Case Study: Missed Diagnosis and Mistreatment of Unrecognized Comorbid Graves Disease

JOSEPH L. WOOLSTON, M.D., AND ANNMARIE CARACANSI, M.D.

ABSTRACT

Comorbid medical conditions are known to complicate the course and treatment of psychiatric disorders. This case study

provides the first published report of Graves disease exacerbating the symptoms of Tourette’s disorder and attention-deficit

hyperactivity disorder (ADHD). The lack of diagnosis of the Graves disease compromised the efficacy of the treatment of

Tourette’s disorder and ADHD. This case study supports the need to the consider increased risk of a second immunoen-

docrinological disorder in the presence of diabetes mellitus type I, one of the several disorders that comprise the syn-

drome of polyglandular autoimmune endocrinopathy type 11. J. Am. Acad. Child Adolesc. Psychiatr): 1999,38(7):861-864. Key Words: comorbid Graves disease, Tourette’s disorder, attention-deficit hyperactivity disorder.

The importance of interaction between psychiatric dis- orders and medical conditions is highlighted by the cur- rent DSM-IV multiaxial diagnostic system (American Psychiatric Association, 1994). However, Bhatara et al. (1998) emphasized the need for further refinement in the DSM classification system so that disruptive dis- orders related to medical conditions can be specified dis- orders. Disorders of thyroid functioning related to disruptive disorders are some of the best-documented examples of this medical-psychiatric interaction. For example, there is a well-established literature linking the rare disorder of generalized resistance to thyroid hormone (GRTH) with familial attention-deficit hyperactivity disorder (ADHD) (Bode et al., 1973; Cooper et al., 1982; Hauser et al., 1993; Magner et al., 1986; Rettig et al., 1987), although general populations with ADHD have no increased incidence of GRTH (Elia et al., 1994). Sev- eral reports have indicated a relationship between impair- ment in attention/concentration and hyperthyroidism (MacCrimmon et al., 1979; Whybrow et al., 1969) and during thyroid replacement in acquired hypothyroidism (Rovet et al., 1993). Other case reports have linked rapid

Accepted December 7, 1998. From the Child Study Center, Yale University School o f Medicine, New

Reprint requests to Dr. Woolston, Childstudy Center, Yak University School of

0890-8567/99/3807-086101997 by the American Academy of Child

Haven, CT.

Medicine, PO. Box 207900, New Haven, CT 06520-7900.

and Adolescent Psychiatry.

onset of attentional problems and disruptive behaviors with endogenous and exogenous thyrotoxicosis (Bhatara and McMillin, 1999; Bhatara et al., 1995; McCune and Ritchie, 1997). In the context of this literature, this is the first case report of the interaction among Graves dis- ease, diabetes mellitus (DM) type I, Tourette’s disorder, and ADHD. In addition, this case report illustrates the phenomenon of polyglandular autoimmune endocrino- pathy type I, in which there is a significantly increased risk of multiple autoimmune enocrinopathies, especially of the thyroid, associated with D M type I. This case report highlights the mechanism by which an unrec- ognized comorbid medical condition may interfere with effective treatment. The complex interaction of these medical and psychiatric disorders highlights the perils of fragmented medical care.

CASE REPORT

At the time of the index consultation at a regional special education school, M.O. presented as a socially well-related, mildly retarded, 11 X-year-old boy with severe, pervasive hyperactivity and impulsivity; intermit- tent physical aggression and defiant behavior; constant adventitious, dyskinetic truncal movements; and nearly continuous tics of the face and hands as well as intermit- tent vocal tics. This array of disruptive behavior symp- toms jeopardized his continued placement in his special educational school despite multiple attempts to contain his symptoms with pharmacotherapy. At the time of the

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index consultation, M.O. was receiving haloperidol, 1 mg 3 times daily; methylphenidate, 10 mg 3 times daily; clonazepam, 0.5 mg twice daily as needed for agitation; clonidine, 0.1 mg at 8 A.M. and 0.05 mg at noon, 4 EM., and at 8 P.M.; and Lentem insulin, 40 U in the morning and Ultralentem insulin, 12 U in the evening to treat DM type I. In addition to his ongoing psychiatric dis- orders, M.O. had 2 recent episodes of transient, idiopa- thic tachycardia which required evaluation in the local hospital emergency department, a IO-lb weight loss, and poor diabetic control as evidenced by hyperglycemia and glycosuria. Aside from the episodes of tachycardia, no abnormalities were noted in his vital signs during med- ical examinations and no evaluation was performed to c l a r i ~ the etiology of his weight loss and poor diabetic control. Prior to his weight loss, M.O. had remained in the 75th percentile for weight and the 50th percentile for height since age 3 years.

By history M.O. met the diagnostic criteria for ADHD at age 3 years. At age 4 years an eye-blink tic and DM type I developed. Because his ADHD symptoms had worsened, his pediatrician started M.O. on methylphenidate, 5 mg in the morning and 2.5 mg at noon at age 4 years 5 months. Six months later a head tic developed in addition to the eye- blink tic. Because of his ongoing tics and because of a pos- itive family history of tic disorder, M.O. was evaluated by a child neurologist, who recommended that the methyl- phenidate be discontinued. Despite the discontinuation of the methylphenidate, M.O. continued to have significant tics. In addition, his ADHD symptoms worsened.

At age 5 years I0 months, M.O. had an intensive out- patient psychiatric evaluation at a psychiatric hospital. He was described as a well-developed, well-proportioned child without dysmorphic features. A genetic evaluation, including an assessment of his chromosomes with a karyotype and fragile X probe, was negative. ADHD, chronic tic disorder, and mild mental retardation were diagnosed and M.O. began a regimen of haloperidol, 0.25 mg twice daily and methylphenidate, 7.5 mg daily. M.O. did not have a treating child psychiatrist, but his medications were prescribed by his pediatrician as rec- ommended in the psychiatric evaluation. Because of ongoing academic and behavioral problems, M.O. was referred to an out-of-district, self-contained special edu- cation school at age 6 years 8 months. For the next 5 years M.O.’s medical and psychopharmacotherapy was provided by his pediatrician with intermittent consulta- tion by a child neurologist.

At the index evaluation, the child and adolescent psy- chiatrist recommended that the methylphenidate be dis- continued because of its probable exacerbation of his tics and that the haloperidol be discontinued because of M.O.’s dyskinesia. In addition, the evaluator recom- mended a trial of nortriptyline to address his problems with attention and impulsivity. However, as a result of M.O.’s complex clinical presentation and medication regimen, his relatively unstable diabetic control and unexplained episodes of tachycardia as well as his esca- lating behavioral dyscontrol, he was referred for an inpa- tient psychiatric hospitalization to accomplish these medication changes after a comprehensive medical eval- uation had been completed.

Upon admission to the hospital M.O. was noted to be hyperactive, impulsive, and restless and displayed inter- mittent truncal dyskinesias. He had difficulty concentrat- ing, and his behavior at times was inappropriate as he would frequently touch or even slap people. He man- ifested prominent motor and vocal tics. He had a family history positive for chronic tic disorder, learning disabil- ities, and anxiety but negative for ADHD or autoimmune endocrinopathies. M.O.’s admission physical examina- tion results, including vital signs and thyroid palpation, were within normal limits. By history and examination, M.O. met the diagnostic criteria for ADHD, Tourette’s disorder, mild mental retardation, and DM type I. Because of his truncal movements, he had a rule-out diagnosis of tardive dystonia. In addition, his history of episodic tachycardia, weight loss, and resistance to diabetic control required that various metabolic disorders including hyperthyroidism be ruled out. During the first 3 days of hospitalization, methylphenidate was discontinued, halo- peridol tapered and discontinued, and clonidine main- tained at 0.1 mg in the morning, 0.05 mg at noon, 0.05 mg at 4 P.M., and 0.05 mg at 8 P.M. M.O.’s admission lab- oratory examination results were consistent with Graves disease with hyperthyroidism (thyroxine, 22.3 pg/dL; free thyroxine, 7.7 ng/dL; thyroid binding capacity, 13.5 pg/dL; thyroid-stimulating hormone, <0.04 pIU/mL). Propranolol was initiated up to 10 mg 4 times a day as well as methimazole 10 mg in the morning, 5 mg at noon, and 5 mg at night. O n the fourth hospital day M.O. developed sinus tachycardia, elevated blood pressure and temperature consistent with thyrotoxicosis, and blood and urine chemistry changes consistent with diabetic ketoacidosis. Because of his unstable medical condition, M.O. was transferred to a pediatric service.

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When M.O. returned to the psychiatry service 3 days later, he displayed continued vocal and motor tics, hypermotoric behavior, and labile, inappropriate affect. At that time his medications included propranolol, 10 mg twice a day; methimazole, 10 mg in the morning, 5 mg at noon, and 5 mg at night; clonidine, 0.05 mg at noon and 4 P.M.; and his insulin regimen. During the following 2 days M.O. displayed psychomotor agitation, rapid speech, and loosened thought processes. The endocrine consultant advised that M.O.’s mental status changes were likely a transient concomitant of thyrotox- icosis. The propranolol and methimazole were contin- ued with monitoring of his blood glucose level and adjustments in his insulin regimen. Within several hours he developed a viral gastroenteritis which required intra- venous hydration for 24 hours.

After this episode, M.O. remained somewhat hyper- motoric and impulsive but was more cooperative and redirectable. His motor and vocal tics diminished and his affect became more appropriate. Etepeated thyroid function tests showed a progressive normalization. The clonidine dosage was increased to 0.1 mg in the morning, at 4 P.M., and at night and 0.05 mg at noon; methimazole remained at 10 mg in the morning, 5 mg in the afternoon, and 5 mg at night. Propranolol was discontinued.

Upon discharge M.O. demonstrated considerable clinical improvement with amelioration of intensity and frequency of all symptoms of his ADHD and Tourette’s disorder. Both his DM and his Graves disease were under good control. His discharge medications were clonidine, 0.1 mg at 8 A.M., 4 EM., and 8 EM. and 0.05 mg at noon; methimazole, 10 mg at 8 A.M. and 8 P.M. and 5 mg at noon; Lente@ insulin, 40 U at 8 A.M. and Ultralente@, 12 U at 8 P.M. His discharge treatment plan included returning to his special education school, receiving med- ical care and psychopharmacotherapy from his pediatri- cian with the consultation of a child and adolescent psychiatrist and pediatric endocrinologist. One month after discharge M.O. continued with his symptomatic improvement but his symptoms of ADHD remained problematic. He was started on nortriptyline 25 mg twice a day, which was titrated up to 50 mg twice a day. This dosage resulted in a trough blood level of 124 ng/mL. The clonidine dosage was reduced to 0.05 mg, 4 times daily. Five months after discharge M.O. was func- tioning well in his special education school setting with minimal symptoms of Tourette’s disorder or ADHD.

DISCUSSION

This case study provides the first published report of undiagnosed comorbid Graves disease complicating the treatment of Tourette’s disorder and ADHD. This report extends the existing literature linking thyroid disorders and disturbance of attention and concentration (Bode et al., 1973; Cooper et al., 1982; Hauser et al., 1993; Magner et al., 1986; MacCrimmon et al., 1979; Rettig et al., 1987; Rovet et al., 1993; Whybrow et al., 1969). In the context of this literature, this is the first case report of the interaction among thyroid disorder and psychiatric disorder also to include exacerbation of preexisting Tourette’s disorder. The clinical course of the case study strongly suggests that the comorbid Graves disease con- tributed to the patient’s poor clinical response to his pharmacotherapy, which led his physicians to prescribe medications in increasing dosage and quantities. In this fashion, a missed diagnosis led to mistreatment.

This case report provides an example of the delete- rious interaction between metabolic and psychiatric dis- orders in childhood. Specifically, this case study should alert child and adolescent psychiatrists who are treating patients with poorly responsive tic and disruptive dis- orders to consider metabolic/endocrine evaluation when the patient has an existing autoimmune endocrinopathy consistent with the syndrome of polyglandular autoim- mune endocrinopathy (Eisenbarth and Verge, 1998). In this syndrome, autoimmune thyroid disorders, DM type I, primary adrenal insufficiency, celiac disease, primary hypogonadism, and myasthenia gravis all co-occur with increased frequency. The reported 14% increased inci- dence of autoimmune thyroiditis occurring subsequent to the onset of DM type I (Eisenbarth and Jackson, 198 1) is not widely know outside of the pediatric endo- crinology field. Other signs of metabolic disturbance such as unexplained weight loss, episodes of idiopathic sinus tachycardia, and increased resistance to insulin are additional indications for a careful metabolic/endocrine evaluation, including thyroid function tests.

This case study also highlights the crucial function of well-coordinated, multidisciplinary medical care, espe- cially for children who have complex medical and psychi- atric difficulties. In this case M.O.’s pediatrician focused on the DM, the neurologist attempted to treat the ADHD and Tourette’s disorder, and the special education school staff grappled with his behavioral problems. Since the 3 care providers had only minimal contact with one another,

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no effort was made to integrate the clinical understanding of the child's worsening symptoms or to view this deterio- ration as a signal for further medical evaluation. Frag- mented medical care for children with complex psychiatric and medical disorders significantly increases the risk for missed diagnosis and subsequent mistreatment.

REFERENCES

American Psychiatric Association (1994), Diagnostic and StatisticalManual of Mental Disorders, 4th edition (DSM-IV). Washington, DC: American Psychiatric Association

Bhatara V, McMillin JM (1999), Behavioral and cognitive abnormalities associated with pediatric thyrotoxicosis. In: Thyroid Diseases of Infancy and Childhood: Effects on Behavior and Intellectual Development, Hauser C Rovert J, eds. Washington, DC: American Psychiatric Press

Bhatara V, McMillin JM, Kummer M (1995), Violent aggressiveness in a 4- year-old boy associated with ingestion of ground beef contaminated with bovine thyroid tissue: a case report and review of neuropsychiatric find- ings in pediatric thyrotoxicosis./ ChildAdolesc Psychphamacol5:255-271

Bhatara VS, Gupta S, McMillin JM (1938), Disruptive disorders, thyrotoxi- cosis, and DSM-IV (letter). J A m Acad ChildAdolesc Psychiatry 37903

Bode HH, Danon M, Weintraub BD, Maloof F, Crawford J D (1973), Par- tial target organ resistance to thyroid hormone. / Clin Invest 52:776-779

Cooper DS, Ladenson PW, Nisula BC, Dunn JF, Chapman EM, hdgway EC (1982), Family thyroid hormone resistance. Metabolism 31:504-509

Eisenbarth GS, Jackson RA (1981), lmmunogenetics of polyglandular failure and related diseases. In: HLA in Endocrine and Metabolic Disorders, Farid N, ed. New York: Academic Press, pp 235-264

Eisenbarth GS, Verge CF (1998), Immunoendocrinopathy syndromes. In: William: Textbook of Endocrinology, 9th ed, Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Philadelphia: Saunders, pp 165 1-1662

Elia J , Gulotta C, Rose S, Marin G, Rapoport JL (1994), Thyroid function and attention deficit hyperactivity disorder. / Am Acad Child Adolesc Psychiatry 33:169-172

Hauser P, Zametkin AJ, Martinez P et al. (1993), Attention-deficit hyper- activity disorder in people with generalized resistance to thyroid hormone. N Englj Med 328:997-100 1

MacCrimmon DJ, Wallace JE, Goldberg WM, Steiner DL (1979), Emo- tional disturbance and cognitive deficits in hyperthyroidism. Psychosom Med41:331-340

Magner JA, Petrick P, Menezes-Ferreira MM, Stelling M, Weintraub BD (1986), Familial generalized resistance to thyroid hormone: report of three kindreds and correlation of patterns of affected tissues with the binding of '''I triiodothyronine to fibroblast nuclei. / Endocrinol Invest 9:459-470

McCune N, Ritchie K (1997), ADHD/thyroid dysfunction (letter). J Am Acad Child Adolerc Psychiatry 36: 1647-1648

Rettig KR, Sargeant DT, Kemp SF (1987), Resistance to the effects of thy- roid hormone in children. South Med/ 80:1316-1318

Rover JF, Daneman D, Bailey JD (1993), Psychologic and psychoeducational consequences of thyroxine therapy for juvenile acquired hypothyroidism. / Pediatr 122:543-549

Whybrow PC, Prange AJ, Treadway CR (196% Mental changes accompa- nying thyroid gland dysfunction. Arch Gen Psychiatry 10:48-63

Efficacy and Safety of Lovastatin in Adolescent Males With Heterozygous Familial Hypercholesterolemia: A Randomized Controlled Trial. Evan A. Stein, MD, PhD, D. Roger Illingworrh, MD, PhD, Peter 0. Kwiterovich, Jr, MD, Chris A. Liacouras, MD, Martti A. Siimes, MD, Marc S. Jacobson, MD, Thomas G. Brewster, MD, Paul Hopkins, M D , Michael Davidson, MD, Kevin Graham, MD, Frederick Arensman, MD, Robert H . Knopp, MD, Carlos DuJovne, MD, Christine L. Williams, MD, Jonathan L. Isaacsohn, MD, Carol A. Jacobsen, JD, Peter M. Laskarzewski, PhD, Sharon Ames, BSRD, Glenn J. Gormley, MD, PhD

Context: Heterozygous familial hypercholesrerolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Objective: To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH. Design: One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1930 and 1994. Setting: Fourteen pediatric out- patient clinics in the United States and Finland. Patients: Boys aged 10 to 17 years with HeFH. O f 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 43 placebo) completed the first and second periods, respectively. Intervention: Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mgld, respectively, or placebo. Main Outcome Measures: The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development. Results: Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly ( P < .001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respec- tively, and remained 25% lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks ( P = .85) and 48 weeks ( P = .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect signif- icant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. Conclusions: This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required. JAMA 1999;281:137-144. Copyright 1939, American Medical Association.

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