Shane Pahlavan, M.D.
May 14, 2009
Disclaimer: The information contained within the Grand Rounds Archive is intended for use by physicians and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No warranties, either express or implied, are made with respect to accuracy, completeness or timeliness of this material. This material does not necessarily reflect the current or past opinions of the faculty of Baylor College of Medicine and should not be used as a basis for diagnosis or treatment, and is not a substitute for professional consultation and/or peer-reviewed medical literature.
NA is 50-year-old female with a history of Graves’ disease and a previous history of a left orbital decompression in 2002. She presented with increased proptosis in the right eye with diplopia and vision changes.
She was previously treated with I-131 to her thyroid gland. She is now taking Synthroid for thyroid replacement. Social history was remarkable for a 30 pack-year smoking history. Recent thyroid stimulating hormone levels have been within normal limits.
On physical examination, the right eye proptosis was present with right upper lid retraction. The left eye was previously operated on and was normal in appearance. She had no palpable thyromegaly on neck examination.
This is a representative image, a coronal scan. I just wanted to point out the rectus muscles here and the lateral, superior, medial and inferior on the right side. To compare the previously operated left side to the right, note the increased cellularity as well as diameter of all rectus muscles of the right eye. You can see here the medial rectus is quite a bit enlarged and we will go into some of the pathophysiology behind this phenomenon.
Today I will give a little background on Graves’ exophthalmos, as well as a brief introduction. We will talk about the pathophysiology, some of the basic science behind it as well as some of the epidemiology and how these patients are affected. Also how often we see these patients in our clinic. I will discuss a little bit about making the diagnosis as well as the plethora of management options for these patients. I would also like to finish with a treatment algorithm and patient follow-up.
The first description of an individual with Graves’ exophthalmos or orbitopathy was by Caleb Hillier Parry. The association of goiter and exophthalmos has been recognized by many clinicians over the years. It was first described by a Persian physician back in the 12th century and by an Irish physician Robert Graves, for which he lends his name to the disease in 1835.
Exophthalmos is a condition of altered thyroid metabolism which results in protein depositions within the extraocular muscles which can increase their bulk as much as eight, even ten fold.
Graves’ disease is a multi-system disorder. It is not just a thyroid disease characterized by hyperthyroidism associated with diffuse hyperplasia of the thyroid gland, which we commonly think of, when we think of Graves’ disease. But, we also have to think of the infiltrative eye disease that leads to exophthalmos as well as dermopathy which leads to pretibial myxoedema.
The pathophysiology behind Graves’ disease is quite intricate. Many patients are euthyroid at the time when the eye symptoms appear. However, usually further testing will reveal some amount of dysthyroidism. The current theory behind the pathophysiology of Graves’ disease is auto reactive T cells which are reactive to the TSH receptor. This is similar to the TSH receptor that is activated in the thyroid gland. The humoral immunity system produces antibodies to this TSH receptor which are stimulatory, resulting in hyperthyroidism.
Extraocular muscles are the site most commonly evident on physical examination in these patients. This directly leads to the exophthalmos, visual changes, visual loss, and diplopia. The muscles are enlarged and there is an intense proliferation of perimysial fibroblasts with lymphocytic infiltration. The fibroblasts in the retrobulbar region secrete glycosaminoglycans, which cause edema. This results in mast cell production and inflammatory cell proliferation including lymphocyte adhesion molecules.
How often do Graves’ patients have difficulty with visual problems? About 50% or greater is what most literature describes for Graves’ disease patients who have some eye complaints. However, luckily only 5% actually warrant intervention. The most common orbital symptom that seems to regress without any treatment is lid retraction.
Proptosis is a little more ominous. It usually peaks four to thirteen months after the onset of the disease and the regression in the range of 3 to 7mm that occurs in about half of these patients over the ensuing one to three months. Patients in whom we do not see regression are the patients that go on to need either further medical management or surgical decompression.
The eye involvement is bilateral in majority of these patients, but it is important to note that 5-14% will have unilateral disease. So, major asymmetry of eye involvement is common. One eye may be affected more than the other. One eye may be affected and the other eye not be affected at all clinically. So, it is important to keep that in mind. For major asymmetry of the eye, Graves’ disease remains the most common etiology of unilateral proptosis in adults.
This is just a diagram showing the prevalence of Graves’ orbitopathy in patients. As I mentioned, approximately 50% of patients with Graves’ disease will have some eye complaints, and 50% are absent. Less than 5% will actually be sight threatening and need extensive management. It is important to realize that 50% of patients will have some degree of involvement.
This is one of the classifications systems used by the Endocrinology Association to grade the involvement of Graves’ exophthalmos. They give a final score of maximum of seven to each of these points to grade how severe the disease is, including pain in the retrobulbar region, pain on gaze, redness of the eyelids, redness of the conjunctiva, swelling, inflammation and hemorrhage.
No signs, only signs with lid aperture and soft tissue involvement, proptosis. You want to measure that exophthalmos in mm extra-ocular muscle movement, corneal involvement and sight loss. So, as we go down, we get more and more involved in the management and strategies and possibly decompression.
How important is this to a Graves’ patient that comes in to see us in clinic? Here we have percentage of Graves’ patients where the quality of life is impaired. This is the 50% group that has eye disease associated with their Graves’. Now, almost 35 to 40% have limitations in driving or leisure activities. Surprisingly, almost 70% have reduced self confidence. They also have social isolation in about 35%. So, it is an important thing to counsel our patients that we see in clinic. It is not something to overlook.
This is a classification by the American Thyroid Association. It gives a full classification of symptoms. We will see patients who will have this classification scheme that involves one through six classifications from increasing ocular involvement, grade six and most severe individual impairment. We usually would see the patients in the class five or six with a severe involvement after they have been unsuccessfully treated by the endocrinologist with medical management.
Patient evaluation: Usually these patients, as I have mentioned, are initially evaluated by the medical specialist. They are initially diagnosed with hyperthyroidism. They are referred to an endocrinologist and full work-up is performed including a full thyroid panel as well as thyroid stimulating immunoglobulin. Any patient with unilateral or bilateral exophthalmos should be considered to have thyroid disease and that should be ruled out. Most patients can be shown to have some amount of thyroid dysfunction in Graves’ disease.
Physical examination: Upper and lower eyelid retraction, proptosis and other signs of hyperthyroidism. Hyperemia of the lateral rectus muscle is considered pathognomonic for Graves’ exophthalmos. I have a picture of that which we will get to. A complete ophthalmologic exam should always be performed in these patients. We can refer those to our ophthalmology colleagues as well. Serial eye exams are necessary to monitor disease progression, and response to therapy. It is important to monitor for soft tissue changes, proptosis, intra-ocular pressure, ocular mobility, strabismus and most importantly, visual function. Also, a complete head and neck examination should include a thyroid status as well.
This is a conglomeration of pictures of patients with Graves’ exophthalmos and disease. You can see multiple patients with severe proptosis, as well as some lid retraction, with a stare affect. The hyperemia over the lateral rectus, you can see a little bit on this patient here and here, is pathognomonic for the disease.
Radiological evaluation: CT scans of the orbit are essential, especially if surgery is planned. You must evaluate the paranasal sinuses to rule out any significant sinus disease for pre-operative planning. Findings may include a two to eight-fold increase in some patients and the extra ocular muscle body is sparing the tendinous forces. The muscle body where the fibroblasts have proliferated and the glycosaminoglycans have caused interstitial edema. The inferior medial rectus muscles are the most commonly involved. This is another image here. You can see the severe proptosis bilaterally. It is important to evaluate the sinuses as well if you are planning on doing any type of endoscopic decompression and any sinus disease should be noted as well for planning those decompressions.
Ultrasound has often been used to demonstrate thickening of the extraocular muscles. It is more used to monitor the response to therapy in patients receiving medical management. MRI is used intermittently and weighted images will show some active inflammation within the orbits. However, it does not provide the bony detail that we would need pre-operatively that a CT scan allows.
The most common diagnosis to consider in patients that present with bilateral proptosis is to rule out any pseudotumor cerebri. Lymphoma of the orbit can produce proptosis usually in a unilateral presentation. Metastatic tumors, vascular anomalies, neurofibromas, retinal blastomas all can produce unilateral proptosis.
Most other disease entities have superficial similarities, but can be ruled out pretty readily. It is important to keep a high index of suspicion if the diagnosis to be made in a timely fashion as these patients can progress relatively rapidly to permanent visual loss.
As far as management, multi-specialty team is recommended because there are multiple organ systems involved. The team should include an endocrinologist, radiologist, nuclear medicine physician, radiation therapist, ophthalmologist, otolaryngologist, as well as a neurosurgeon in some cases. Both medical and surgical management options are available in the treatment of Graves’ disease.
I will start with medical management. All patients will require management of the hyperthyroidism. Mainly this centers on the suppression of the thyroid activity, whether that is with medications or radioactive iodine ablation. After euthyroid status is achieved for six months, often times we will see the orbital status usually stabilizes at that point. One or two percent will develop deterioration in the visual status and the treatment in the acute setting is steroids. Some adjuncts treatments include topical lubricants, artificial tears, moisture chambers, taping the eyelid, if necessary. Often patients will wear dark rimmed glasses. One of the newer approaches is for low dose radiation in these patients that have chronic exophthalmos using a low dose of 20 Gy in 10 fractions for two weeks. Patients early in the disease process can benefit from this process if found early enough.
One interesting point that comes up in the literature quite often is the association between eye disease and Graves’ disease patients with smoking. The smoking worsens the outcome. Smokers are noted here and non-smokers noted here. There are a quite a few non-responders too. This is a variety of treatments from a Barcelona study in 1998, which reported a larger proportion, almost even ten fold increase in non-responders in patients that were smoking at the time of diagnosis. Most literature reports that about 50% of patients with eye disease are actually smoking at the time of diagnosis. So, this would definitely hinder their response to our treatments that we have available.
I mentioned steroids for the treatment of the acute phase. This is a study comparing oral and IV steroid treatment for patients with acute Graves’ exophthalmos. It showed that increased responses were seen in the IV form compared to the oral form.
This is a group of studies, since 2000, evaluating the effects of orbital radiotherapy on the Graves exophthalmos. We see that Marcocci in 2001 reported that he had quite a good result, over 80% of his patients were low dose, about 20 Gy, over two weeks of radiation therapy was effective in treating quite a few of his patients. But, across the board generally the literature supports about a 40 to 50% improvement with radiotherapy in Graves patients.
This is a follow-up study of orbital radiotherapy with concern that this may increase evidence of precipitation of cataracts, precipitate retinopathy or even cancer. It did show in 204 patients that there was not any increased cataract incidence and no evidence of cancer. Some patients did develop some arterial hypertension, but these are patients that had diabetes as well. There conclusion is that orbital radiotherapy is safe for a certain subset of patients as shown here.
As for the surgical management in acute or subacute stages, as I mentioned, steroids are going to be first line of treatment. If patients fail to resume visual acuity with steroids, then consideration of surgical decompression is indicated at that point. In the late stage, when the proptosis and lid reaction is evident, an increasing number of procedures are being performed for cosmetic decompression.
The usual functional indications for decompression are decreasing visual acuity, visual field defects, abnormal visual evoked potentials, disc edema, corneal exposure with keratitis, and those who have failed medical management. Multiple surgical approaches have been discussed in the literature over the years, including decompressing the supraorbital rim, lateral rim, medial or infraorbital rims or decompressing both at the same time. Some described the medial and inferior orbital rim decompression simultaneously.
The gains and advantages of each of these revolve around how much decompression you can get and how many walls of the orbit you take down. Single orbit decompression allows 0 to 4 mm. Take down the medial and inferior walls, and you can get 3 to 6 mm of decompression, and 6 to 10 mm in a three wall decompression. Since this is a very patient specific, it is very important to have a thorough ophthalmological exam in order to delineate exactly how much proptosis is evident pre-operatively.
So let’s briefly go over some of the surgical techniques. Super orbital rim decompression is usually reserved for severe cases due to associated morbidity. It involves unroofing the entire superior orbital wall with a frontal craniotomy, identifying the optic nerve and then removing the superior and periosteum in an H fashion, allowing the orbital fat to herniate into the cranial vault. This needs to be reconstructed with mesh or paracranial flap to close the defect.
Medial orbital decompression can be performed through a standard external ethmoidectomy incision, or through a coronal forehead approach. Ethmoidectomy approach distally to the medial canthal tendon and elevates the lacrimal sac out of the way to avoid injury. Ethmoid arteries are identified and clipped to prevent injury. After complete ethmoidectomy is performed, the posterior ethmoid cells are removed and the periosteum is incised longitudinally.
Inferior orbital decompression creates a large orbital floor blow out fracture while sparing injury to the infraorbital nerve. It can be done through multiple approaches, subciliary, transconjunctival. Historically, a Caudwell Luc incision was used. But, some prefer combined approaches for better visualization, which I will discuss shortly, with endoscopic approaches as well.
Skin muscle flap can be elevated through the lower eyelid to identify the orbital rim and the periosteum is incised and elevated off of the orbital floor to allow for decompression. It is important to identify the infraorbital nerve and the bone medial and lateral to the nerve can be removed. Periorbita is incised longitudinally and the number of incisions can be determined intraoperatively, but four to six is usually adequate. The fat is then able to herniate through the defect on either side of the nerve, but a bridge of bone is left near the infraorbital nerve.
Oftentimes today we use endoscopic orbital decompression. The medial and medioinferior floors of the orbit can be removed transnasally. You can’t decompress the orbit lateral to the infraorbital nerve from this method, but it does allow one to extensively open up the periorbita and have the fat extrude. It may require a septoplasty for exposure as in any sinus work. A portion or all of the middle turbinate will need to be resected and a total ethmoidectomy is performed. The medial orbital wall is exposed from the fovea ethmoidalis to the anterior face of the sphenoid. This gives access to the lamina propecia so it can be fractured and removed. This can give quite a bit of decompression medially. You can move approximately 2 mm of fovea ethmoidalis posteriorly to the base of the sphenoid and stay lateral to the nerve.
Importantly, the buttress of bone needs to be preserved anteriorly at the junction between the inferior and medial orbital wall to avoid inferior displacement of the globe. One of the complications of this procedure can be hypoglobus. So it is important to leave that ledge of bone there. The orbital periosteum can be incised with a sickle knife and orbital fat will protrude into the ethmoid cavity.
Some of the complications to keep in mind include progressive optic neuropathy, which can lead to blindness. One of the major complications of medical management is the failure to recognize the medical failure and delayed surgery. Complications of steroid therapy include gastric ulcer, irritable personality, and reactivation of dormant infection. The study for radiation on complications show that there are pretty minimal complications, although we should be concerned about cataracts and pituitary suppression and optic fibrosis anytime that we are giving radiation to the eye.
Decompressive surgery, as in any sinus patient, has post-operative complications, including diplopia, unsatisfactory result, corneal abrasion and importantly, retrobulbar hematoma. This is just a list of some common complications to keep in mind when performing any open or endoscopic decompression of these patients.
Retrobulbar hematoma should always be evacuated immediately to control any further bleeding. We should open the skin immediately with a retrobulbar hematoma and evacuate the clot. As far as vascular occlusion, it is usually related to intraocular pressure and it is an ophthalmologic emergency. This is most commonly followed by excessive retraction intra-operatively, so it is important to make note of that.
We should maintain these patients post-operatively with appropriate eye protection to avoid any corneal ulceration. Patients should seek immediate medical attention for change in their vision or increasing pain in the eye.
So, let’s go back to our case. NA underwent a combined transorbital transnasal decompression of the inferior and medial orbital walls by our service in conjunction with Dr. Soparker of oculoplastics. Postoperatively her proptosis has improved and she is recovering well and her visual acuity has improved as well.
In summary, otolaryngologists will continue to be involved in treatment of Graves’ exophthalmos and eye disease. Early intervention, as I mentioned, can prevent visual compromise and it is important to have a good knowledge of the anatomy so you can have a safe and successful decompression.Girod DA, Orcutt JC, Cummings CW. Orbital decompression for preservation of vision in Graves' ophthalmopathy.
M.A. is a 50-year-old female with a history of Graves’ disease and previous history of left orbital decompression in 2002 presenting with increased proptosis of the right eye with diplopia and recent visual loss. She was previously treated with I-131 and currently takes Synthroid 0.175mg daily. Her recent TSH levels have been within normal limits.
On physical exam, she was noted to have right eye proptosis with right upper lid retraction. The left eye examination was normal. M.A. underwent combined transorbital-transnasal decompression of the inferior and medial orbital walls by our service in conjunction with Dr. Soparker of oculoplastics. Her proptosis has resolved and she has recovered well with improvement in her vision.
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