Central diabetes insipidus: clinical profile that suggests ... · or a serum sodium > 150 mEq/L with a water deprivation test docu-menting CDI or with an MRI showing a structural

J Pediatr Endocrinol Metab 2016; aop

Miguel Angel De los Santos*, Carlos Manuel Del Águila, Maria Isabel Rojas, Juan Manuel Falen, Oswaldo Nuñez, Eliana Manuela Chávez, Oscar Antonio Espinoza, Paola Marianella Pinto and Martha Rosario Calagua

Central diabetes insipidus: clinical profile that suggests organicity in Peruvian children: Lima – Peru 2001–2013DOI 10.1515/jpem-2016-0140Received April 13, 2016; accepted September 26, 2016

Abstract

Background: Central diabetes insipidus (CDI) is a het-erogeneous disease caused by arginine vasopressin defi-ciency; its management implies a profound understand-ing of the pathophysiology and the clinical spectrum. The aim of the study was to describe the clinical characteris-tics that indicate organicity in children and adolescents with central diabetes insipidus treated at the Department of Endocrinology from The Child Health’s Institute during 2001 to 2013.Methods: Cross-sectional, retrospective study. 79 cases of patients diagnosed with CDI (51 males and 28 females) from 1 month to 16 years of age were reviewed. For the descriptive analysis, measures of central tendency and dispersion were used; groups of organic and idi-opathic CDI were compared using χ2-test and t-test. A p-value < 0.05 was considered significant.Results: The average age of patients was 8.1 ± 4.2 years. Organic causes were intracranial tumors, 44 (55.7%), Langerhans cell histiocytosis (LCH), 11 (13.9%) and cer-ebral malformations in 7 (8.9%) patients, while the idi-opathic group was 14 (17.7%) patients. Regarding clini-cal characteristics suggestive of organicity, headache (p = 0.02) and visual disturbances (p = 0.01) were found statistically significant. The anterior pituitary hormonal abnormalities were documented in 34 (52.3%) organic

CDI patients. Furthermore, we did not find a significant difference in the average daily dose of desmopressin between patients with permanent vs. transitory CDI (0.81 ± 0.65 vs. 0.59 ± 0.62; p = 0.363).Conclusions: The main clinical features suggestive of organicity in pediatric patients with central diabetes insipidus were headache and visual disturbances; fur-thermore, anterior pituitary hormonal abnormalities sug-gest an underlying organic etiology.

Keywords: central diabetes insipidus; idiopathic; organic.

IntroductionCentral diabetes insipidus (CDI) is a complex and some-times even challenging to diagnose disorder [1, 2] charac-terized by abnormally large volumes of dilute urine due to a deficiency in arginine vasopressin secretion which results in polyuria, polydipsia, increased plasma osmolality, and decreased urine osmolality. In many patients, especially children, it is caused by the destruction or degeneration of neurons that originate in the supraoptic and paraventricu-lar nuclei of the hypothalamus [3]. Despite its low preva-lence of 1 : 25,000 [4], the Child Health’s Institute, being a referral tertiary level hospital, receives a great number of patients from all over the country.

Clinical presentation is wide. Urine output usually exceeds the 2 L/m2 per day, associated with increased fluid intake, nocturia, short stature, headache, vomiting, and visual disturbances, being polyuria and polydipsia the two most common complaints [4–6]. Common causes of CDI in childhood can be clustered in three major cat-egories: acquired: intracranial tumors [craniopharyn-gioma, germinoma, glioma, astrocytoma, Langerhans cell histiocytosis (LCH), granulomatous disease, autoim-mune, central nervous system (CNS) infections, trauma (accidents, neurosurgical interventions); congenital: mainly CNS malformations and hereditary (mutations in arginine vasopressin gene – chromosome 20; p.13)].

*Corresponding author: Miguel Angel De los Santos, MD, Department of Endocrinology and Metabolism of The Child Health´s Institute (Instituto Nacional de Salud del Niño) Lima - Perú, Brazil Avenue 600, Phone: 005113300066, Option 2380, Personal number: 0051997067728, E-mail: [email protected] Manuel Del Águila, Maria Isabel Rojas, Juan Manuel Falen, Oswaldo Nuñez, Eliana Manuela Chávez, Oscar Antonio Espinoza, Paola Marianella Pinto and Martha Rosario Calagua: Department of Endocrinology and Metabolism, The Child Health’s Institute. Breña, Lima PE

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2 De los Santos et al.: Central diabetes insipidus in peruvian children

Patients with intracranial tumors, specifically crani-opharyngioma suffer from multiple deficits of hypotha-lamic–pituitary function, which can extend to complete pituitary deficiency. Irreversible CDI follows after 80%–93% of all complete resections [7]. Second to tumors, LCH represents the most common etiology of organic CDI in childhood, being isolated CDI the initial presentation of LCH in some children and adolescents [8]. Clinical series data report 12%–54% of childhood cases initially are clas-sified as idiopathic [9–11]. Nonetheless, these numbers are decreasing with recognition of vasopressin-cell anti-bodies and others markers of autoimmunity [12, 13] and molecular analysis of arginine–vasopressin neurophysin II gene in children with idiopathic CDI and in familial cases [14–16].

In this report, we retrospectively investigated the clinical profile of 79 children with CDI, especially those characteristics that suggest organic etiology that would be important in the follow-up of these patients, dose of daily desmopressin acetate in permanent and transitory cases and the presence of anterior pituitary hormonal abnor-malities. This study represents the first investigation of CDI in our country in a pediatric sample.

Materials and methodsThis cross-sectional retrospective study was conducted in The Child Health’s Institute in Lima – Peru, a referral tertiary level health facil-ity, and was approved by the Local Ethics Committee. Patients with diagnosis of CDI that attend to the department of Endocrinology, from 1 month to 16 years of age were selected from January 2001 to Decem-ber 2013. CDI diagnosis in the outpatient was made upon the clini-cal history of polyuria, polydipsia, urine osmolality < 300 mOsm/kg or a urinary density < 1010 and plasma osmolality > 300 mOsm/kg or a serum sodium > 150 mEq/L with a water deprivation test docu-menting CDI or with an MRI showing a structural lesion affecting the hypothalamic – pituitary area, having a clinical response that show an increase in urine osmolality/urinary density, normalization of serum sodium and clinical improvement of polyuria and polydip-sia with desmopressin acetate administration. In the perioperative period following surgical removal of an intracranial tumor, CDI was diagnosed with a serum sodium > 150 mEq/L and polyuria > 4 cc/kg/h in the first 2 consecutive hours after surgery. Clinical, anthro-pometric and hormonal characteristics of 79 children were reviewed to identify age of diagnosis, group of age more affected, presenting features in particular those suggestive of organicity, anterior pitui-tary hormone deficiencies and average daily dose of desmopressin.

Patients were classified on the basis of cause and duration of CDI. Cases without any identifiable cause were regarded as idi-opathic, whereas cases with a history of an intracranial tumor, LCH, granulomatous disease, autoimmune, CNS infections, trauma, mal-formations, and Wolfram disease were considered organic. Regard-ing duration, patients with CDI lasting < 10 days in the postoperative course of a neurosurgical procedure or during a CNS infection were

considered transient cases. SPSS version 22 was used for analysis. For the descriptive analysis, measures of central tendency and dis-persion were used; groups of organic vs. idiopathic and permanent vs. transient CDI were compared using χ2-test and t-test. A p-value < 0.05 was considered significant. During the study, the researchers acted accordingly to the ethical principles of investigation stated in the Helsinki’s Declaration.

ResultsSeventy-nine children (51 males and 28 females) with CDI were included in the analysis. The frequency of CDI according to sex and group age is shown in Table 1. Overall, the mean age at diagnosis was 8.1 ± 4.2 years (range 0.08–16 years), being more frequent between 6 and < 12 years old (36.7%).

The presenting clinical manifestations of CDI are described in Table 2. The clinical characteristics more prevalent were polyuria and polydipsia, 98.5% and 84.6%, respectively, in organic CDI, and 100% for both characteristics in idiopathic CDI. The clinical spectrum is wide in this entity with presenting manifestations such as headache, short stature, visual disturbances, vomit-ing, nocturia, fatigue, sensitive/motor weakness, loss of weight. Of these characteristics, headache (47.7% vs. 14.3%; p = 0.02) and visual disturbances (33.8% vs. 0%; p = 0.01) were statistically significant differences between the two groups.

The different etiologies of CDI are explained in Table 3. In 65 (82.3%) patients, an organic etiology was identified. The most common cause of CDI in children was intracranial tumors (n = 44) craniopharyngioma being the leading one (n = 30) followed by pituitary adenoma (n = 5) pilocytic astrocytoma (n = 3), germinoma (n = 2). 43/44 of

Table 1: Age, sex, and group age of children with central diabetes insipidus.

Parameter

Age, years Mean ± SD (range) Age 8.1 ± 4.2 (0.08–16)

Sex n % Boys 51 64.6% Girls 28 35.4%

Group age n % < 1 years 2 2.5% 1–5 years 21 26.6% 6 < 12 years 29 36.7% > 12–16 years 27 34.2%Total 79 100.0%



De los Santos et al.: Central diabetes insipidus in peruvian children 3

these patients underwent surgery; the only exception was a hypothalamic hamartoma that was medically treated with hormonal replacement and antiepileptic drugs. CDI was diagnosed before surgery in 7/43 (16.2%) patients. CDI persisted through the perioperative period and became permanent in 6/7 of them. Of the 36/43 (83.7%)

patients diagnosed of CDI after surgery, only seven were considered transitory cases. Idiopathic CDI was present in 17.7% patients and LCH in 13.9%. CNS malformations rep-resented 8.9%, while Wolfram syndrome and CNS infec-tions represented 2.5% and 1.3%, respectively.

The frequency of anterior pituitary abnormalities is shown in Table 4. Of the organic CDI patients, 34 (52.3%) presented at onset with an anterior pituitary abnormal-ity. The most common accompanying deficiency was secondary hypothyroidism (44.6%), followed by second-ary adrenal insufficiency (43.0%) and multiple anterior pituitary deficiencies (12.3%). In our sample, no idi-opathic CDI patient had a documented anterior pituitary abnormality.

Comparison of the daily dose of desmopressin used in permanent and transient CDI children is presented in Table 5. The treatment of choice in CDI patients was desm-opressin acetate administered intranasally one or two times daily. The daily dose of desmopressin was some-what higher in patients with idiopathic CDI (0.81 ± 0.58 µg/kg/day) comparing with organic CDI (0.79 ± 0.66 µg/kg/day) but not a statistically significant difference was met (p = 0.907). Whereas comparing permanent vs. tran-sient CDI the daily dose of desmopressin was also higher in the former but without a statistically significant differ-ence (0.81 ± 0.65 vs. 0.59 ± 0.62; p = 0.362).

DiscussionWe report the first data from Peru on the clinical profile of CDI in children, underscoring the paramount importance of those that indicate organicity. Although the clinical study does not represent the entire country, it was con-ducted in a referral tertiary level hospital that receives a great number of patients from all over the territory.

Table 2: Presenting manifestations in organic and idiopathic central diabetes insipidus.

Parameter

Central diabetes insipidus p-Value

Organic (n = 65)

Idiopathic (n = 14)

n % n %

Polyuria 64 98.5% 14 100.0% 0.64Polydipsia 55 84.6% 14 100.0% 0.12Headache 31 47.7% 2 14.3% 0.02Short stature 22 33.8% 2 14.3% 0.15Visual disturbances 22 33.8% – – 0.01Vomiting 11 16.9% – – 0.09Nocturia 9 13.8% 3 21.4% 0.47Fatigue 5 7.7% 1 7.1% 0.94Sensitive/motor weakness 3 4.6% – – 0.41Loss weight 3 4.6% 1 7.1% 0.69Others 5 7.7% – – 0.28

Table 3: Etiology of central diabetes insipidus in children.

Etiology n %

Intracranial tumors 44 55.7% Craniopharyngioma 30 37.9% Pituitary adenoma 5 6.4% Pilocytic astrocytoma 3 3.7% Germinoma 2 2.5% Othersa 4 5.2%Idiopathic 14 17.7%Langerhans cell histiocytosis 11 13.9% Eosinophilic granuloma 2 2.5% Not specified 9 11.4%CNS malformation 7 8.9% Septo-optic dysplasia 1 1.3% Pituitary hypoplasia 1 1.3% Agenesis of the corpus callosum 2 2.5% Ectopic posterior pituitary 1 1.3% Empty sella syndrome 1 1.3% Arachnoid cystic 1 1.3%CNS infection 1 1.3% Cerebral abscess 1 1.3%Hereditary 2 2.5% Wolfram syndrome 2 2.5%Total 79 100%

CNS, central nervous system. aChoroid plexus papilloma, hypotha-lamic hamartoma, medulloblastoma, and suprasellar teratoma.

Table 4: Frequency of anterior pituitary hormonal abnormalities in central diabetes insipidus patients.

Anterior pituitary abnormalities

Central diabetes insipidus

Organic

Idiopathic

n % n %

Any anterior pituitary abnormality 34 52.3% – –TSH deficiency 29 44.6% – –ACTH deficiency 28 43,0% – –LH/FSH deficiency 7 10.7% GH deficiency 3 4.6% – –Hyperprolactinemia 1 1.5% – –Multiple anterior pituitary deficiencies 8 12.3% – –




Central diabetes insipidus is a clinical disorder char-acterized for the excretion of large volumes of dilute urine consequence of a total or partial vasopressin deficiency. CDI diagnosis in the outpatient was made upon the clinical history of polyuria, polydipsia, urine osmolality < 300 mOsm/kg, or a urinary density < 1010 and plasma osmolality > 300 mOsm/kg or a serum sodium > 150 mEq/L with a water deprivation test documenting CDI or with an MRI showing a structural lesion affecting the hypo-thalamic – pituitary area. In the perioperative period fol-lowing surgical removal of an intracranial tumor, CDI was diagnosed with a serum sodium > 150 mEq/L and polyuria > 4cc/kg/h in the first 2 consecutive hours after surgery. In this way, CDI was diagnosed before surgery in a small number of patients (7/43) although CDI persisted through the perioperative period and became permanent in 6/7 of them. Of the 36/43 (83.7%) patients diagnosed of CDI after surgery, only seven were considered transitory cases. Similarly to the data described by Di lorgi et al. [17], 8/79 (10.1%) of our CDI patients were regarded as transitory. We found that the mean age of diagnosis was 8.1 years old and more prevalent in boys, comparable to the data that report Maghnie et al. [6] of 7 years old, Di Lorgi et al. [17], 7.5 and De Buyst et al. [11] of 8.6 years old. Regarding clini-cal characteristics, polyuria and polydipsia were the more frequent presenting manifestations in organic and idi-opathic CDI, similar findings reported by Wendong et al. [5], De Buyst et al. [11], and Luoreiro et al. [18]. Headache and visual disturbances were statistically significant dif-ferent between organic and idiopathic CDI patients. This is in agreement with the data reported by Wacharasindhu et al. [19], headache (36%), and visual disturbances (58%) more frequent in intracranial tumors. Growth retardation/short stature has been suggested also as an indicator of organic CDI [10, 20]; however, in our study although short stature was more common in organic CDI patients, it was not statistically different.

The causes of CDI are diverse in pediatric popula-tion [21–26] having intracranial tumors (55.7%) and LCH (13.9%) as the leading causes of organic CDI in our sample. Similar data was reported by Catli et al. [20] attributing 38.5% of CDI patients to intracranial tumors,

however, a lesser number was determined by Al-Agha et al. [27] of 12.8% being CNS tumors. Whereas Wacha-rasindhu et al. [19] report distinctively higher numbers than ours (70.6%) while in contrast De Buyst et al. [11] somewhat lower (29.0%). In our region, in Chile, Luoreiro et al. [18] describe 40% cases of CDI in children corre-sponding to CNS tumors. In agreement with previous studies, that establish 12%–54% patients are regarded as idiopathic [10, 11] we reported 17.7% idiopathic CDI patients. The higher proportion of CNS tumors responsi-ble of CDI in our data can be explained for the fact that The Child’s Health Institute in Lima is one of the few hos-pitals that receives patients of high neurosurgical com-plexity, especially intracranial tumors, and the larger sample we reported.

Thirty four (52.3%) organic CDI patients had a docu-mented anterior pituitary abnormality similar to the data reported by Wendong et al. [5] that 53.5% of CDI patients had at least one anterior pituitary hormone deficiency. According to our data, TSH deficiency (44.6%) and ACTH deficiency (43.0%) are the most common hormonal abnormalities in organic CDI while no idiopathic cases documented any hormonal deficiency besides vasopres-sin secretion alteration. Catli et al. [20] report similar find-ings, secondary hypothyroidism (44%) and secondary adrenal insufficiency (38%) the primordial accompanying hormonal dysfunctions, concluding that anterior pitui-tary deficiency suggests organic etiology [10, 20]. None-theless, Wendong et al. [5] and Hunter and kalikoglu [28] agree that isolated growth hormone deficiency was the most frequent abnormality at diagnosis (37.5% and 34%, respectively), hormonal deficiency that was less frequent in our sample. Furthermore, Richards et al. [29] addresses that 33% of children with CDI manifest anterior pituitary deficiencies in some moment during follow-up, obtaining an underlying organic etiology in 37% patients initially classified as idiopathic. In our study, an organic cause was identified in 82.3% children with CDI, similarly to previous reports in Turkey (70.6%) [20], India (67.8%) [10], Italy (96%) [17], and Spain (100%) [9]. Transitory CDI rep-resented 10.1% of our patients corresponding to the data reported by Di Lorgi et al. [17].

Table 5: Comparison of the daily dose of desmopressin acetate in permanent and transient cases.

Daily dose of intranasal desmopressin acetate

Central diabetes insipidus p-Value

Permanent (n = 71)

Transient (n = 8)

Mean ± SD (range) Mean ± SD (range)

Average daily dose, µg/kg/day 0.81 ± 0.65 (0.20–5.00) 0.59 ± 0.62 (0.19–2.08) 0.363



De los Santos et al.: Central diabetes insipidus in peruvian children 5

In our study, the daily dose of desmopressin administered was evaluated to determine possible impor-tant key points for replacement hormonal therapy. We found no significant statistically difference between organic and idiopathic CDI, although permanent CDI, which in most cases had an identifiable etiology (80%), required higher dose of desmopressin acetate when com-pared with transitory cases, this difference also was not statistically significant.

Our study is a cross-sectional one so it has important limitations. We did not determine the long-term outcome of idiopathic cases, the conversion figures of some of these patients from idiopathic to organic etiology. Also, we did not analized the neuroimaging of the pituitary stalk size at onset and follow-up, a parameter that possibly correlates with frequency of anterior pituitary defects in the final outcome of these patients [17, 30]. For a better clinical, hormonal and neuroimaging evaluation and understand-ing of this complex entity in children we recommend lon-gitudinal and multicenter studies.

In conclusion, the main clinical features suggestive of organicity in pediatric patients with CDI were headache and visual disturbances; furthermore, anterior pituitary hormonal abnormalities suggest an underlying organic etiology. Permanent and transitory CDI patients will need similar doses of desmopressin acetate replacement therapy.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.Research funding: None declared.Employment or leadership: None declared.Honorarium: None declared.Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Central diabetes insipidus: clinical profile that suggests ... · or a serum sodium > 150 mEq/L with a water deprivation test docu-menting CDI or with an MRI showing a structural