Chronic Progressive External Ophthalmoplegia (CPEO) H49.4

Dr PS Deb, DM NeurologyDirector Neurology

GNRC Medical, Guwahati, Assam, India

HistoryVon Graefe 1868. Chronic progressive external

ophthalmoplegia (CPEO)Beaumont 1890 – Progressive nuclear ophthalmoplegiaFuchs 1890 – Restricted form of muscular dystrophyLangdon-Cadwalder 1928 – Autopsy – neuronal abnormalityKilch & Nevin 1951 – Myopathic with myopathic changes in

limb musclesDrachmann & Rosenberg 1968 – Progressive

ophthalmoplegia and plusZeviani 1988 – mtDNA rearrangement in sporadic cases

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

Definition1. Progressive ptosis and immobility of the eyes2. Bilateral muscles of more than one nerve3. Pupil spared4. No response to cholinergic drugs5. Gradual progression6. No remission or acute exacerbation7. No evidence of thyroid or myotonic dystrophy.

Spectrum of CPEOCPEO 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.

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

Chronic Progressive External Ophthalmoplegia (CPEO)

Onset at any age but constant in a familySlowly progressivePtosis an early or sometime only

manifestation, bilateral, rarely asymmetric or unilateral onset.

Ophthalmoplegia late or only manifestationDownward gaze is preserved till late Dryness of eye and exposure keratitis +

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

HistologyImpaired 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.

Ophthalmoplegia Plus (Drachmann 1968)A. Ocular muscular dystrophy with limb myopathy or descending

ocular myopathy or PEO with extraocular extension1. Limb weakness rarely sever2. Often proximal rarely distal with areflexia and wasting without

myotonia3. Usually limb and ocular symptom proceed together, rarely follow

other4. Some cases endocrine abnormalities – premature menopause,

testicular atrophy but no myotonia B. Oculopharyngeal muscular dystrophy

Myasthenic oculopathy (Myoneural Junction).

1. Early ptosis, cholinergic sensitive2. Late ptosis ophthalmoplegia neostigmine insensitive3. 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 oculopathy1. No fluctuation2. No cholinergic responsiveness3. No decrimental response to repetitive stimulation4. Sensitive to curare 1/10th of normal dose

D. Dysthyroid OculopathyUsually Exophthalamic ophthalmoplegia with

hyperthyroidismRarely Exophthalamic ophthalmoplegia

without hyperthyroidismRarely PEO like with euthyroid state

CPEO Plus …E. Myotonic dystrophy

Late manifestationF. Myotubular Centronuclear Myopathy

Ptosis, ophthalmoplegia, sometime facial weaknessLimb weaknessSlowly progressive

H. Congenital ptosis and ophthalmoplegiaIsolated ophthalmoplegia

I. Orbital MyositisSoft tissue swelling of periorbital muscles Painful exophthalamos with ophthalmoplegiaNo evidence of thyroid diseaseSteroid responsiveness

J. Neuropathic OphthalmoplegiaGullain Barre SyndromeRefsum’s diseaseBessen Kornzweig syndromeSymptomatic ophthalmoplegia

Pseudo PEOMobius syndromeAbnormal insertion of musclesFibrosis of ocular musclesProgressive Supranuclear palsy

Neuronal disease with PEOA. Retinitis pigmentosa ophthalmoplegia and

spastic quadriplegiaB. Retinitis pigmentosa, external

ophthalmoplegia and heart block, cerebellar ataxia( Kearn Sayre Syndrome)

Kerns-Sayre Syndrome (KSS)Age of onset – Before 20

yearsSex – BothRetinitis PigmentosaExternal OphthalmoplegiaCardiac Conduction

defectsCerebellar AtaxiaPendular nystagmus

Vestibular dysfunction and/or hearing loss

Endocrine dysfunctionShort statureHypoparathyroidismDiabetesGonadal dysfunctionHyperaldosteronism

Neuronal disease with CPEO cont.C. Spongiform encephalopathy with PEO

1. Retinitis pigmentosa2. Complete heart block3. Sexual infentilism4. Abnormal EEG5. Elevated CSF protein6. Seizure7. Weakness of limb and hyporeflexia8. Died after 1 month with aseptic meningitis9. Autopsy – Vacuolation of hemispheric nuclei, reduced neurones of

oculomotor nuclei

Neuronal disease with CPEO cont.D. Generalized CNS and Cardiac disease with PEOE. Familial Ataxia with PEO

1. Stephens – Cerebellar Ataxia with Peripheral Neuropathy with PEO

2. Sanger Brown Ataxia with late PEO3. Schaumberg – Nigro Spinodental degeneration

with nuclear ophthalmoplegia4. OPCA type V

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

Features CPEO MG Graves OPD

Ophthalmoplegia + + + +Pupil - + - -Ptosis + + + +Fluctuation - + - -Facial weakness + + - +Limb weakness Mild + Mild MildForced duction test + + COMG - + AdvancedDry eye + + + +Congested Conjunctiva - - + -Lid retraction - + + -Proptosis - - + -Dysphagia - + - +

CPEO – Chronic Progressive External Ophthalmoplegia, MG – Myasthenia Gravis, OPD – Oculopharyngeal dystrophy

InvestigationsAetiological

Thyroid -T3 suppression testMyasthenic - Tensilon test, Curare sensitivityMyotonic – EMG, Serum enzyme, BiopsyOculopharyngeal – Family Hx, Barium swallowBessen Konrzweig – Acanthocyte, S. cholesterol,

B lipoproteinRefsum – Phytanic acid serum

ImagingMRI

Symmetrical extraocular musclesNormal brainCortical and cerebellar atrophyIncreased T2 signal in subcortical cerebral white matter,

cerebellar white matter, globi pallidi, thalami, and substantia nigra

A barium swallowto differentiate oculopharyngeal dystrophy

Other TestsMay be abnormal with or without retinal pigmentary abnormalitiesElectroretinography

typically shows reduction of oscillatory potentials, scotopic b-wave amplitudes, and photopic b-wave amplitudes

Visual-evoked potential may be abnormalMuscle 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

Medical CareCoQ10

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

diseaseExposure keratopathy a combination spectacle-

mounted lid crutch and moisture chamber.

Surgical careBell 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.

ReferenceProgressive External Ophthalmoplegia

LP Rowland -Vinken and Bruyn 1968Ophthalmoplegia PlusThe Neurodegenerative

Disorders Associated With Progressive External OphthalmoplegiaDavid 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

Thank you