Is there an optimal approach for managing thyroid eye disease? Steroids, radiation and surgery each have advocates, and neuro-ophthalmologists have a variety of opinions on their relative risks and benefits. But there is a consensus within the subspecialty on two points: A novel approach to treating this disease is long overdue, and the disease itself does not attract the attention that it should from either research funding or the ophthalmic news media.
“Treatment approaches for active thyroid eye disease have not evolved dramatically in years,” noted Kimberly P. Cockerham, MD, associate clinical professor of ophthalmology at Stanford University. “Most of the new strategies have not been proven to be more efficacious than the old standards.”
The Eye, the Thyroid and Graves’
Thyroid eye disease (TED), also called Graves’ ophthalmopathy or orbitopathy, is an autoimmune inflammation that results in lymphocyte infiltrates in orbital connective tissue and collagen deposits in extraocular muscle. The typical results are edema, fibrosis, optic neuropathy and the hallmark presentation of exophthalmos. TED is almost always associated with Graves’ disease, although it has also been linked to Hashimoto’s thyroiditis, and primary hypothyroidism. Systemic Graves’ disease is characterized by hyperthyroidism, and may include goiter, fatigue, weight loss, edema and thickening of the skin. TED may precede, follow or coincide with systemic Graves’ disease, and, in fact, TED is sometimes thought to have a Graves’-independent pathogenesis.
“Thyroid eye disease is complex in that both genetic as well as lifestyle components factor into the condition,” Dr. Cockerham noted. Many Graves’ patients have family members with thyroid and other autoimmune disorders, and smoking worsens the severity and prolongs the duration of TED, she added. It affects women much more frequently than men, though paradoxically, the most severe cases occur more often in men than in women. Some individuals suffer recurrences many years after an initial episode.
A life-dampening disorder. “TED is an especially devastating disorder to cope with,” Dr. Cockerham said. “It occurs in our patients’ most productive decades of life and completely transforms their appearance with proptosis, tearing, puffiness, irritation, hair loss and thickened, ruddy skin. This impacts every aspect of their lives, including family, work and the willingness to interact in social situations. Divorce and long-term disabilities are not uncommon. Even though surgical restoration can return a majority of patients to their premorbid functionality, they are often forever changed by their altered self-perception.”
Diagnosis and Misdiagnosis
Ocular symptoms of thyroid disease are often misdiagnosed as other conditions. For example, Dr. Cockerham has seen patients who were initially diagnosed with allergic conjunctivitis, dry eye or even glaucoma, but who actually have thyroid eye disease. “On a weekly basis, I see patients with undiagnosed thyroid eye disease prescribed drops for glaucoma or allergies, for months and even years at a time,” she said. “These drops contain toxic preservatives that actually exacerbate the thyroid eye disease.”
In patients with suspicious symptoms, such as tearing and irritation with normal tear lake and Schirmer’s measurement, increased intraocular pressure in upgaze, puffy lower eyelids in patients under age 30, and red, itchy eyes without allergic rhinitis, Dr. Cockerham said, physicians should consider testing for thyroid stimulating immunoglobulin. This widely available test can be positive in otherwise euthyroid patients, and so can confirm the diagnosis and plot the level of disease activity.
Iatrogenic progression questioned. The role of radioactive iodine (RAI) in the exacerbation of thyroid eye disease has been controversial, according to Dr. Cockerham. There is a consensus now that RAI does not cause TED in Graves’ patients without eye signs; yet for their patients with existing TED, some of whom may progress after RAI, many orbital specialists do offer corticosteroids to those patients currently getting RAI.
Corticosteroids. For mild TED, artificial tears without preservatives, avoiding dietary salt and monosodium glutamate, and sleeping with the head elevated can be helpful for many patients. For more serious symptoms, the first-line treatment for TED is corticosteroids, which can be given by different delivery routes—oral, intravenous, intranasal and retrobulbar, said Dr. Cockerham. “In our review of the literature and several larger studies, intravenous corticosteroids appear to be more effective than oral steroids for moderate to severe disease.1 Intranasal Nasonex can be helpful in some patients as it penetrates directly through the lamina papyracea into the orbit. Topical corticosteroids are not helpful.”
Radiation. “The other main medical intervention is external beam radiation for the treatment of moderate to severe orbital inflammation or optic neuropathy,” said Dr. Cockerham. But radiation has been the subject of much debate ever since James A. Garrity, MD, and colleagues published a radiation study six years ago in Ophthalmology.2 Dr. Garrity is professor of ophthalmology at the Mayo Clinic in Rochester, Minn., and his study stimulated more lively discussion just last February at the North American Neuro-Ophthalmology Society (NANOS). “Jim Garrity and his colleagues challenged the dogma that radiation is effective, but some questioned the patient selection of that study,” Dr. Cockerham said.
In the study, one eye in each of 42 nondiabetic, nonoptic neuropathy patients with mild to moderate orbitopathy randomly received 20 Gy of external beam therapy while the fellow eye received sham therapy. No steroids were given, and six months later, the treatment/placebo arms were reversed. “Using the parameters of extraocular muscle volume, fat volume, proptosis, area of diplopia fields, single-muscle range of motion, and lid fissure width, we were not able to detect any statistically significant change in any parameter,” Dr. Garrity said. “We concluded that the effect of treatment could not be distinguished from the natural history.”
Dr. Cockerham noted that the main concern about the study was that some subjects already had chronic disease for more than one year. “They also excluded the patients that I would personally have chosen to radiate: optic neuropathy in patients with minimal or no proptosis.”
Dr. Garrity noted that ethical issues came into play in patients with optic neuropathy because it would be difficult to have a control group in this patient population. “In addition, this study was criticized because the mean time to treatment after onset of orbitopathy was 1.3 years,” he added. “However, there was no detectable difference when we went back to evaluate separately the patients with more recent onset compared to the subset with longer than 1.3 years.” Dr. Garrity added that his practice has changed because of this research. Instead of radiation, he chooses to manage these patients with corticosteroids or surgery.
Steven E. Feldon, MD, professor and chairman of ophthalmology at the University of Rochester, moderated the NANOS session and noted that he is closer to Dr. Garrity’s perspective on radiation. “I don’t use radiation, and I believe in decompression surgery without radiation. Almost all patients who have radiation require surgery anyway, so why expose patients to unnecessary risk? In addition, radiation therapy delays definitive management because it takes at least a month to demonstrate results.”
Surgical decompression or reconstruction. Surgery is considered effective for relieving optic neuropathy and—once the active phase of the disease has subsided—for correcting deforming proptosis, dysmotility and lid lag.
Dr. Garrity explained that options for orbital decompression fall into two broad categories: taking bone out or removing the fat. Bone decompression is the traditional classic decompression done when the disease is active, as opposed to fat decompression, which is typically done when the disease is quiescent. Dr. Garrity tends to view the bone decompression as the primary procedure, and performs the fat decompression on an exception basis.
Robert L. Lesser, MD, clinical professor of ophthalmology and neurology at Yale University, said that when dealing with thyroid optic neuropathy, in which enlarged muscles compress the optic nerve and lead to visual field loss, the ophthalmologist must act quickly. Patients may or may not have disc edema and often don’t have significant proptosis. “Given the choices of steroids, decompression surgery and radiation, I recommend surgery after possibly a short-term course of IV steroids.”
For bone removal, Dr. Garrity prefers a transantral approach to the orbital floor. Dr. Cockerham employs an external laugh line approach and works with computer-guided endoscopic experts to maximize the medial bone removal and achieve a balance that minimizes postoperative diplopia.
Searching for Better Answers
Dr. Feldon added that arguments concerning treatment really have not changed because the cause of thyroid eye disease has been difficult to understand. There may be some forward movement on that, however:
- Finding a biomarker would allow ophthalmologists to intervene with treatment at an earlier state, and Dr. Feldon’s own recent research suggests that activated human T lymphocytes drive fibroblasts to differentiate into adipocytes and cause scarring. The discovery that inflammation can stimulate the development of new fat cells may have implications beyond TED, including other autoimmune diseases and, perhaps, even obesity.
- Dr. Lesser pointed to research on the antibiotic rapamycin for the treatment of thyroid optic neuropathy. “As we learn more about the pathogenesis of thyroid eye disease, therapies can be targeted more specifically.” One paper reported that rapamycin, a fibroblast and T cell inhibitor, was used in a patient with thyroid optic neuropathy who had not responded to steroids or decompression surgery. Visual acuity, color vision and visual fields improved in this patient.3 These results are promising, Dr. Lesser said, and warrant further investigation.
- An International Thyroid Eye Disease Study Group was recently launched by Raymond S. Douglas, MD, PhD, and Terry J. Smith, MD, researchers at the University of California, Los Angeles, in collaboration with Drs. Cockerham, Garrity and Feldon, among others, to develop a global, multicenter study to standardize the language and tests used in TED and to explore the role of host-response inflammation and anti-inflammatory therapy.
Compassionate counseling. In the meantime, the biggest challenge in treating TED, according to Dr. Garrity, is managing patient expectations. “Some patients think they can come into the office, obtain a diagnosis, take a pill and everything will get back to normal. Most of our time is spent counseling patients, discussing the imperfect options and what they might expect in the future.”
1 Zoumalan, C. and Cockerham, K. et al. J Neuroophthalmol
2007, in press.
2 Gorman, C. A. and Garrity, J. A. et al. Ophthalmology.
3 Chang et al. Ophthal Plast Reconstr Surg
___________________________ The physicians interviewed for this story report no related financial interests.