Pituitary DOI 10.1007/s11102-013-0547-4

Evaluation of hypothalamic–pituitary function in children following acute bacterial meningitis Eda Karadag-Oncel • Meltem Cakir • Ates Kara • Nazli Gonc • Ali Bulent Cengiz • Alev Ozon • Ergin Ciftci Ayfer Alikasifoglu • Mehmet Ceyhan • Nurgun Kandemir



Ó Springer Science+Business Media New York 2013

Abstract Background Previous studies in adults and case reports in children have shown increased frequency of hypothalamopituitary dysfunction after infectious diseases of the central nervous system. The aim of this study was to evaluate the function of hypothalamo-pituitary axis in children with a history of bacterial meningitis. Methods Patients diagnosed with bacterial meningitis between April 2000 and June 2011 was included. Baseline and stimulated hormonal tests were performed as required for hormonal evaluations following a diagnosis of meningitis. Results Pituitary function was assessed following a period of 8–135 months (mean 53 months) after bacterial meningitis. Thirty-seven cases (27 male, 15 pubertal) with mean age of 11.1 ± 4.4 years were included. Mean height SDS was 0.01 ± 1.07 and mean BMI SDS was 0.54 ± 1.15 all patients had a SDS above -2 SD. Baseline cortisol and low dose ACTH stimulation revealed normal adrenal functions in all patients. Gonadotropin deficiency was not detected in any of the pubertal cases. Four cases (10.8 %) had low IGF1 and IGFBP3 z-scores (\-2 SD) according to age, sex and Tanner stage, but peak GH

E. Karadag-Oncel (&)  A. Kara  A. B. Cengiz  M. Ceyhan Department of Pediatric Infectious Disease, Faculty of Medicine, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey e-mail: [email protected] M. Cakir  N. Gonc  A. Ozon  A. Alikasifoglu  N. Kandemir Department of Pediatric Endocrinology, Faculty of Medicine, Hacettepe University, Ankara, Turkey E. Ciftci Department of Pediatric Infectious Disease, Faculty of Medicine, Ankara University, Ankara, Turkey

response in clonidin test was [10 ng/ml in three of them suggesting neurosecretary dysfunction of GH in these cases. The fourth case has died before the test. No one had TSH deficiency and diabetes insipidus, only one case had mild hyperprolactinemia. Conclusions Our findings suggest that hypothalamopituitary dysfunction is not as common in childhood as in adulthood. The most remarkable finding was neurosecretary dysfunction of GH in some cases. Keywords Children  Bacterial meningitis  Hypopituitarism

Introduction Bacterial meningitis is a clinical condition characterized by inflammation of the meninges as a response to bacteria or bacterial products. It is associated with severe morbidity and mortality, particularly in neonates and children. Almost all microorganisms are potential causes of meningitis [1]. A delay in disruption of the inflammatory process during meningitis has detrimental effects on cerebrospinal fluid (CSF) dynamics. The ensuing brain edema and increased intracranial pressure eventually take their toll on brain metabolism resulting in significant disruption of cerebrovascular autoregulation. Decreased cerebral blood flow facilitates the production of free oxygen radicals, excitatory amino acids and metalloproteinases, which along with caspases lead to acceleration of cellular apoptosis and hence neuronal damage [2, 3]. Apoptosis-related neuronal cell death and ensuing tissue necrosis in the neocortex as well as in the dental gyrus and CA1-4 sectors of the hippocampus as a result of meningitis have been demonstrated in experimental studies and human

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autopsy series [4–6]. Although the effects of infections of the central nervous system (CNS) on the hypothalamic and pituitary areas in adult populations have been well-documented [7], data on the effects on children remains limited. Hypothalamic–pituitary failure has been reported in association with tuberculous meningitis [8, 9]. However, an association with other causes of bacterial meningitis has not yet been established. To date, studies on childhood CNS infections have involved both viral and bacterial etiologies [10, 11], with no study focusing on just bacterial causes of meningitis. The aim of this study was to determine the incidence of hypothalamic–pituitary dysfunction in pediatric patients with a history of bacterial meningitis of different etiologies.

obtained from the patients’ records. Patients were requested to present to the outpatient clinic after an 8–12 h overnight fast. Basal hormone levels were obtained at 8.00 a.m. after a fasting. A detailed menstrual history was obtained from female adolescents. Clinical evaluation included height and weight measurements, as well as assessment of pubic hair and genital development according to Tanner’s stages of pubertal development. Height SDS was calculated with CDC 2000 charts using the following formula; Height SDS :

Height  Mean SD

Body mass index (BMI) SDS was calculated by BMI with L, M, S values according to the age and sex ðBMI=MÞL  1 LS

Materials and methods

BMI SDS :

Patient selection and study design

Hormone assays

This study was undertaken at Hacettepe University Ihsan Dogramacı Children’s Hospital with the approval of the local ethics committee, in accordance with the Helsinki Declaration. The medical records of children under the age of 18 years who were diagnosed with bacterial meningitis between April 2000 and June 2011 were retrieved. Patients for which at least 6 months had elapsed following the diagnosis of meningitis were selected for enrolment. Parents were contacted by phone using the contact details available on the medical records, and those who could be contacted were kindly invited with the children to the outpatient clinic to discuss the study details. After obtaining parental consent, patients were screened for eligibility. A diagnosis of bacterial meningitis in the clinically suspected cases was primarily based on a positive cerebrospinal fluid culture (CSF) result. In the even of a negative culture result, a diagnosis required the presence of typical CSF findings consistent with bacterial meningitis (white blood cell count, protein and glucose levels) [1]. Children with diabetes mellitus or a previously diagnosed endocrinological disorder, tuberculous meningitis, a history of a hematological or solid organ malignancy, known immune deficiency disorder, malnutrition, congenital or acquired condition of the central nervous system such as hydrocephalus or head trauma, or an intracranial complication as a sequela of bacterial meningitis (brain abscess or subdural empyema) were excluded from the study. Patients receiving inhaler or topical glucocorticoids, neuroleptics or any other medication that may affect hormone levels were also excluded from the study. Information regarding the date of diagnosis, age at diagnosis, presenting symptom(s), results of blood workup (complete blood count, blood biochemistry), CSF findings and results of CSF cultures were

Serum levels of thyrotropin (TSH), free thyroxine (fT4), insulin-like growth factor 1 (IGF1), insulin-like growth factor-binding protein 3 (IGFBP3), adrenocorticotropin (ACTH), cortisol, prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (in males [14 years), estradiol (in females [13 years) were measured by immunoradiometric assay and radioimmunoassay using commercially available kits (RIA, Kit Coat-ACount, USA). Patients with a baseline serum cortisol level of\15 lg/dl were subjected to a low dose ACTH stimulation test; 0.5 mcg/m2 tetracosactrin (SynacthenÒ) was injected intravenously as a bolus dose. Serum cortisol was obtained before and at 20, 30, 40 min after injection. The cut off level of plasma cortisol level of 19.6 mcg/dl indicates an intact HPA axis [12]. Central hypothyroidism was defined as the presence of a low serum fT4 level without appropriate elevation in serum TSH (normal range 0.27–4.2 mIU/ml). Square root transformation was used for IGF-1 data since this transformation gave the best approximation to a normal distribution of the data. In IGFBP3 levels, no transformation was required. According the age, sex and Tanner stage, the a, b and SD values were used to determine the age, sex and puberty corrected z-score for IGF1 and IGFBP3 using the following formulas [12, 13];

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y ¼ bxageðyearÞ þ a z-scoreðIGF-1Þ ¼ ðSQR of IGF-3 value  yÞ=SD z-scoreðIGFBP-3Þ ¼ ðSQR of IGFBP-3 value  yÞ=SD Patients whose IGF-1 and IGF-BP3 Z-scores were 2 SD below the mean, were underwent growth hormone (GH) stimulation test [13, 14]. Clonidine test was carried out

Pituitary

between 8.00 and 9.00 am after fasting overnight. Blood samples were collected at before and 30, 60, 90 and 120 min after the administration of 150 mg/m2 clonidine perorally for GH determination. Whereas a diagnosis of hyperprolactinemia required an elevated baseline serum PRL above the upper limit of normal, taking into account gender differences and menstrual history (male 1.9–25, female 10–25 ng/ml). A normal hypothalamic–pituitary–gonadal axis was indicated by normal estradiol and gonadotropin levels in menstruating females, or the presence of normal testosterone and gonadotropin levels in males. Patients with a history of polyuria, polydipsia and/or hypernatremia were planned to the further investigated for vasopressin deficiency. Statistical analysis Statistical analyses were performed using the SPSS packet program for Windows version 15.0. Categorical variables were provided as numbers and percentages. Continuous variables were given as mean ± standard deviation or median, minimum and maximum depending on normality of distribution. A p value of \0.05 was considered indicative of statistical significance.

Results Patient characteristics During the period of April 2000–June 2011, there were 70 patients who fulfilled the inclusion criteria, 30 could not be contacted via the contact details on record. Out of the

remaining 40 patients who could be contacted by phone, three did not consent to participation (Fig. 1). Overall, 37 patients (27 male, 10 female) were recalled for a detailed endocrine assessment at the outpatient clinic of the Pediatric Endocrinology Department. The mean age at the time of diagnosis with acute bacterial meningitis was 73 months (1–169). In 34 (91.8 %) of the patients, fever was the presenting symptom, followed by vomiting in 25 patients (67.5 %), headache in 11 patients (29.7 %), neurological findings (lethargy, convulsions) in eight patients (21.6 %) and a rash in two patients (5.4 %). Mean hemoglobin concentration at the time of diagnosis was 11.7 ± 1.88 g/dl with a median total leukocyte count of 14,000/mm3 (3,600–26,800). In terms of blood biochemistry, seven patients (18.9 %) had a serum Na level \135 mEq/l on presentation. A growth occurred on the CSF culture of 17 of the 37 patients (45.9 %) with bacterial meningitis (Table 1). Streptococcus pneumonia was the most commonly isolated microorganism in nine patients (52.9 %) followed by Haemophilus influenza type b in four patients (23.5 %), other members of the Neisseria meningitides in one patient (5.8 %), Streptococcus mitis in one patient (5.8 %), Staphylococcus capitis in one patient (5.8 %) which rule out contamination with biochemical confirmation, and Acinetobacter baumannii in one patient (5.8 %). Monotherapy with a third generation cephalosporin (cefotaxime or ceftriaxone) was the most frequently administered antibiotic protocol in 81 % of patient. A thirdgeneration cephalosporin was combined with vancomycin in six patients (16.2 %) and with ampicillin in one patient (2.7 %). The median duration of treatment was 10 days (7–21). There is no statistically difference in CSF glucose and protein between microbiologically or biochemically

Fig. 1 Study assignment and follow-up

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Pituitary Table 1 Summary of clinical and laboratory findings of study population during meningitis Parameter

Patients (n = 37)

Age (months)a

73 (2–169)

Gender

b

Male

27 (73 %)

Female

10 (27 %)

Presenting symptomb Fever

34 (91.8 %)

Vomiting Headache

25 (67.5 %) 11 (29.7 %)

Neurologic symptoms

8 (21.6 %)

Rash

2 (5.4 %)

Laboratory findings Hb (g/dl)c

11.7 ± 1.88

Leukocyte count (/mm3)a

14,000 (3,600–26,800)

Platelet count (/mm3)a

346,000 (94,000–940,000)

Hyponatremia (\135 meq/L)b

7 (18.9 %)

CSF culture positivityb

17 (45.9 %)

Hb hemoglobin, CSF cerebrospinal fluid a

Values are given as median (minimum–maximum)

b

Values are given as percentage Values are given as mean ± standard deviation

c

confirmed groups (34.0 ± 25.7 vs. 42.5 ± 13.9 mg/dl; p = 0.13 and 113.0 ± 65.0 vs. 90.5 ± 32.0 mg/dl; p = 0.74, respectively). Hormonal evaluation Evaluation of hormones of the hypothalamic–pituitary axis was performed a median of 53 months (8–135) after a diagnosis of acute bacterial meningitis. Mean height SDS was 0.01 ± 1.07 and mean BMI SDS was 0.54 ± 1.15 all patients had a SDS above -2 SD. All patients had normal TSH and fT4 values, with a median fT4 level of 16.4 pmol/l

(12.1–21.29). Four patients had IGF1 and IGFBP3 z-scores of 2 SD below the mean, all of whom had normal height SDS values at the time of diagnosis (Table 2). While in three of the patients meningitis infection had resulted in a decrease in height SDS, the fourth patient had already achieved final height before getting meningitis. Three patients had decreased levels of IGF1 and IGFBP3 along with a reduction in height SDS, albeit without developing short stature. Three of these patients had a peak GH response [10 ng/ml in clonidine stimulation test (Table 2) who did not have a history of malnutrition or other diseases. Fourth patient died due to traffic accident before the clonidine stimulation test. The median cortisol level of the study population was 12.3 lg/dl (5.90–23.60). Although 20 patients (54 %) had a baseline cortisol level of \15 lg/dl, a sufficient cortisol response was observed in all of them following a low dose ACTH stimulation test. With a median PRL level of 12.1 ng/ml (5.16–30.2) one patient had mild hyperprolactinemia (Table 3). Tanner’s stage was assessed in patients, 23 (62 %) of them were at stage 1, one (2.7 %) was stage 2, three (8.1 %) were stage 3, two (5.4 %) were stage 4 and 8 (21.6 %) were stage 5. Serum levels of gonadotropins and sex steroids were measured in 14 patients, in all of whom hormone levels were within normal range. None of the patients had clinical symptoms and electrolyte disturbances suggestive of central diabetes insipidus. Comparisons of patients with and without positive CSF cultures did not reveal the presence of any statistically significant difference in terms of hormone levels (p [ 0.05 for all comparisons).

Discussion Acute infectious meningitis is a well-documented cause of hypothalamic and/or pituitary insufficiency in adults,

Table 2 Results of GH stimulation tests, IGF1, and IGFBP3 z-scores in four patient whom had IGF1 and IGFBP3 z-scores of 2 SD below the mean Cases

Age at the time of hormonal evaluation

Age at the time of meningitis

Sex

H-SDS1

H-SDS2

BMI SDS

IGF1 z-score

IGFBP3 z-score

Clonidine peak GH response (ng/ml)

1

19 year

13 year 5 months

Male

-0.22

-0.5

-0.02

-2.5

-2.66

19.6

2

18 year

8 year 6 months

Female

-0.06

-1.99

-0.8

-4.6

-2.53

13.3

3

17 year 7 months

13 year 9 months

Male

0.84

-2.2

-3.3

11.5

4*

18 year 6 months

16 year 10 months

Female

-1.12

-4.2

-2.43



0.12 -1.63

-0.4 -1.63

H-SDS1 height-standard deviation score at the time of diagnosis, H-SDS2 last height-standard deviation score, BMI body mass index, IGF-1 insulin like growth factor-1, IGFBP-3 insulin like growth factor binding protein-3 * Died before performing a GH stimulation test

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Pituitary Table 3 Summary of hormone assay results of the study population Hormones

Patient results

Normal range

TSH (uIU/ml)a

2.65 (1.32–5.82)

0.27–4.2

fT4 (pmol/l)a

16.40 (12.1–21.29)

12–22

ACTH (pg/ml)a

18.90 (6.29–59.20)

0–46

a

Kortizol (lg/dl)

12.30 (5.90–23.60)

5–25

PRL (ng/ml)a

12.10 (5.16–30.20)

2.58–18.12

IGF-1 (ng/ml)b

201.5 ± 95.5

IGF-1 z scoreb

-1.05 ± 1.22

IGFBP-3 (ng/ml)b

3,113 ± 393

IGFBP-3 z scoreb

-0.953 ± 1.07

TSH thyrotropin, fT4 free thyroxine, ACTH adrenocorticotropin, PRL prolactin, IGF-1 insulin-like growth factor-1, IGFBP-3 insulin-like growth factor-binding protein-3 a

Values are given as median (minimum–maximum)

b

Values are given as mean ± standart deviation

tuberculous meningitis being the most widely recognized [8, 15]. Hypopituitarism has been reported to occur many years after recovery from an acute illness in a subset of patients who suffered from tuberculous meningitis during childhood, the clinical spectrum of which may range from an isolated deficiency of a pituitary hormone to panhypopituitarism [15, 16]. To date, pituitary insufficiency following acute infectious meningitis has been studied in only four systematic studies [7, 10, 11, 17], all of which involving adult populations. Furthermore, these studies included patients with acute meningitis regardless of the causative pathogen (bacterial, viral and fungal). In two of these studies, pituitary function was evaluated both during and 12 months after an acute infection [10, 11]. To the best of our knowledge, our study is the first of its kind to evaluate the hypothalamic–pituitary axis following acute bacterial meningitis of the childhood period, and hormone assays were performed a median of 53 months after an acute infection. In the study by Tsiakalos et al. [10], seven of the 16 participants had bacterial meningitis with N. meningitidis isolated in three patients and S. pneumoniae in two patients. L. monocytogenes and S. oralis were isolated in the CSF cultures of one patient each. Endocrine dysfunction in the acute period was observed in five patients. In two of these patients, endocrine function returned to normal after the acute period. Out of the two patients with growth of N. meningitis on CSF culture who also had an endocrine deficit in the acute period, an evaluation 12 months after the acute infection revealed the presence corticotropin deficiency in one patient and corticotropin with somatotropin deficiency in the other. The most commonly encountered endocrine deficit in studies on adult acute infectious meningitis is GH

deficiency. In a study from Turkey, four adult patients with acute bacterial meningitis had isolated GH deficiency diagnosed 6–48 months after the initial infection. GH deficiency has been reported at rate of 28.6 % [17]. In our study, four patients (10.8 %) had IGF1 or IGFBP3 z score 2 SD below the mean, 8–135 months after an acute infection. Measurement of circulating levels of IGF1 and IGFBP3 is widely believed by many experts to be the test of choice for a diagnosis of GHD, with a reported sensitivity and specificity of 70 and 95 %, respectively [18]. Combining IGF1 measurement with an evaluation of growth rate increases the sensitivity of the test to 95 % with a specificity of 96 %. Despite there is a decrease in height SDS in three of the four patient, patients with low IGF1 and IGFBP3 z-scores, none of them had height SDS \-2 SD in our study. This may be attributed to the fact that these patients developed meningitis at the end of the pubertal period, by which time they had already completed their height potential. In retrospective analysis of pituitary function in adult patients with previous CNS infections showed some patients had low IGF-1 concentration but normal GH peak at GH stimulation test [7, 10]. In a study of Schaefer et al. [7], there was no patient with GH deficiency in a cohort of 19 adults, although one patient had a very low IGF-1 concentration. In our study, GH stimulation test could have been performed in three of the four patients with IGF1, IGFBP3 z-score\-2SD, all of them had a peak GH response [10 ng/ml. These patients had a GH increase after stimulation but the parameters showing the activity of GH, IGF1 and IGFBP3 were found to be low. Although there is a lack of data analyzing 24 h GH profiles in these patients, these results showed that there may be a neurosecretory dysfunction of GH in these patients. Unfortunately, it can not be possible to administer GH therapy for these patients as they have already attained adult height. In previous studies, neurosecretory dysfunction was not evaluated in patients with the history of meningitis who had normal GH peak but low IGF levels. Accurate assessment of the hypothalamic–pituitary– adrenal axis is essential to avoid missing a diagnosis of central adrenal insufficiency and also prevent over diagnosis of this condition. Due diligence was exercised in our study, and all patients with a baseline serum cortisol level of \15 lg/dl were subjected to a low dose ACTH stimulation test [19]. A sufficient cortisol response was observed in all of the patients. In another adult study from Turkey [11], ACTH deficiency was reported in 10 % of patients 12 months after an attack of acute meningitis. In a study on 49 children with tuberculous meningitis, ACTH deficiency was present in only one patient [14]. Overall, ACTH deficiency in association with acute infectious meningitis has been reported less often than GH deficiency.

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In our study, PRL levels in most of participants were within normal range but one of them had mild hyperprolactinemia. Sporadic increases in PRL levels during the acute phase of a CNS infection have been described in some of case reports [20, 21]. In another study, despite transient hyperprolactinemia during an acute infection, normalization of PRL levels was observed after a 12-month follow-up [10]. Meningitis-related hypothalamic dysfunction has been reported to occur more frequently than pituitary disorders in studies on adult populations. Isolated posterior pituitary insufficiency as a result of a childhood CNS infection has been described in several case reports. In a retrospective study on 73 children with a severe CNS infection, central diabetes insipidus was observed in eight patients. Infectious agents isolated in this study include Group B streptococcus, H. influenza, S. pneumonia, and an unknown virus [22]. In adults, on the other hand, S. pneumonia and herpes simplex have been implicated as cause of diabetes insipidus, particularly in immunocompromised patients. Diabetes insipidus related to viral agents has been reported to occur in children [23, 24]. The development of diabetes insipidus in patients with tuberculous meningitis is suggestive of a more destructive clinical course and more extensive hypothalamic involvement in association with this pathogen compared to other causes of acute bacterial meningitis. None of our patients had any clinical or laboratory evidence supporting a diagnosis of posterior pituitary. Our findings are consistent with the results of other studies [7, 10, 17]. The pathogenic mechanisms responsible for hypothalamic pituitary insufficiency in acute meningitis remain unknown. In a very recent study [11], frequent elevations in levels of anti-pituitary and anti-hypothalamus antibodies following an attack of acute meningitis have been reported. Authors speculated that acute meningitis triggers an autoimmune process which may play a role in the development of hypopituitarism. In a study evaluating magnetic resonance findings of patients with traumatic brain injury, diffuse axonal damage was observed in 29 % of patients [25]. In another autopsy series on 26 patients with a history of bacterial meningitis, 25 patients had varying degrees of axonal injury ranging from mild to very severe [26]. It may be speculated that hypothalamo-pituitary insufficiency may indeed be a result of axonal injury. Alike in studies on adult populations, five of the cases in our study had hypothalamo-pituitary insufficiency. These of the four patients have GH secretory dysfunction which has not been reported before. The question as to why bacterial meningitis-related hypothalamo-pituitary insufficiency occurs less frequently in children compared to adults and does neurosecretary dysfunction seen in adults remains unanswered. Further

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prospective studies are needed to help elucidate the pathophysiology behind this entity. Conflict of interest

None.

Ethical standards Hacettepe University Faculty of Medicine Local Ethics Committee.

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Evaluation of hypothalamic-pituitary function in children following acute bacterial meningitis.

Previous studies in adults and case reports in children have shown increased frequency of hypothalamo-pituitary dysfunction after infectious diseases ...
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