Neuromuscular Disorders

Updated 10.02.2023
Released 09.17.1993
Expires For CME 10.02.2026

Chronic progressive external ophthalmoplegia

Authors: Michelangelo Mancuso MD PhD, Piervito Lopriore MD

Editor: Nicholas E Johnson MD MSCI FAAN

Introduction

Overview

Progressive external ophthalmoplegia, also known as chronic progressive external ophthalmoplegia, is a clinical syndrome of diverse causes that all share the combination of progressive ptosis and impaired mobility of the eyes, bilaterality, affection of muscles innervated by more than one nerve, sparing of pupils, gradual progression over months or years, absence of remissions or exacerbations, and absence of evidence of a specific disorder. Indeed, progressive external ophthalmoplegia represents the most common mitochondrial phenotype linked to pathogenic variants of mitochondrial or nuclear DNA that are critical for mitochondrial functions. Most cases are sporadic. Progress in understanding pathogenesis is lagging and, like many genetic diseases, treatment is needed. As newly discovered mutations continue to be found, more roads to etiology and pathogenesis continue to emerge.

Key points

	• Progressive external ophthalmoplegia represents the most common mitochondrial phenotype.
	• Single large-scale deletions of mtDNA are the most frequent causes of sporadic chronic progressive external ophthalmoplegia.
	• Mitochondrial DNA and nuclear-encoded gene mutations are responsible for inherited cases.
	• Although muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms.
	• Progressive external ophthalmoplegia can be isolated or associated with extramuscular features or present in the context of more complex mitochondrial syndromes.
	• Progress in understanding the pathogenesis is lagging, and, like many inherited diseases, disease-modifying treatments are needed.

Historical note and terminology

In 1890 Beaumont introduced the term “progressive nuclear ophthalmoplegia.” For the next half century, it was uncertain whether the cause was neurogenic or myopathic. That question was never resolved because none of the usual methods were sufficient to make the differentiation, nor EMG, ocular muscles biopsy, or even postmortem examination. In 1968, Rosenberg and colleagues found that 5 of 27 cases of ocular myopathy were associated with neurogenic syndromes, and David A Drachman introduced the term "ophthalmoplegia-plus" because the syndrome was often associated with neurologic multisystem diseases. A clinically distinct form of ophthalmoplegia-plus, known as Kearns-Sayre syndrome, was characterized by the triad of external ophthalmoplegia, retinitis pigmentosa, and heart block (43).

In 1975, Rowland suggested that Kearns-Sayre syndrome could be defined clinically and noted that it was almost never familial. In the next decade this was debated; many investigators thought it premature to separate individual syndromes because so many patients had symptoms and signs that overlapped classifications. However, with the 1972 recognition by Olson and colleagues that finding “ragged-red fibers” in a muscle biopsy stained with the Gomori method is a sign of mitochondrial proliferation, followed by the later recognition of maternal inheritance in syndromes called “myoclonus epilepsy with ragged red fibers” (ie, MERRF) and “mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes” (ie, MELAS), the importance of mtDNA was recognized (64). In 1988, Holt and colleagues found mitochondrial DNA (mtDNA) single large-scale deletions in some mitochondrial diseases; then, Zeviani, DiMauro, and Schon found major deletions only in Kearns-Sayre syndrome or sporadic cases of progressive external ophthalmoplegia itself. Subsequently, the phenotypic spectrum of mtDNA single large-scale deletions was expanded by the identification of these large rearrangements in infants with Pearson syndrome, a severe, often fatal, infantile onset sideroblastic anemia (74). Simultaneously, in 1988 Wallace found an mtDNA point mutation in Leber hereditary optic neuropathy, and others soon identified point mutations in MELAS and MERRF. Nevertheless, mtDNA point mutations may cause progressive external ophthalmoplegia (82; 07). Finally, chronic progressive external ophthalmoplegia can be associated with mutations in nuclear encoded genes required for mtDNA maintenance, as evidenced by the presence of mtDNA multiple deletions or depletion in muscle or other postmitotic tissues (49).

These discoveries might have ended the debates, and, in a way, they did. The significance of the clinical syndromes is no longer disputed. Pathogenesis is uncertain because a single mutation is often associated with more than one clinical syndrome (phenotypic heterogeneity) (21); conversely, a single clinical disorder is likely to be associated with more than one mutation in the same gene (allelic heterogeneity) or different genes (locus heterogeneity). It is still useful to define the syndromes clinically, but mutations of mtDNA or nuclear DNA, either autosomal dominant and, less commonly, autosomal recessive, are being identified more readily and more frequently (86; 88; 49). As a result, some experts prefer a genetic classification (91). Van Goethem introduced the term “mtDNA maintenance” to account for mutations that lead to depletion of mtDNA or multiple deletions (90).

Clinical manifestations

Presentation and course

Chronic progressive external ophthalmoplegia is one of the most common clinical manifestations of primary mitochondrial disease. In the Nationwide Italian Collaborative Network of Mitochondrial Disease, more than half of the genetically confirmed primary mitochondrial disease subjects had ocular myopathy (399/722, 55.3%), whereas in the North American Mitochondrial Disease Consortium Registry, ptosis or progressive external ophthalmoplegia were present in 29.4% (196/666) and 20.6% (137/666, 20.6%) of patients, respectively (65; 04).

The defining feature of chronic progressive external ophthalmoplegia is ptosis, which is usually but not always associated with symmetrical and progressive limitation of eye movements, with normal pupils. Sometimes, there is only ptosis--without ophthalmoplegia--for years, often leading to the gradual acquisition of a chin-up compensatory head position. Traditionally diplopia is considered to be rare because both eyes are affected simultaneously; however, numerous studies of patients with progressive external ophthalmoplegia have found high rates of transient or constant diplopia (54). Facultative suppression preventing diplopia is common among progressive external ophthalmoplegia patients with strabismus and may reflect the long-time course over which ocular misalignment develops (54). On examination, the eyelids may appear thin. It is worth nothing that some clinicians consider chronic progressive external ophthalmoplegia to be a pure extraocular myopathy, whereas others consider it a generalized myopathy with extraocular, oropharyngeal, and skeletal muscle involvement (51; 65; 04; 20). In most patients with chronic progressive external ophthalmoplegia, clinical evidence of skeletal muscle weakness or specific mitochondrial histological alterations (such as ragged-red fibers or cytochrome oxidase-negative fibers) are present. The syndrome usually begins in childhood or adolescence, but it may start later.

In primary mitochondrial diseases, progressive external ophthalmoplegia may appear as the unique/predominant sign of disease, in this case it is denoted as simple “progressive external ophthalmoplegia,” or may be part of a multisystem manifestation of mitochondrial alteration. Ocular myopathy may be a feature of a multisystem mitochondrial encephalomyopathy when associated with gastrointestinal dysmotility (mitochondrial neurogastrointestinal encephalomyopathy; MNGIE), sensory ataxic neuropathy (sensory ataxic neuropathy, dysarthria, and ophthalmoplegia; SANDO), cognitive impairment and ataxia (Kearns-Sayre syndrome), or other signs, such as myoclonus (MERRF) or stroke-like episodes (MELAS). Moreover, progressive external ophthalmoplegia may also be part of a set of manifestations without involvement of the central nervous system, newly defined as “progressive external ophthalmoplegia–plus” by the Italian Network (different from Drachman) (65).

Orsucci and associates performed a retrospective study on mitochondrial ocular myopathy based on the Nationwide Italian Collaborative Network of Mitochondrial Diseases patients’ web Italian registry of 1300 patients, defining among the progressive external ophthalmoplegia group: “pure progressive external ophthalmoplegia” as the patients with isolated ocular myopathy and “progressive external ophthalmoplegia-plus” as those with ocular myopathy and other features of neuromuscular and multisystem involvement (65). Ocular myopathy was the most common feature in the cohort of mitochondrial patients, representing the 55.3% of patients with definite genetic diagnosis. Patients with pure progressive external ophthalmoplegia were one third of all progressive external ophthalmoplegia patients. The most common CNS features associated were ataxia (19.8%), cognitive impairment (13.5%), seizures (7.5%), pyramidal signs (7.3%), tremor (4.5%), stroke-like episodes (3.8%), impaired consciousness (3.8%), dystonia (3.5%), microcephaly (3.0%), nystagmus (2.8%), myoclonus (2.3%), and parkinsonism (2.0%) (65). Considering the progressive external ophthalmoplegia patients, ocular myopathy was associated with muscle weakness (42.9%), exercise intolerance (23.1%), muscle wasting (17.5%), hearing loss (15.3%), and swallowing impairment (14.9%) without association with specific genotypes, except for mutations in TYMP that were associated with muscle wasting (65).

The associated clinical syndrome is more likely to be severe and involve brain, retina and auditory nerves if it starts before 9 years of age, and much less likely to be severe if it starts after 20 years of age (03).

Chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Pearson marrow pancreas syndrome are the three sporadic clinical syndromes classically associated with three classical overlapping phenotypes caused by mtDNA single large-scale deletions, which are the first mtDNA aberrations to be associated with human primary mitochondrial diseases (36). mtDNA deletion syndromes usually occur as simplex cases (ie, a single occurrence in a family) as single mtDNA deletions mostly arise de novo. Progressive external ophthalmoplegia represents the common basis of the syndromic continuum related to these three clinical syndromes. An invariant triad defines Kearns-Sayre syndrome: PEO, pigmentary retinopathy, and onset before 20 years of age. In addition, there should be at least one of the following: heart block (with need for pacemaker), cerebrospinal fluid protein content of 100 mg/dl or greater, and a disabling cerebellar syndrome. Cardiac conduction abnormalities may be present at the time of progressive external ophthalmoplegia onset or may develop years later mandating serial cardiac evaluations (54).

Interestingly, features of Kearns-Sayre syndrome may appear in survival infants affected by Pearson syndrome later in life. Moreover, it has been reported than one mother with ophthalmoplegia, but no other features of Kearns-Sayre syndrome, had a child with Pearson anemia; both mother and child had the same single mtDNA deletion (79).

However, these classic criteria of Kearns-Sayre syndrome present some limitations: the age limit is arbitrary, CSF protein levels have very limited use in current clinical practice in those patients, multisystem clinical features strongly associated with Kearns-Sayre syndrome are excluded from the current criteria (for instance hearing loss, failure to thrive/short stature, cognitive involvement, tremor, and cardiomyopathy), and finally, many patients with progressive external ophthalmoplegia due to an mtDNA single large-scale deletion did not fulfill the criteria for Kearns-Sayre syndrome or for ‘‘pure’’ progressive external ophthalmoplegia; for instance, patients with progressive external ophthalmoplegia (who do not fit the diagnostic criteria of Kearns-Sayre syndrome) may also demonstrate pigmentary retinopathy, often described as a “salt and pepper” retinopathy with a speckled pattern of retinal pigment epithelium clumping alternating with areas devoid of normal epithelium (60).

To resolve these limitations, the Italian Network of mitochondrial diseases tested in a large cohort of 228 patients from the database of the Nationwide Italian Collaborative Network of Mitochondrial Diseases simplified criteria for a new category that could be defined ‘‘Kearns-Sayre syndrome spectrum’’ (ptosis and/or ophthalmoparesis due to an mtDNA single large-scale deletion and at least one of the following: retinopathy, ataxia, cardiac conduction defects, hearing loss, failure to thrive/short stature, cognitive involvement, tremor, cardiomyopathy), as opposed to progressive external ophthalmoplegia (ptosis and/or ophthalmoparesis due to an mtDNA single large-scale deletion not fulfilling the new ‘‘Kearns-Sayre syndrome spectrum’’ criteria or criteria for Pearson disease) (51). In this view, ‘‘classic’’ Kearns-Sayre syndrome represents the most severe extreme of the Kearns-Sayre syndrome spectrum. With the new criteria, it is possible to classify nearly all single-deletion patients: 64.5% progressive external ophthalmoplegia, 31.6% Kearns-Sayre syndrome spectrum (including classic Kearns-Sayre syndrome 6.6%), and 2.6% Pearson disease. The deletion length was greater in Kearns-Sayre syndrome spectrum than in progressive external ophthalmoplegia whereas heteroplasmy was inversely related with age at onset (51).

In March 2020, Rodríguez-López and colleagues reported a retrospective analysis of the clinical, pathological, and genetic features of 89 cases with chronic progressive external ophthalmoplegia (73). Although they have observed three main phenotypes: pure progressive external ophthalmoplegia (42%), Kearns-Sayre syndrome (10%), and progressive external ophthalmoplegia plus (48%), they have also concluded that phenotype-genotype correlations cannot be brought in mitochondrial progressive external ophthalmoplegia, and a muscle biopsy should be the first step in the diagnostic flow of progressive external ophthalmoplegia when mitochondrial etiology is suspected. Additional national cohorts of chronic progressive external ophthalmoplegia have been reported in Poland (44) and the Czech Republic (02).

Prognosis and complications

A retrospective analysis of 69 patients with chronic progressive external ophthalmoplegia harboring mtDNA single large-scale deletions revealed that patients with progressive external ophthalmoplegia without neurologic involvement had later onset (median: 17.5 years old vs. 12 years old with neurologic manifestations) and slower progression (03). In a 12-month follow-up study of a large primary mitochondrial myopathy cohort, Montano and colleagues found that patients with chronic progressive external ophthalmoplegia had better motor performance and lower disease clinical severity than other patients with mitochondrial myopathy with skeletal muscle involvement.

Thus, the prognosis of chronic progressive external ophthalmoplegia depends on the associated features, primarily whether there is severe limb weakness or a cerebellar disorder that may be mild or disabling. In Kearns-Sayre syndrome, the cerebellar and heart involvement are probably the most incapacitating component, and life span may be shortened. When there is myopathic limb weakness, disability is usually mild and motor performance is worse.

Clinical vignette

At 30 years of age, a woman noted bilateral ptosis with no diurnal variation or diplopia. Soon after, she started complaining about exercise intolerance and cramps. EMG was consistent with mild proximal myopathy. Serum level of creatine kinase was 251 units (normal was 0 to 165). Cardiac evaluation showed no abnormality.

Family history was unremarkable, and no history of neuromuscular diseases was detected.

Examination. Bilateral ptosis was evident, and eye closure was weak. Eye movements were asymmetric. On lateral gaze in either direction, the adducting eye moved completely, but the abducting eye movement was incomplete. Vertical movements were normal. Speech and oropharynx were normal, as were the sternomastoids. Mild deltoid weakness was observed. There was no myotonia of grasp or percussion. Tendon reflexes were not elicited.

Diagnostic test. mtDNA next-generation sequencing in blood was negative, but analysis in urine reveled a heteroplasmic (about 30%) mtDNA single, large-scale deletion.

Biological basis

Etiology and pathogenesis

Chronic progressive external ophthalmoplegia is sporadic in approximately 50% of cases, with the remaining 50% inherited through autosomal dominant, autosomal recessive, or maternal transmission.

Sporadic chronic progressive external ophthalmoplegia and sporadic Kearns-Sayre syndrome are the most common forms (85) due to a single large-scale de novo mtDNA deletion typically not transmitted to offspring (16). Sporadic cases may also be associated with mutations in tRNA genes (09; 83) or other mtDNA point mutations (41).

Autosomal dominant ophthalmoplegia and autosomal recessive MNGIE are associated with multiple deletions or depletion of mtDNA; the deletions and the clinical syndromes are attributed to impaired interaction between nuclear and mtDNA (33; 89); in fact, the maintenance of mtDNA depends on a large number of nuclear gene-encoded proteins that function in mtDNA synthesis and the maintenance of a balanced mitochondrial nucleotide pool. Mutations in numerous nuclear-encoded genes cause autosomal dominant progressive external ophthalmoplegia, both the pure and plus forms, including POLG1, POLG2, ANT1, TWNK (previously designated as C10orf2), RRM2B, DNA2, GMPR, and OPA1, with POLG1 being the most common (54; 08; 37; 35). There is often a striking variety of phenotypes even within related probands carrying the same mutation. SPG7 has been also described as cause of PEO associated with multiple mtDNA deletions (67).

Autosomal recessive progressive external ophthalmoplegia is less common and is due to mutations in TYMP, POLG1, DGUOK, TK2, MGM1, RRM2B, RNASEH1, RRM1, and C1QBP genes, leading to either multiple mtDNA deletions or mtDNA depletion (35). In those disorders, progressive external ophthalmoplegia is typically not an isolated syndrome but rather part of a more complex syndrome such as MNGIE, due to TYMP mutations, that causes multiple deletions, depletion, and point mutations of mtDNA, leading to abnormalities of respiratory chain function. The resulting syndrome of young adults comprises progressive external ophthalmoplegia, sensorimotor peripheral neuropathy, gastroenteropathy, cachexia, and leukoencephalopathy leading to early death (33; 34; 56; 30). Above TYMP, RRM2B also encodes a cytosolic enzyme that is involved in nucleotide metabolism and is important for maintaining a balanced mitochondrial nucleotide pool resulting in the reduction of cytosolic synthesis of deoxyribonucleosides, causing the same MNGIE syndrome (19). Evidence of the association of biallelic ENDOG variants with progressive external ophthalmoplegia and segmental mitochondrial myopathy has been provided, indicating a possible role of ENDOG in mtDNA replication or repair (61).

Both POLG1 and RRM2B are able to cause both autosomal dominant and autosomal recessive forms of progressive external ophthalmoplegia; pathogenic variants of RRM2B leading to the recessive forms of the disease are predicted to be loss-of-function whereas those associated with dominant inheritance are predicted to have dominant negative effects (19).

Pathogenic variants in POLG1 result in a reduction in polymerase gamma activity leading to stalling at the replication fork finally with mitochondrial DNA maintenance defects. POLG-related syndromes constitute a continuum of phenotypes from childhood to late adulthood. These disorders include over autosomal recessive and autosomal dominant forms of progressive external ophthalmoplegia, Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy spectrum, POLG-related MNGIE, myoclonic epilepsy-myopathy-sensory ataxia, ataxia-neuropathy spectrum, and SANDO (12).

Maternally inherited progressive external ophthalmoplegia may also be associated with point mutations, especially the m.3243A>G MELAS mutation, with or without other manifestations of that multisystem disease (53; 76; 93; 82; 65) and mutations in other tRNA genes (54). Progressive external ophthalmoplegia is less often associated with MERRF (78; 87), being present in about 5% patients in an Italian cohort, whereas eyelid ptosis occurred in 25% of cases (50).

Cherry and colleagues generated pluripotent stem cell lines harboring an mtDNA deletion by direct reprogramming of somatic cells from a patient with Pearson syndrome (11). These cells were derived with low efficiency and delayed kinetics and showed impaired mitochondrial function and growth compared to mtDNA wild-type cells. Peron and colleagues generated human-induced pluripotent stem cells (hiPSCs) from two patients with Pearson marrow pancreas syndrome carrying different types of large-scale deletions (66).

Moreover, the effects of compound heterozygous POLG1 mutations resulting in autosomal recessive progressive external ophthalmoplegia were analyzed using patient-derived iPSC-derived neural stem cells (iPSC-NSCs) and iPSC-derived dopaminergic neurons (iPSC-DANs), which displayed reduced mtDNA copy numbers and mitochondrial complex I subunit expression and, consequently, a reduction in the intracellular NAD+:NADH ratio (55).

The in vitro modeling approach, which exploits pluripotent stem cell capacity to differentiate into many cell types, permits both detailed investigation of cellular pathomechanisms and validation of promising treatment options.

Epidemiology

The prevalence of all forms of childhood-onset (< 16 years of age) primary mitochondrial disease has been estimated to range from 5 to 15 cases per 100,000 individuals (26).

A study performed in a cohort in the North East of England determined that in adults, the prevalence of mitochondrial diseases caused by mutations in mtDNA is estimated at 9.6 cases per 100,000 individuals, and the prevalence of mitochondrial diseases caused by mutations in nDNA is 2.9 cases per 100,000 individuals (27).

In this study the number of adult cases per 100,000 individuals with a single, large-scale mtDNA deletion was 1.5 whereas the prevalence of autosomal dominant progressive external ophthalmoplegia was 0.7, point mutation of mtDNA was 3.5 for 3243A>G and 0.2 for 8344A>G, autosomal dominant OPA1 mutations was 0.4, autosomal recessive POLG-related disorders was 0.3, autosomal dominant RRM2B related disorders was 0.2, and adults with chronic progressive external ophthalmoplegia and multiple mtDNA deletions in muscle that have not been genetically determined was 0.2 (27).

Based again on the Nationwide Italian Collaborative Network of Mitochondrial Diseases database, among the 1400 patients with a fully reported clinical picture, ocular myopathy with eyelid ptosis or ophthalmoparesis was the first clinical feature observed in 42.8%. Among the 722 patients with a definite genetic diagnosis, the term “ocular myopathy” was present in 55.3% of cases, being positively associated with mtDNA single deletions (94.4% of patients with single deletion present ocular myopathy) and POLG1 mutations (82.6%). Ocular myopathy was less common in patients with OPA1 mutations (93.1% of patients with OPA1 mutation did not present ocular myopathy) and all the mtDNA point mutations (62.9%) (65). Among the patients with ocular myopathy, 32.8% of individuals had also an encephalomyopathy whereas 67.2% had no sign of central nervous system involvement. Age at onset was higher in the progressive external ophthalmoplegia group (28.1 ± 15.9 years) compared to the progressive external ophthalmoplegia encephalomyopathy group (17.6 ± 18.3 years) (P < 0.05). The difference in male proportion (higher in the progressive external ophthalmoplegia encephalomyopathic group) was also significant (p = 0.03) and is fully explained by the already known increased proportions of stroke-like episodes among m.3243A>G male patients, and the male proportion was significantly lower in pure progressive external ophthalmoplegia than progressive external ophthalmoplegia-plus (progressive external ophthalmoplegia patients with multisystem disease without signs of central nervous system involvement). Patients with “pure” progressive external ophthalmoplegia were 36.6% and did not show a different age at onset nor disease duration from the other progressive external ophthalmoplegia patients. In the progressive external ophthalmoplegia encephalomyopathy group there was an increased prevalence of m.3243A>G carriers (66.7%) whereas single deletions (83.6%) and TWNK (96%) mutations were associated with the progressive external ophthalmoplegia phenotype. Other rare nuclear and mtDNA mutations were usually associated with progressive external ophthalmoplegia encephalomyopathic features (65).

Differential diagnosis

Confusing conditions

Extraocular muscles have fundamentally distinct functional, structural, biochemical, and immunological characteristics compared to other skeletal muscles. Although these properties enable high fatigue resistance and precise and speedy control of motility, they might also explain why extraocular muscles are selectively involved in certain disorders (96).

The most common forms of ophthalmoplegia are recognized by distinctive clinical patterns and modes of inheritance. Clues to mitochondrial disorders include maternal inheritance and personal or family history of retinopathy, deafness, diabetes mellitus, short stature, or lipomatosis and other mitochondrial red flags. Finding ragged-red fibers in the muscle biopsy implies a mitochondrial myopathy. For syndromic entities (MNGIE, SANDO, Kearns-Sayre syndrome, Pearson marrow pancreas syndrome) the constellation of signs usually makes the diagnosis evident. In MNGIE the neuropathy may be mistaken for chronic inflammatory demyelinating polyneuropathy (CIDP) (06).

However, other genetic neuromuscular disorders manifest progressive external ophthalmoplegia and need to be considered in the differential diagnosis of mitochondrial chronic progressive external ophthalmoplegia. The most common are myotonic dystrophy (type I and II), oculopharyngeal muscular dystrophy (OPMD), oculopharyngodistal myopathy (OPDM), congenital myopathies (such as central core myopathy, centronuclear myopathies), and limb-girdle muscular dystrophy with ophthalmoplegia.

In congenital fibrosis of the extraocular muscles (CFEOMs), a syndrome belonging to a larger group of congenital cranial dysinnervation syndromes, congenital maldevelopment of ocular motor cranial nerves leads to a secondary fibrosis of corresponding extraocular muscles and, thus, various degrees of ophthalmoparesis and ptosis. Unlike progressive external ophthalmoplegia, the symptoms are stable and not progressive in this case (95).

The primary condition in the differential diagnosis is autoimmune ocular and generalized myasthenia gravis. Myasthenia gravis can almost always be recognized by features that are not seen in progressive external ophthalmoplegia, including diurnal variation in severity of symptoms and signs, lack of lid atrophy, and presence of respiratory weakness. Symptoms of double vision are also important clues. Fatigable weakness is by far the most prominent feature of neuromuscular junction disorder; rest test, sleep test, sustained upgaze test, heat test, and the ice-pack test are helpful at the patient’s bedside. The edrophonium test is helpful but almost never performed in different countries. Association with thymoma is frequent in myasthenia gravis. Detection of autoantibodies against the acetylcholine receptor (Ach-R), muscle-specific kinase (MUSK), or lipoprotein-related protein 4 (LRP4) confirm the diagnosis of myasthenia gravis, but the detection rate is lower in ocular forms. These distinguishing features are important because both progressive external ophthalmoplegia and myasthenia may be associated with dysarthria, dysphagia, and limb weakness. Single-fiber EMG does not contribute to the differential diagnosis as both cases have been shown to demonstrate abnormal jitter (46).

Myasthenic syndromes can be genetically determined (genetic congenital myasthenic syndromes) and typically present with generalized weakness with ptosis and ophthalmoparesis. Isolated ocular forms have been described (22).

Other acquired disorders that may present with progressive external ophthalmoplegia are ophthalmic Graves disease, Miler Fisher syndrome, and Wernicke encephalopathy. Note that these acquired disorders can be distinguished from genetic forms by acute to subacute onset, in contrast to the gradual onset and chronic slow progression of chronic progressive external ophthalmoplegia.

Ophthalmic Graves disease may present with diplopia and subacute progression of mild to severely restricted extraocular motility but is recognized by exophthalmos and soft tissue signs; however, these clues are occasionally lacking, and appropriate laboratory tests are needed. Extraocular muscles may be thickened on orbital MRI as opposed to atrophic muscles seen in progressive external ophthalmoplegia (84).

Miller Fisher syndrome is a postinfectious, immune-mediated acute- to subacute-onset neuropathy characterized in typical instances by the clinical triad of ataxia, areflexia, and ophthalmoplegia; this disease is considered to be a variant of Guillain-Barre syndrome. Anti-GQ1b antibodies are present in more than 90% of patients.

Wernicke encephalopathy is an acute- to subacute onset condition characterized by the triad ophthalmoplegia, ataxia, and confusion and is due to thiamine deficiency. Thiamine supplementation can lead to improvement of the symptoms and often complete resolution.

In neurogenic multisystem diseases, progressive ophthalmoplegia could still be myopathic, coexisting with neurogenic disease. One certainly neurogenic form of progressive ophthalmoplegia appears late in survivors of amyotrophic lateral sclerosis (57).

When progressive external ophthalmoplegia is combined with evidence of multisystem disease (as in Machado-Joseph syndrome or other inherited spinocerebellar ataxias), the condition may be defined clinically, but other tests are needed for complete evaluation, including DNA analysis.

Progressive external ophthalmoplegia is also associated with ataxia and peripheral neuropathy in abetalipoproteinemia. This can be suspected clinically by the clinical triad of childhood onset, retinopathy, and chronic fatty diarrhea. It can be identified preliminarily by finding a low value for serum cholesterol, finding evidence of malabsorption, and then demonstrating the absence of beta lipoprotein or by DNA analysis.

Oculomotor apraxia may simulate ophthalmoparesis. In children with gait and limb ataxia, those with oculomotor apraxia do not fixate normally. If asked to look to one side, they turn the head first, with contraversion of the eyes, and then the eyes follow to the same side in slow saccades with head thrusts. Ocular movements on command are slightly limited, and eye movement stops before reaching extreme positions of gaze. These slow eye movements appear equally on lateral and vertical gaze. If the head is immobilized, the eyes cannot move. Blinking is exaggerated. Ocular pursuit movements may be normal at first, but progressive external ophthalmoplegia often ensues. In ataxia with oculomotor apraxia type 1 (AOA1) (MIM 208920), the autosomal recessive mutation affects aprataxin (APTX) on chromosome 9p13.3. In a family, there was also CoQ10 deficiency (69; 70).

Progressive supranuclear palsy is characterized by abnormal eye signs early in the course. This may progress to complete ophthalmoplegia, but by then there is evidence of parkinsonism, usually with early-onset postural instability (falls and retropulsion), dementia, and corticospinal tract disease, which may be misdiagnosed as a primary mitochondrial disease.

Progressive external ophthalmoplegia may sometimes be attributed to environmental toxicity; for instance, the syndrome appeared in five patients who had been given antiretroviral therapy for 10 years and had no antibodies to AChR. Orbital MRI showed patchy bright signal within ocular muscles with “conserved volume”, as in progressive external ophthalmoplegia (68). It was not clear whether the disorder had been caused by the disease or drug.

Statins may cause myopathic toxicity, also with ptosis, diplopia, or ophthalmoplegia, with symptom resolution with drug cessation and possible symptom recurrence with reintroduction of the drug (24).

Note that if the pupils do not react to light, the condition is called “complete ophthalmoplegia” and is not strictly “external.” Complete ophthalmoplegia may be seen in some central disorders or in peripheral neuropathies.

Associated or underlying disorders

Although the frequency of diabetes mellitus is probably higher in patients with mitochondrial diseases in general, including chronic progressive external ophthalmoplegia, the association is not well understood. Mitochondrial dysfunction might play an important role in diabetes pathophysiology. When mtDNA defects are located in the pancreas, slow destruction of the beta cells may occur, causing a decrease in insulin production (as opposed to insulin resistance). However, peripheral skeletal muscle insulin resistance has also been reported in some mitochondrial disorders (40).

Both mtDNA mutations and nuclear genes mutations may be associated with diabetes: maternally inherited diabetes is likely to be caused by the MELAS m.3243A>G mutation (71). In patients with POLG-related chronic progressive external ophthalmoplegia, 11% have diabetes, and diabetes has also been seen in OPA1 mutations (40). Therefore, copy number variations of mtDNA are known to be associated to diabetes. In looking at all patients with mtDNA deletions causing either Kearns-Sayre syndrome or the milder isolated progressive external ophthalmoplegia, 11% to 14% have diabetes (40).

Parkinsonism has been described in patients with chronic progressive external ophthalmoplegia, first associated with three genes—ANT1 (SLC25A4), TWNK (PEO1/C10orf2), and POLG1 (14)—and afterwards with MPV17 (25). Patients with TWNK-related autosomal dominant chronic progressive external ophthalmoplegia have been described to develop late-onset mild and stable parkinsonism, with bilateral postural and rest tremor and mild rigidity of upper limbs and axial muscles typically responsive to L-dopa (45). In a clinical cross-sectional investigation of movement disorders in an Italian cohort of individuals with childhood-onset primary mitochondrial diseases, parkinsonism was widely found in adult patients, with an overall prevalence of 30.5% at last follow-up (58; 59). Not surprisingly, parkinsonism was commonly observed in POLG1 mutations.

Progressive external ophthalmoplegia is also among the many reported neuromuscular manifestations exhibited in patients with dominant optic atrophy “plus” in whom numerous neurologic sequelae, including sensorineural hearing loss, ataxia, and peripheral neuropathy, are present in addition to the optic atrophy. Dominant optic atrophy is well known to be caused by OPA1 gene mutations in 60% to 70% of cases, so when bilateral optic atrophy is observed in a patient with progressive external ophthalmoplegia, OPA1 gene mutation should be considered (01; 48). Most patients with chronic progressive external ophthalmoplegia didn’t show visual complaints but subclinical loss of retinal nerve fibers at optical coherence tomography (10).

Sleep disorders may be encountered more often in chronic progressive external ophthalmoplegia than in the general population (81). Similarly, esophageal disorders may be uncovered by physiological tests, but frank dysphagia is uncommon (18).

It is noteworthy that psychiatric conditions were far more common in patients with mitochondrial disease than in the general population and included major depression, agoraphobia or panic disorder, generalized anxiety disorder, social anxiety disorder, and psychotic syndromes (52; 42). This is in contrast to other chronic neuromuscular disorders, such as myotonic dystrophy type 1, hereditary motor and sensor neuropathy type 1, and facioscapulohumeral dystrophy (38), which are not associated with an increased risk of depression, suggesting a causative relationship between mitochondrial dysfunction and an increased risk of depression. Correlation studies between psychiatric disorders and mtDNA have long been performed, with inconsistent results (42). Studies on somatic mtDNA mutations in tissues have also been performed and demonstrate an increase in the level of the common deletion in the brain of bipolar disorder patients, especially the frontal lobes (42). Patients with progressive external ophthalmoplegia reported a high frequency of severe fatigue (67.9%), pain (96.2%), depression (32.1%), and dependency in daily life (46.4%). Patients with POLG1 mutations had more functional impairments, but fatigue severity, depression, and pain did not differ between patients with or without POLG1 mutations (80). Respiration may be impeded (80).

Diagnostic workup

The “biopsy-first approach” to diagnose suspected mitochondrial myopathy has been overtaken, in most cases, by the “genetic-first approach,” which uses next-generation sequencing techniques. These phenotype-driven approaches are both based on clinical characterization and followed by biochemical and histochemical laboratory analyses. Thus, the clinical phenotyping is traditionally followed by targeted genetic testing (mtDNA or nuclear DNA gene panel sequencing). However, given the high clinical heterogeneity of primary mitochondrial diseases, especially in the absence of suggestive phenotypes, “unbiased approaches” (WES or WGS) are becoming widely used.

Several algorithms have been proposed to guide the physicians through the labyrinth of mitochondrial diseases. An international group of experts has proposed a practical approach for suspected slowly progressive neurologic presentations of mitochondrial disease in adults, including progressive external ophthalmoplegia (62).

Family history should be scrutinized for possible evidence of maternal inheritance considering that the same mtDNA mutation may be associated with different clinical syndromes in the same family. However, in the majority of cases, pure progressive external ophthalmoplegia presents as a simplex case. Some cases show a Mendelian inheritance pattern.

The initial evaluation in blood for mitochondrial disease should include complete blood count, creatine phosphokinase, transaminases, albumin, lactate, and pyruvate. EMG is useful to demonstrate signs of proximal myopathy.

For Kearns-Sayre syndrome, tests include brain CT or MRI, ECG, cerebrospinal fluid examination, EMG, nerve conduction velocity, retinal examination, and audiogram. Identification of diabetes mellitus, hypoparathyroidism, or hypoadrenalism may have implications for treatment.

Genetic testing may be performed in blood when a nuclear gene defect is suspected. If a mtDNA mutation is suspected, mtDNA sequencing should be performed from muscle specimen. Urine analysis could be useful for testing the m.3243A>G mutation. A new method to study the occurrence of mtDNA single deletion in urine has been presented, and the authors concluded that urine can be used to screen patients suspected clinically of having a single mtDNA deletion (92). If MNGIE is a possible diagnosis, assay of blood thymidine level may be diagnostic (63). Muscle biopsy should be considered in patients with a typical phenotype and negative genetic testing result to search for specific mitochondrial histological hallmarks, such as ragged-red fibers. When muscle is collected, a sample should be sent for analysis of mitochondrial DNA and, possibly, assay or mitochondrial enzymes.

For possible myasthenia gravis, all patients with sporadic progressive external ophthalmoplegia should perform measurement of antibodies to the acetylcholine receptor or anti-MUSK. Other tests might include the response to repetitive nerve stimulation and chest CT for possible thymoma.

To evaluate possible Graves disease, all patients with PEO should have thyroid function tests, including a test for thyroid-stimulating hormone.

In presence of chronic diarrhea or other evidence of malabsorption, tests should be done to evaluate the possibilities of abetalipoproteinemia or mitochondrial gastroneuropathy (ie, MNGIE). If ophthalmoplegia is associated with spinocerebellar or motor neuron signs, the correct diagnosis is usually clinically evident (57).

Although the clinical manifestations of mitochondrial diseases are diverse, only rarely do they replicate syndromes of motor neuron disease (31).

Table 1 sums up a clinical-molecular classification of chronic progressive external ophthalmoplegia.

Table 1. Genetic Causes of Chronic Progressive External Ophthalmoplegia and Related Syndromes

Genetic alteration	Inheritance	PEO phenotypes
Single large-scale mtDNA deletion	Sporadic	cPEO/KSS/PMPS
AFGL2	AD	cPEO plus
C1QBP	AR	cPEO
DGUOK	AR	cPEO
DNA2	AD	cPEO
ENDOG	AR	cPEO
GMPR	AD	cPEO
LIG3	AR	MNGIE-like
MGME1	AR	cPEO
OPA1	AD	cPEO plus (optic atrophy)
POLG	AD/AR	cPEO/cPEO plus/SANDO/MNGIE-like
POLG2	AD/AR	cPEO
RNASEH1	AR	cPEO/cPEO plus
RRM1	AD/AR	cPEO/MNGIE-like
RRM2B	AD/AR	cPEO/KSS/MNGIE-like
SLC25A4 (ANT1)	AD/AR	cPEO
SPG7	AR	cPEO plus
TK2	AR	cPEO/cPEO-plus
TOP3A	AR	cPEO plus
TWNK	AD/AR	cPEO
TYMP	AR	MNGIE
MT-TF	matrilinear	cPEO
MT-TL1 (m 3243A> G the most common)	matrilinear	cPEO/cPEO plus
MT-TA	matrilinear	cPEO
MT-TI	matrilinear	cPEO/cPEO plus
MT-TN	matrilinear	cPEO
AD: autosomal dominant; AR: autosomal recessive; cPEO: chronic progressive external ophthalmoplegia; KSS: Kearns-Sayre syndrome; MNGIE: mitochondrial neurogastrointestinal encephalomyopathy; PMPS: Pearson marrow pancreas syndrome; SANDO: sensory ataxic neuropathy, dysarthria and ophthalmoplegia

Single, large-scale mtDNA deletions or nuclear gene defects associated with disordered mtDNA maintenance resulting in multiple mtDNA deletions are frequently associated with progressive external ophthalmoplegia. mtDNA point mutations are rarely detected in patients with progressive external ophthalmoplegia. For mtDNA point mutations, only the name of the mt-gene, and not the specific variants reported in the literature, are reported. Note that all these genes may be associated with other mitochondrial syndromes here not repositioned. More information can be found at https://www.mitomap.org/.

Management

For the most part, management involves the treatment of symptoms. Multisystem disease manifestations often occur in mitochondrial patients, leading to a need for comprehensive and multidisciplinary care.

The major questions for all people with chronic progressive external ophthalmoplegia are whether to elevate the lid surgically and how to do that. Surgical correction of the ptosis requires careful consideration due to the risks of postoperative corneal exposure or recurrence of ptosis due to the recurrent nature of the conditions.

There is debate about the indications for any surgery and for the different forms of lid surgery (94). Some prefer levator resection (39) or creation of a sling (77).

In a study published in 2013, Doherty and coauthors surgically treated 21 patients with progressive external ophthalmoplegia, 7 patients with myotonic dystrophy, and 1 with oculopharyngeal muscular dystrophy with 61 procedures comprising levator resection, brow suspension, anterior lamellar repositioning, lower lid elevation, and upper lid lowering. Palpebral aperture was significantly increased in all patient groups more significantly following brow suspension compared with levator resection. Postoperative complications were few, included corneal exposure and ulceration, ptosis recurrence, arched brow, and sling infection, all of which were successfully treated (17). In selecting the appropriate corrective procedure for these patients, levator function is usually a decisive factor given the progressive nature of the ptosis, such that early levator resection may not correct the ptosis in the long term (17).

Binocular diplopia and strabismus may be treated with prismatic glasses but also with surgery.

Children with Kearns-Sayre syndrome are all candidates for a cardiac pacemaker; the major question is when to implant the pacemaker. Diabetes mellitus, hearing loss, and hypoparathyroidism may require specific treatment (29). Attention has to be given to cerebellar disability and school performance.

The diseases with malabsorption syndromes (abetalipoproteinemia) include severe neurologic disability. Some of the disability in these disorders and Kearns-Sayre syndrome can be reversed by vitamin E therapy, but nothing yet has been effective in other forms of progressive external ophthalmoplegia, although coenzyme Q has been given (72).

For MNGIE, beside hemodialysis and peritoneal dialysis, enzyme replacement therapy with encapsulated thymidine phosphorylase within erythrocytes in order to prolong the half-life of circulatory enzyme and reduce the immunogenic reactions has been tested in a single observational study without controls providing class 4 evidence of clinical benefit (05). In one patient the graft failed, but in a second patient, nucleoside levels decreased in blood and symptoms improved (32; 47). Based on high thymidine phosphorylase expression in the liver, a 25-year-old severely affected patient underwent liver transplantation. Serum levels of toxic nucleosides rapidly normalized. At 400 days of follow-up, the patient's clinical condition is stable, suggesting liver transplantation as a possible therapy for MNGIE (13).

With advances in molecular technologies, the understanding of the pathophysiology of mitochondrial disorders has been widely expanded. There are an increasing number of clinical trials in mitochondrial disorders aiming for more specific and effective therapies, with the purpose of finding alternatives to symptomatic treatment. More information can be accessed at www.clinicaltrials.gov.

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Chronic progressive external ophthalmoplegia

Associated Disorders

diabetes mellitus
parkinsonism
dominant optic atrophy
sleep disorders
psychiatric conditions

Differential Diagnosis

chronic inflammatory demyelinating polyneuropathy (CIDP)
myotonic dystrophy (type I and II)
oculopharyngeal muscular dystrophy (OPMD)
oculopharyngodistal myopathy (OPDM)
congenital myopathies
- central core myopathy
- centronuclear myopathies)
- limb-girdle muscular dystrophy with ophthalmoplegia
- congenital fibrosis of the extraocular muscles (CFEOMs)
- autoimmune ocular and generalized myasthenia gravis
- Graves disease
- Miler Fisher syndrome
- Wernicke encephalopathy
- amyotrophic lateral sclerosis
- multisystem disease
- Machado-Joseph syndrome
- inherited spinocerebellar ataxias
- abetalipoproteinemia
- oculomotor apraxia
- progressive supranuclear palsy
- environmental toxicity
- myopathic toxicity
- complete ophthalmoplegia

Also Relevant

Kearns-Sayre syndrome
MELAS
Mitochondrial disorders
Myoclonus epilepsy with ragged-red fibers
POLG-related disorders

Chronic progressive external ophthalmoplegia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Table 1. Genetic Causes of Chronic Progressive External Ophthalmoplegia and Related Syndromes

Management

Special considerations

Pregnancy

Anesthesia

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