- Email: [email protected]
Hypothalamic-pituitary dysfunction following group B beta hemolytic streptococcal meningitis in a neonate
February 1976 The Journal o f P E D I A T R I C S
289
Hypothalamic-pituitary dysfunction following group B beta hemolytic streptococcal meningitis in a neonate K. Gopalkrishna Pat,* Harvey M. Rubin, Phillips P. Wedemeyer, and Louie G. Linarelli, Pittsburgh, Pa.
W I T H NEONATAL I N F E C T I O N d u e to group B strepto-
cocci b e c o m i n g m o r e p r e v a l e n t in r e c e n t years, 1; 2 u n u s u a l c o m p l i c a t i o n s m a y b e seen m o r e f r e q u e n t l y . This r e p o r t describes a n infant with "late o n s e t "
group
B beta
h e m o l y t i c streptococcal m e n i n g i t i s w h o d e v e l o p e d h y p o t h a l a m i c - p i t u i t a r y d y s f u n c t i o n m a n i f e s t e d by d i a b e t e s
day. Seizures occurring on the second day required anticonvulsant therapy. Suspected cerebral edema was treated with dexamethasone and limitation of intravenous fluid to two-thirds of the calculated daily maintenance. There were no seizures after the sixth day. Two electroencephalograms performed one month apart were reported as within normal limits for age.
insipidus, t e m p e r a t u r e instability, a n d i m p a i r e d s e c r e t i o n of growth hormone, adrenocorticotrophic hormone, and thyrotrophic hormone.
CASE REPORT Patient D. L., a 1-month-old Caucasian male, presented after 24 hours of marked irritability and refusal to feed. He was born to a 23-year-old primigravida following an uncomplicated pregnancy, labor, and delivery. Birth weight was 3,799 gm; he remained well until the onset of this illness. On admission he was hypotonic and extremely irritable. Rectal temperature was 40.4~ pulse 160/minute, and respirations (grunting) 56/minute. Head circumference was 37.5 cm; the anterior fontanelle was bulging. Hemoglobin concentration was 14.9 gm/dl; white blood cell count was 3,100/mm ~ (60% neutrophils, 29% lymphocytes, 4% monocytes, and 7% band forms). Concentration of serum sodium was 146 mEq/1, potassium 5.3 mEq/l, and blood urea nitrogen 12 mg/dl. Cerebrospinal fluid contained 2,200 leukocytes/mm ~ (2,000 were polymorphonuclear) and the protein concentration was 985 mg/dl; there was no measurable glucose. Cultures of spinal fluid, blood, throat, and subdural fluid (2 ml) grew beta hemolytic streptococci, group B. Initial therapy with kanamycin and ampicillin was replaced with aqueous penicillin (300,000 U/kg/24 hours) on the second
From the Department of Pediatrics, Mercy Hospital and Children's Hospital, University of Pittsburgh, School of Medicine. *Reprint address: Department of Pediatrics, Mercy Hospital, 1400 Locust St., Pittsburgh, Pa. 15219.
See related articles, pp. 292 and 295. A serum sodium concentration of 159 mEq/1, noted on day 6, was initially attributed to fluid restriction. Subsequently, during rehydration the serum sodium level fell to normal range, but by the ninth day a persistent hypernatremia and hyperchloremia developed (NA + range 153-165 mEq/l, C1 range 118-131 m E q / 1) with a serum osmolality of 400 m O s m / k g and urine osmolality of 87 mOsm/kg. Urine output was intermittently over 300 ml/ hour; the specific gravity was less than 1.005, and the urinary sodium concentration was 10 mEq/1, while he was receiving 1/4 isotonic saline at daily maintenance rate. Pitressin tannate in oil, 0.2 ml, was administered intramuscularly; the serum sodium concentration fell from 165 mEq/1 to 134 mEq/1, and the urine osmolality increased to 402 mOsm/kg. Continued administration of 0.1 to 0.3 ml pitressin tannate in oil has been necessary every 1 to 3 days. Hypothermia (with temperature as low as 33 ~ was first noted on the ninth day, when it became necessary to care for him in an incubator. His rectal temperature varied directly with that of the incubator. When placed in room air his body temperature fell precipitously. By the seventh week o f hospitalization the temperature fluctuations were less marked inside the incubator and he was finally able to maintain normothermia in room air. Although spinal fluid cultures became sterile by the third day, spinal fluid glucose values ranging from 20-30 m g / d l into the fourth week of penicillin therapy suggested ventriculitis. A ventriculogram demonstrated an enlarged but patent ventricular system. The ventricular fluid contained 22 mononuclear cells/
Vol. 88, No. 2, pp. 289-291
290
Pai et aL
The Journal of Pediatrics February 1976
Table I. Endocrine studies at 5 weeks of age
Time Glucagon 0.5 mg subcutaneously Metyrapone
ACTH stimulation
0 1 hour 2 hour 3 hour Baseline Day of metyrapone Day after metyrapone Baseline Day 1 Day 2
Growth hormone (ng/ml)
17 Hydroxysteroids (mg/m~/24 hoHr
excretion)
2.6 1.34
2.7 4.0 0.40
0.25 0.45 0.30 7.50 6.50
mm) protein 66 mg/dl, and glucose 18 mg/dl. Culture of this fluid was sterile by both routine and L-form culture techniques. Repeat subduraI taps were negative. During the fifth week of hospitalization horizontal nystagmus and bilateral optic atrophy were detected. At this time it was also noted that the infant's cry was hoarse and his skin mottled. (See special studies section and Table I for endocrine evaluation.) The patient was discharged after 68 days of hospitalization on Thyrolar (equivalent to 1 grain of thyroid extract daily), and cortisone acetate (to provide 12 mg/mZ/day intramuscularly on alternate days). The diabetes insipidus was difficult to manage; it required variable doses of pitressin in oil from 0.1 to 0.3 ml intramuscularly every one to three days with close observation of daily weights, periodic determination of serum electrolytes, and osmolality, and his mother's impression of his urinary output. He was hospitalized again at 7 months of age with lethargy, feeding difficulty, and bulging fontanelle. Height was 69 cm (seventy-fifth percentile) and weight 7.3 kg (fiftieth percentile). His height during the first 7 months of life had paralleled the seventy-fifth percentile. A ventriculogram revealed massive obstructive hydrocephalus and a ventriculoatrial shunt was required. Recurrence of seizures required increased anticonvulsant medication. Severe psychomotor retardation was noted. At l I months of age his height was at the fiftieth percentile and weight at the twentieth percentile. SPECIAL
STUDIES
At 5 weeks of age the serum thyroxine level (MurphyPatee) was 5.1 /~g/dl with a repeat value of 3.8 /zg/dl (normal for age, 7.1 - !5.0 /~g/dl). 3 Thyroid-stimulating hormone value was 5.5 /~ units/ml. At that time a metyrapone (SU4885) test was performed, administering 300 m g / m 2 every four hours for 24 hours (Table I). The baseline value for urinary 17 hydroxysteroids (Porter Silber) was tow and there was no response to metyrapone.
(Normal baseline values for age are in a range of 0.5-4.4 mg/m2/24 hours.) 4 An A C T H stimulation test (20 units/ m 2 every 12 hours) showed a greater than 20-fold increase in 17 hydroxysteroids over a two-day period (Table I). A glucagon stimulation test with 0.5 m g subcutaneously failed to elicit a growth hormone response. Two nocturnal growth hormone values during sleep were 3.4 n g / m l and 2.6 ng/ml, respectively. A repeat glucagon stimulation test at 6 months of age showed a fasting growth h o r m o n e value of 2.2 ng/ml; the one-hour value was 3.0 n g / m l ; and a two-hour value was 3.4 n g / m l . DISCUSSION Pituitary-hypothalamic deficiency has been reported as a rare complication of bacterial meningitides such as pneumococcal) listerial, 6 and tuberculous. 7 Isolated diabetes insipidus was previously described in two neonates following group B streptococcal meningitis. 6 o u r patient, in addition to diabetes insipidus, manifested impairment of temperature regulation and several manifestations of hypopituitarism. The frank diabetes insipidus points to destruction of the hypothalamic centers involving the supraoptic and p a r a v e n t r i c u l a r nuclei or division of the supraoptic hypophysial tract above the median eminence: Hypopituitarism was exemplified by impaired release of growth hormone, adrenocorticotrophic hormone, and thyroid-stimulating hormone. Other manifestations ~ such as a b n o r m a l sleep pattern, obesity, and impaired sexual d e v e l o p m e n t may reveal themselves at a later date. This infant continued to have linear growth in spite of growth h o r m o n e deficiency as evidenced by provocative tests. It is u n c l e a r whether growth hormone is necessary for adequate growth in the first 6 months of life; some postcraniopharyngioma patients with unmeasurable growth h o r m o n e levels have grown well. 1~ REFERENCES
1. Barton LL, Feigin RD, and Lins R: Group B beta hemolytic streptococcal meningitis in infants, J PEDIATR 82:707, 1973. 2. Baker CJ, Barrett FF, Gordon RC, and Yow MD: Suppurative meningitis due to streptococci of Lancefield group B, J PEDIATR82:724, 1973. 3. Fisher DA: Advances in the laboratory diagnosi s of thyroid disease. Part I. J PEDIATR82:1, 1973. 4. Kenny FM, Richard s C, and Taylor FH: Reference standards for cortisol production and 17-hydroxycorticosteroid excretion during growth: Variation in the pattern of excretion of radiolabeled cortisol metabolites, Metabolism 19:280, 1970. 5. Abramsky O, Softer D, and Marks ES: Diabetes insipidus as a complication of pneumoccal meningitis, J Am Oeriatr Soc 21-232, 1973.
Volume 88 Number 2
6. Fenton LJ, and Kleinman LI: Transient di/tbetes insipidus in a newborn infant, J PEDIATR 85:79, 1974. 7. Haslam RHA, Winternitz WW, and Howieson J: Selective hypopituitarism following tuberculous meningitis, Am J Dis Child 188:903, 1969, 8. McReynolds EW, and Roy S: Diabetes insipidus secondary to group B beta hemolytic streptococcal meningitis, Tenn Med Assoc Vol. 117, 1974.
Hypothalarnic-pituitary dysfunction
29 1
Bauer HG: Endocrine and other clinical manifestations of hypothalamic disease, J Clin Endocrinol 14:13, 1954. 10. Kenny FM, Iturzaeta NF, Mintz D, Drash A, Garces Y, Susen A, and Askari HA: Iatrogenic hypopituitarism in craniopharyngioma: Unexplained catch-up growth in three children, J P~mATR 72:766, 1968. 9.
289
Hypothalamic-pituitary dysfunction following group B beta hemolytic streptococcal meningitis in a neonate K. Gopalkrishna Pat,* Harvey M. Rubin, Phillips P. Wedemeyer, and Louie G. Linarelli, Pittsburgh, Pa.
W I T H NEONATAL I N F E C T I O N d u e to group B strepto-
cocci b e c o m i n g m o r e p r e v a l e n t in r e c e n t years, 1; 2 u n u s u a l c o m p l i c a t i o n s m a y b e seen m o r e f r e q u e n t l y . This r e p o r t describes a n infant with "late o n s e t "
group
B beta
h e m o l y t i c streptococcal m e n i n g i t i s w h o d e v e l o p e d h y p o t h a l a m i c - p i t u i t a r y d y s f u n c t i o n m a n i f e s t e d by d i a b e t e s
day. Seizures occurring on the second day required anticonvulsant therapy. Suspected cerebral edema was treated with dexamethasone and limitation of intravenous fluid to two-thirds of the calculated daily maintenance. There were no seizures after the sixth day. Two electroencephalograms performed one month apart were reported as within normal limits for age.
insipidus, t e m p e r a t u r e instability, a n d i m p a i r e d s e c r e t i o n of growth hormone, adrenocorticotrophic hormone, and thyrotrophic hormone.
CASE REPORT Patient D. L., a 1-month-old Caucasian male, presented after 24 hours of marked irritability and refusal to feed. He was born to a 23-year-old primigravida following an uncomplicated pregnancy, labor, and delivery. Birth weight was 3,799 gm; he remained well until the onset of this illness. On admission he was hypotonic and extremely irritable. Rectal temperature was 40.4~ pulse 160/minute, and respirations (grunting) 56/minute. Head circumference was 37.5 cm; the anterior fontanelle was bulging. Hemoglobin concentration was 14.9 gm/dl; white blood cell count was 3,100/mm ~ (60% neutrophils, 29% lymphocytes, 4% monocytes, and 7% band forms). Concentration of serum sodium was 146 mEq/1, potassium 5.3 mEq/l, and blood urea nitrogen 12 mg/dl. Cerebrospinal fluid contained 2,200 leukocytes/mm ~ (2,000 were polymorphonuclear) and the protein concentration was 985 mg/dl; there was no measurable glucose. Cultures of spinal fluid, blood, throat, and subdural fluid (2 ml) grew beta hemolytic streptococci, group B. Initial therapy with kanamycin and ampicillin was replaced with aqueous penicillin (300,000 U/kg/24 hours) on the second
From the Department of Pediatrics, Mercy Hospital and Children's Hospital, University of Pittsburgh, School of Medicine. *Reprint address: Department of Pediatrics, Mercy Hospital, 1400 Locust St., Pittsburgh, Pa. 15219.
See related articles, pp. 292 and 295. A serum sodium concentration of 159 mEq/1, noted on day 6, was initially attributed to fluid restriction. Subsequently, during rehydration the serum sodium level fell to normal range, but by the ninth day a persistent hypernatremia and hyperchloremia developed (NA + range 153-165 mEq/l, C1 range 118-131 m E q / 1) with a serum osmolality of 400 m O s m / k g and urine osmolality of 87 mOsm/kg. Urine output was intermittently over 300 ml/ hour; the specific gravity was less than 1.005, and the urinary sodium concentration was 10 mEq/1, while he was receiving 1/4 isotonic saline at daily maintenance rate. Pitressin tannate in oil, 0.2 ml, was administered intramuscularly; the serum sodium concentration fell from 165 mEq/1 to 134 mEq/1, and the urine osmolality increased to 402 mOsm/kg. Continued administration of 0.1 to 0.3 ml pitressin tannate in oil has been necessary every 1 to 3 days. Hypothermia (with temperature as low as 33 ~ was first noted on the ninth day, when it became necessary to care for him in an incubator. His rectal temperature varied directly with that of the incubator. When placed in room air his body temperature fell precipitously. By the seventh week o f hospitalization the temperature fluctuations were less marked inside the incubator and he was finally able to maintain normothermia in room air. Although spinal fluid cultures became sterile by the third day, spinal fluid glucose values ranging from 20-30 m g / d l into the fourth week of penicillin therapy suggested ventriculitis. A ventriculogram demonstrated an enlarged but patent ventricular system. The ventricular fluid contained 22 mononuclear cells/
Vol. 88, No. 2, pp. 289-291
290
Pai et aL
The Journal of Pediatrics February 1976
Table I. Endocrine studies at 5 weeks of age
Time Glucagon 0.5 mg subcutaneously Metyrapone
ACTH stimulation
0 1 hour 2 hour 3 hour Baseline Day of metyrapone Day after metyrapone Baseline Day 1 Day 2
Growth hormone (ng/ml)
17 Hydroxysteroids (mg/m~/24 hoHr
excretion)
2.6 1.34
2.7 4.0 0.40
0.25 0.45 0.30 7.50 6.50
mm) protein 66 mg/dl, and glucose 18 mg/dl. Culture of this fluid was sterile by both routine and L-form culture techniques. Repeat subduraI taps were negative. During the fifth week of hospitalization horizontal nystagmus and bilateral optic atrophy were detected. At this time it was also noted that the infant's cry was hoarse and his skin mottled. (See special studies section and Table I for endocrine evaluation.) The patient was discharged after 68 days of hospitalization on Thyrolar (equivalent to 1 grain of thyroid extract daily), and cortisone acetate (to provide 12 mg/mZ/day intramuscularly on alternate days). The diabetes insipidus was difficult to manage; it required variable doses of pitressin in oil from 0.1 to 0.3 ml intramuscularly every one to three days with close observation of daily weights, periodic determination of serum electrolytes, and osmolality, and his mother's impression of his urinary output. He was hospitalized again at 7 months of age with lethargy, feeding difficulty, and bulging fontanelle. Height was 69 cm (seventy-fifth percentile) and weight 7.3 kg (fiftieth percentile). His height during the first 7 months of life had paralleled the seventy-fifth percentile. A ventriculogram revealed massive obstructive hydrocephalus and a ventriculoatrial shunt was required. Recurrence of seizures required increased anticonvulsant medication. Severe psychomotor retardation was noted. At l I months of age his height was at the fiftieth percentile and weight at the twentieth percentile. SPECIAL
STUDIES
At 5 weeks of age the serum thyroxine level (MurphyPatee) was 5.1 /~g/dl with a repeat value of 3.8 /zg/dl (normal for age, 7.1 - !5.0 /~g/dl). 3 Thyroid-stimulating hormone value was 5.5 /~ units/ml. At that time a metyrapone (SU4885) test was performed, administering 300 m g / m 2 every four hours for 24 hours (Table I). The baseline value for urinary 17 hydroxysteroids (Porter Silber) was tow and there was no response to metyrapone.
(Normal baseline values for age are in a range of 0.5-4.4 mg/m2/24 hours.) 4 An A C T H stimulation test (20 units/ m 2 every 12 hours) showed a greater than 20-fold increase in 17 hydroxysteroids over a two-day period (Table I). A glucagon stimulation test with 0.5 m g subcutaneously failed to elicit a growth hormone response. Two nocturnal growth hormone values during sleep were 3.4 n g / m l and 2.6 ng/ml, respectively. A repeat glucagon stimulation test at 6 months of age showed a fasting growth h o r m o n e value of 2.2 ng/ml; the one-hour value was 3.0 n g / m l ; and a two-hour value was 3.4 n g / m l . DISCUSSION Pituitary-hypothalamic deficiency has been reported as a rare complication of bacterial meningitides such as pneumococcal) listerial, 6 and tuberculous. 7 Isolated diabetes insipidus was previously described in two neonates following group B streptococcal meningitis. 6 o u r patient, in addition to diabetes insipidus, manifested impairment of temperature regulation and several manifestations of hypopituitarism. The frank diabetes insipidus points to destruction of the hypothalamic centers involving the supraoptic and p a r a v e n t r i c u l a r nuclei or division of the supraoptic hypophysial tract above the median eminence: Hypopituitarism was exemplified by impaired release of growth hormone, adrenocorticotrophic hormone, and thyroid-stimulating hormone. Other manifestations ~ such as a b n o r m a l sleep pattern, obesity, and impaired sexual d e v e l o p m e n t may reveal themselves at a later date. This infant continued to have linear growth in spite of growth h o r m o n e deficiency as evidenced by provocative tests. It is u n c l e a r whether growth hormone is necessary for adequate growth in the first 6 months of life; some postcraniopharyngioma patients with unmeasurable growth h o r m o n e levels have grown well. 1~ REFERENCES
1. Barton LL, Feigin RD, and Lins R: Group B beta hemolytic streptococcal meningitis in infants, J PEDIATR 82:707, 1973. 2. Baker CJ, Barrett FF, Gordon RC, and Yow MD: Suppurative meningitis due to streptococci of Lancefield group B, J PEDIATR82:724, 1973. 3. Fisher DA: Advances in the laboratory diagnosi s of thyroid disease. Part I. J PEDIATR82:1, 1973. 4. Kenny FM, Richard s C, and Taylor FH: Reference standards for cortisol production and 17-hydroxycorticosteroid excretion during growth: Variation in the pattern of excretion of radiolabeled cortisol metabolites, Metabolism 19:280, 1970. 5. Abramsky O, Softer D, and Marks ES: Diabetes insipidus as a complication of pneumoccal meningitis, J Am Oeriatr Soc 21-232, 1973.
Volume 88 Number 2
6. Fenton LJ, and Kleinman LI: Transient di/tbetes insipidus in a newborn infant, J PEDIATR 85:79, 1974. 7. Haslam RHA, Winternitz WW, and Howieson J: Selective hypopituitarism following tuberculous meningitis, Am J Dis Child 188:903, 1969, 8. McReynolds EW, and Roy S: Diabetes insipidus secondary to group B beta hemolytic streptococcal meningitis, Tenn Med Assoc Vol. 117, 1974.
Hypothalarnic-pituitary dysfunction
29 1
Bauer HG: Endocrine and other clinical manifestations of hypothalamic disease, J Clin Endocrinol 14:13, 1954. 10. Kenny FM, Iturzaeta NF, Mintz D, Drash A, Garces Y, Susen A, and Askari HA: Iatrogenic hypopituitarism in craniopharyngioma: Unexplained catch-up growth in three children, J P~mATR 72:766, 1968. 9.