Chronic progressive external ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is a descriptive term for a heterogeneous group of disorders characterized by chronic, progressive, bilateral, and usually symmetric ocular motility deficit and ptosis, without pain, proptosis and pupil involvement. Commonly a syndrome of Mitochondrial Cytopathy.

1. Chronic Progressive External Ophthalmoplegia (CPEO) H49.4 Dr PS Deb, DM Neurology Director Neurology GNRC Medical, Guwahati, Assam, India

2. History Von Graefe 1868 . 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 Oculomotor nuclei 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 Progressive ptosis and immobility of the eyes Bilateral muscles of more than one nerve Pupil spared No response to cholinergic drugs Gradual progression No remission or acute exacerbation 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 Study 2014 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 DNA encodes 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

9. Histology Impaired protein synthesis 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.

10. Ophthalmoplegia Plus (Drachmann 1968) Ocular muscular dystrophy with limb myopathy or descending ocular myopathy or PEO with extraocular extension Limb weakness rarely sever Often proximal rarely distal with areflexia and wasting without myotonia Usually limb and ocular symptom proceed together, rarely follow other Some cases endocrine abnormalities – premature menopause, testicular atrophy but no myotonia Oculopharyngeal muscular dystrophy

11. Myasthenic oculopathy (Myoneural Junction) . Early ptosis, cholinergic sensitive Late ptosis ophthalmoplegia neostigmine insensitive 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. Curare sensitive oculopathy No fluctuation No cholinergic responsiveness No decrimental response to repetitive stimulation Sensitive to curare 1/10 th of normal dose

12. D. Dysthyroid Oculopathy Usually Exophthalamic ophthalmoplegia with hyperthyroidism Rarely Exophthalamic ophthalmoplegia without hyperthyroidism Rarely PEO like with euthyroid state

13. 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

14. I. Orbital Myositis Soft tissue swelling of periorbital muscles Painful exophthalamos with ophthalmoplegia No evidence of thyroid disease Steroid responsiveness

15. J. Neuropathic Ophthalmoplegia Gullain Barre Syndrome Refsum’s disease Bessen Kornzweig syndrome Symptomatic ophthalmoplegia

16. Pseudo PEO Mobius syndrome Abnormal insertion of muscles Fibrosis of ocular muscles Progressive Supranuclear palsy

17. Neuronal disease with PEO Retinitis pigmentosa ophthalmoplegia and spastic quadriplegia Retinitis pigmentosa, external ophthalmoplegia and heart block, cerebellar ataxia( Kearn Sayre Syndrome)

18. 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

19. Neuronal disease with CPEO cont. Spongiform encephalopathy with PEO Retinitis pigmentosa Complete heart block Sexual infentilism Abnormal EEG Elevated CSF protein Seizure Weakness of limb and hyporeflexia Died after 1 month with aseptic meningitis Autopsy – Vacuolation of hemispheric nuclei, reduced neurones of oculomotor nuclei

20. Neuronal disease with CPEO cont. Generalized CNS and Cardiac disease with PEO Familial Ataxia with PEO Stephens – Cerebellar Ataxia with Peripheral Neuropathy with PEO Sanger Brown Ataxia with late PEO Schaumberg – Nigro Spinodental degeneration with nuclear ophthalmoplegia OPCA type V

21. 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

22. Features CPEO MG Graves 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

23. 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

24. Imaging MRI Symmetrical extraocular 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

25. Other Tests May be 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

26. 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.

27. Surgical care Bell phenomenon 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.

28. Reference Progressive External Ophthalmoplegia 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

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