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into the intestinal lumen, or (3) alteration of the cytoskeletal architecture in the perivascular space to augment resorption of protein into the lymphatic return. It is possible that the therapeutic effect of heparin in this condition is related to its anticoagulative properties, because other components of the coagulation system have been implicated in the pathogenesis of PLE.15 Hypoproteinemia and subsequent intravascular volume depletion combined with the relatively static venous flow patterns created by a cavopulmonary connection predispose these patients to thrombosis. Chronic microemboli in the mesenteric circulation may be a potential mechanism of enteric protein loss in this clinical setting. Heparin may exert its therapeutic effect through lysis of these microemboli or by inhibiting their formation. This mechanism is unlikely for two reasons. First, neither Coumadin nor low molecular weight heparin had any therapeutic effect on PLE in Our patients despite laboratory evidence showing an adequate anticoagulative effect for each drug. Second, heparin reversed enteric protein loss at doses that are considered subtherapeutic for anticoagulation. This notion was supported by the normal partial thromboplastin time in our patients during heparin therapy. REFERENCES

1. Davidson JD, Waldmann TA, Goodman DS, Gordon RS. Protein-losing gastroenteropathy in congestive heart failure. Lancet 1961;1:899-902. 2. Jeejeebhoy KN. Cause of hypoalbuminemia in patients with gastrointestinal and cardiac disease. Lancet 1962;1:343-8. 3. Petersen VP, Mastrup J. Protein-losing enteropathy in constrictive pericarditis. Acta Med Scand 1963;173:401-3.

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4. Valberg LS, Corbett WEN, McCorriston JR. Excessive loss of plasma protein into the gastrointestinal tract associated with primary myocardial disease. Am J Med 1965;39:668-73. 5. Kmeger SK, Burney DW, Ferric RM. Protein-losingenteropathy compricafingthe Mustard procedure. Surgery 1977; 81:305-6. 6. Gleason WA, Rodman ST, Laks H. Protein-losing enteropathy and intestinal lymphangiectasia after superior vena cava-right pulmonary artery (Glenn) shunt. J Thorac Cardiovasc Surg 1984;88:606-9. 7. Hess J, Kruizinga K, Bijleveld CMA. Protein-losing enteropathy after Fontan operation. J Thorac Cardiovasc Surg 1979; 77:843-6. 8. Davis CA, Driscoll DJ, Perrault J, Greenwood DJ, Schaff HV, Puga FJ, et al. Enteric protein loss after the Fontan operation. Mayo Clin Proc 1994;69:112-4. 9. Warshaw AL, Waldmann TA, Laster L. Protein-losing enteropathy and malabsorption in regional enteritis: cure by limited ileal resection. Ann Surg 1973;178:578-80. 10. Rychik J, Piccoli DA, Barber G. Usefulness of corticoid steroid therapy for protein-losing enteropathy after the Fontan procedure. Am J Cardiol 1991;68:819-21. 11. Rothman A, Snyder J. Protein-losing enteropathy following the Fontan operation: resolution with prednisone therapy. Am Heart J 1991;121:618-9. 12. Jacobs ML, Rychik J, Bymm CJ, Norwood WI. Protein-losing enteropathy after Fontan operation: resolution after baffle fenestration. Ann Thorac Surg 1996;61:206-8. 13. Lane DA, Lindahl U, editors. Heparin: chemical and biological properties, clinical applications. London: E. Arnold, 1989. 14. Kanwar YS, Linker A, Farquhar MG. Increased permeability of the glomerular basement membrane to ferritin after removal of glycosaminoglycans (heparin sulfate) by enzyme digestion. J Cell Biol 1980;86:688-93. 15. Kondo M, Bamba T, Hosokawa K, Hosoda S, Kawai K, Masuda M. Tissue plasminogen activator in pathogenesis of protein-losing enteropathy. Gastroenterology 1976;70:1045-7.

Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism Susan R a g h a v a n , MD, J o a n DiMartino-Nardi, MD, Paul Saenger, MD, a n d Barbara Linder, MD, PhD From the Division of Pediatric Endocrinology, Depaffment of Pediatrics, Montefiore Medical Center, Albert EinsteinCollege of Medicine, Bronx, New York

Pseudotumor cerebri is generally a benign disorder. It has been reported to occur in hypothyroidism, particularly after the initiation of L-thyroxine replacement therapy. Previous case reports have involved children primarily in the peripubertal age range ( - 8 to 13 years). We report here the development of pseudotumor cerebri in an infant who required treatment with L-thyroxine for transient neonatal hypothyroidism as a result of maternal thyroid-stimulating hormone receptorblocking antibodies. (J Pediatr 1997;130:478-80) Submitted for publication June 18, 1996; accepted September 13, 1996. Reprint requests: Barbara Linder, MD, PhD, Division of Pediatric

Endocrinology, Montefiore Medical Center, 1l 1 East 210th Street, Bronx, NY 10467. Copyright © 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/22/78227

The Journal ~,f Pediatrics Volume 130, Number 3 CASE REPORT The patient was a 2580 gm female product of a term pregnancy and was born to a 38-year-old mother (G7, P6, 06) by spontaneous vaginal delivery. She appeared well at birth (Apgar scores, 7 at 1 minute and 9 at 5 minutes). The mother received no prenatal care but denied any problems during the pregnancy. The maternal medical history, however, was significaxlt for Graves disease, treated in the past with radioiodine ablation and currently with thyroxine replacement. The mother also had a history of cocaine abuse, although she denied having used drugs, alcohol, or tobacco during this pregnancy. At age 25 hours the baby was noted to be jittery and to have tachyeardia and respiratory distress. There was no exophthalmos, goiter, hepatusplenomegaly, lymphadenopathy, or thrombocytopenia. The baby was transferred to the neonatal intensive care unit, with a working diagnosis of drug withdrawal or sepsis. The maternal history of Graves disease was apparently not known at this time. The baby underwent a full diagnostic study for sepsis, and antibiotic therapy was started. All culture results were subsequently negative. A chest radiograph and an electrocardiogram were normal. Results of a urine toxicology screen were negative. The baby remained jittery and continued to have tachycardia, with poor feeding and progressive weight loss. On day 5 of life, thyroid function tests revealed thyrotoxicosis (T4, 528 nmol]L [41 ~g/dl]; triiodothyronine, 8.2 pmol/L [537 ng/ml]; free T~, 187 pmol/L [14.5 lag/dl]; thyrotropin, <0.1 mU/L [<0.1 oU/ml]). Therapy with propylthiouracil, propranolol, and Lugol iodine was started. The medication doses and the baby's clinical course are detailed ha the Table. Subsequent evaluation of both the mother and the baby revealed transplacental passage of both thyroid stimulatory and inhibitory immunoglobulins (thyroid-stimulating immunoglobulin, and thyrotropin-binding inhibitory immunoglobulin). Within 48 hours of the start of therapy, the baby's condition im proved significantly, with normalization of heart rate, improvedfeeding, and weight gain. By age 3 weeks, however, she had become hypothyroid (see Table). It was not clear whether the hypothyroidism was a result of the treatment with propylthiouracil alone, or whether it was the result of the presence of the blocking antibodies. Initially the patient was treated with thyroxine replacement, as well as propylthiouracil, because of concern that she might still be at risk of having thyrotoxieosis because of circulating TSI. Eventually her TSI levels declined, and she was weaned from propylthiouracil and treated with L-thyroxine alone. The initial thyroxine dose of 50 btg was based on the recommended dose I of 10 to 15 ~g/kg in the hypothyroid newborn infant. At age 2 months the dose was decreased to 37.5 gg because the patient's T4 level was elevated. With this dosage she appeared clinically and biochemically euthyroid and grew steadily on the 25th to 50th percentile for height, weight, and head circumference. At age 5 raonths the patient was noted to have split sutures and a bulging anterior fontanel and to have had a rapid increase in head circumference. She was afebrile and had no history of vomiting or altered sensorium. There were no focal signs on neurologic evaluation, and there was no papilledema. A cranial computed tomographic scan with contrast medium showed an increased cerebrospinal fluid volume with normal ventricular size and split sutures; there

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was no cerebral atrophy. A lumbar puncture revealed slightly elevated opening pressure, normal cerebrospinal fluid cytologic and chemistry findings, and negative culture results. Serum electrolyte levels were normal. At this time, the infant appeared clinically and biochemically euthyroid, with her thyroid values in keeping with current recommendations1 to maintain the serum T4 concentration in the upper half of the normal range (total T4, 129 to 206 nmol/L [10 to 16 gg/dl]; free T4, 18 to 30 pmol/L [1.4 to 2.3 ng/dl]). A diagnosis of pseudotumor cerebri was made. Because the infant appeared well, no therapy was instituted, and she was monitored closely as an outpatient in the neurology clinic. She continued to demonstrate normal growth and development with L-thyroxine, 37.5 ~ag daily. By age 8 months, her anterior fontanel was again flat; by age 12 months, her head circumference had become normal. At age 1 year the infant's thyroid antibodies had essentially been cleared, and L-thyroxine therapy was discontinued. Thyroid function, growth, and development continued to be normal.

DISCUSSION Pseudotumor cerebri or benign, idiopathic intracranial hypertension is characterized by increased intracranial pressure in the absence of a space-occupying lesion. Ven-

T4 TSI

Thyroxine Thyroid-stimulating immunoglobulin

1

tricular size is normal or small, and there is no cerebral atrophy. There are no focal neurologic signs, and as the name implies, the clinical course is generally benign, although visual impairment may rarely occur. In older children and adults the complaints are usually headache, nausea and vomiting, and visual disturbances. Papilledema is noted on physical examination. Infants and young children may initially have irritability and somnolence; papilledema is usually absent, presumably because pressure is somewhat dissipated through open fontanels and sprit sutures. 2 The mechanism involved in increasing intracranial pressure in pseudotumor cerebri is not known, and most cases are idiopathic. The majority of adult patients are female and obese, 3 but the sex distribution is equal in the pediatric population. 4 Some cases of pseudotumor are associated with endocrinopathy, 2 including Addison disease, the abrupt discontinuation of corticosteroid therapy, hypoparathyroidism, hyperthyroidism, and growth hormone treatment. Other associated conditions include hypophosphatasia, toxic effects of excessive amounts of vitamin A, and tetracycline use.

In addition, there are multiple case reports of the occurrence of pseudotumor within days and up to 4 months after initiation of L-thyroxine therapy for hypothyroidism in both adults 5 and children. There have been eight reports of children in whom pseudotumor developed after the initiation of

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T a b l o . Time course of biochemical findings and management

Age

Weight (kg)

1 Day 5 Days

2.58

9 Days 13 Days 16 Days 3 Wk 4 Wk 6 Wk 8 Wk 9.5 Wk 5 Mo 8 Mo 12 Mo 15 Mo

2.38 2.48 2.56 2.95 3.45 3.72 4.4 4.9 6.56 7.84 8.2 9.5

T4 (nmol/L)

]'3 (pmol/L)

582

8.2

564 127

11.6 4.3

42 184 192 221 190 192 116 121 111

0.9 2.5

FT4 (pmol/L)

Thyrotropin (mU/L)

187

<0.1

<0.1 0.01 24 5

2.1 2.5 2.3 3.1

0.5 0.01 0.09 0.01 0.02 0.23 0.47 1.49 2.9

TSI (%)

TBII (%)

Clinical course and management Onset of thyrotoxic symptoms Lugol iodine, 1 drop q8h; PT]U, 4 mg q8h; propranolol, 1 mg q8h

87 (N <14) Lugol iodine discontinued Propranolol discontinued L-Thyroxine, 50 lag daily added 111 (N <130) 93 (N<130) 107 (N <130)

62 (N <10) PTU discontinued L-Thyroxine, 37.5 ttg 43(N<10) 25 (N <10) Pseudotumor cerebri diagnosed 11

L-Thyroxine discontinued Normal growth parameters

To convertto metric units, multiplyT4 by 0.0777 to obtain microgramsper deciliter;multiplyT3 by 65.1 to obtain nanogramsper milliliter,or multiplyFT4 by 0.0777 to obtain nanogramsper deciliter. 7"3,Triiodothyronine;FT4,free thyroxine;TBII, thyrotropin-bindinginhibitoryimmunoglobulin;PTU, propylthiouracil.

thyroid-replacement therapy. 612 In most cases, treatment for increased intracranial pressure was not required, and symptoms resolved spontaneously. In some cases, reduction of the thyroxine dose appeared to be beneficial. 12 The origin of the hypothyroidism appears to be of no importance. These previous reports all involved children in the peripubertal age range (8 to 13 years), and it has been suggested 8 that hormonal changes during this period may predispose some children to the development of pseudotumor, albeit through unknown mechanisms. Our patient demonstrates that pseudotumor in association with thyroxine replacement therapy may also occur in an infant. In general, pseudotumor cerebri is a self-limited, benign disorder. If there is no visual impairment, no treatment is necessary.2 In the case of a child in whom pseudommor develops during the initiation of L-thyroxine therapy, biochemical evaluation of the child's thyroid status should be performed, ff thyrotropin is suppressed to less than 0.1 mU/L, 13 it would be prudent to decrease the dosage sfightly. However, given the transient nature of pseudotumor itself, it may not be possible definitively to attribute a resolution of symptoms to reduction of the dose. Care should be taken to maintain the T4 concenlration in the upper end of the normal range in the infant with hypothyroidism, because lower values are clearly associated with poorer intellectual outcomes. 14

REFERENCES

1. American Academy of Pediatrics. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1993;91:1203-9.

2. Lessell S. Pediatric pseudotumor cerebri (idiopathic intracranial hypertension). Surv Ophthalmol 1992;37:155-66. 3. Wall M, George D. Idiopathic intracranial hypertension. Brain 1991;114:155-80. 4. Grant DN. Benign intracranial hypertension. Arch Dis Child 1971 ;46:65 i-5. 5. Press OW, Ladenson PW. Pseudotumor cerebri and hypothyroidism. Arch Intern Med 1983; 143:167-8. 6. Wan Wyk JJ, Grumbach MM. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960;57:416-34. 7. Prendes JL, McLean WT. Pseudotumor cerebri during treatment for hypothyroidism. South Med J 1978;71:977. 8. VanDop C, Conte FA, Koch TC, Clark SJ, Wilson-Davies SL, Gmmbach MM. Pseudotumor cerebri associated with initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med 1983;308:1076-80. 9. McVie R. Pseudotumor cerebri and thyroid replacement therapy [letter]. N Engl J Med 1983;309:731. 10. Hymes LC, Warsaw BL, Schwartz JF. Pseudotumor cerebri and thyroid replacement therapy. N Engl J Med 1983;309: 732. 11. Huseman CA, Torkelson RD. Pseudotumor cerebri following treatment of hypothalamic and primary hypothyroidism. Am J Dis Child 1984;138:927-31. 12. Campos S, Olitsky S. Idiopathic intracranial hypertension after L-thyroxine therapy for acquired primary hypothyroidism. Clin Pediatr 1995;34:334-7. 13. Germak JA, Foley TP. Longitudinal assessment of L-thyroxine therapy for congenital hypothyroidism. J Pediatr 1990;117: 211-9. 14. Heyerdahl S, Kase BF, Lie SV. Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment. J Pediatr 1991;118: 850-7.