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gradually advancing in extent
a tense of verbs used in describing action that is on-going (同)progressive tense, imperfect, imperfect tense, continuous tense
favoring or promoting reform (often by government action) (同)reformist, reform-minded
(of a card game or a dance) involving a series of sections for which the participants successively change place or relative position; "progressive euchre"; "progressive tournaments"
(of taxes) adjusted so that the rate increases as the amount of income increases
advancing in severity; "progressive paralysis"
favoring or promoting progress; "progressive schools"
purely outward or superficial; "external composure"; "an external concern for reputation"- A.R.Gurney,Jr.
outward features; "he enjoyed the solemn externals of religion"
coming from the outside; "extraneous light in the camera spoiled the photograph"; "relying upon an extraneous income"; "disdaining outside pressure groups" (同)extraneous, outside
from or between other countries; "external commerce"; "international trade"; "developing nations need outside help" (同)international, outside
happening or arising or located outside or beyond some limits or especially surface; "the external auditory canal"; "external pressures"
being long-lasting and recurrent or characterized by long suffering; "chronic indigestion"; "a chronic shortage of funds"; "a chronic invalid"
of long duration; "chronic money problems" (同)continuing
habitual; "a chronic smoker" (同)inveterate
a nonresident doctor or medical student; connected with a hospital but not living there (同)medical extern
paralysis of the motor nerves of the eye

PrepTutorEJDIC

(行列などが)『前進する』,進んで行く / (事態が)進展する,進行する / 『進歩的な』,革新的な / (病気・暴力などが)次第に悪くなる(広がる) / (課税が)累進的な / (文法で)進行[形]の / 進歩的な人,革新主義者
『外側の』,外部の / (作用・動作などが)『外側からの』,外部からの / 表面上の,見せかけの / 体外の;体外用の / 外国の(foreign) / (…の)外観,外形《+『of』+『名』》
(病気が)長期にわたる,慢性の / 《名詞の前にのみ用いて》常習の,癖になった

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/08 07:13:37」(JST)

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Chronic progressive external ophthalmoplegia (CPEO), also known as progressive external ophthalmoplegia (PEO), is a type of eye disorder characterized by slowly progressive inability to move the eyes and eyebrows.^[1] It is often the only feature of mitochondrial disease, in which case the term CPEO may be given as the 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.

Introduction

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 (drooping eyelids). Other diseases like Graves' disease, myasthenia gravis and glioma that may cause an external ophthalmoplegia must be ruled out.

Signs and symptoms

Of CPEO itself

CPEO is a slowly progressing disease. It may begin at any age and progresses over a period of 5–15 years.^[1] The first presenting symptom of 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.

Ophthalmoplegia or the inability/difficulty to move the eye is usually symmetrical. As such, double vision is sometimes a complaint of these patients. In fact, 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 lost 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.

Occurring alongside CPEO

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.

Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14).^[2]

The ciliary muscles that control the lens shape and the iris muscles are often unaffected by CPEO.

Additional symptoms are variable, and may include exercise intolerance, cataracts, hearing loss, sensory axonal neuropathy, ataxia, clinical depression, hypogonadism, and parkinsonism.

Kearns-Sayre syndrome, is characterized by onset before 15 years of age of CPEO, heart block and pigmentary retinopathy.^[1]

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).^[3]

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 Twinkle gene which encodes specific mitochondrial protein; Twinkle.^[4]

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.^[5] 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 ANT1, POLG, POLG2 and PEO1 genes.^[6]^{[citation needed]}

Diagnosis

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.^[7]

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.^[8]

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.^[9] Coenzyme Q₁₀ has also been used to treat this condition.^[10] However, most neuro-ophthalmologists do not ascribe to any treatment.

Ptosis associated with CPEO may be corrected with surgery to raise the lids, 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 findings is large angle exotropias which can be treated by maximal bilateral eye surgery, but due to the progressive nature of the disease, strabismus may recur.^[11] Those that have diplopia as a result of asymmetric ophthalmoplegia maybe corrected with prisms or with surgery to create a better alignment of the eyes.

References

^ ^a ^b ^c ^d John P.Whitcher, Paul Riordan-Eva. Vaughan & Asbury's general ophthalmology. (17th ed.). McGraw-Hill Medical. p. 293. ISBN 978-0071443142.
^ Yu Wai Man CY et al. (2006). "Assessment of visual function in chronic progressive external ophthalmoplegia". Eye 20 (5): 564–8. doi:10.1038/sj.eye.6701924. PMID 15920569.
^ Millar, N; Newman N (1999). Walsh & Hoyt’s Clinical Neuro-Ophthalmology, The Essentials (5th ed.).
^ Houshmand M et al. (2006). "Investigation on mtDNA deletions and twinkle gene mutation (G1423C) in Iranian patients with chronic progressive external ophthalmoplegia". Neurol India 54 (2): 182–5. PMID 16804265.
^ Zeviani M, Di Donauto S (2004). "Mitochondrial disorders". Brain 127 (10): 2153–2172. doi:10.1093/brain/awh259. PMID 15358637.
^ Copeland, WC. (2008) Inherited Mitochondrial Diseases of DNA Replication Annu Rev Medicine 59, 131-146. PMID=17892433
^ Behbehani R et al. (2007). "Mitochondrial ophthalmoplegia with fatigable weakness and elevated acetylcholine receptor antibody". J Neuroophthalmol 27 (1): 41–4. doi:10.1097/WNO.0b013e31803312fa. PMID 17414872.
^ Ortube, MC; Bhola, R; Demer, JL (October 2006). "Orbital magnetic resonance imaging of extraocular muscles in chronic progressive external ophthalmoplegia: specific diagnostic findings". Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus 10 (5): 414–8. doi:10.1016/j.jaapos.2006.04.012. PMC 1850670. PMID 17070475.
^ Omar A, Johnson LN (2007). "Tetracycline delays ocular motility decline in chronic progressive external ophthalmoplegia". Neurology 68 (14): 1159–60. doi:10.1212/01.wnl.0000258659.21421.b0. PMID 17404203.
^ Rodriguez, MC; MacDonald, JR; Mahoney, DJ; Parise, G; Beal, MF; Tarnopolsky, MA (February 2007). "Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders". Muscle & nerve 35 (2): 235–42. doi:10.1002/mus.20688. PMID 17080429.
^ Tinley, C; Dawson, E; Lee, J (June 2010). "The management of strabismus in patients with chronic progressive external ophthalmoplegia". Strabismus 18 (2): 41–7. doi:10.3109/09273971003758388. PMID 20521878.

External links and images

http://www4.ocn.ne.jp/~nurophth/CPEO1.jpg
http://webeye.ophth.uiowa.edu/eyeforum/cases/case24.htm
http://journals.tubitak.gov.tr/medical/issues/sag-04-34-3/sag-34-3-9-0401-8.pdf

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. ミトコンドリアミオパシー：臨床的特徴および診断 mitochondrial myopathies clinical features and diagnosis
2. 眼筋型重症筋無力症 ocular myasthenia gravis
3. 小児における外眼筋に影響するミオパチー myopathies affecting the extraocular muscles in children
4. 眼瞼下垂症の概要 overview of ptosis
5. 重症筋無力症の鑑別診断 differential diagnosis of myasthenia gravis

English Journal

Novel mitochondrial tRNAIle m.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype.

Jackson CB1, Neuwirth C2, Hahn D3, Nuoffer JM3, Frank S4, Gallati S5, Schaller A5.
The British journal of ophthalmology.Br J Ophthalmol.2014 Jul 17. pii: bjophthalmol-2014-305300. doi: 10.1136/bjophthalmol-2014-305300. [Epub ahead of print]
BACKGROUND/AIM: To investigate the underlying pathomechanism in a 33-year-old female Caucasian patient presenting with chronic progressive external ophthalmoplegia (CPEO) plus symptoms.METHODS: Histochemical anaylsis of skeletal muscle and biochemical measurements of individual oxidative phosphoryla
PMID 25034047

High cytochrome c oxidase expression links to severe skeletal energy failure by (31)P-MRS spectroscopy in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

Liu AH1, Niu FN, Chang LL, Zhang B, Liu Z, Chen JY, Zhou Q, Wu HY, Xu Y.
CNS neuroscience & therapeutics.CNS Neurosci Ther.2014 Jun;20(6):509-14. doi: 10.1111/cns.12257. Epub 2014 Mar 27.
AIMS: The purpose of this study was to evaluate the energy metabolism and mitochondrial function in skeletal muscle from patients with Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) or chronic progressive external ophthalmoplegia (CPEO) using phosphorus magnetic r
PMID 24674659

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.

Pfeffer G1, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF.
Brain : a journal of neurology.Brain.2014 May;137(Pt 5):1323-36. doi: 10.1093/brain/awu060. Epub 2014 Apr 10.
Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple m
PMID 24727571

Japanese Journal

慢性進行性外眼筋麻痺と筋緊張性ジストロフィ各1例の外眼筋の臨床病理

大平明彦,西川俊郎,種田積子
日本眼科學会雜誌 116(7), 657-663, 2012-07-10
NAID 10030791187

Paralytic Exophthalmos in Chronic Progressive External Ophthalmoplegia

Maeda Kengo,Idehara Ryo
Internal Medicine 51(8), 989-989, 2012
NAID 130002061887

An autopsy case of chronic progressive external ophthalmoplegia with renal insufficiency

YURI Takashi,KONDO Yaeko,KOHNO Keiko,LEI Yen-Chang,KANEMATSU Seika,KUWATA Maki,IWASAKA Toshiji,TSUBURA Airo
Medical molecular morphology : official journal of the Japanese Society for Clinical Molecular Morphology 41(4), 233-237, 2008-12-01
NAID 10025859458

Related Pictures

★リンクテーブル★

リンク元	「慢性進行性外眼筋麻痺症候群」「CPEO」
関連記事	「external」「chronic」「progressive」「ophthalmoplegia」

「慢性進行性外眼筋麻痺症候群」

Chronic progressive external ophthalmoplegia
	Classification and external resources
ICD-10	H49.4
ICD-9	378.72
OMIM	157640
DiseasesDB	29124
eMedicine	oph/510
MeSH	D017246