J Oral Maxillofac Surg 53:1091-1096, 1995

Glucocorticoid Therapy for Myasthenia Gravis Resulting in Resorption of the

Mandibular Condyles JAY COWAN, DDS,* JOHN E. MOENNING, DDS, MSD,t

AND DAVID A. BUSSARD, DDS, MSt

Glucocor t icoids are essential therapeut ic agents in the t reatment of some chronic diseases. These agents p rovide ant i - inf lammatory, immunosuppress ive , and ant i -neoplast ic activity. However , g lucocor t icoids are not wi thout side effects. In 1932, Cushing first not iced that g lucocor t icoids were l inked to bone loss and skele- tal fracture. ~ Af ter Cush ing ' s findings, other reports descr ib ing hormonal effects on the skeleton and nu- merous examples of cor t icos tero id- induced os teoporo- sis also have been published. However , a rev iew of the oral and maxi l lofac ia l surgery l i terature produced no reports of cor t icos tero id- induced os teoporosis o f the mandibu la r condyle , a l though other causes for mandib- ular condyla r resorpt ion have been noted. 2-4 W e de- scribe a pat ient who deve loped condylar resorpt ion subsequent to cor t icosteroid therapy for myas then ia

gravis.

Report of Case

A 21-year-old woman presented for presurgical evaluation of a musculoskeletal deformity in 1992 (Fig 1). The patient had no allergies but suffered from severe asthma that was controlled with Theo-dur (Key Pharmaceuticals, Kenilworth, NJ), an Azmacort Inhaler (Rorer Pharmaceuticals, Ft Wash- ington, PA), and a Provental Inhaler (Schering, Kenilworth, NJ). She reported being diagnosed with myasthenia gravis 2 years ago, and subsequently had her thymus gland removed to control the disease. She had returned to most normal activities after removal of the thymus gland and was not taking medications for myasthenia gravis.

The panoramic radiograph and corrected-axis tomograms showed abnormalities of the mandibular condyles (Fig 2). Magnetic resonance imaging of the right joint showed an intermediate to advanced (stage III to IV) internal derange-

* Chief Resident, Division of Oral and Maxillofacial Surgery, University of Cincinnati Medical Center, Cincinnati, OH.

t In group private practice, Indianapolis, IN. Address correspondence and reprint requests to Dr Moenning:

8140 Knue Rd, Suite 200, Indianapolis,.IN 46250.

© 1995 American Association of Oral and Maxillofacial Surgeons

0278-2391/95/5309-001653.00/0

ment with regressive remodeling of the mandibular condyle and marked anterior displacement and deformity of the disc. The left temporomandibular joint (TMJ) showed an interme- diate to advanced (stage III to IV) internal derangement. There was joint space narrowing and close approximation of the mandibular condyle to the glenoid fossa. The disc was markedly deformed and degenerated. Comparison of the corrected-axis tomograms with transcranial radiographs (Fig 3) taken by the original dentist in 1992 showed that gross condylar resorption had occurred.

A detailed history of the progress of the patient's myasthe- nia gravis and TMJ dysfunction indicated that during her first year in college (1992) she had noticed increased fatigue with dancing. During this same time she also noticed diffi- culty chewing some of her food and opening her mouth. The following summer she had her third molars removed, but continued to experience limited opening, fatigue of the jaw muscles, and popping and clicking in her TMJs. The patient saw her dentist, who attempted to treat her for TMJ dysfunc- tion with bite appliance therapy. This produced only partial relief of symptoms. During the fall semester in 1988 she noticed her eyelids drooping, and she saw an ophthalmolo- gist. During the second semester the dentist recommended she undergo orthodontic treatment. Throughout this time she continued to have ocular problems and saw a neurologist. In May 1990 she was diagnosed with myasthenia gravis. Initial treatment was with systemic steroids. She took 60 mg Prednisone per day for a prolonged time. She was hospital- ized three times for severe muscular weakness and was treated with intravenous steroid therapy and had five treat- ments with plasmapheresis. The condition remained recalci- trant to treatment. Two and one-half years after the onset of symptoms, the patient's thymus gland was removed. Since removal of the thymus gland she has been in remission from her disease.

Because the patient had severe radiographic changes in the mandibular condyles it was believed that any orthognathic surgery to correct her musculoskeletal deformity should be accomplished in the maxilla. A Le Fort I maxillary osteot- omy was performed, and rigid fixation and an autogenous bone graft from the chin area were used. She was hospital- ized for 3 days postsurgically, primarily for observation of her disease, and had a normal postoperative course. Twenty- six months postoperatively the occlusion remains stable, and her opening is 38 mm (compared with her preoperative open- ing of 35 mm). Her protrusive and lateral movements are similar to the preoperative values of 8 mm (Fig 4). Her occlusion has remained stable, and she has no headaches or joint pain.

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] 092 GLUCOCORT1COID THERAPY

FIGURE 1. Preoperative views of patient A, frontal view; B, lateral view; C, view of occlusion.

Discussion

Myasthenia gravis is a disorder involving neuromus- cular transmission that affects approximately 1 in 20,000 persons. 5 It was first described in 1868 by the French clinician, Herard. 6 Myasthenia gravis can occur at any age; however, it most often begins during young adulthood and affects women twice as often as men. There is no racial or geographic predilection, and fa- milial cases are rare. 5

Myasthenia gravis is characterized by weakness and abnormal fatigability of any or all of the skeletal mus-

cles. The muscles innervated by the cranial nerves are affected as well as those of the neck and extremities. In most patients the extraocular muscles are affected within the first year. In one fourth of the patients the initial symptom is ptosis, one fourth present with diplo- pia, and weakness o f the arms, legs, face, neck, or generalized fatigue is the initial complaint in one fourth o f the patients. The remaining one fourth of the patients have initial clinical symptoms consisting of chewing, swallowing, and coughing difficulties or nasal speech. 7 The weakness and fatigability in this disease are attrib- utable to the development of autoantibodies to the ace-

COWAN, MOENNING, AND BUSSARD "1093

FIGURE 2. Right (A) and left (B) lateral tomograms of the

tylcholine receptor proteins of skeletal muscles. The antibodies decrease both the number of acetylcholine receptors at the neuromuscular junction and their reac- tivity to the neurotransmitter acetylcholine.

Thymus gland abnormalities are frequently seen in patients with myasthenia gravis. At least 10% have thy- momas. Most of these patients are older than 30 years of age at the time of their diagnosis. The presence of a thymoma is usually detected by chest radiographs, medi- astinal tomography, or computed tomography. The clini- cal diagnosis of myasthenia gravis is based on the history of fluctuating weakness and the demonstration of skeletal

ternporomandibular joints. Note the erosion of the articular surfaces,

muscle weakness examination. Diagnostic confirmation is obtained by demonstrating improvement after injection of anticholinesterase medication)

The daily management of the disease relies mainly on pyridostigmine (Mestinon, Roche Laboratories, Nutley, N J) given orally or neostigmine (Prostigmin, Roche) administered parenterally. The side effects may include salivation, sweating, lacrimation, abdominal cramps, nausea, vomiting, diarrhea, bronchorrhea, bradycardia, and occasional headaches. 5 The optimal dose of these medications is the smallest one that pro- duces maximal improvement in strength.

094 GLUCOCORTICOID THERAPY

FIGURE 3. Transcranial ra- diographs taken before steroid therapy.

In patients whose weakness interferes with normal activity despite anticholinesterase medication, the next step is administration of corticosteroids. Small doses of corticosteroids are increased over several weeks to produce less frequent and less marked exacerbation. Patients with mild, generalized myasthenia gravis can be treated as outpatients with low-dose alternate-day corticosteroids, beginning with 20 mg prednisone or 2.5 mg dexamethasone. Improvement begins in 10 to 30 days and is maximal in 15 to 40 days. The mainte- nance dose for corticosteroids should be gradually re- duced to the lowest level compatible with adequate strength, and then discontinued whenever possible. High dosage or prolonged administration of corticoste- roids may produce peptic ulcer, glucose intolerance, hypertension, weight gain, mood changes, cataracts, osteoporosis, aseptic necrosis of the femural head, ste- roid myopathy, and increased susceptibility to infec- tion.

In vivo glucocorticoid administration has a direct inhibitory effect on osteoblastic activity by decreasing collagen synthesis and suppressing progenitor cell pro- liferation. Dempster and others have demonstrated that the longevity of active osteoblasts and the mean wall thickness of completed tubular osteons are decreased in steroid-treated patients. 8 Prummel et al 9 noted that the reduction in bone formation during corticosteroid treatment is reflected in low levels of serum osteocalcin and alkaline phosphatase. Corticosteroid therapy indi- rectly increases bone resorption by creating a second- ary hyperparathyroidism through loss of calcium in the urine and gastrointestinal (GI) tract. Glucocorticoids

reduce calcium absorption by the GI tract. Studies in mice have shown that glucocorticoids downregulate the number of 1-25 dihydroxy vitamin D receptors; in chickens, glucocorticoids decreased the amount of soluble calcium-binding protein as well as the alkaline phosphatase activity. ~ Glucocorticoids also increase the renal excretion of phosphorus and calcium. The hypercalciuria may be caused by a direct steroid effect on the renal tubule. The excess production of parathor- mone further potentiates osteoclastic activity.

Recent data demonstrate that glucocorticoids also amplify the response of bone cells to parathormone. 8 The combined primary effects of glucocorticoids on osteoblastic activity and the secondary effects of hy- perparathyroidism result in bone loss, or osteoporosis. According to Tervonen et al, ~° avascular necrosis of the bone is an entity of unclear pathogenesis that has been reported as a complication of a wide variety of disorders. It has been well established that the disease also occurs as a complication of corticosteroid therapy. The most common site of avascular necrosis is the femural head. Tervonen et al examined 100 MRIs of asymptomatic renal transplant patients being treated with corticosteroids. All patients were older than 18 years, had been treated with corticosteroids for at least 6 months, and had no symptoms of avascular necrosis before MR imaging. Six of the 100 patients had clini- cally occult avascular necrosis on MR imagingJ ° In another study, Ono et al jj found that the incidence of avascular necrosis in the femural head of patients with systemic lupus erythematosus receiving high-dose cor- ticosteroid therapy ranged from 2.8% to 16%. They

COWAN, MOENNING, AND BUSSARD "1095

FIGURE 4. Postoperative views of patient. A, frontal view; B, lateral view; C, view of occlusion.

postulated that the sudden introduction of high-dose corticosteroid therapy significantly enhanced the risk for avascular necrosis of the femural head. A minimum or moderate amount of glucocorticoid preloading les- sened the r isk. II Arlet ~ stated that the relationship be- tween avascular necrosis of the femural head and corti- costeroid treatment ranged anywhere from 12% to 30%. He stated that corticosteroid therapy in the treat- ment of renal transplant patients leads to a higher inci- dence of avascular necrosis of the femural head.

Researchers have documented that corticosteroid treatment in rabbits produced an increased volume of

marrow fat and cells, associated with an increase in intramedullary pressure and reduction of bone blood flow. They reversed these changes with lipid-clearing agents and core decompression. 12 In another study dealing with experimental steroid-induced osteo- necrosis in adult rabbits, Matsui et al ~3 showed the presence of intermedullary hemorrhage and structural damage to arteriolar walls that were closely related to the necrosis of the trabeculae and bone marrow. In their review they stated that most patients with osteonecrosis suffer from a second underlying disease producing vas- culitis, in addition to their receiving the high-dose cor-

1096 GLUCOCORTICOID THERAPY

ticosteroids. They be l ieved that such ar ter iopathy may p lay an important role in the pathogenes is of os- teonecrosis . They poin ted out that patients with ste- ro id- induced osteonecrosis have been treated with high-dose, p ro longed steroid therapy. Use o f cort ico- steroids alone has not p roduced osteonecrosis exper i - mental ly . This indicates that the pathogenes is of ste-

ro id- induced osteonecrosis may be found in the

combined effect of steroids and vasculi t is . The vasculi- tis that is induced by deposi t ion of immune complex in the wall of ar ter ioles has frequently been found

i n patients with connect ive t issue disease and renal transplants. Converse ly , cor t icosteroids can inhibit the biosynthesis o f co l lagen and elastin through the necro-

sis o f smooth muscle cells in the tunica media. This pa thologic process is accelera ted when the vascular

t issue is a l ready injured before steroid administrat ion. Cor t icos teroids also may augment vasoconstr ic t ion,

platelet aggregat ion, and int imal cel lular prol i fera t ion in injured vessels. 13

In the case presented the pat ient had myas thenia gravis and asthma, thus leading to an under ly ing vascu- litis. Moreover , the skeletal deformi ty of the maxi l la

very l ikely p laced the condyles under increased stress and strain. Wi th these under ly ing problems and a previ-

ous his tory of TMJ symptoms, the cor t icosteroid ther-

apy was p robab ly enough to induce osteonecrosis in the mandibu la r condyles . The M R / c o n f i r m e d this di-

agnosis. It is important that oral and maxi l lofac ia l surgeons

are aware of the re la t ionship between steroids and the potent ia l for condyle resorpt ion, especia l ly when treat- ing dentofacia l deformit ies . In such patients, a thor-

ough medica l his tory should be obta ined and, i f high-

dose steroids have been used in the past, a careful c l inical and radiographic examinat ion of the mandibu- lar condyles should be done before init iating ortho- gnathic surgery.

References

1. Mitchell DR, Lyles KW: Glucocorticoids-induced osteoporosis: mechanisms for bone loss: Evaluation of strategies for pre- vention. Gerontol 45:153, 1990

2. Iizuka T, Lindquist C, Hallikainen D, et al: Severe bone resorp- tion and osteoarthrosis after miniplate fixation of high condy- lar fractures: A clinical and radiologic study of thirteen pa- tients. Oral Surg Oral Med Oral Pathol 72:400, 1991

3. Moore KE, Gooris PJ, Stoelinga PJ: The contributing role of condylar resorption to skeletal relapse following mandibular advancement surgery: A report of five cases. J Oral Maxillo- fac Surg 49:448, 1991

4. Nitzan DW, Dolwick MF: Temporomandibular joint fibrous an- kylosis following orthognathic surgery: Report of eight cases. Int J Adult Orthodontics Orthognathic Surg 1:7, 1989

5. Stein JH: Internal Medicine (ed 2). Boston, MA, Little, Brown, 1987

6. Oosterhuis H: Myasthenia Gravis. New York, NY, Churchill, Livingston, 1984

7. Rakel R: Conn's Current Therapy. Philadelphia, PA, Saunders, 1992, pp 864-872

8. Coe F, Favus M: Disorders of Bone and Mineral Metabolism. New York, NY, Raven Press, 1992, pp 891-892

9. Prummel HF, Wiersinga WH, Lips P, et al: The course of bio- chemical parameters of bone turnover during treatment with corticosteroids. J Clin Endocrinol Metabol 72(2):382, 1991

10. Tervonen O, Mueller D, Matteson E, et al: Clinically occult avascular necrosis of the hip: Prolapse in an asymptomatic population at risk. J Radiol 182:845, 1992

11. Ono K, Tohjima T, Komazawa T: Risk factors of avascular necrosis of the femoral head in patients with systemic lupus erythematosis under high dose corticosteroid therapy. Clin Orthop 89, 1991

12. Arlet J: Nontraumatic avascular necrosis of the femoral head. Clin Orthop 12, 1992

13. Matsui M, Saito S, Ohzono K, et al: Experimental steroid in- duced osteonecrosis in adult rabbits with hypersensitivity vas- culitis. Clin Orthop 61:277, 1992