Chronic Progressive External Ophthalmoplegia -CEW

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====== Chronic Progressive External Ophthalmoplegia ======
abbreviated CPEO 

===== Overview =====

**CPEO** is a **mitochondrial myopathy** that predominantly affects the extraocular muscles and the levator palpebrae, producing slowly progressive, generally **symmetric ophthalmoparesis** and **ptosis**. Because progression is gradual and symmetric, patients frequently do **not** report diplopia (<30%) and may be unaware of their motility deficit, often adopting a compensatory chin-up head posture.

===== Onset and Course =====

  * Typical onset in **adulthood** (commonly 18–40 years), with **ptosis** often the first sign.
  * **Slowly progressive** over years; forced ductions are free (myopathic, not restrictive) and **pupils are spared**.
  * **"CPEO-plus"**: pigmentary retinopathy, cerebellar ataxia, peripheral neuropathy, sensorineural hearing loss, cardiac conduction block, and diabetes. 
  * **Kearns-Sayre syndrome** defined as early-onset ophthalmoplegia and ptosis, pigmentary retinopathy, and cardiac conduction disease.

===== Genetics =====

  * Most commonly caused by a **single large-scale mtDNA deletion** (sporadic), but also by **mtDNA point mutations** and **nuclear mtDNA-maintenance genes** (e.g., **POLG, RRM2B, TWNK**).
  * **Heteroplasmy** matters: mutant load is far higher in skeletal muscle than in blood, so **negative peripheral blood testing does not exclude CPEO**.

===== Diagnostic Evaluation =====

  * **Clinical eye and systemic exam** — motility, lids, pupils, dilated fundus, cardiac review.
  * **Screening labs** — resting/post-exercise lactate and pyruvate, lactate:pyruvate ratio, creatine kinase, glucose/HbA1c; plus **ECG** given conduction-block risk.
  * **Exclude mimics** — myasthenia gravis (AChR/MuSK antibodies), oculopharyngeal and myotonic dystrophy.
  * **Muscle biopsy** (most accurate single test) — **ragged-red fibers** (Gomori trichrome) and **COX-negative / SDH-hyperintense fibers**; also enables respiratory-chain enzyme assays.
  * **Genetic testing** — whole mtDNA sequencing plus long-range PCR for deletions; **muscle is the optimal tissue**; nuclear gene panels when multiple deletions/depletion or a familial pattern is present.

===== Key Points =====

  * No blood test is confirmatory; diagnosis is **clinical + histochemical + genetic**.
  * A **negative blood mtDNA test does not rule out** the disease — proceed to muscle if suspicion is high.
  * Screen for and monitor **cardiac conduction disease**, a source of preventable morbidity/mortality.

====Compare CPEO with Congenital Fibrosis of EOM (CFEOM)====
^Feature  ^CPEO	^CFEOM ^
|Nature of disorder	|Mitochondrial myopathy of extraocular muscle	|Congenital cranial dysinnervation disorder (neurogenic; abnormal CN III/IV/VI development with secondary muscle fibrosis)|
|Onset	|Adult, typically 18–40 yrs; ptosis first sign	|Congenital / present at birth |
|Course	|Slowly progressive over years	|Non-progressive (rare exceptions)|
|Symmetry / gaze |Generally symmetric, diffuse limitation of all directions; superior rectus often prominently involved |Fixed characteristic pattern — CFEOM1: eyes fixed in infraduction, absent upgaze; CFEOM2: large-angle exotropia|
|Ptosis	|Common, may be uni- or bilateral, progressive	|Congenital, typically bilateral; chin-up head posture|
|Diplopia |Usually absent (<30%) due to gradual symmetric onset|Absent; binocular vision typically never develops|
|Pupils	|Spared	|Spared in CFEOM1; poorly reactive in CFEOM2|
|Inheritance / genetics	|Single large-scale mtDNA deletion (~50%, sporadic); also nuclear mtDNA-maintenance genes (POLG, RRM2B, TWNK) and mtDNA point mutations |Mendelian: CFEOM1 (AD, KIF21A); CFEOM2 (AR, PHOX2A); CFEOM3 (AD, TUBB3/TUBB2B/TUBA1A/KIF21A)|
|Systemic/associated features	|"CPEO-plus": retinopathy, ataxia, neuropathy, deafness, cardiac conduction block, diabetes (Kearns-Sayre) |Usually isolated; CFEOM3 may have developmental/CNS anomalies (e.g., Tukel syndrome)|
|Muscle biopsy	|Ragged-red / COX-negative fibers; mitochondrial abnormalities| Not a mitochondrial biopsy diagnosis; muscle shows fibrosis/denervation changes|
|Orbital MRI	|Mild EOM atrophy with fatty/spongiform T1 signal| EOM hypoplasia + hypoplastic ocular motor nerves|

===== References =====

  - [[https://link.springer.com/article/10.1007/s11910-016-0652-7|McClelland C, Manousakis G, Lee MS. Progressive External Ophthalmoplegia. Curr Neurol Neurosci Rep. 2016.]]
  - [[https://pubmed.ncbi.nlm.nih.gov/12849395/|McFarland R, Taylor RW, Turnbull DM. The Neurology of Mitochondrial DNA Disease. Lancet Neurol. 2002.]]
  - [[https://pubmed.ncbi.nlm.nih.gov/41105897/|Li BY, Greenberg JH, Steigerwald C, et al. Pearls and Oy-Sters: Chronic Progressive External Ophthalmoplegia With Electrical Myotonia and Negative Initial Genetic Testing. Neurology. 2025.]]
  - [[https://www.nature.com/articles/nrdp201680|Gorman GS, Chinnery PF, DiMauro S, et al. Mitochondrial diseases. Nat Rev Dis Primers. 2016.]]
  - [[https://pubmed.ncbi.nlm.nih.gov/32161153/|Rodriguez-Lopez C, Garcia-Cardaba LM, Blazquez A, et al. Clinical, Pathological and Genetic Spectrum in 89 Cases of Mitochondrial Progressive External Ophthalmoplegia. J Med Genet. 2020.]]
  - [[https://pubmed.ncbi.nlm.nih.gov/34146515/|Ng YS, Bindoff LA, Gorman GS, et al. Mitochondrial Disease in Adults: Recent Advances and Future Promise. Lancet Neurol. 2021.]]