History

Chronic progressive external ophthalmoplegia (CPEO) tends to begin in young adulthood. Ptosis usually is the first clinical sign, and ophthalmoplegia may not become apparent for months to years. The ptosis is usually bilateral and symmetrical. As the ptosis progresses, the patient may use the frontalis muscle to elevate the eyelids, adopt a chin-up head position, and eventually resort to manual elevation of the eyelids, as ptosis often becomes complete.^[20]Cases have been documented of patients who develop ophthalmoplegia but not ptosis. Unilateral or asymmetric ptosis may develop.

Because of the symmetric nature of this disorder, patients often do not complain of diplopia. They may be unaware of their decreased motility until it becomes severe. In many cases, downward gaze is preserved to a greater extent than up-gaze or horizontal movement. The course of CPEO is characterized by constant progression without periods of remission or exacerbation. Patients also may complain of dryness of the eyes due to exposure keratopathy.

In contrast to myasthenia gravis, patients with CPEO usually report little to no variability in their ptosis.

In KSS, children are usually healthy at birth. Boys and girls are affected equally. CPEO and pigmentary retinopathy appear before age 20 years. The retinal pigment undergoes atrophy, usually in a salt-and-pepper pattern without the bony spicule formation typical of retinitis pigmentosa. Ophthalmoplegia generally precedes the development of cardiac conduction disturbances. Sudden death may occur from these disturbances, and patients should have regular cardiac exams, regardless of age. Patients also may have the following: intraventricular septal hypertrophy, mitral valve prolapse, and left ventricular dysfunction.

Weakness of somatic muscles is often noted with progressive facial muscle weakness and neck and shoulder weakness. Extremities tend to be involved to a lesser degree.

Neurologic abnormalities may include the following:

Cerebellar ataxia
Pendular nystagmus
Vestibular dysfunction and/or hearing loss

Endocrine dysfunction is common and may include the following:

Short stature
Hypoparathyroidism
Diabetes
Gonadal dysfunction
Hyperaldosteronism

Physical

A complete ophthalmologic examination should be performed, to include the following:

Dilated retinal examination
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.

Note the image below.

This table outlines the differential diagnoses of chronic progressive external ophthalmoplegia.

However, many atypical presentations of CPEO have been reported.^{[21, 22, 23]}

Causes

The mitochondrial myopathies and encephalopathies are a complex group of disorders arising from mtDNA mutations. 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.

The entire mitochondrial DNA (mtDNA) from a 54-year-old man with chronic progressive ophthalmoplegia and hyperCKemia has been sequenced.^[24]

Physical Examination

A thorough ophthalmic examination is required.focus would be on the function of the levator muscle (blepharoptosis) and extraocular motility and limitations of movement (ophthalmoplegia) in addition to assessment of the anterior segment of the eye is required.Dilated retinal exam looking for pigmentary changes in the peripheral retina is also important.

A comprehensive medical evaluation would also be required looking for concomitant conditions.

Complications

Complications can include cardiac problems and esophageal dysfunction.

Other organ systems can also be adversely affected such as hearing.

Differential Diagnoses

Taysha Gene Therapies Announces Collaboration with AllStripes on SURF1-Associated Leigh Syndrome Clinical Development and Natural History. www.businesswire.com. Available at https://www.businesswire.com/news/home/20210104005195/en/Taysha-Gene-Therapies-Announces-Collaboration-with-AllStripes-on-SURF1-Associated-Leigh-Syndrome-Clinical-Development-and-Natural-History#:~:text=TSHA-104%20is%20an%20investigational%20AAV9-based%20. 01/04/2021; Accessed: 03/04/2023.
Lee AG, Kini A, Hasegawa N, et. al. Chronic Progressive External Ophthalmoplegia (CPEO). EyeWiki (aao.org). Available at https://eyewiki.aao.org/Chronic_Progressive_External_Ophthalmoplegia_(CPEO). Accessed: 3/4/2023.
Chinnery PF. Mitochondrial Disorders Overview. GeneReviews® [Internet]. Available at http://www.ncbi.nlm.nih.gov/books/NBK1224/. August 14, 2014; Accessed: March 6, 2023.
Shemesh A, Margolin E. Kearns Sayre Syndrome. StatPearls. 2022 Jan. [QxMD MEDLINE Link]. [Full Text].
Yoshimi A, Ishikawa K, Niemeyer C, Grünert SC. Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure. Orphanet J Rare Dis. 2022 Oct 17. 17 (1):379. [QxMD MEDLINE Link].
Bresolin N, Bet L, Binda A, et al. Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Q10. Neurology. 1988 Jun. 38(6):892-9. [QxMD MEDLINE Link].
Chen T, Pu C, Shi Q, Wang Q, Cong L, Liu J, et al. Chronic progressive external ophthalmoplegia with inflammatory myopathy. Int J Clin Exp Pathol. 2014. 7 (12):8887-92. [QxMD MEDLINE Link].
Ogasahara S, Nishikawa Y, Yorifuji S, et al. Treatment of Kearns-Sayre syndrome with coenzyme Q10. Neurology. 1986 Jan. 36(1):45-53. [QxMD MEDLINE Link].
Radelfahr F, Klopstock T. [Diagnostic and Therapeutic Approaches for Mitochondrial Diseases]. Fortschr Neurol Psychiatr. 2018 Sep. 86 (9):584-591. [QxMD MEDLINE Link].
Berio A, Piazzi A, Traverso CE. Kearns-Sayre syndrome with facial and white matter extensive involvement: a (mitochondrial and nuclear gene related?) neurocristopathy?. Pediatr Med Chir. 2017 Dec 15. 39 (4):169. [QxMD MEDLINE Link].
Bacalhau M, Simões M, Rocha MC, Hardy SA, Vincent AE, Durães J, et al. Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant. Neuromuscul Disord. 2018 Apr. 28 (4):350-360. [QxMD MEDLINE Link].
Lv ZY, Xu XM, Cao XF, Wang Q, Sun DF, Tian WJ, et al. Mitochondrial mutations in 12S rRNA and 16S rRNA presenting as chronic progressive external ophthalmoplegia (CPEO) plus: A case report. Medicine (Baltimore). 2017 Dec. 96 (48):e8869. [QxMD MEDLINE Link].
Carlow TJ, Depper MH, Orrison WW Jr. MR of extraocular muscles in chronic progressive external ophthalmoplegia. AJNR Am J Neuroradiol. 1998 Jan. 19(1):95-9. [QxMD MEDLINE Link].
Ohnuki Y, Takahashi K, Iijima E, Takahashi W, Suzuki S, Ozaki Y, et al. Multiple deletions in mitochondrial DNA in a patient with progressive external ophthalmoplegia, leukoencephalopathy and hypogonadism. Intern Med. 2014. 53 (12):1365-9. [QxMD MEDLINE Link].
Hedermann G, Dahlqvist JR, Løkken N, Vissing CR, Knak KL, Andersen LK, et al. Progressive fat replacement of muscle contributes to the disease mechanism of patients with single, large-scale deletions of mitochondrial DNA. Neuromuscul Disord. 2018 May. 28 (5):408-413. [QxMD MEDLINE Link].
Kiyomoto BH, Tengan CH, Moraes CT, et al. Mitochondrial DNA defects in Brazilian patients with chronic progressive external ophthalmoplegia. J Neurol Sci. 1997 Nov 25. 152(2):160-5. [QxMD MEDLINE Link].
Understanding Mitochondrial Disease. United Mitochondrial Disease Foundation. Available at https://www.umdf.org/what-is-mitochondrial-disease-2/. Accessed: 3/6/2023.
Carelli V, La Morgia C. Clinical syndromes associated with mtDNA mutations: where we stand after 30 years. Essays Biochem. 2018 Jul 20. 62 (3):235-254. [QxMD MEDLINE Link].
https://rarediseases.org/rare-diseases/kearns-sayre-syndrome/. rarediseases.org. Available at https://rarediseases.org/rare-diseases/kearns-sayre-syndrome/. 03/22/2016; Accessed: 03/04/2023.
Ahn J, Kim NJ, Choung HK, et al. Frontalis sling operation using silicone rod for the correction of ptosis in chronic progressive external ophthalmoplegia. Br J Ophthalmol. Sept 11,2008.
Finsterer J, Zarrouk-Mahjoub S. Unilateral Ptosis and Homolateral Hemifacial Weakness in Chronic Progressive External Ophthalmoplegia. Neuroophthalmology. 2017 Jun. 41 (3):165-166. [QxMD MEDLINE Link].
Murdock J, Thyparampil PJ, Yen MT. Late-Onset Development of Eyelid Ptosis in Chronic Progressive External Ophthalmoplegia: A 30-Year Follow-up. Neuroophthalmology. 2016 Feb. 40 (1):44-46. [QxMD MEDLINE Link].
Bucelli RC, Lee MS, McClelland CM. Chronic Progressive External Ophthalmoplegia in the Absence of Ptosis. J Neuroophthalmol. 2016 Sep. 36 (3):270-4. [QxMD MEDLINE Link].
Souilem S, Chebel S, Mancuso M, et al. A novel mitochondrial tRNA(Ile) point mutation associated with chronic progressive external ophthalmoplegia and hyperCKemia. J Neurol Sci. 2011 Jan 15. 300(1-2):187-90. [QxMD MEDLINE Link].
Rajput R, Sachdev A, Din N, Damato EM, Murray A. False positive acetylcholine receptor antibodies in a case of unilateral chronic progressive external ophthalmoplegia: case report and review of literature. Orbit. 2018 Jan 15. 1-4. [QxMD MEDLINE Link].
McAfee JL, Warren CB, Prayson RA. Ultrastructural examination of skin biopsies may assist in diagnosing mitochondrial cytopathy when muscle biopsies yield negative results. Ann Diagn Pathol. 2017 Aug. 29:41-45. [QxMD MEDLINE Link].
Domenis DR, Granzotti RB, Sobreira CF, Dantas RO. Pharyngeal transit in patients with chronic progressive external ophthalmoplegia. Int J Speech Lang Pathol. 2015 Aug. 17 (4):384-9. [QxMD MEDLINE Link].
De Coo IF, Gussinklo T, Arts PJ, et al. A PCR test for progressive external ophthalmoplegia and Kearns-Sayre syndrome on DNA from blood samples. J Neurol Sci. 1997 Jul. 149(1):37-40. [QxMD MEDLINE Link].
Peterson PL. The treatment of mitochondrial myopathies and encephalomyopathies. Biochim Biophys Acta. 1995 May 24. 1271(1):275-80. [QxMD MEDLINE Link].
Cohen JM, Waiss B. Combination ptosis crutch and moisture chamber for management of progressive external ophthalmoplegia. J Am Optom Assoc. 1997 Oct. 68(10):663-7. [QxMD MEDLINE Link].
Soejima K, Sakurai H, Nozaki M, et al. Surgical treatment of blepharoptosis caused by chronic progressive external ophthalmoplegia. Ann Plast Surg. 2006 Apr. 56(4):439-42. [QxMD MEDLINE Link].
Wallace DK, Sprunger DT, Helveston EM, et al. Surgical management of strabismus associated with chronic progressive external ophthalmoplegia. Ophthalmology. 1997 Apr. 104(4):695-700. [QxMD MEDLINE Link].
Ewart RM, Burrows RF. Pregnancy in chronic progressive external ophthalmoplegia: a case report. Am J Perinatol. 1997 May. 14(5):293-5. [QxMD MEDLINE Link].
Fraunfelder FT, Roy FH, Randall J. Chronic progressive external ophthalmoplegia. Current Ocular Therapy. 5th ed. 2000. 208-210.
Galetta F, Franzoni F, Mancuso M, Orsucci D, Tocchini L, Papi R, et al. Cardiac involvement in chronic progressive external ophthalmoplegia. J Neurol Sci. 2014 Oct 15. 345 (1-2):189-92. [QxMD MEDLINE Link].
Progressive external ophthalmoplegia. NIH U.S. National Library of Medicine. Genetics Home Reference. Available at https://ghr.nlm.nih.gov/condition/progressive-external-ophthalmoplegia. May 2016; Accessed: March 6, 2023.
Davis RL, Liang C, Sue CM. A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases. Neurology. 2016 May 24. 86 (21):2010-5. [QxMD MEDLINE Link].
Morovat A, Weerasinghe G, Nesbitt V, Hofer M, Agnew T, Quaghebeur G, et al. Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice. J Clin Med. 2017 Aug 21. 6 (8):[QxMD MEDLINE Link].
Scholle LM, Lehmann D, Deschauer M, Kraya T, Zierz S. FGF-21 as a Potential Biomarker for Mitochondrial Diseases. Curr Med Chem. 2018. 25 (18):2070-2081. [QxMD MEDLINE Link].
Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, et al. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol. 2015 Nov. 78 (5):814-23. [QxMD MEDLINE Link].
Pfeiffer MJ. [Chronic Progressive External Ophthalmoplegia Ptosis: Problems with Diagnostics and Treatment]. Klin Monbl Augenheilkd. 2018 Jan. 235 (1):31-33. [QxMD MEDLINE Link].
Gammage PA, Moraes CT, Minczuk M. Mitochondrial Genome Engineering: The Revolution May Not Be CRISPR-Ized. Trends Genet. 2018 Feb. 34 (2):101-110. [QxMD MEDLINE Link].
Loutre R, Heckel AM, Smirnova A, Entelis N, Tarassov I. Can Mitochondrial DNA be CRISPRized: Pro and Contra. IUBMB Life. 2018 Sep 5. [QxMD MEDLINE Link].
Leigh Syndrome (Leigh's Disease). Available at https://my.clevelandclinic.org/health/diseases/6037-leigh-syndrome-leighs-disease. 08/13/2022; Accessed: 03/04/2023.
Ing EB. Thyroid-Associated Orbitopathy. Medscape. Available at https://emedicine.medscape.com/article/1218444-overview. 03/07/2019; Accessed: 03/04/2023.
Congenital fibrosis of the extraocular muscles. MedlinePlus. Available at https://medlineplus.gov/genetics/condition/congenital-fibrosis-of-the-extraocular-muscles/. 11/01/2019; Accessed: 03/04/2023.

Media Gallery

This table outlines the differential diagnoses of chronic progressive external ophthalmoplegia.

of 1

Author

Michael Mercandetti, MD, MBA, FACS Private Practice

Michael Mercandetti, MD, MBA, FACS is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, Sarasota County Medical Society, American Academy of Ophthalmology, American College of Surgeons, American Society for Laser Medicine and Surgery, American Society of Ophthalmic Plastic and Reconstructive Surgery, The Society of Federal Health Professionals (AMSUS)

Disclosure: Nothing to disclose.

Coauthor(s)

Adam J Cohen, MD Physician/CEO, Eyelid and Facial Plastic Surgery and MediSpa; Assistant Professor, Director of Oculoplastic and Reconstructive Surgery, Department of Ophthalmology, Rush University Medical Center

Adam J Cohen, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Ophthalmic Plastic and Reconstructive Surgery

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Triad Inc.<br/>Serve(d) as a speaker or a member of a speakers bureau for: Mimedx; InMode.

Specialty Editor Board

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, American Glaucoma Society

Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy, Sr, MD † Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Additional Contributors

Edsel B Ing, MD, PhD, MBA, MEd, MPH, MA, FRCSC Professor, Department of Ophthalmology and Vision Sciences, Sunnybrook Hospital, University of Toronto Faculty of Medicine; Incoming Chair of Ophthalmology, University of Alberta Faculty of Medicine and Dentistry, Canada

Edsel B Ing, MD, PhD, MBA, MEd, MPH, MA, FRCSC is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Society of Ophthalmic Plastic and Reconstructive Surgery, Canadian Medical Association, Canadian Ophthalmological Society, Canadian Society of Oculoplastic Surgery, Chinese Canadian Medical Society, European Society of Ophthalmic Plastic and Reconstructive Surgery, North American Neuro-Ophthalmology Society, Ontario Medical Association, Royal College of Physicians and Surgeons of Canada, Statistical Society of Canada

Disclosure: Nothing to disclose.