echocardiogram showed prominent left atrial enlargement and mild left ventricular hypertrophy that cardiology felt could be attributable to mitochondrial cardiomyopathy or partially controlled hypertension. Bucelli et al: J Neuro-Ophthalmol 2016; 36: 270-274 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Case 1: There is mild-to-moderate bilateral ophthalmoplegia with relative sparing of downgaze and without ptosis. CASE 2 A 53-year-old woman noted intermittent diplopia for 11 years with marked worsening in the past 3 years. Medical history included possible Sjogren syndrome with keratoconjunctivitis sicca (SS-A and SS-B antibody negative), fibromyalgia, chronic depression and anxiety, hypothyroidism, migraine headaches, and a small fiber polyneuropathy (length dependent on skin biopsy) causing bilateral lower extremity pain for 10 years. She reported diffuse muscle fatigue and dyspnea with mild exercise dating back to her adolescence. Thirteen years ago, she had a subarachnoid hemorrhage and underwent emergent clipping of a right anterior cerebral artery aneurysm. There was no family history of ptosis, diplopia, or abnormal eye movements. Afferent visual function, pupillary testing, and structural eye examination were unremarkable in both eyes aside from mild dry eye keratopathy. Efferent neuro-ophthalmic testing revealed bilateral moderate ophthalmoplegia (Fig. 4) that failed to improve with VOR testing. There was no ptosis with MRD1 measurements of 3.5 and 3 mm in the right and left eye, respectively. There was no facial weakness. Alternate cover testing revealed comitant 2-3 prism diopter esotropia at distance and 4 prism diopter exophoria at near. Saccades were markedly slow without dysmetria. Single binocular vision was achieved at distance with a 3 base-out Fresnel prism that was subsequently ground into her glasses after a stable 5-week follow-up examination. The remainder of her neurologic examination was notable for diminished pinprick sensation over the distal upper and lower extremities. TSH, TSI, CMP, acetylcholine receptor binding/modulating antibodies, thiamine, vitamin B-12, folate, hemoglobin A1c, and homocysteine blood test results were normal. Transthoracic echocardiogram and electrocardiogram were unremarkable. MRI of the orbits showed atrophic extraocular muscles bilaterally (Fig. 5). A biopsy of the right deltoid showed findings consistent with a mitochondrial myopathy including an average of 22.33 "ragged blue" fibers, per lower power (·40) field. There were also a comparable number of fibers with reduced staining on COX stains (Figs. 3C, D). Scattered fibers with increased lipid droplet size were present on Sudan black staining. Mitochondrial enzymatic activities were normal. DISCUSSION FIG. 2. Postcontrast coronal T1 magnetic resonance imaging with fat suppression shows symmetric atrophy of the extraocular muscles. Bucelli et al: J Neuro-Ophthalmol 2016; 36: 270-274 Progressive external ophthalmoplegia is a myopathic sequelae of mitochondrial dysfunction associated with a wide spectrum of mitochondrial syndromes (Table 1) (1-3). Some of these disorders have been referred to as "CPEO plus" syndromes. Although the term CPEO is typically reserved for patients with few other systemic features of mitochondrial disease, the lines distinguishing syndromes can be blurred. Mutations in the same gene can cause multiple different syndromes (4). CPEO typically presents in isolation after age 20 years but can occur with numerous systemic features more commonly described in childhood-onset mitochondrial 271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Case 1: (A) Quadriceps muscle biopsy reveals scattered cytochrome oxidase (COX) "negative" muscle fibers (arrows); (B) there is not a concurrent increase in "positive"/"ragged blue" fibers with succinate dehydrogenase (SDH) staining. Case 2: (C) Deltoid muscle biopsy shows scattered COX-negative fibers (arrows), with (D) a corresponding increase in the number of "ragged blue" fibers (arrows) with SDH staining (A-D ·200). cytopathies including nonocular skeletal myopathy, fatigue, neurologic sequelae (peripheral neuropathy, migraine headaches, seizures, stroke-like episodes, ataxia, sensorineural hearing loss), skin findings, gastrointestinal involvement (dysphagia, liver failure, diarrhea, constipation), neuro-psychiatric abnormalities, endocrinopathies, and cardiac disorders (cardiomyopathy and conduction defects) (5). Ocular motility deficits in association with mitochondrial cytopathies are often asymptomatic and may be easily overlooked. One study of patients with mitochondrial myopathy found that only 8 of 49 (16.3%) patients with ophthalmoplegia on examination complained of restricted eye movements (6). Ophthalmoparesis in CPEO patients without other obvious systemic features is often present for years before diagnosis (3). Bilateral ptosis is a hallmark early feature of both CPEO and progressive external ophthalmoplegia associated with other mitochondrial syndromes. One adult-onset CPEO study listed the presence of both ptosis and ophthalmoplegia as required for study inclusion (5). FIG. 4. Case 2: Eye movements demonstrate moderate ophthalmoplegia in both eyes with relative sparing of downgaze and absence of ptosis. 272 Bucelli et al: J Neuro-Ophthalmol 2016; 36: 270-274 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. Case 2: Postcontrast, fat-suppressed coronal T1 scan reveals symmetric atrophy of the extraocular muscles. The artifact signal in both orbits (right . left) is from a right anterior cerebral artery aneurysm clip. The literature on CPEO without ptosis is scarce. Many studies on mitochondrial cytopathies were retrospective and did not describe a detailed ophthalmic or neuro-ophthalmic examination. From an estimated combined clinical experience of 50-75 CPEO patients, Walsh and Hoyt (7) describe only 2 patients, a brother and sister, who had near-complete ophthalmoplegia from CPEO in the absence of ptosis. Interestingly, their father had a classic CPEO phenotype with profound bilateral ophthalmoplegia and ptosis. Twenty years after her initial examination, his daughter still had "minimal, even questionable" ptosis. Petty et al (6) reported 37 patients with biopsy-confirmed CPEO and found 1 patient with ophthalmoplegia in the absence of ptosis. Gronlund et al (8) provided examination results of 57 children with assorted mitochondrial syndromes and found that 9/57 (15.8%) of cases demonstrated reduced eye motility in the absence of ptosis (n = 1 Alpers syndrome, n = 3 Leigh syndrome, n = 1 Kearns-Sayre syndrome, n = 2 mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, and n = 2 myoclonus epilepsy with red ragged fibers) (8). Of the 9 patients with severely reduced eye motility, ptosis was present in all cases. Although these syndromes differ from adult-onset CPEO, the underlying pathophysiology for impaired extraocular motility is likely similar in some. Cases involving syndromes with encephalopathy or stroke could have an alternative pathophysiology for ophthalmoparesis other than a mitochondrial myopathy. The absence of ptosis exclusively seen in patients with less than "severely" reduced ocular motility suggests that these may be early presentations of extraocular myopathy. Ptosis from clinically significant LPS myopathy could develop later in the disease course. Clinical heterogeneity is a hallmark of mitochondrial diseases; CPEO without ptosis likely represents one variant along the spectrum of atypical progressive external ophthalmoplegia phenotypes including unilateral ptosis with TABLE 1. Syndromes associated with progressive external ophthalmoplegia Syndrome CPEO Kearns-Sayre syndrome Sensory ataxic neuropathy, dysarthria, ophthalmoparesis Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Myoclonus epilepsy with ragged red fibers Mitochondrial neurogastrointestinal encephalomyopathy Leigh syndrome Pearson syndrome Alpers syndrome Clinical Features (Predominate Features Bolded) Onset usually .20 y of age with progressive external ophthalmoplegia with the following variable features: facial weakness, systemic muscle weakness, endocrine abnormalities, dementia, ataxia, peripheral neuropathy, sensorineural hearing loss, cardiomyopathy, cardiac conduction defects, and migraines Onset in childhood (,20 y) with progressive external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy, short stature, sensorineural hearing loss, ataxia, dementia, and migraines Nearly all the features of CPEO may be seen; progressive external ophthalmoplegia, sensory ataxic neuropathy, dysarthria, and limb girdle paresis predominate Onset in childhood or early adulthood. Short stature, migraines, seizures, stroke-like episodes, dementia, ataxia, sensorineural hearing loss, generalized muscle weakness, progressive external ophthalmoplegia Onset in late childhood to adolescence; myoclonic and generalized seizures, ataxia, generalized muscle weakness, progressive external ophthalmoplegia Onset before age 20; progressive external ophthalmoplegia, limb weakness, abdominal pain, diarrhea, and peripheral motor and sensory neuropathy Onset in infancy; ataxia, seizures, sensorineural hearing loss, dysphagia, dysarthria, progressive external ophthalmoplegia Onset in infancy; anemia, pancreatic failure, progressive external ophthalmoplegia, cardiac conduction defects, and pigmentary retinopathy Onset in infancy; seizures, liver dysfunction, dementia, spasticity, central blindness CPEO, chronic progressive external ophthalmoplegia. Bucelli et al: J Neuro-Ophthalmol 2016; 36: 270-274 273 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution ophthalmoplegia (6,9), asymmetric extraocular muscle paresis (3,6,10), and the widely variable systemic manifestations seen even among patients with the same genetic mutation (4). One proposed mechanism for the heterogeneity in mitochondrial disease that could also explain the relative sparing of the LPS muscles in these CPEO cases is heteroplasmy. If a patient with CPEO harbored a pathogenic mitochondrial DNA (mtDNA) mutation and the LPS contained a higher ratio of wild-type to mutated mitochondrial DNA compared with the extraocular muscles, a phenotype without ptosis or with late-onset ptosis could occur. Similar to clinical manifestations, muscle biopsy findings supportive of a clinical diagnosis of CPEO are often heterogenous (11-13). In Case 1, the classic findings of ragged red fibers and ragged blue fibers were absent but the presence of a significant number of COX-negative fibers supports the diagnosis. Timely diagnosis of CPEO with early detection of latent systemic disease is important, particularly given its association with cardiomyopathy and cardiac arrhythmias (5,14). Although CPEO almost always presents with myopathic ptosis at the time of diagnosis, clinicians should be cognizant that exceptions to the rule occur. Considering that ophthalmoparesis is usually asymptomatic and ptosis is the most common presenting feature of the disease, CPEO without ptosis is likely underdiagnosed. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: R. C. Bucelli, C. M. McClelland, and M. S. Lee; b. acquisition of data: R. C. Bucelli and C. M. McClelland; c. analysis and interpretation of data: R. C. Bucelli, C. M. McClelland, and M. S. Lee. Category 2: a. Drafting the manuscript: R. C. Bucelli and C. M. McClelland; b. revising it for intellectual content: R. C. Bucelli, C. M. McClelland, and M. S. Lee. Category 3: a. Final approval of the completed manuscript: R. C. Bucelli, C. M. McClelland, and M. S. Lee. 274 REFERENCES 1. Lee AG, Brazis PW. Chronic progressive external ophthalmoplegia. Curr Neurol Neurosci Rep. 2002;2:413-417. 2. Miller NR, Walsh FB, Hoyt WF. Walsh and Hoyt's Clinical Neuroophthalmology, 6th edition. Philadelphia, PA: Lippincott Williams & Wilkins, 2005. 3. Caballero PE, Candela MS, Alvarez CI, Tejerina AA. Chronic progressive external ophthalmoplegia: a report of 6 cases and a review of the literature. Neurologist. 2007;13:33-36. 4. Hanisch F, Kornhuber M, Alston CL, Taylor RW, Deschauer M, Zierz S. SANDO syndrome in a cohort of 107 patients with CPEO and mitochondrial DNA deletions. J Neurol Neurosurg Psychiatry. 2015;86:630-634. 5. Pfeffer G, Sirrs S, Wade NK, Mezei MM. Multisystem disorder in late-onset chronic progressive external ophthalmoplegia. Can J Neurol Sci. 2011;38:119-123. 6. Petty RK, Harding AE, Morgan-Hughes JA. The clinical features of mitochondrial myopathy. Brain. 1986;109:915-938. 7. Walsh FB, Hoyt WF. Clinical Neuro-ophthalmology, 3rd edition. Baltimore, MD: Williams & Wilkins, 1969. 8. Gronlund MA, Honarvar AK, Andersson S, Moslemi AR, Oldfors A, Holme E, Tulinius M, Darin N. Ophthalmological findings in children and young adults with genetically verified mitochondrial disease. Br J Ophthalmol. 2010;94:121-127. 9. Okulla T, Kunz WS, Klockgether T, Schroder R, Kornblum C. Diagnostic value of mitochondrial DNA mutation analysis in juvenile unilateral ptosis. Graefes Arch Clin Exp Ophthalmol. 2005;243:380-382. 10. Richardson C, Smith T, Schaefer A, Turnbull D, Griffiths P. Ocular motility findings in chronic progressive external ophthalmoplegia. Eye (Lond). 2005;19:258-263. 11. Cardaioli E, Da Pozzo P, Gallus GN, Malandrini A, Gambelli S, Gaudiano C, Malfatti E, Viscomi C, Zicari E, Berti G, Serni G, Dotti MT, Federico A. A novel heteroplasmic tRNA(Ser(UCN)) mtDNA point mutation associated with progressive external ophthalmoplegia and hearing loss. Neuromuscul Disord. 2007;17:681-683. 12. Sotiriou E, Coku J, Tanji K, Huang HB, Hirano M, DiMauro S. The m.3244G.A mutation in mtDNA is another cause of progressive external ophthalmoplegia. Neuromuscul Disord. 2009;19:297-299. 13. Fassati A, Bordoni A, Amboni P, Fortunato F, Fagiolari G, Bresolin N, Prelle A, Comi G, Scarlato G. Chronic progressive external ophthalmoplegia: a correlative study of quantitative molecular data and histochemical and biochemical profile. J Neurol Sci. 1994;123:140-146. 14. Pfeffer G, Mezei MM. Cardiac screening investigations in adultonset progressive external ophthalmoplegia patients. Muscle Nerve. 2012;46:593-596. Bucelli et al: J Neuro-Ophthalmol 2016; 36: 270-274 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
