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Chronic progressive external ophthalmoplegia
Chronic Progressive External Ophthalmoplegia (CPEO) is a mitochondrial myopathy characterized by progressive ptosis and ophthalmoplegia, often associated with skeletal muscle weakness. It has clinical and genetic heterogeneity, with possible onset at any age, and can be part of other mitochondrial diseases such as Kearns-Sayre syndrome. Epidemiological studies indicate a prevalence of approximately 1 in 30,000, with multiple genetic defects often contributing to its manifestation.
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Chronic progressive external ophthalmoplegia
- 1. Dr PS Deb,DM Neurology Director Neurology GNRC Medical, Guwahati, Assam, India
- 2. History Von Graefe1868. Chronic progressive external ophthalmoplegia (CPEO) Beaumont 1890 – Progressive nuclear ophthalmoplegia Fuchs 1890 – Restricted form of muscular dystrophy Langdon-Cadwalder 1928 – Autopsy – neuronal abnormality Kilch & Nevin 1951 – Myopathic with myopathic changes in limb muscles Drachmann & Rosenberg 1968 – Progressive ophthalmoplegia and plus Zeviani 1988 – mtDNA rearrangement in sporadic cases
- 3. Autopsy Daroff Oculomotornuclei changes Myopathic changes in muscles Stephens Clinical motor neuron disease Spinal cord sensory pathway involved Oculomotor nuclei normal Ocular myopathy Langdon and Cadwalder Neuronal disease with loss of neuron Kiloch – Nevin 16 Autopsies 50% Oculomotor neuron involvement other normal Drachmann 1968 IIIrd nerve section produce myopathic changes
- 4. Definition 1. Progressive ptosisand immobility of the eyes 2. Bilateral muscles of more than one nerve 3. Pupil spared 4. No response to cholinergic drugs 5. Gradual progression 6. No remission or acute exacerbation 7. No evidence of thyroid or myotonic dystrophy.
- 5. Spectrum of CPEO CPEO is the most frequent manifestation of mitochondrial myopathies There is both clinical and genetic heterogeneity within the syndrome of CPEO but relative homogeneity within the family Usually associated with skeletal muscle weakness. CPEO may be a part of syndrome of other mitochondrial disease, such as Kearns-Sayre syndrome. Occasionally CPEO may be caused by conditions other than mitochondrial diseases.
- 6. UK Cohort Study2014 Prevalence 1 in 30,000 255/631 (40.4.%) have CPEO 181/255 (71%) have typical ocular features of CPEO Age of onset 1-79y (mean 29.9y) Associated features in 221 (86.7%) Myopathy (62%) Ataxia (51%) Genetic Defects Point mutation of mtDNA in 31.4% Single mtDNA deletion in 28.2% Point mutation within nuclear-encoded CPEO genes (n = 70, 27.5%). The degree of ptosis and ophthalmoplegia was found to be more severe among patients harbouring single mtDNA deletions. A national epidemiological study of chronic progressive external ophthalmoplegia in the United Kingdom - molecular genetic features and neurological burden April 2014 Vol. 55 Issue 13
- 7. Chronic Progressive External Ophthalmoplegia(CPEO) Onset at any age but constant in a family Slowly progressive Ptosis an early or sometime only manifestation, bilateral, rarely asymmetric or unilateral onset. Ophthalmoplegia late or only manifestation Downward gaze is preserved till late Dryness of eye and exposure keratitis +
- 8. Pathophysiology Mitochondrial DNAencodes for essential components of the respiratory chain Deletions of various lengths of mtDNA results in defective mitochondrial function Little correlation exists between the size and the location of the deletion and the clinical phenotype (ie, CPEO vs KSS) Mutations usually occur sporadically, but they also can be inherited as a point mutation of maternal mitochondrial tRNA or as autosomal dominant and autosomal recessive deletions of mtDNA. A variable proportion of deleted mtDNA has been found to be present in different tissues from the same patient The balance of oxidative demands of a given tissue and the proportion of deleted mtDNA it contains will ultimately determine whether the tissue is affected clinically. Particularly in highly oxidative tissues (eg, muscle, brain, heart). Extraocular muscles are affected preferentially because their fraction of mitochondrial volume is several times greater than that of other skeletal muscle
- 10. Histology Impaired proteinsynthesis in these mitochondria accounts for the histological hallmark of the mitochondrial myopathies. Gomori trichrome stain, an abnormal accumulation of enlarged mitochondria is seen beneath the sarcolemma. Muscle fibers are called ragged red fibres due to their unusual appearance and dark red color on staining.
- 11. Ophthalmoplegia Plus (Drachmann1968) A. Ocular muscular dystrophy with limb myopathy or descending ocular myopathy or PEO with extraocular extension 1. Limb weakness rarely sever 2. Often proximal rarely distal with areflexia and wasting without myotonia 3. Usually limb and ocular symptom proceed together, rarely follow other 4. Some cases endocrine abnormalities – premature menopause, testicular atrophy but no myotonia B. Oculopharyngeal muscular dystrophy
- 12. Myasthenic oculopathy (MyoneuralJunction). 1. Early ptosis, cholinergic sensitive 2. Late ptosis ophthalmoplegia neostigmine insensitive 3. Lid twitch sign Cogan’s – Patient gaze down at a target for several seconds then abruptly looks upwards at another target. Transient upward overshoot of the lid, followed by return to ptotic position. 4. Curare sensitive oculopathy 1. No fluctuation 2. No cholinergic responsiveness 3. No decrimental response to repetitive stimulation 4. Sensitive to curare 1/10th of normal dose
- 13. D. Dysthyroid Oculopathy Usually Exophthalamic ophthalmoplegia with hyperthyroidism Rarely Exophthalamic ophthalmoplegia without hyperthyroidism Rarely PEO like with euthyroid state
- 14. CPEO Plus … E.Myotonic dystrophy Late manifestation F. Myotubular Centronuclear Myopathy Ptosis, ophthalmoplegia, sometime facial weakness Limb weakness Slowly progressive H. Congenital ptosis and ophthalmoplegia Isolated ophthalmoplegia
- 15. I. Orbital Myositis Soft tissue swelling of periorbital muscles Painful exophthalamos with ophthalmoplegia No evidence of thyroid disease Steroid responsiveness
- 16. J. Neuropathic Ophthalmoplegia Gullain Barre Syndrome Refsum’s disease Bessen Kornzweig syndrome Symptomatic ophthalmoplegia
- 17. Pseudo PEO Mobiussyndrome Abnormal insertion of muscles Fibrosis of ocular muscles Progressive Supranuclear palsy
- 18. Neuronal disease withPEO A. Retinitis pigmentosa ophthalmoplegia and spastic quadriplegia B. Retinitis pigmentosa, external ophthalmoplegia and heart block, cerebellar ataxia( Kearn Sayre Syndrome)
- 19. Kerns-Sayre Syndrome (KSS) Age of onset – Before 20 years Sex – Both Retinitis Pigmentosa External Ophthalmoplegia Cardiac Conduction defects Cerebellar Ataxia Pendular nystagmus Vestibular dysfunction and/or hearing loss Endocrine dysfunction Short stature Hypoparathyroidism Diabetes Gonadal dysfunction Hyperaldosteronism
- 20. Neuronal disease withCPEO cont. C. Spongiform encephalopathy with PEO 1. Retinitis pigmentosa 2. Complete heart block 3. Sexual infentilism 4. Abnormal EEG 5. Elevated CSF protein 6. Seizure 7. Weakness of limb and hyporeflexia 8. Died after 1 month with aseptic meningitis 9. Autopsy – Vacuolation of hemispheric nuclei, reduced neurones of oculomotor nuclei
- 21. Neuronal disease withCPEO cont. D. Generalized CNS and Cardiac disease with PEO E. Familial Ataxia with PEO 1. Stephens – Cerebellar Ataxia with Peripheral Neuropathy with PEO 2. Sanger Brown Ataxia with late PEO 3. Schaumberg – Nigro Spinodental degeneration with nuclear ophthalmoplegia 4. OPCA type V
- 22. Undifferentiated Ophthalmoplegia Plus Mental – Dementia, EEG Changes Cerebellar Ataxia Corticospinal Signs Ocular – Optic atrophy, RP, Proptosis Cranial – Hearing loss, Vestibular abnormality, dysphagia, dysphonia, facial weakness, small tongue Limb – Proximal or distal weakness, peripheral neuropathy, autonomic neuropathy Elevated CSF protein Cardiac conduction defects Small stature Steroid excretion reduced
- 23. Features CPEO MGGraves OPD Ophthalmoplegia + + + + Pupil - + - - Ptosis + + + + Fluctuation - + - - Facial weakness + + - + Limb weakness Mild + Mild Mild Forced duction test + + COMG - + Advanced Dry eye + + + + Congested Conjunctiva - - + - Lid retraction - + + - Proptosis - - + - Dysphagia - + - + CPEO – Chronic Progressive External Ophthalmoplegia, MG – Myasthenia Gravis, OPD – Oculopharyngeal dystrophy
- 24. Investigations Aetiological Thyroid-T3 suppression test Myasthenic - Tensilon test, Curare sensitivity Myotonic – EMG, Serum enzyme, Biopsy Oculopharyngeal – Family Hx, Barium swallow Bessen Konrzweig – Acanthocyte, S. cholesterol, B lipoprotein Refsum – Phytanic acid serum
- 25. Imaging MRI Symmetricalextraocular muscles Normal brain Cortical and cerebellar atrophy Increased T2 signal in subcortical cerebral white matter, cerebellar white matter, globi pallidi, thalami, and substantia nigra A barium swallow to differentiate oculopharyngeal dystrophy
- 26. Other Tests Maybe abnormal with or without retinal pigmentary abnormalities Electroretinography typically shows reduction of oscillatory potentials, scotopic b-wave amplitudes, and photopic b-wave amplitudes Visual-evoked potential may be abnormal Muscle Biopsy Oculopharyngeal dystrophy shows a marked reduction in muscle fibers without the characteristic ragged red fibers seen in mitochondrial disorders due to red- rimmed vacuoles and intranuclear inclusions Polymerase chain reaction (PCR) for mitochondrial DNA or mRNA deletion
- 27. Medical Care CoQ10 A decrease in serum levels of pyruvate and lactate were observed, and general neurologic function was noted to improve Alpha lipoic acid, creatine monohydrate and vitamin E Adhesive tape and lid crutches in ptosis of advanced disease Exposure keratopathy a combination spectacle-mounted lid crutch and moisture chamber.
- 28. Surgical care Bellphenomenon is absent in many patients with CPEO; therefore, ptosis surgery often is contraindicated A silicone sling is reversible, it could be a possibility for some patients. Strabismus surgery can be helpful in carefully selected patients if diplopia occurs and the patient has had a stable deviation for several months.
- 29. Reference Progressive ExternalOphthalmoplegia LP Rowland -Vinken and Bruyn 1968 Ophthalmoplegia PlusThe Neurodegenerative Disorders Associated With Progressive External Ophthalmoplegia David A. Drachman, MD, Arch Neurol. 1968;18(6):654-674. doi:10.1001/archneur.1968.00470360076008. Chronic Progressive External Ophthalmoplegia Hampton Roy, Sr, MD; Chief Editor: Hampton Roy, Sr, MD
Editor's Notes
- #9 Genetics Mitochondrial DNA which is transmitted from the mother, encodes proteins that are critical to the respiratory chain required to produce adenosine triphosphate (ATP). Deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation. This may be made evident in highly oxidative tissues like skeletal muscle and heart tissue. However,extraocular muscles contain a volume of mitochondria that is several times greater than any other muscle group. As such, this results in the preferential ocular symptoms of CPEO. Multiple mtDNA abnormalities exist which cause CPEO. One mutation is located in a conserved region of mitochondrial tRNA at nucleotide 3243 in which there is an A to G nucleotide transition. This mutation is associated with both CPEO and Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).[3] A common deletion found in one-third of CPEO patients is a 4,977 base pair segment found between a 13 base pair repeat. The mtDNA that is affected maybe a single or multiple point deletion, with associated nuclear DNA deletions. One study showed that mtDNA deletion seen in CPEO patients also had an associated nuclear DNA deletion of the Twinkle gene which encodes specific mitochondrial protein; Twinkle.[4] Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion. In most cases, PEO occurs due to a sporadic deletion or duplication within the mitochondrial DNA.[5] However, transmission from the mother to the progeny appears only in few cases. Both autosomal dominant and autosomal recessive inheritance can occur, autosomal recessive inheritance being more severe. Dominant and recessive forms of PEO can be caused by genetic mutations in the ANT1, POLG, POLG2 and PEO1 genes
- #20 Physical A complete ophthalmologic exam should be performed, to include the following: Dilated retinal exam Cranial nerve testing Forced duction testing In KSS, the salt-and-pepper retinopathy usually occurs initially in the posterior fundus. Pallor of the optic disc, attenuation of retinal vessels, visual field defects, and posterior cataract formation common to retinitis pigmentosa rarely, if ever, occur. CPEO must be differentiated from myasthenia gravis, Graves disease, and oculopharyngeal dystrophy. The table presented below may also be helpful for categorizing physical findings.
- #25 Laboratory Studies Patients with Kearns-Sayre syndrome (KSS) have been reported to have the following: Low magnesium Low parathyroid hormone Increased lactic acid Increased pyruvic acid Increased creatine phosphokinase (CPK) Increased aldolase Increased protein in CSF Thyroid studies can confirm suspicion of Graves disease. A positive acetylcholine receptor antibody test may establish the diagnosis of myasthenia gravis. A negative acetylcholine receptor antibody assay does not differentiate chronic progressive external ophthalmoplegia (CPEO) from myasthenia gravis. Tensilon testing can be helpful in differentiating myasthenia gravis from CPEO. However, the clinician must remain wary of the effects of edrophonium in a patient harboring a possible cardiac conduction defect, that is, KSS.