Researchers seek therapies to address the root causes of thyroid eye disease

Little is known of the underlying mechanisms that cause eye disease in patients with thyroid disorders. Current treatments are palliative.

Medical and surgical strategies for treating thyroid-associated ophthalmopathy are effective, but they share a common drawback: They treat the symptoms, not the underlying disease.

Scientists are seeking therapeutic strategies that will address the root causes of thyroid-associated ophthalmopathy (TAO), not just its effects.

Treatments such as steroids to reduce ocular inflammation and oculoplastic surgery for orbital decompression or to alleviate eyelid retraction are aimed at correcting existing conditions.

“These methods have been used for years, but none of them are ideal,” said Steven E. Feldon, MD, MBA, of the University of Rochester Eye Institute in Rochester, N.Y. “The best cure for thyroid-related ophthalmopathy would be to prevent the progression of the disease.”

“Progress has been made, but the great mysteries of this disease still remain,” said Allen M. Putterman, MD, SC, FACS, of Chicago, an OSN Oculoplastics and Reconstructive Surgery Board member. “Patients often have to wait a very long time for surgery. They become frustrated and are, therefore, among the unhappiest of patients.”

A number of reports at the American Thyroid Association (ATA) meeting in Palm Beach, Fla., highlighted recent progress in the ability of researchers to identify patients at risk for thyroid eye disease. Other reports at the meeting addressed new surgical and medical approaches to treating the symptoms of TAO.

This article recaps some of the most recent developments in TAO research presented at the ATA meeting and elsewhere.

Incidence of TAO

According to ATA data, 2.2% of the population is affected by Graves’ disease. The ocular manifestations of Graves’ disease, called Graves’ ophthalmopathy or TAO, affect up to 80% of patients with hyperthyroidism.

“The aesthetic and psychological impact of this disease can be significant in patients,” said Stephen M. Soll, MD, FACS, director of ophthalmology at the Robert Wood Johnson Medical School in Camden, N.J.

“Inflammation and edema in the extraocular muscles progress into muscle hypertrophy and enlargement. The orbit has a fixed volume, so proptosis usually results,” Dr. Soll explained. Optic neuropathy can occur due to increased pressure on the nerve.

“Between 10% and 15% of hyperthyroid patients have clinically severe eye findings,” said Dr. Feldon.

The elderly and patients with a family history of thyroid disease are at increased risk for TAO, and researchers have found that women and smokers between the ages of 20 and 60 are at the highest risk.

“There is no question that women are more frequently afflicted with thyroid eye disease than men,” said L. Neal Freeman, MD, MBA, FACS, an oculoplastic surgeon at Florida Eye Associates in Melbourne, Fla.

According to the American Medical Women’s Association, women are five to eight times more likely than men to develop thyroid problems.

Inflammatory pathway

Researchers in endocrinology, ocular science and genetics are trying to determine the mechanisms of action behind TAO.

“If we could determine the exact role that thyroid hormone plays in eye disease, we would have a better understanding of it,” Dr. Feldon said.

Researchers are aware that TAO is autoimmune in nature.

“Follicular cells in the thyroid gland and the orbital tissues are targets of abnormal antibody production. The thyroid gland often reacts by excessive hormone secretion, and the orbit manifests characteristic signs of inflammation,” Dr. Freeman said.

Researchers at the University of Rochester Eye Institute have identified changes in the inflammatory pathway experimentally.

“We are identifying the role of cytokines … in inflammation,” Dr. Feldon said. “We look at specific antigens, antibodies and chemicals in different environments to see the tissue response.”

In the mid-1990s, Dr. Feldon and colleagues determined that orbital venous obstruction and capillary collapse due to inflammation or smoking contributed significantly to the clinical manifestations of TAO.

“Oxygen delivery to the orbit slows down because the small capillaries that carry venous blood collapse from increased tissue pressure. Since there is high venous pressure in the orbit, there’s less arterial pulse pressure,” Dr. Feldon explained. Less oxygenated blood circulates into the eye, causing more inflammation.

“A vicious cycle occurs that promotes more and more congestion in the orbit, results in less oxygenation and causes more inflammation within the extraocular muscles that eventually compress the optic nerve, resulting in visual loss,” Dr. Feldon said.

To understand the reason for this response, factors within the immune pathway and inflammatory response must be determined, he said. With such data, a preventive treatment could be developed to interfere with the autoimmune response mechanism and halt progression.

“We want to isolate the groups at risk and find a very specific targeted treatment. Research is the only thing that will lead us to finding such a solution,” Dr. Feldon said. “If we could develop some sort of blood test or marker to identify who’s at risk for developing eye disease, we could avoid the inflammation/congestion cycle and help patients early on.”

Severe lid retraction and periorbital edema characterize this patient who also has optic disc swelling and visual loss from optic neuropathy. (All photographs are courtesy of Steven E. Feldon, MD, MBA.)	The exophthalmometer is used to measure the forward protrusion of the eye in this patient with mild disease.
Some patients with Graves' ophthalmopathy develop a subacute clinical presentation with frank lid edema and erythema, even in the absence of marked exophthalmos.	Side view demonstrates exophthalmos associated with Graves' ophthalmopathy.

TSH levels predict disease

One such test was discussed at the recent ATA meeting. A test for thyroid-stimulating hormone (TSH) receptor antibodies can be used to predict the severity of TAO in at-risk patients, according to a presentation at the meeting.

Anja K. Eckstein, MD, PHD, and colleagues at the University Eye Hospital in Essen, Germany, found that levels of TSH receptor antibodies were significantly higher in patients with a severe course of TAO compared to patients with a mild course. Their work was described in a press release from the ATA.

In their study, 66 patients underwent TSH blood testing at 4, 8, 12, 16, 20 and 24 months after onset of TAO. At 24 months, the patents’ disease condition was classified according to its severity by a physician unaware of the patients’ antibody levels.

Based on this information, physicians may now predict a good or bad course of eye disease, the researchers said. The predictions, based on guidelines developed in the study, will be accurate in nearly 50% of patients, they said.

“A number of recent clinical and experimental studies … found evidence that TSH receptor antibodies trigger the autoimmune process in TAO,” Dr. Eckstein said in the press release. “But we are the first who have shown that TSH receptor antibodies not only trigger but also constantly maintain the autoimmune process in the eye.”

Low FRP-1 stops inflammation

Genetic researchers are also searching for the causes of TAO. A recent study at the Mayo Clinic in Rochester, Minn., determined that genetic therapy to lower the levels of a gene called frizzled protein-1 (FRP-1) in the eye socket might reduce the inflammatory response in TAO.

Rebecca S. Bahn, MD, and fellow researchers studied fat tissue samples from patients with TAO to try to determine what caused the tissue to engorge and expand. By comparing the tissue from TAO patients with fat samples from normal eyes, researchers determined that the expression of FRP-1 is 5.5 times higher in patients with TAO than patients with normal ocular conditions. FRP-1 acts by inhibiting the gene Wnt from producing new fat cell tissue, the researchers said.

“Results of this study suggest that lowering levels of the gene FRP-1 within the eye socket might be a way to decrease the harmful growth of new fat tissue,” Dr. Bahn said in a press release from the ATA. “Other approaches might include clocking the action of FRP-1 on Wnt, or stimulating the Wnt system directly.”

Octreotide: marginal benefit

Some researchers are exploring alternative pathways to treat the inflammatory symptoms of TAO. Pat Kendall-Taylor, MD, and colleagues at the University of Newcastle upon Tyne, England, studied the effect of the drug Sandostatin (octreotide, Novartis) in patients with TAO.

They found that treatment with the drug, which has been used to decrease the secretion of growth hormone in other conditions, showed a marginal improvement in the ophthalmopathy index of patients with TAO.

Fifty thyroid patients in the trial were randomized to receive a daily dose of either 30 mg of octreotide or placebo for the first 16 weeks of study. After the initial 16 weeks, patients in both groups received 30 mg of octreotide for the next 16 weeks.

At week 32, treatment was stopped and all patients were followed for another 24 weeks. Researchers then conducted an assessment of individual parameters for each patient.

Patients treated with octreotide in the first 16 weeks showed a significant reduction in soft tissue inflammation, subjective diplopia and clinical activity score (CAS). However, soft tissue inflammation and CAS were also reduced among patients who were given placebo during the first 16 weeks.

The ophthalmopathy index was reduced by 1.12 in patients treated with octreotide and 0.23 in patients receiving placebo. Although the difference was marginal, researchers considered it indicative of a significant treatment effect.

As the study continued, the difference between the placebo group and the treatment group became less significant. During weeks 16 through 32 of the study, there was no significant change in the ophthalmopathy index between the two groups of patients.

Overall results, taken at the end of week 32, showed a reduction in soft tissue inflammation and CAS among patients in both groups. More study is needed to fully understand the benefits of octreotide, the researchers concluded.

Surgical strategies address needs of patients with TAO

Until a way is found to address the underlying disease, surgery will remain one of the mainstays in managing patients with thyroid-associated ophthalmopathy (TAO). Palliative surgical procedures can be used to address the external and internal results of the swelling associated with the diseases, said Allen M. Putterman, MD, SC, FACS. “The current procedures are very effective in resolving orbital and eyelid problems. There are surgical procedures for nearly every entity involved in thyroid-associated ophthalmopathy,” he said. Dr. Putterman was one of the first ophthalmologists in the United States to specialize exclusively in oculoplastic surgery of which TAO is a part. He has performed oculoplastic procedures to relieve symptoms of the disease for more than 34 years. Before opting for surgery, surgeons must wait until TAO symptoms related to eye muscle dysfunction or eyelid position are stable, Dr. Putterman said. “This process can take from 6 months to 3 years,” he noted. During this waiting period, patients may be selectively treated with prednisone to reduce inflammation and discomfort or with radiation therapy, he said. As ocular lubricants may be used for keratopathy. Orbital decompression Patients with severe inflammation affecting the optic nerve may benefit from orbital decompression, Dr. Putterman said. In this procedure, the eye is entered through a single incision at the outer corner of the eyelid and another on the inside of the lower eyelid. Through these incisions, the lateral orbital wall, orbital floor and medial orbital wall are then removed. Finally, the roof of the orbit is burred down to accommodate fatty tissue. “At this point, the tissues that are bulging out around the eye are released. Fatty tissue falls into these spaces, and the eye sinks down and into place,” he said. This procedure relieves compression of the optic nerve and resolves the proptotic look of the eye, he said. There are some surgical risks. “The main risks of surgery are double vision and numbness over the cheek,” Dr. Putterman said. “The numbness usually resolves, but the double vision requires surgery, usually the recession of the inferior rectus muscle.” Dr. Putterman said surgeons can predict a patient’s risk of double vision before surgery by looking at a CT scan. “If the protrusion of the eyes is due to fatty tissue, there is a 5% to 10% chance that double vision will occur,” Dr. Putterman said. “If the protrusion of the eyes is due to enlarged orbital muscles, then double vision is likely 50% of the time.” The surgical procedure for double vision is performed with an adjustable “shoelace” suture. After surgery, the suture can be released or tightened according to the patient’s degree of residual double vision. Eyelid retraction After orbital decompression surgery, patients may need eyelid surgery to reposition the upper or lower lids. On the other hand, patients with TAO who do not require orbital decompression or muscle surgery may benefit from primary eyelid surgery. In his early years of practice, Dr. Putterman developed a surgical procedure for the upper eyelids that he still uses today. “The inner lining of the upper eyelid is released to expose the Mueller’s muscle and the levator muscle,” Dr. Putterman said. These muscles are released incrementally as patients, anesthetized with topical and minimal subconjunctival medication, are asked to sit up and lie down until the eyelid appears correctly placed. Then the excess muscle is removed and the eyelid wound is sealed. “This surgery is effective 90% of the time,” Dr. Putterman said. “Patients look more normal and are relieved of their corneal discomfort because the eyelid is in a better position.” A similar procedure is carried out on the lower eyelids if too much sclera is exposed beneath the cornea. The lower eyelid muscles are recessed. A tissue transplant from the inside of the mouth is used to lift the lower eyelid upward. If patients’ eyes still appear to protrude after surgery, a lateral tarsorrhaphy can be performed to mend together the upper and lower eyelids at their margins. Eyelid herniation Patients with TAO may also develop baggy eyelids due to fat herniation. “The strong orbital septum that connects the inferior orbital rim to the lower lid contains the fat behind the eye. This tissue breaks off and fat slips forward into the eyelid,” Dr. Putterman said. The hernia is corrected by removing the fatty tissue, alleviating unnecessary weight on the eyelid. “A small incision is made on the inside of the eyelid and pressure is put on the globe to allow the fat to protrude and be excised by cautery,” Dr. Putterman said. The internal approach avoids a scar and reduces risk of further eyelid retraction, he said. If frown lines between the eyebrow remain after a patient has been treated with orbital decompression or eyelid surgery, Botox (botulinum toxin type A, Allergan) injections may be administered. “Injections are performed two to three times per year in 5-minute office procedures,” Dr. Putterman said. When frown lines are severe, patients may need surgical removal of overactive frown muscles. Performing these procedures in the proper sequence individualized for each patient can effectively correct symptoms of TAO with good long-term results, Dr. Putterman said.

Adiponectin levels not related

Other research at the University of Essen determined that levels of serum adiponectin are not associated with the severity of TAO.

Marco Plicht, MD, led a study to investigate whether an increase in adiponectin levels in the serum of patients with TAO was related to eyelid swelling and proptosis. Adiponectin, a protein hormone in the bloodstream, is produced by fat tissue and inflammation.

In this study, 166 patients with TAO at different stages of disease activity and severity were examined.

Among patients with active TAO, the average adiponectin level was 4.31 mg/mL for those with mild severity of the disease. Patients with impaired mobility due to the disease had 4.33 mg/mL, those with marked proptosis had 4.89 mg/mL, and patients with severe TAO had 5.51 mg/mL of adiponectin.

For patients with inactive TAO, the average adiponectin level was slightly higher. Among patients in this group, median adiponectin level was 5.59 mg/mL for patients with mild severity of the disease, 5.59 mg/mL for patients with impaired motility, 5.65 mg/mL for patients with marked proptosis and 5.37 mg/mL for patients with severe TAO. The median adiponectin level for the healthy people in a control group was 4.77 mg/mL.

Total thyroid ablation beneficial

Francesca Menconi, MD, and colleagues at the University of Pisa, Italy, investigated a surgical approach to improving some TAO symptoms. They determined that total thyroid ablation is effective in improving diplopia in TAO.

In the study, patients with moderate Graves’ disease were randomized to three types of thyroid treatment. One group was treated with methimazole, a second group underwent near-total thyroidectomy and a third group underwent total thyroid ablation plus iodine-131 radiotherapy. Patients in all three treatment groups also received glucocorticoid pulse therapy.

Sixty-nine patients completed treatment and were followed for a minimum of 6 months.

Proptosis was slightly reduced in all patient groups. Patients undergoing total thyroid ablation had a greater reduction in eyelid width than either of the other two groups.

Diplopia improved or disappeared altogether in a greater percentage of patients treated with total thyroid ablation than in the other two groups.

Additional reporting by correspondent Jay Lewis

For Your Information:

• Steven E. Feldon, MD, can be reached at the University of Rochester School of Medicine and Dentistry, Department of Ophthalmology, MC 8659, Rochester, NY 14642-8659; (323) 442-6488; fax: (323) 442-6407.
• Allen M. Putterman, MD, SC, FACS, can be reached at 111 N. Wabash, Suite 1722, Chicago, IL 60602; (312) 372-2256; fax: (312) 372-1762.
• Stephen M. Soll, MD, can be reached at 5001 Frankford Ave., Philadelphia, PA 19124; (215) 288-5000; fax: (215) 288-5601.
• L. Neal Freeman, MD, MBA, FACS, can be reached at 502 E. New Haven Ave., Melbourne, FL 32901; (321) 727-2020; fax: (321) 726-4061.

• The American Thyroid Association can be reached at 6066 Leesburg Pike, Suite 650, Falls Church, VA 22041; (703) 998-8890; (703) 998-8893.

References:

• Plicht M. Adiponectin levels in the serum of patients with thyroid-associated ophthalmopathy. Presented at the 75th Annual Meeting of the American Thyroid Association. Sept. 16-21, 2003, Palm Beach, Fla.
• Menconi F. Effects of total thyroid ablation (TTA) on the short-term outcome of graves’ ophthalmopathy (GO) in patients treated with glucocorticoids (GC): Preliminary results of a randomized clinical trial. Sept. 16-21, 2003, Palm Beach, Fla.
• Kendall-Taylor P. Double-blind placebo-controlled trial of octreotide in thyroid-associated orbitopathy: Clinical outcomes. Presented at the 75th Annual Meeting of the American Thyroid Association. Sept. 16-21, 2003, Palm Beach, Fla.