Progressive External Ophthalmoplegia

Update item information
Identifier 946-1
Title Progressive External Ophthalmoplegia
Ocular Movements Bilateral Ptosis; Facial Weakness; Complete External Ophthalmoplegia; Normal Pupils; Absent Convergence
Creator Shirley H. Wray, M.D., Ph.D., FRCP, Professor of Neurology Harvard Medical School, Director, Unit for Neurovisual Disorders, Massachusetts General Hospital
Contributor Primary Shirley H. Wray, MD, PhD, FRCP, Professor of Neurology, Harvard Medical School; Director, Unit for Neurovisual Disorders, Massachusetts General Hospital
Subject Bilateral Ptosis; Facial Weakness; Complete External Ophthalmoplegia; Bilateral Progressive External Ophthalmoplegia (PEO); Mitochondrial Myopathy; PEO plus Atypical Retinitis Pigmentosa, Heart Block, Deafness, Proximal Myopathy and Cerebellar Degeneration with Ataxia; Kearns-Sayre Syndrome
Supplementary Materials PowerPoint Presentations: Progressive External Ophthalmoplegia: Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical School Mitochondrial Myopathy: Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical School
Presenting Symptom Droopy eyelids
History In 1995 I published this case alongside eleven personal cases, three with the Kearns-Sayer Syndrome (KSS) and five with Progressive External Opthalmoplegia (PEO). Am J of Neuroradiol:16 (5);1167-1173. This patient with KSS is still alive in 2009. In 1968, at the age of 15 he presented with a history of childhood strabismus treated surgically and the insidious onset of slowly progressive asymmetrical ptosis right eye greater than left eye. In 1971 at age 18, he was referred to rule out myasthenia gravis prior to ptosis surgery. Neuro-ophthalmological examination: Visual acuity was 20/20 OU Pupils, visual fields and fundus examination normal. Ocular Motility : Bilateral ptosis, palpebral fissure 2 to 3 mm, eyebrows immobilized. Conjugate limitation of eye movements in all directions Absent Bell's (deviation upwards of the eyes under forced eye closure). Diagnosis: Progressive external ophthalmoplegia (PEO) In 1973 at age 20, he developed atypical retinitis pigmentosa. Fundus examination showed normal optic discs and a mottled salt and pepper pigmentary retinal disturbance was evident fairly uniform in all areas but without any typical bone corpuscles characteristic of retinitis pigmentosa. (Fundus photographs Figures 1-4) Lumbar Puncture: CSF normal apart from elevated CSF protein > 100 mg/dl. Skeletal Muscle Biopsy: The muscle biopsy showed ragged red fibers and a 3.8 kilobase mtDNA deletion. Diagnosis: Mitochondrial Myopathy. (Figures 5-8). Electrocardiogram: Showed incomplete right bundle branch block Chest X-ray: Cardiomegaly Audiometry: In 1974 at age 21, audiologic testing documented a sensory neural hearing loss Brain MRI at age 22 showed significant cortical and cerebellar atrophy. (Figures 9-11. Table 2 (14)) At age 24 he developed complete heart block and required a pacemaker. (Table 1). These findings completed the triad for the Kearns-Sayer Syndrome. Progress: Over the next 10 years, follow-up examinations revealed multisystem involvement known to occur in the KSS - - bilateral deafness - night blindness - dysphagia - cerebellar ataxia - all alongside marked neurasthenia and depression. In 2000 at age 47, a cricopharyngeal myotomy was performed to correct dysphagia due to pharyngeal dystrophy. In 2002 at age 49, he developed bilateral maculopathy and a granular and tigroid appearance of the fundus with impaired vision. By 2003 at age 50, he had the insidious onset of proximal muscle weakness in the legs and nasal speech. By this time, the fundi showed pallor of the optic discs and extensive retinal atrophy (Figure 4). The term Mitochondrial Cytopathy is used to emphasize multisystem involvement in KSS as in this case with: Progressive External Ophthalmoplegia Atypical Pigmentary Retinal Degeneration Heart Block and Cardiomegaly Deafness Pharyngeal Dystrophy Ataxia with Cerebellar Atrophy Proximal Myopathy High CSF protein Cognitive impairment
Clinical This 43 year old man with KSS has advanced multisystem disease due to a large 8.6 mtDNA deletion. The muscle involvement is diagnostic. The myopathic signs are: • Bilateral ptosis with overaction of the frontalis muscle. • Weakness of the orbicularis oculi muscle with impaired eye closure. • A complete external ophthalmoplegia with gaze fixed in primary position and total absence of horizontal and vertical eye movements on command. • Absent eye movements on horizontal Doll's Head movement. • Weakness of the lower face impairing the ability to grip the lips tightly together • Marked weakness of flexion of the head against moderate resistance.
Neuroimaging Brain MRI in this case (patient 2) and in other cases with PEO show: Figure 9. A 61-year old woman (patient 1) with KSS, moderately severe truncal and appendicular ataxia, and a documented mtDNA deletion. A T1-weighted sagittal image demonstrates severe cerebellar vermian atrophy (arrow) Figure 10. A 23-year old man (patient 2) with KSS, cognitive impairment, ataxia and an mtDNA deletion. A. T2 weighted image demonstrates regions of hyperintense signal (arrows) in the subcortical white matter. The periventricular regions were spared. B. T2-weighted image shows foci of hyperintense signal (arrows) in the dorsal midbrain. Figure 11. A 37-year old woman (patient 8) with CPEO manifested by external ophthalmoplegia, ataxia, and sensorineural hearing loss. A. Long-repetition-time/short-echo-time (proton density) axial image. In the frontal lobes, abnormal hyperintense signal predominates in the subcortical white matter (arrows), whereas in the posterior temporal and parietal lobes the abnormal signal extended from the subcortical regions to the ventricular surface (curved arrows). B. T2-weighted axial MR image demonstrates bilateral hyperintense signal abnormalities in the globus pallidus (arrows). Hyperintense white matter abnormalities and ventricular dilatation are also present. C. T1-weighted sagittal image demonstrates cerebral cortical and cerebellar vermian atrophy (arrow) and thinning of the corpus callosum. Other PEO patients are reported to show predominantly white matter damage that correlated with spongiform degeneration of the brain verified by autopsy examinations.
Pathology A skeletal muscle biopsy is diagnostic in mitochondrial myopathy due to a mtDNA deletion. In mitochondrial myopathy defective oxidative phosphorylation results in mitochondrial proliferation in Type 1 and 2A muscle fibers. Fibers with the most severe biochemical defects may degenerate and adjacent fibers with less severe or no defects may appear normal. (Figure 5-8) The combination of a patchy moth-eaten appearance in individual muscle fibers along with mitochondrial proliferation gives rise to the ragged-red fiber seen on modified Gomori trichrome staining (Figure 6). NADH staining shows abnormal subsarcolemmal mitochondria in the muscle fibers (Figure 7). The electron microscopic sections of skeletal muscle show abnormal mitochondria. (Figure 8).
Etiology Mutations in mtDNA are maternally inherited in a graded fashion. A single mtDNA mutation can lead to dramatically different clinical phenotypes, creating a very large spectrum of expressivity. For example, the A3243G mutation associated with mitrochondrial encephalomyopathy, lactic academia, stroke-like episodes (MELAS) can also cause cardiomyopathy, diabetes and deafness, or external ophthalmoplegia. Deletions of mtDNA in skeletal muscle, ranging in size from 3.8 to 9.1 kilobases, were found in an identical location on muscle biopsy in five of eleven personal cases (3 KSS, 8 PEO). (Table 1). The deletion encompasses structural genes for the mitochondrial respiratory chain and is associated with impaired mitochondrial function. The variable involvement of multiple organs, (e.g. heart, brain and retina in PEO and KSS) may be attributable to a mixed population of mutant and normal genomes in varying amounts in different tissues. Both muscle and brain are also involved in patients with mitochondrial encephalomyopathy, namely, the MELAS syndrome which is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and MERRF, characterized by myoclonic epilepsy associated with ragged-red fibers. In MELAS, dysfunction of the central nervous system dominates the clinical picture. While there is considerable overlap of symptoms and signs between PEO, KSS, MELAS, and MERRF, there is general agreement that cases of mitochondrial myopathy, PEO and KSS, with or without clinical involvement of the brain, should be considered separately. The term mitochondrial encephalomyopathy or cytopathy has been applied to the multisystem diseases involving brain, skeletal muscle, and other organs. These disorders and the clinical phenotypes of mtDNA disease span the spectrum of all known oxidative phosphorylation disorders and include PEO., deafness, cardiomyopathy, MELAS and MERRF.
Disease/Diagnosis Progressive External Ophthalmoplegia; Mitochondrial Cytopathy; Kearns-Sayre Syndrome.
Treatment Co-enzyme Q (ubiquinone) deficiency is present in KSS and treatment strategies for KSS are based on supplying electron transport chain cofactors and substraits, and antioxidants in an attempt to protect against mtDNA free-radical damage. Co-enzyme Q10 (ubiquinone) 4 mg-kg/day has the largest literature-supported efficacy in mitochondrial disease. This 43 year old patient has taken Co-enzyme Q10 for over 8 years.
References 1. DiMauro S, Bonilla E. Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol 1985; 17:521-538. 2. Evans OB, Parker CC, Haas, RH, Naidu S, Moser HW, Bock, HGO. Clinical and Laboratory Features of Mitrochondrial Encephalomyopathy Syndromes. In Inborn Errors of Metabolism of the Nervous System. In Neurology in Clinical Practice, 3rd Ed. Vol II. Butterworth Henemann 2000;68:1595-1662. 3. Gallastegui J, Hariman RJ, Handler B, Lev M, Bharati S. Cardiac involvement in the Kearns-Sayre syndrome. Am J Cardiol 1987 Aug 1:60(4): 385-8. 4. Holt IJ, Harding, AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:717-719. 5. Holt IJ, Harding AE, Cooper JM, Schapira AH, Toscano A, Clark JB, Morgan-Hughes JA. Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol. 1989 Dec;26(6):699-708. 6. Kearns TP, Sayre GP, Retinitis pigmentosa, external ophthalmoplegia and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch Ophthalmol. 1958 Aug:60(2):280-9. 7. Kosmorsky G, Johns DR. Neuro-ophthalmologic manifestations of mitochondrial DNA disorders: chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Leber's hereditary optic neuropathy. Neurol Clin. 1991 Feb;9(1):147-61. Review. 8. Mitsumoto H, Aprille JR, Wray SH, Nemni R, Bradley WG. Progressive External Ophthalmoplegia (PEO): clinical, morphologic and biochemical studies. Neurology. 1983 Apr:33(4):452-61. 9. Moraes CT, DiMauro S, Zevani M et al Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre Syndrome. N Eng J Med. 1989;320:1293-1299. 10. Naviauz RK. Mitochondrial DNA Disorders. Eur J Pediatr. 2000;159 (Suppl 3):S219-226. Review. 11. Van Goethem G, Martin JJ, Van Broeckhoven C. Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular Med. 2003;3(3):129-46. Review. 12. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242:1427-1430. 13. Wallace DC Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992 May 1;256(5057):628-32. 14. Wray SH, Provenzale JM, Johns DR, Thulborn KR. MR of the brain in mitochondrial myopathy. Am J Neuroradiol. 1995;16(5):1167-73. 15. Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988; 38:1339-1346.
Relation is Part of 906-2, 926-2, 926-3, 945-3
Contributor Secondary Tessa Hedley-Whyte, MD, Massachusetts General Hospital, Pathology; James M. Provenzale, MD, Duke University Medical Center, Neuroimaging; Steve Smith, Videographer; Ray Balhorn, Digital Video Compressionist
Publisher Spencer S. Eccles Health Sciences Library, University of Utah
Date 1996
Type Image/MovingImage
Format video/mp4
Source 3/4" Umatic master videotape
Rights Management Copyright 2002. For further information regarding the rights to this collection, please visit:
Holding Institution Spencer S. Eccles Health Sciences Library, University of Utah, 10 N 1900 E, SLC, UT 84112-5890
Collection Neuro-ophthalmology Virtual Education Library: NOVEL
Language eng
ARK ark:/87278/s6gx783g
Setname ehsl_novel_shw
Date Created 2005-08-23
Date Modified 2017-11-27
ID 188503
Reference URL
Back to Search Results