Progressive external ophthalmoplegia a diagnostic challenge

Madison, WI-Diagnosing chronic progressive external ophthalmoplegia (CPEO) can be problematic because of overlap in clinical presentation with other ocular and neurologic diseases. In most cases, the disease is associated with a serious multi-system disease, but the ocular manifestations may be the first patient complaints.

Jacqueline Shimko, CO, a certified orthoptist in the Department of Ophthalmology, University of Wisconsin, Madison, described the optimal course of action for ophthalmologists to establish the correct diagnosis.

"CPEO is a painless, slowly progressive, bilateral loss of all extraocular muscle rotation without pupillary involvement. Eye movement in all directions to voluntary or vestibulo-ocular stimulation eventually is lost. Levator muscle involvement might result in bilateral ptosis. CPEO can be an isolated ocular condition but is also recognized as a frequent component of multi-system disease," explained Shimko at the combined Orthoptic and American Orthoptic Council Symposium during the American Academy of Ophthalmology annual meeting in New Orleans.

"When CPEO is associated with a non-ocular disease, ptosis or eye muscle involvement may be the initial patient complaint," Shimko said. "Reviewing family photographs may be valuable to detect subtle signs of ptosis or strabismus, with the goals of establishing the time of onset and the chronology of the disease progression."

Diseases included in the differential diagnosis of CPEO are neuromuscular junction disorders (myasthenia gravis), multiple muscle paralysis, restrictive disorders (congenital muscle fibrosis), thyroid ophthalmopathy, and neurogenic disorders (progressive supranuclear palsy). Differentiating CPEO can be facilitated by using specialized diagnostic testing. Slow saccadic eye movements are an early sign.

"The eye movements of CPEO do not show the variability of those associated with myasthenia gravis. However, the Tensilon test may be positive in some patients. Forced duction testing is positive, particularly late in the disease when muscles are myopathic and become fibrotic," she said. Computed tomography reportedly shows marked atrophy of rectus muscles.

Shimko pointed out that initial asymmetry resulting from CPEO may cause strabismus. The most common deviation found is exotropia.

Testing for disease Testing for CPEO includes prism and alternate cover measurements in all gaze positions. Use of the Lancaster red-green test or the Hess-Lees Screen test can be helpful to document motility deficits.

Diplopia has been reported to be rare in association with CPEO but actually does occur frequently in these patients, according to Shimko. She suggested using prism correction in primary gaze and for reading to control the diplopia.

Some patients with CPEO have pigmentary retinopathy, which may not be readily apparent without examining the fundus and performing fluorescein angiography. The effect on visual acuity is modest, she noted.

CPEO can occur along with diseases that are myopathic or myogenic in nature and especially with mitochondrial dysfunction.

"The mitochondria are responsible for generating energy for cellular metabolism, maintenance, and repair. Abnormalities of mitochondrial function would most substantially affect those tissues with high energy demands. Tissues, such as the brain, central nervous system, cardiac tissue, and the extraocular muscles, have greater numbers of mitochondria and are therefore acutely susceptible to decreased mitochondrial function. Populations of normal and mutant mitochondria may coexist in tissues, and organs can display different levels of involvement. This leads to variability in the clinical presentation and makes diagnosis a challenge," Shimko explained.

Patients with neurodegenerative disease and CPEO (referred to as ophthalmoplegia plus) were once grouped together. However, investigators proposed not classifying diseases with unique characteristics together, notably Kearns-Sayre syndrome, a form of mitochondrial disease and ophthalmoplegia plus and characterized by onset before age 20 years, CPEO, and retinal pigmentary degeneration.

Laboratory testing can pinpoint multi-system diseases in patients with CPEO. Defects in the mitochondrial function cause increased anaerobic metabolism in blood, serum, and cerebrospinal fluid; the protein level in the cerebrospinal fluid also may be elevated. Evidence of metabolic disturbance, spongiform encephalopathy, and basal ganglia calcification has been seen on traditional and functional magnetic resonance imaging.