Progressive External Ophthalmoplegia

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Identifier 906-2
Title Progressive External Ophthalmoplegia
Ocular Movements Bilateral Ptosis; Facial Weakness; Complete External Ophthalmoplegia; Normal Pupils
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; Normal Pupils; Bilateral Progressive External Ophthalmoplegia (PEO); Mitochondrial Myopathy
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 The patient is an 18 year old girl, first seen in 1990 with a 6 year history of progressive ptosis. In 1986, at age 14, she was seen by an ophthalmologist and pediatric neurologist and investigated. Myasthenia Gravis was ruled out by a negative Tensilon test, negative anti-acetylcholine receptor antibodies, and normal electromyography and repetitive nerve stimulation studies of the right upper extremity. She was given a trial on Mestinon 50 mg. t.i.d. and 180 mg. time span overnight for 1 month without any improvement. In 1987, at age 15, she had bilateral ptosis surgery repeated on the right eye in August 1990. By this time she had developed limitation of all conjugate eye movements due to progressive external ophthalmoplegia (PEO). In 1990, at age 18, a muscle biopsy performed at Johns Hopkins showed ragged-red fibers and scattered atrophic myofibers. Diagnosis: Mitochondrial Myopathy. The fundus exam showed no abnormality. Cardiac and endocrine evaluations normal. The patient moved out of Boston and was lost to follow up. The term mitochondrial cytopathy has been used to emphasize multisystem involvement in PEO.
Clinical This 18 year old girl, who had the insidious onset of bilateral ptosis, has progressive external ophthalmoplegia (PEO) due to an mtDNA deletion. Muscle involvement is diagnostic. The myopathic signs illustrated are: 1. Bilateral ptosis with overaction of the frontalis muscle 2. Weakness of the orbicularis oculi muscle with impaired eye closure.<br> 3. No recovery of ptosis on gentle eye closure (which is a sign seen in ptosis due to myasthenia gravis). 4. No fatigue of the eyelids with increased ptosis on sustained up gaze. 5. No overaction of the eyelid on suddenly looking up (a technique used to detect a myasthenic lid twitch, a sign described by Dr. David Cogan). 6. A complete external ophthalmoplegia with gaze fixed in primary position. (Noteworthy is that the patient was unaware that she could not move her eyes fully until the time of her neurovisual examination). 7. Weakness of the lower face impairing the ability to grip the lips tightly together.
Neuroimaging Neuroimaging studies were not done in this case. MR of the Brain in Mitochondrial Myopathy published in 1995 illustrates MR images in KSS and PEO (14). The figures included: 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) 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. 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 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. 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. NADH staining shows abnormal subsarcolemmal mitochondria in the muscle fibers. The electron microscopic sections of skeletal muscle show abnormal mitochondria.
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). 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.
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.
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) Provenzale JM, Wray SH, Thulborn KR, Brown RH. Magnetic Resonance Imaging findings in patients with the Kearns-Sayre Syndrome. Am Society of Neurorad. 1992. 12) 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. 13) 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. 14) Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992 May 1;256(5057):628-32. 15) Wray SH, Provenzale JM, Johns DR, Thulborn KR. MR of the brain in mitochondrial myopathy. AJNR Am J Neuroradiol. 1995 May;16(5):1167-73. 16) 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. Metadata: 2005-12-06
Relation is Part of 926-2, 926-3, 945-3, 946-1
Contributor Secondary Steve Smith, Videographer; Ray Balhorn, Digital Video Compressionist
Publisher Spencer S. Eccles Health Sciences Library, University of Utah
Date 1990
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/s679727d
Setname ehsl_novel_shw
Date Created 2005-06-08
Date Modified 2020-08-17
ID 188536
Reference URL