Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40 and slowly worsens over time. The first sign of progressive external ophthalmoplegia is typically drooping eyelids (ptosis), which can affect one or both eyelids. As ptosis worsens, affected individuals may use the forehead muscles to try to lift the eyelids, or they may lift up their chin in order to see. Another characteristic feature of progressive external ophthalmoplegia is weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals have to turn their head to see in different directions, especially as the ophthalmoplegia worsens. People with progressive external ophthalmoplegia may also have general weakness of the muscles used for movement (myopathy), particularly those in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).
ophthalmoplegia
Although muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, and depression.
Progressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.
Progressive external ophthalmoplegia is a condition caused by defects in mitochondria, which are structures within cells that use oxygen to convert the energy from food into a form cells can use. This process is called oxidative phosphorylation. Although most DNA is packaged in chromosomes within the nucleus (nuclear DNA), mitochondria also have a small amount of their own DNA, called mitochondrial DNA or mtDNA. This DNA contains genes essential for oxidative phosphorylation.
Progressive external ophthalmoplegia can result from mutations in one of several different genes. In some cases, mutations in nuclear DNA are responsible for the condition, including mutations in the POLG, TWNK, RRM2B, and SLC25A4 genes, among others. These genes are critical for the production and maintenance of mtDNA. Although the mechanism is unclear, mutations in these genes lead to the deletion of large segments of mtDNA in muscle cells. The size of the deleted region can range from 2,000 to 10,000 DNA building blocks (nucleotides).
Less commonly, mutations that change single nucleotides in genes found in mtDNA, such as the MT-TL1 gene, cause progressive external ophthalmoplegia. These mutations occur in genes that provide instructions for making molecules called transfer RNAs. Transfer RNAs help assemble protein building blocks (amino acids) into functioning proteins. The transfer RNAs associated with progressive external ophthalmoplegia are present in mitochondria and help assemble the proteins that carry out the steps of oxidative phosphorylation.
Researchers have not determined how deletions of mtDNA or mutations in mtDNA genes lead to the specific signs and symptoms of progressive external ophthalmoplegia, although the features of the condition are probably related to impaired oxidative phosphorylation. It has been suggested that eye muscles are commonly affected by mitochondrial defects because they are especially dependent on oxidative phosphorylation for energy.
When the nuclear genes POLG, TWNK, RRM2B, or SLC25A4 are involved, progressive external ophthalmoplegia is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Chronic progressive external ophthalmoplegia typically appears in adults between the ages of 18 and 40 years. It typically begins with drooping eyelids and difficulty controlling the muscles that coordinate the eyes.
People affected by ophthalmoplegia may have double or blurred vision. They may also experience an inability to position the eyes in sync. Some may also have a hard time moving both eyes in every direction, and many will have drooping of their eyelids.
Ophthalmoplegia is slightly more likely to occur in people with diabetes. Men with diabetes who are over the age of 45 and have had type 2 diabetes for more than 10 years were recently identified as a higher risk category for developing ophthalmoplegia.
Treatment for ophthalmoplegia will depend on the type, symptoms, and underlying cause. Children born with this condition usually learn to compensate and may not be aware of vision problems. Adults can be fitted for special glasses, or wear an eye patch to relieve double vision and help achieve normal vision.
Internuclear ophthalmoplegia or ophthalmoparesis (INO) is an ocular movement disorder that presents as an inability to perform conjugate lateral gaze and ophthalmoplegia due to damage to the interneuron between two nuclei of cranial nerves (CN) VI and CN III (internuclear).[1] This interneuron is called the medial longitudinal fasciculus (MLF). The MLF can be damaged by any lesion (e.g., demyelinating, ischemic, neoplastic, inflammatory) in the pons or midbrain. The MLF is supplied by branches of the basilar artery and ischemia in the vertebrobasilar system can produce an ischemic INO.[2]
Other names for this entity include reverse INO and pseudo abducens palsy. This syndrome is a rare ophthalmoplegia, either bilateral or unilateral that exhibits contralateral adducting eye (rather than abducting eye) nystagmus with abduction restriction on physical exam. It is the reverse of the typical INO, and although the lesion localization is not consistent, it likely is due to CN VI pre-nuclear input asymmetry.[22]
A lesion in the MLF interrupts the neural communication to the CN III subnuclei that allows for conjugate horizontal gaze arising from the final common pathway for horizontal gaze (CN VI nuclei). An INO is a common presentation of multiple sclerosis (MS) in younger patients. Demyelination of the MLF in MS can involve any segment and is frequently bilateral. [23] Internuclear ophthalmoplegia can serve as an important sign for diagnosing MS as it can occur as its first symptom. [24] The relationship between INO and MS has also been extended showing that INO can be used as a biomarker of axonal and myelin integrity in MS. [25]
Internal ophthalmoplegia means involvement limited to the pupillary sphincter and ciliary muscle. External ophthalmoplegia refers to involvement of only the extraocular muscles. Complete ophthalmoplegia indicates involvement of both.
Mitochondrial diseases that involve ocular symptoms as a major manifestation include chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS), among others.5 CPEO, a comparably mild mitochondrial disease, is characterized by weakness in the extraocular muscles and ptosis, and it is often accompanied by limb weakness.6 Ptosis typically progresses to ophthalmoparesis over months or years.7 KSS is defined as CPEO that begins before 20 years of age, is accompanied by pigmentary retinopathy, and is associated with at least one of the following: cardiac conduction deficits, cerebellar ataxia, or an elevated cerebrospinal fluid protein concentration.6
In one of the few studies that have reported on this topic, Grönlund, et al.13 found that the prevalence of ophthalmoplegia in patients with mitochondrial disease was 38.6% (22/57), and ophthalmoscopy, which is performed in patients with mitochondrial disease, revealed pigmentation in the macula and/or periphery in 29.6% (16/54) patients. Although a few previous studies have reported on the prevalence of ophthalmoplegia, results vary depending on how the patient groups were formed. Consequently, ophthalmoplegia symptoms may be an important issue in patients with mitochondrial disease. Moreover, it is important to perform an ophthalmological evaluation, including precise retinal examinations, such as ophthalmoscopy, in patients with mitochondrial disease who exhibit ocular symptoms, such as ophthalmoplegia. Six percent of the patients with mitochondrial disease in our study had ophthalmoplegia. In addition, more than 80% patients had pigmentary retinopathy.
In a study by García-Cazorla, et al.,18 most of the patients with mitochondrial disease died within the first 3 months (16 of 33). Similarly, the prognosis of other mitochondrial diseases is usually poor.19,20,21 However, the clinical severity of patients in our study was relatively mild. In cases of mitochondrial disease, the prognosis differs depending on the type of syndrome or pattern of organ involvement. The prognosis for mitochondrial diseases with ophthalmoplegia as a main symptom may be better than expected and reported. The reason for this would be that the main symptom is different and its onset age is later. Because of these varying prognoses, care and family counseling should be implemented according to the type of mitochondrial disease. The major prognostic factor in KSS is cardiac involvement, and indeed, complete heart block has been found to be a major cause of death in patients with KSS.22 Eight of the 16 patients in our study underwent cardiac treatment, and three received a pacemaker. Therefore, while the overall prognosis of KSS and CPEO may be good, the prognosis of patients with cardiac involvement could be different. Moreover, there are a few known protocols for determining the prognosis of the various phenotypes and genotypes of this disease, and thus, a protocol for obtaining a disease-specific prognosis is desired. 2ff7e9595c
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