Chronic progressive external ophthalmoplegia: Difference between revisions

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{{Infobox medical condition
{{Infobox medical condition
| name            = Chronic progressive external ophthalmoplegia
| name            = Chronic progressive external ophthalmoplegia
| synonyms        = '''Progressive external ophthalmoplegia'''
| synonyms        = CPEO
| image          =
| field          = [[Neurology]]
| caption        =
| symptoms        = [[Ptosis]], [[ophthalmoplegia]], [[muscle weakness]]
| pronounce      =
| onset          = Typically in [[adulthood]]
| field          =  
| duration        = [[Chronic (medicine)|Chronic]]
| symptoms        =  
| causes          = [[Mitochondrial DNA]] mutations
| complications  =
| risks          = Family history of mitochondrial disorders
| onset          =  
| diagnosis      = [[Clinical diagnosis]], [[genetic testing]]
| duration        =  
| differential    = [[Myasthenia gravis]], [[Kearns-Sayre syndrome]]
| types          =
| treatment      = [[Supportive care]], [[eyelid surgery]]
| causes          =  
| prognosis      = Variable, generally progressive
| risks          =  
| frequency      = Rare
| diagnosis      =  
| differential    =  
| prevention      =
| treatment      =  
| medication      =
| prognosis      =  
| frequency      =  
| deaths          =
}}
}}
 
{{Short description|A mitochondrial disorder affecting eye muscles}}
'''Chronic progressive external ophthalmoplegia''' ('''CPEO'''), is a type of eye disorder characterized by slowly progressive inability to move the eyes and eyebrows.<ref name=vaughan>{{cite book|author1=John P.Whitcher |author2=Paul Riordan-Eva |title=Vaughan & Asbury's general ophthalmology.|publisher=McGraw-Hill Medical|isbn=978-0071443142|page=293|edition=17th|date=2007-10-18 }}</ref> It is often the only feature of [[mitochondrial disease]], in which case the term CPEO may be given as the [[Medical diagnosis|diagnosis]]. In other people suffering from mitochondrial disease, CPEO occurs as part of a [[syndrome]] involving more than one part of the body, such as [[Kearns–Sayre syndrome]]. Occasionally CPEO may be caused by conditions other than mitochondrial diseases.
{{Infobox medical condition
 
| name            = Chronic progressive external ophthalmoplegia
== Signs and symptoms ==
| synonyms        = '''Progressive external ophthalmoplegia''', '''CPEO'''
CPEO is a rare disease that may affect those of all ages, but typically manifests in the young adult years.  CPEO is the most common manifestation of [[mitochondrial myopathy]], occurring in an estimated two-thirds of all cases of mitochondrial myopathy. Patients typically present with [[ptosis (eyelid)|ptosis]] (drooping eyelids). Other diseases like [[Graves' disease]], [[myasthenia gravis]] and glioma that may cause an external [[ophthalmoplegia]] must be ruled out.
| image          = [[File:Ragged red fibers in MELAS.jpg]]
 
| caption        = Muscle biopsy showing ragged red fibers, a hallmark of mitochondrial myopathy seen in CPEO.
=== CPEO itself ===
| pronounce      = /Àà…ífŒ∏…ôlmo äÀåpliÀêd í…ô/
CPEO is a slowly progressing disease. It may begin at any age and progresses over a period of 5–15 years.<ref name=vaughan/> The first presenting symptom of [[ptosis (eyelid)|ptosis]] is often unnoticed by the patient until the lids droop to the point of producing a visual field defect. Often, patients will tilt the head backwards to adjust for the slowly progressing ptosis of the lids. In addition, as the ptosis becomes complete, the patients will use the frontalis (forehead) muscle to help elevate the lids. The ptosis is typically bilateral, but may be unilateral for a period of months to years before the fellow lid becomes involved.
| field          = [[Neurology]], [[Ophthalmology]], [[Genetics]]
 
| symptoms        = Gradual paralysis of the [[extraocular muscles]], [[ptosis]], limited eye movement, [[muscle weakness]], [[exercise intolerance]]
Ophthalmoplegia or the inability or difficulty to move the eye is usually symmetrical. As such, double vision is sometimes a complaint of these patients. The progressive ophthalmoplegia is often unnoticed till decreased ocular motility limits peripheral vision. Often someone else will point out the ocular disturbance to the patient. Patients will move their heads to adjust for the loss of peripheral vision caused by inability to abduct or adduct the eye. All directions of gaze are affected; however, downward gaze appears to be best spared. This is in contrast to [[progressive supranuclear palsy]] (PSP), which typically affects vertical gaze and spares horizontal gaze.
| complications  = [[Dysphagia]], [[cardiomyopathy]], [[sensorineural hearing loss]], [[diabetes mellitus]]
 
| onset          = Typically in [[young adulthood]] or [[middle age]]
=== Occurring alongside CPEO ===
| duration        = Chronic and progressive
 
| types          = CPEO, CPEO plus (includes systemic symptoms)
Weakness of extraocular muscle groups including, the [[orbicularis oculi]] muscle as well as facial and limb muscles may be present in up to 25% of patients with CPEO. As a result of the orbicularis oculi weakness, patients may suffer from exposure keratopathy (damage to cornea) from the inability to close the eyes tightly. Frontalis muscle weakness may exacerbate the ptotic lids with the inability to compensate for the ptosis. Facial muscles may be involved which lead to atrophy of facial muscle groups producing a thin, expressionless face with some having difficulty with chewing.  Neck, shoulder and extremity weakness with atrophy may affect some patients and can be mild or severe.
| causes          = Mutations in [[mitochondrial DNA]] (mtDNA) or [[nuclear DNA]], such as [[POLG]], [[TWNK]], [[RRM2B]]
 
| risks          = Family history of [[mitochondrial disease]], [[genetic mutations]]
Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14).<ref>{{cite journal |author= Yu Wai Man CY |year= 2006 |title= Assessment of visual function in chronic progressive external ophthalmoplegia |journal= Eye |volume= 20 |issue=5 |pages=564–568 |pmid= 15920569 |doi= 10.1038/sj.eye.6701924 |displayauthors= etal |doi-access= free }}</ref>
| diagnosis      = [[Muscle biopsy]], [[genetic testing]], [[EMG]], [[MRI]], [[ophthalmological exam]]
 
| differential    = [[Myasthenia gravis]], [[Graves' ophthalmopathy]], [[Kearns‚ÄìSayre syndrome]], [[oculopharyngeal muscular dystrophy]]
The [[ciliary muscles]] that control the lens shape and the iris muscles are often unaffected by CPEO.
| prevention      = None known; [[genetic counseling]] may be helpful
 
| treatment      = Supportive care, [[eyelid surgery]], [[eye protection]], [[physical therapy]], [[aids for ptosis]]
Additional symptoms are variable, and may include exercise intolerance, [[cataracts]], hearing loss, sensory axonal neuropathy, [[ataxia]], clinical depression, [[hypogonadism]], and [[parkinsonism]].
| medication      = No disease-specific drugs; [[coenzyme Q10]] and [[vitamins]] may be used supportively
 
| prognosis      = Slowly progressive; often compatible with normal life expectancy
[[Kearns–Sayre syndrome]] is characterized by onset before 15 years of age of CPEO, heart block and pigmentary retinopathy.<ref name="vaughan"/>
| frequency      = Rare; exact incidence unknown
 
| deaths         = Not typically fatal; related systemic complications may affect prognosis
== Genetics ==
[[Mitochondrial DNA]] which is transmitted from the mother, encodes proteins that are critical to the respiratory chain required to produce [[adenosine triphosphate]] (ATP).  Deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation.  This may be made evident in highly oxidative tissues like skeletal muscle and heart tissue.  However, [[extraocular muscles]] contain a volume of mitochondria that is several times greater than any other muscle group.  As such, this results in the preferential ocular symptoms of CPEO.
 
Multiple mtDNA abnormalities exist which cause CPEO.  One mutation is located in a conserved region of mitochondrial tRNA at nucleotide 3243 in which there is an A to G nucleotide transition.  This mutation is associated with both CPEO and [[Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes]] (MELAS).<ref>{{cite book |title=Walsh & Hoyt's Clinical Neuro-Ophthalmology, The Essentials |last=Millar |first=N |author2=Newman N |year=1999 |edition=5th}}</ref>
 
A common deletion found in one-third of CPEO patients is a 4,977 base pair segment found between a 13 base pair repeat.
 
The mtDNA that is affected maybe a single or multiple point deletion, with associated nuclear DNA deletions.  One study showed that mtDNA deletion seen in CPEO patients also had an associated nuclear DNA deletion of the [[PEO1|Twinkle gene]] which encodes specific mitochondrial protein; Twinkle.<ref name="pmid16804265">{{cite journal |vauthors = Houshmand M, Panahi MS, Hosseini BN, Dorraj GH, Tabassi AR |title=Investigation on mtDNA deletions and twinkle gene mutation (G1423C) in Iranian patients with chronic progressive external opthalmoplagia |journal=Neurol India |volume=54 |issue=2 |pages=182–5 |year=2006 |pmid=16804265}}</ref>
 
Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion.
 
In most cases, PEO occurs due to a sporadic deletion or duplication within the mitochondrial DNA.<ref name="pmid15358637">{{cite journal |vauthors=Zeviani M, Di Donauto S |title=Mitochondrial disorders |journal=Brain |volume=127 |issue=10 |pages=2153–2172 |year=2004 |pmid=15358637 |doi=10.1093/brain/awh259|doi-access=free }}</ref> However, transmission from the mother to the progeny appears only in few cases. Both [[autosomal dominant]] and [[autosomal recessive]] inheritance can occur, autosomal recessive inheritance being more severe.  Dominant and recessive forms of PEO can be caused by genetic mutations in the ''[[SLC25A4|ANT1]]'', ''[[POLG]]'', ''[[POLG2]]'' and ''[[PEO1]]'' genes.<ref>{{cite journal | author = Copeland WC | year = 2008 | title = Inherited Mitochondrial Diseases of DNA Replication | journal =  Annual Review of Medicine| volume = 59 | issue = | pages = 131–146 | pmid = 17892433 | doi = 10.1146/annurev.med.59.053006.104646 | pmc = 2271032 }}</ref><ref name="Van GoethemDermaut2001">{{cite journal|last1=Van Goethem|first1=Gert|last2=Dermaut|first2=Bart|last3=Löfgren|first3=Ann|last4=Martin|first4=Jean-Jacques|last5=Van Broeckhoven|first5=Christine|title=Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions |journal=Nature Genetics|volume=28|issue=3|year=2001|pages=211–212|issn=1061-4036|doi=10.1038/90034|pmid=11431686}}</ref>
 
== Diagnosis ==
[[File:Ragged red fibers in MELAS.jpg|thumb|An example of ''ragged red fibers'']]
It is important to differentiate CPEO from other pathologies that may cause an ophthalmoplegia.  There are specific therapies used for these pathologies.
 
CPEO is diagnosed via muscle biopsy. On examination of muscle fibers stained with [[Gömöri trichrome stain]], one can see an accumulation of enlarged mitochondria. This produces a dark red staining of the muscle fibers given the name “ragged red fibers”.  While ragged red fibers are seen in normal aging, amounts in excess of normal aging give a diagnosis of a mitochondrial myopathy.
 
[[Polymerase chain reaction]] (PCR), from a sample of blood or muscle tissue can determine a mutation of the mtDNA.
 
Elevated acetylcholine receptor antibody level which is typically seen in myasthenia gravis has been seen in certain patients of mitochondrial associated ophthalmoplegia.<ref name="pmid17414872">{{cite journal |vauthors = Behbehani R, Sharfuddin K, Anim JT |title=Mitochondrial ophthalmoplegia with fatigable weakness and elevated acetylcholine receptor antibody |journal=J Neuroophthalmol |volume=27 |issue=1 |pages=41–4 |year=2007 |pmid=17414872 |doi=10.1097/WNO.0b013e31803312fa }}</ref>
It is important to have a dilated eye exam to determine if there is pigmentary retinopathy that may signify [[Kearns–Sayre syndrome]] which is associated with cardiac abnormalities.
 
MRI may be helpful in the diagnosis, in one study volumes of medial rectus, lateral rectus, and inferior rectus muscles in CPEO were not smaller than normal (in contrast to the profound atrophy typical of neurogenic paralysis). Although volumes of the superior rectus muscle-levator complex and superior oblique were significantly reduced.<ref>{{cite journal|last=Ortube|first=MC|author2=Bhola, R |author3=Demer, JL |title=Orbital magnetic resonance imaging of extraocular muscles in chronic progressive external ophthalmoplegia: specific diagnostic findings|journal=Journal of AAPOS|date=October 2006|volume=10|issue=5|pages=414–8|pmid=17070475|doi=10.1016/j.jaapos.2006.04.012|pmc=1850670}}</ref>
 
== Treatment ==
There is currently no defined treatment to ameliorate the muscle weakness of CPEO.  Treatments used to treat other pathologies causing ophthalmoplegia has not been shown to be effective.
 
Experimental treatment with tetracycline has been used to improve ocular motility in one patient.<ref>{{cite journal |vauthors=Omar A, Johnson LN |year=2007 |title=Tetracycline delays ocular motility decline in chronic progressive external ophthalmoplegia |journal=Neurology |volume=68 |issue=14 |pages=1159–60 |pmid=17404203 |doi=10.1212/01.wnl.0000258659.21421.b0}}</ref> Coenzyme Q<sub>10</sub> has also been used to treat this condition.<ref>{{cite journal|last=Rodriguez|first=MC|author2=MacDonald, JR |author3=Mahoney, DJ |author4=Parise, G |author5=Beal, MF |author6= Tarnopolsky, MA |title=Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders|journal=Muscle & Nerve|date=February 2007|volume=35|issue=2|pages=235–42|pmid=17080429|doi=10.1002/mus.20688}}</ref> However, most neuro-ophthalmologists do not ascribe to any treatment.
 
Ptosis associated with CPEO may be corrected with surgery to raise the lids,<ref name="pmid18786957">{{cite journal |vauthors = Ahn J, Kim NJ, Choung HK, Hwang SW, Sung M, Lee MJ, Khwarg SI |title=Frontalis sling operation using silicone rod for the correction of ptosis in chronic progressive external ophthalmoplegia |journal=Br J Ophthalmol |volume=92 |issue=12 |pages=1685–8 |year=2008 |pmid=18786957 |doi=10.1136/bjo.2008.144816 |hdl=10371/62025 |hdl-access=free }}</ref> however due to weakness of the orbicularis oculi muscles, care must be taken not to raise the lids in excess causing an inability to close the lids.  This results in an exposure keratopathy.  Therefore, rarely should lid surgery be performed and only by a neuro-ophthalmologist familiar with the disease.
 
The most common strabismus finding is large angle exotropia which can be treated by maximal bilateral eye surgery, but due to the progressive nature of the disease, strabismus may recur.<ref>{{cite journal|last=Tinley|first=C|author2=Dawson, E |author3=Lee, J |title=The management of strabismus in patients with chronic progressive external ophthalmoplegia|journal=Strabismus|date=June 2010|volume=18|issue=2|pages=41–7|pmid=20521878|doi=10.3109/09273971003758388}}</ref> Those that have [[diplopia]] as a result of asymmetric ophthalmoplegia may be corrected with prisms or with surgery to create a better alignment of the eyes.
 
== See also ==
*[[Ophthalmoparesis]]
 
==References==
{{Reflist}}
 
== Further reading==
*https://web.archive.org/web/20060925130130/http://journals.tubitak.gov.tr/medical/issues/sag-04-34-3/sag-34-3-9-0401-8.pdf
== External links ==
{{Medical resources
| DiseasesDB    = 29124
| ICD10         = {{ICD10|H|49|4|h|49}}
|  ICD9          = {{ICD9|378.72}}
|  ICDO          =
|  OMIM          = 157640
|  MedlinePlus    =
|  eMedicineSubj  = oph
|  eMedicineTopic = 510
|  MeshID        = D017246
|  Orphanet      = 254892
}}
}}
'''Chronic progressive external ophthalmoplegia''' (CPEO) is a rare [[neuromuscular disorder]] characterized by slowly progressive paralysis of the [[extraocular muscles]], which are responsible for controlling eye movements. This condition leads to [[ptosis]] (drooping of the eyelids) and limited eye movement, often resulting in [[diplopia]] (double vision). CPEO is primarily associated with [[mitochondrial myopathy]], a type of [[mitochondrial disease]].
==Pathophysiology==
CPEO is caused by defects in the [[mitochondria]], the energy-producing structures within cells. These defects can result from mutations in [[nuclear DNA]] or [[mitochondrial DNA]] (mtDNA). The mutations lead to impaired energy production, particularly affecting tissues with high energy demands, such as the [[muscles]] controlling eye movement. The accumulation of dysfunctional mitochondria in these muscles results in their progressive weakness and paralysis.
==Clinical Features==
The hallmark of CPEO is the gradual onset of [[ophthalmoplegia]], which typically begins in adulthood. Patients often present with:
* '''Ptosis''': Drooping of one or both eyelids, which may be the initial symptom.
* '''Ophthalmoplegia''': Limited movement of the eyes in all directions, leading to difficulty in tracking objects and [[diplopia]].
* '''Facial Weakness''': Some patients may experience mild weakness of the facial muscles.
* '''Muscle Weakness''': In some cases, CPEO may be associated with generalized muscle weakness, particularly in the limbs.
==Diagnosis==
The diagnosis of CPEO is based on clinical examination, family history, and specialized tests. Key diagnostic tools include:
* '''Ophthalmologic Examination''': To assess the extent of eye movement limitation and ptosis.
* '''Muscle Biopsy''': May reveal characteristic "ragged-red fibers," indicative of mitochondrial myopathy.
* '''Genetic Testing''': To identify mutations in mtDNA or nuclear DNA associated with CPEO.
* '''Electromyography (EMG)''': To evaluate muscle function and detect abnormalities.
==Management==
There is currently no cure for CPEO, and treatment is primarily supportive. Management strategies include:
* '''Ptosis Surgery''': To improve eyelid function and vision.
* '''Prism Glasses''': To alleviate diplopia by correcting eye alignment.
* '''Physical Therapy''': To maintain muscle strength and function.
* '''Genetic Counseling''': For affected individuals and their families to understand the inheritance patterns and risks.
==Prognosis==
CPEO is a progressive condition, but the rate of progression can vary widely among individuals. While the disorder primarily affects eye muscles, some patients may develop additional symptoms related to mitochondrial dysfunction, such as [[cardiac conduction defects]] or [[sensorineural hearing loss]].
==Related Pages==
* [[Mitochondrial disease]]
* [[Ophthalmoplegia]]
* [[Ptosis]]
* [[Diplopia]]
* [[Mitochondrial myopathy]]
{{Eye pathology}}
{{Eye pathology}}
{{Mitochondrial diseases}}
{{Mitochondrial diseases}}
{{Diseases of myoneural junction and muscle}}
{{Diseases of myoneural junction and muscle}}
{{DEFAULTSORT:Chronic Progressive External Ophthalmoplegia}}
{{DEFAULTSORT:Chronic Progressive External Ophthalmoplegia}}
[[Category:Autosomal recessive disorders]]
[[Category:Autosomal recessive disorders]]
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[[Category:Mitochondrial diseases]]
[[Category:Mitochondrial diseases]]
[[Category:Muscular disorders]]
[[Category:Muscular disorders]]
{{dictionary-stub1}}
{{stub}}

Latest revision as of 01:24, 4 April 2025


Chronic progressive external ophthalmoplegia
Synonyms CPEO
Pronounce N/A
Specialty N/A
Symptoms Ptosis, ophthalmoplegia, muscle weakness
Complications N/A
Onset Typically in adulthood
Duration Chronic
Types N/A
Causes Mitochondrial DNA mutations
Risks Family history of mitochondrial disorders
Diagnosis Clinical diagnosis, genetic testing
Differential diagnosis Myasthenia gravis, Kearns-Sayre syndrome
Prevention N/A
Treatment Supportive care, eyelid surgery
Medication N/A
Prognosis Variable, generally progressive
Frequency Rare
Deaths N/A


A mitochondrial disorder affecting eye muscles


Chronic progressive external ophthalmoplegia
Synonyms Progressive external ophthalmoplegia, CPEO
Pronounce /ˈɒfθəlmoʊˌpliːdʒə/
Specialty N/A
Symptoms Gradual paralysis of the extraocular muscles, ptosis, limited eye movement, muscle weakness, exercise intolerance
Complications Dysphagia, cardiomyopathy, sensorineural hearing loss, diabetes mellitus
Onset Typically in young adulthood or middle age
Duration Chronic and progressive
Types CPEO, CPEO plus (includes systemic symptoms)
Causes Mutations in mitochondrial DNA (mtDNA) or nuclear DNA, such as POLG, TWNK, RRM2B
Risks Family history of mitochondrial disease, genetic mutations
Diagnosis Muscle biopsy, genetic testing, EMG, MRI, ophthalmological exam
Differential diagnosis Myasthenia gravis, Graves' ophthalmopathy, Kearns–Sayre syndrome, oculopharyngeal muscular dystrophy
Prevention None known; genetic counseling may be helpful
Treatment Supportive care, eyelid surgery, eye protection, physical therapy, aids for ptosis
Medication No disease-specific drugs; coenzyme Q10 and vitamins may be used supportively
Prognosis Slowly progressive; often compatible with normal life expectancy
Frequency Rare; exact incidence unknown
Deaths Not typically fatal; related systemic complications may affect prognosis


Chronic progressive external ophthalmoplegia (CPEO) is a rare neuromuscular disorder characterized by slowly progressive paralysis of the extraocular muscles, which are responsible for controlling eye movements. This condition leads to ptosis (drooping of the eyelids) and limited eye movement, often resulting in diplopia (double vision). CPEO is primarily associated with mitochondrial myopathy, a type of mitochondrial disease.

Pathophysiology[edit]

CPEO is caused by defects in the mitochondria, the energy-producing structures within cells. These defects can result from mutations in nuclear DNA or mitochondrial DNA (mtDNA). The mutations lead to impaired energy production, particularly affecting tissues with high energy demands, such as the muscles controlling eye movement. The accumulation of dysfunctional mitochondria in these muscles results in their progressive weakness and paralysis.

Clinical Features[edit]

The hallmark of CPEO is the gradual onset of ophthalmoplegia, which typically begins in adulthood. Patients often present with:

  • Ptosis: Drooping of one or both eyelids, which may be the initial symptom.
  • Ophthalmoplegia: Limited movement of the eyes in all directions, leading to difficulty in tracking objects and diplopia.
  • Facial Weakness: Some patients may experience mild weakness of the facial muscles.
  • Muscle Weakness: In some cases, CPEO may be associated with generalized muscle weakness, particularly in the limbs.

Diagnosis[edit]

The diagnosis of CPEO is based on clinical examination, family history, and specialized tests. Key diagnostic tools include:

  • Ophthalmologic Examination: To assess the extent of eye movement limitation and ptosis.
  • Muscle Biopsy: May reveal characteristic "ragged-red fibers," indicative of mitochondrial myopathy.
  • Genetic Testing: To identify mutations in mtDNA or nuclear DNA associated with CPEO.
  • Electromyography (EMG): To evaluate muscle function and detect abnormalities.

Management[edit]

There is currently no cure for CPEO, and treatment is primarily supportive. Management strategies include:

  • Ptosis Surgery: To improve eyelid function and vision.
  • Prism Glasses: To alleviate diplopia by correcting eye alignment.
  • Physical Therapy: To maintain muscle strength and function.
  • Genetic Counseling: For affected individuals and their families to understand the inheritance patterns and risks.

Prognosis[edit]

CPEO is a progressive condition, but the rate of progression can vary widely among individuals. While the disorder primarily affects eye muscles, some patients may develop additional symptoms related to mitochondrial dysfunction, such as cardiac conduction defects or sensorineural hearing loss.

Related Pages[edit]









Mitochondrial diseases
Carbohydrate metabolism
Primarily nervous system
Myopathies
No primary system
Chromosomal


Diseases of muscle, neuromuscular junction, and neuromuscular disease
Neuromuscular-
junction disease
Myopathy
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