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. 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
1. Progressive ptosis and 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 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

10. 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.

11. Ophthalmoplegia Plus (Drachmann 1968)
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 (Myoneural Junction).
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
 Mobius syndrome
 Abnormal insertion of muscles
 Fibrosis of ocular muscles
 Progressive Supranuclear palsy

18. Neuronal disease with PEO
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 with CPEO 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 with CPEO 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 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

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
 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

26. 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

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
 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.

29. 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