Exotropia Associated With Mental Illness
Pouring over the medical records of residents of Olmsted County, Minn., a few years ago, a Mayo medical student wondered aloud about a connection that had only been hinted at previously: the possible link between strabismus and mental illness. A single earlier report had shown an association between adult schizophrenia and constant exotropia, a rare type of childhood strabismus.
Brian G. Mohney, MD, and co-investigators decided to follow up. They retrospectively reviewed the medical records of 407 children (< 19 years of age) who were diagnosed with the more-prevalent forms of esotropia (n = 266) or exotropia (n = 141) between Jan. 1, 1985, and Dec. 31, 1994, and compared them to age- and gender-matched controls with normal eye alignment.1
The investigators found that patients with eyes that diverged were 3.1 times more likely to develop at least one of more than 20 psychiatric disorders than were control subjects when monitored to a mean age of 20.3 years. Individuals with intermittent exotropia were particularly prone to developing significant psychiatric disorders by the time they reached their 30s—and were more likely to use psychotropic medications or outpatient psychiatric services, as well as experience thoughts of suicide or homicide.
Patients with esotropia, on the other hand, showed no increased incidence of mental illness when followed to the same age.
“What was interesting was that, in this study, only kids whose eyes drifted out had an increased risk of mental illness,” said Dr. Mohney, who is associate professor of ophthalmology and program director for the pediatric ophthalmology and adult strabismus fellowship at Mayo Clinic in Rochester, Minn. “At the beginning, we thought there might just be a self-esteem or appearance issue,” he said, particularly given the stigma attached to this visual disorder. If this were the case, however, one would expect to see a higher incidence of mental disorders associated with all kinds of strabismus, said Dr. Mohney, especially since previous studies have revealed no differences in the psychosocial burden borne by these individuals.
If not stress, then which factors were suspect?
In the study, children with intermittent exotropia were more likely to have mothers with a history of chemical abuse during pregnancy, and it’s possible that unidentified environmental factors could yet be implicated. But none of the study children was diagnosed with fetal alcohol syndrome or disorders associated with chemical abuse during pregnancy.
“Instead, there may be a genetic link that occurs in kids with eyes that drift outward,” said Dr. Mohney. Neither strabismus nor mental illness is well described from a genetic biochemistry stand-point, he said, but multiple susceptibility genes appear to be interacting for both. This theory gains some traction considering the wide variety of mental disorders associated with strabismus.
Further studies with a less homogenous population in more diverse geographic areas may further elucidate the connection between strabismus and mental illness. At this time, it is not known whether Asians or other populations are equally at risk as the predominantly Caucasian group involved in this study.
“Whether there’s a way to ameliorate or decrease the incidence of mental illness in this population is unknown,” said Dr. Mohney. But his hope is that awareness of the link is potentially helpful to the many patients who harbor divergent strabismus.
1 Mohney, B. G. et al. Pediatrics
Possible Uveal Melanoma Mutation Identified
Researchers have identified a genetic mutation in melanocytes that cripples a key membrane protein, GNAQ, making the protein unable to stop cellular proliferation. The mutation may play a role in initiating as many as half of all uveal melanomas.
GNAQ is a G protein subunit involved in regulating cell growth through G-protein-coupled receptors.
The somatic mutation was present in 46 percent of uveal melanomas (n = 48) and in only one of the 78 cutaneous melanomas that were tested, according to a December Nature letter1 written by a U.S./Canadian team. Also that month, a second group reported confirmation; they found the GNAQ mutation in about half (49 percent) of 67 primary uveal melanomas.2
Stefan Seregard, MD, PhD, an ocular oncologist and professor of ophthalmology at the Karolinska Institute in Stockholm, called these results “one of the most interesting findings in the molecular pathology of uveal melanoma that I’ve seen in the past five to 10 years. I wouldn’t say this is the Holy Grail of uveal melanoma, but it’s certainly an important step.”
It is too early to view mutant-GNAQ as the oncogene responsible for uveal melanoma, Dr. Seregard added. But, even at this early stage, the story of GNAQ suggests an explanation for why uveal and cutaneous melanomas are similar yet biologically distinct from each other. The researchers found that GNAQ acts along the same mitogen-activated protein (MAP) kinase pathway by which well-known cutaneous oncogenes stimulate tumor formation. But the mutated GNAQ acts at a different location along the MAP kinase pathway.
Normally, GNAQ facilitates protein synthesis within cells by binding to energy-rich guanosine triphosphate (GTP) during mitosis. A catalytic region on GNAQ eventually breaks this growth-stimulating bond by hydrolysis of the GTP. The researchers found that the GNAQ-mutant lacks catalytic ability and instead stays locked into an active, GTP-bound state.
Because of the unique position of GNAQ on the MAP kinase pathway, it is a good candidate for potential therapies based on RNA interference (RNAi), said Boris C. Bastian, MD, professor of dermatology and pathology at the University of California San Francisco (UCSF), who was a senior author of the Nature paper. RNAi works particularly well in the liver, the organ to which ocular melanomas usually metastasize, Dr. Bastian noted.
To that end, UCSF and Dr. Bastian have begun working with Alnylam Pharmaceuticals to develop RNAi-based therapy for uveal melanoma.
“RNAi tends to be sucked up by the liver,” Dr. Bastian said. “Here, we have a deadly cancer that metastasizes directly from the eye to the liver. Median survival after metastasis becomes apparent is seven months. As quickly as we can, we aim to develop a treatment that improves that prognosis.”
1 Van Raamsdonk, C. D. et al. Nature
2008 Dec. 10. [Epub ahead of print.]
2 Onken, M. D. et al. Invest Ophthalmol Vis Sci
Update on Side Effects
Statins Linked to Diplopia, Ptosis, Ophthalmoplegia
In a database study,1 Frederick W. “Rick” Fraunfelder, MD, and Amanda B. Richards, MD, found an association between statins and diplopia, blepharoptosis and ophthalmoplegia.
This finding made “perfect sense” to Dr. Fraunfelder, who pointed out that 0.1 percent of patients taking a statin develop a myopathy affecting skeletal muscles. “Thus it is not surprising that some of these patients will experience a myopathy of the skeletal musculature around the eye,” he said.
Dr. Fraunfelder, who is director of cornea and refractive surgery at Oregon Health & Science University in Portland and also director of the National Registry of Drug-Induced Ocular Side Effects, became interested in this research after receiving spontaneous adverse events reports by physicians about droopy eyelids and double vision associated with statin use. “This prompted me to look worldwide for these ocular side effects,” Dr. Fraunfelder said. “We mined data from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization and the FDA on statins and ptosis, diplopia and ophthalmoplegia.”
These data included the type of statin, patient age and gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of ADR, concomitant drugs, other systemic disease, and dechallenge and rechallenge data.
“We found 256 cases of diplopia or ptosis associated with all classes of statins,” Dr. Fraunfelder said. The average time from the start of statin therapy to the appearance of the ADR was 3.5 months. “Sixty-two case reports showed that when the statin was stopped, the diplopia and ptosis went away,” he said. “That is a good sign because it gave people reassurance that the effects of the statins weren’t permanent.”
Writing in the study, Dr. Fraunfelder notes that it is rare to receive positive rechallenge case reports because most physicians will not prescribe—and most patients will not take—a drug if they suspect it will cause an adverse drug reaction. Yet Dr. Fraunfelder and his colleague identified 14 positive rechallenge case reports in which the patients stopped the statins, then started them again, and the side effect came back. “This provides pretty solid evidence that the association between the statins and the adverse ocular side effects are real,” he said.
Dr. Fraunfelder said there are two key take-away messages from this study. First, while a probable association exists between statins and ptosis, diplopia and ophthalmoplegia, it is a rare side effect. Given that statin use increased from 47 percent of all lipid-lowering medications in 1992 to 87 percent a decade later, with atorvastatin (Lipitor), “256 cases out of millions of patients is rare,” he noted.
Second, the side effect is reversible; the reported ocular adverse side effects went away when the drug was discontinued.
Dr. Fraunfelder encouraged ophthalmologists to contact the patient’s primary care physician or cardiologist should they identify diplopia, ptosis or ophthalmoplegia in individuals taking statins.
In addition, he invites clinicians to report statin-associated adverse ocular events at www.eyedrugregistry.com or www.aao.org/eyedrugregistry.cfm.com.
—Lori Baker Schena
Promoting Eye Care
Anne L. Coleman, MD, PhD, who recently was appointed as planning committee chairwoman to the National Eye Health Education Program, wants to promote vision care not only through individual treatment but also by circulating information through communities. “It is a preventive perspective. We have a tremendous amount of information available; organizing and disseminating information effectively remains an important challenge,” she said.
Dr. Coleman, professor of ophthalmology and epidemiology at the University of California, Los Angeles, explained the need for a public health paradigm at NEHEP: “For example,” she said, “those who do not have glaucoma, or who have it and are not aware of it, are probably not receiving the preventive care and information they need. We need to promote visits for a comprehensive eye examination as a way to address all eye conditions at one time.”
EyeNet thanks Susan B. Bressler, MD, for her help with this issue’s News in Review.