ORI­GI­NAL AR­TIC­LE DO­I: 10.4274/jcrpe.galenos.2020.2020.0007 J Clin Res Pediatr Endocrinol 2021;13(2):146-151 Growth Hormone Treatment and Papilledema: A Prospective Pilot Study Nieves Martín-Begué1, Eduard Mogas2, Charlotte Wolley Dod1, Silvia Alarcón1, María Clemente2,3,4, Ariadna Campos-Martorell2,3, Ana Fábregas2, Diego Yeste2,3,4 1Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain 2Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain 3Universitat Autònoma de Barcelona (UAB), Barcelona, Spain 4Centro de Investigación Biomédica en Red: Enfermedades Raras (CIBERER), Madrid, Spain What is already known on this topic? Growth hormone (GH) replacement therapy is a risk factor for secondary pseudotumor cerebri. The incidence of this complication can vary depending on different GH indications. What this study adds? Children with intracranial hypertension could be asymptomatic, so the diagnosis should be based on fundus examination and not on patient’s symptoms. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. A previous history of pseudotumor cerebri should be investigated. Abstract Objective: To investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication. Methods: Prospective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later. Results: Two hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before. Conclusion: GH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms. Keywords: Growth hormone treatment, pseudotumor cerebri syndrome, idiopathic intracranial hypertension, papilledema, risk factors Introduction vascular abnormality, intracranial space-occupying lesion or hydrocephalus (1,2). It can be primary, or secondary if Pseudotumor cerebri syndrome (PTCS) is a condition defined there are any identifiable risk factors. Primary PTCS most by elevated intracranial pressure (ICP) in the absence of commonly occurs in obese adult women of childbearing age clinical, laboratory or radiologic evidence of infection, (12-32/100,000). However, it is a rare condition in childhood Address for Correspondence: Nieves Martín-Begué MD, Hospital Universitari Vall d’Hebron, Department of Conflict of interest: None declared Paediatric Ophthalmology, Barcelona, Spain Received: 16.01.2020 Phone: +034934893166 E-mail: nmartin@vhebron.net ORCID: orcid.org/0000-0003-0365-1266 Accepted: 16.09.2020 ©Copyright 2021 by Turkish Pediatric Endocrinology and Diabetes Society The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House. 146 J Clin Res Pediatr Endocrinol Martín-Begué N et al. 2021;13(2):146-151 Growth Hormone and Papilledema (0.5-0.9/100,000) with an identifiable risk factor in 53- vomiting or other presenting symptoms suggestive of 77% of paediatric cases (3,4,5). Papilledema is a hallmark intracranial hypertension arose. Prior fundus examination in PTCS, which is not a benign disorder; there is a risk of identified possible cases of pseudopapilledema and avoided severe and permanent visual loss. Even patients with mild possible confusion between this entity and newly developed visual loss experience reduction in quality of life (6). papilledema in subsequent fundus follow-up examinations. Growth hormone (GH) replacement therapy was first Fundus examination was carried out with indirect associated with PTCS by The Food and Drug Administration ophthalmoscopy and retinography was taken in cases of in 1993 (7). Since then, multiple publications have described pseudopapilledema to facilitate follow up. In cases when this association. Reeves and Doyle (8) found that the papilledema was detected, GH was stopped and fundus prevalence in the GH treated population was approximately examination was repeated four weeks later. If papilledema 100 times greater than in the general paediatric population. persisted, the patient was referred for neurological This complication usually occurs in the first weeks after assessment, lumbar puncture and possible medical initiating treatment (approximately 2-12 weeks) and the treatment with acetazolamide. Once papilledema resolved, papilledema (optic disc swelling from raised ICP) resolves if GH treatment was still considered necessary, treatment on stopping treatment (8,9). was re-initiated at a lower dose and progressively increased Pseudopapilledema is an elevated optic disc with obscured until the objective dose was achieved, with monthly margins that may occur in hyperopic eyes and in the presence ophthalmology visits until four months were completed at of buried optic disc drusen, rather than from raised ICP. the target GH dose. Optic disc drusen are acellular deposits located within the Cerebral magnetic resonance imaging (MRI) of the optic disc. Sometimes it can be very difficult to differentiate hypothalamic-pituitary axis was performed in all patients between pseudopapilledema and papilledema, requiring with GH deficiency, prior to treatment. Initial GH doses were the opinion of a suitably experienced ophthalmologist and as indicated: 0.028-0.035 mg/kg/day for patients with GH complementary tests (10). deficiency and small for gestational age (SGA), 0.042 mg/kg/ The aim of this study was to investigate the incidence of day for those with mutations in the SHOX gene and 1 mg/ PTCS in children treated with GH in a paediatric hospital and m2/day for patients with Prader-Willi syndrome (PWS). to identify risk factors for this complication. A secondary Ethics approval was obtained from the Ethic Review aim was to identify which children really need fundus Committee of the Hospital Universitario Vall d’Hebron examination during GH treatment in order to detect this complication. (approval number: 383). All subjects (or their parents or guardians) gave their written informed consent. Methods Statistical Analysis A prospective pilot study was conducted in paediatric In this case series, simple descriptive statistics were sufficient patients who started GH treatment from February 2013 to to delineate our populations. Variables are expressed as September 2017. Inclusion criteria were patients under 16 number, mean and percent (%) or range, as appropriate. years of age prescribed GH by the Paediatric Endocrinology Department. Exclusion criteria were: absence of fundus Results examination prior to or at 3-4 months from starting treatment; severe optic disc atrophy where optic disc swelling would There were 306 patients to whom GH was prescribed by the not develop; and cases where GH was prescribed by the Paediatric Endocrinology Department between February Paediatric Nephrology Department. Predisposing pathology 2013 and September 2017. Only 289 patients were for intracranial hypertension was not considered an enrolled in this study, 17 were excluded because of loss of exclusion criterion, as fundus examinations were conducted ophthalmological follow up. before initiating treatment to rule out prior pathology of the The mean age was nine years (range 1-16) and 53% of the optic nerve. The following variables were recorded: previous patients were male. The patients were categorized according medical history; anthropometric data; and compliance with to their indication for GH treatment: 244 patients (84.4%) treatment. with GH deficiency; 36 patients (12.5%) with short stature Fundus was explored prior to and after 3-4 months of starting associated with SGA; six patients (2%) with a mutation treatment or at any time when severe constant headache, in the SHOX gene; and three (1%) with PWS. Patients 147 Martín-Begué N et al. J Clin Res Pediatr Endocrinol Growth Hormone and Papilledema 2021;13(2):146-151 diagnosed with chronic kidney disease were not included in puncture confirmed the diagnosis and was also therapeutic. the study as their indication for GH treatment and follow up The opening pressure was 25 cm H2O. The glucose was was made by the Paediatric Nephrology Department. 61 mg/dL (38-82); protein 20 mg/dL (15-45) and there In the first visit, prior to starting GH treatment, there were were neither leukocytes nor red blood cells present in 546 eyes with normal optic discs, 16 eyes with pale optic the cerebrospinal fluid (CSF). Medical treatment was not discs, 11 eyes with pseudopapilledema, two eyes with optic required. In four cases GH treatment was reintroduced at a disc and chorioretinal coloboma and one eye with dysplastic lower dose with progressive incremental doses, without the optic disc. Pale optic discs and optic disc and chorioretinal reappearance of papilledema. coloboma were secondary to the patient background pathology, suprasellar cerebral tumours and CHARGE Discussion anomaly respectively. In the follow up visit, five patients had optic disc swelling, suggesting papilledema, despite there GH treatment is a risk factor for developing secondary being no symptoms of intracranial hypertension. None PTCS although the mechanism is little understood. Two of the patients who presented with headache, who were hypotheses have been proposed. The first is that GH could visited urgently, presented with papilledema on fundus have a physiological antidiuretic effect, causing retention examination. of sodium and water and expansion in blood volume, and reducing CSF resorption by the arachnoid villi. The second Table 1 outlines the characteristics of the five patients with papilledema. All these patients had GH deficiency: three hypothesis proposes that GH would cross the blood-brain had hypothalamic-pituitary axis abnormalities on brain barrier, resulting in raised cerebral levels of GH and its MRI; two were congenital cases; and one was secondary to mediator, insulin-like growth factor 1, and finally increasing a suprasellar tumour. The patient with a suprasellar tumour CSF production (11,12,13,14). had a ventriculoperitoneal shunt and was treated with GH was initially obtained from human pituitary gland, and external radiotherapy. The only patient with an isolated GH was given at lower doses and frequency, and prescribed in deficiency with normal MRI, had developed primary PTCS fewer clinical situations. Since 1985, when recombinant five years before and he was obese. The incidence of obesity human GH became commercially available, more patients in children without PTCS in our population is 10.3%. were treated with larger doses and more often. Since then, The papilledema resolved on discontinuing GH treatment in indications for GH treatment have increased, as well as the four patients, whereas in the remaining patient, a lumbar potential adverse effects (15). Table 1. Characteristics of patients treated with growth hormone who developed papilledema Patients Gender/age Papilledema W (kg)/H GH dose Other pathology/MRI anomalies Risk factors Treatment (years) onset time (cm) (mg/kg/ PTCS PTCS (months) week) 1 M/14 2 71.4/144.7 0.20 -- PTCS 2010, GH stopped obesity 2 M/3 3 11.4/86 0.23 Polymalformative syndrome, None GH stopped pituitary gland anomaly and partial agenesis of corpus callosum on brain MRI 3 M/11 3 26.5/128.3 0.21 PDR None GH stopped Dysmorphic phenotype +LP Incomplete hippocampal inversion on brain MRI 4 M/10 3 36.4/132 0.19 Craniopharyngioma, radiation None GH stopped therapy 5 F/4 3 10.7/80.4 0.32 Microcephaly None GH stopped Pituitary gland compression by an arachnoid cyst Hypoparathyroidism PDR F: female, GH: growth hormone, H: height, LP: lumbar puncture, M: male, MRI: magnetic resonance imaging, PDR: psychomotor development retardation, PTCS: pseudotumor cerebri syndrome, W: weight 148 J Clin Res Pediatr Endocrinol Martín-Begué N et al. 2021;13(2):146-151 Growth Hormone and Papilledema Table 2. Distribution of patients with growth hormone deficiency according to our classification in subgroups GH deficiency subgroups Nº patients Nº papilledema 1 Isolated GH deficiency with normal H-P axis on MRI 164 1 2 GH deficiency (isolated or not) with abnormal H-P axis on MRI and/or RT 62 3 3 Genetic or chromosome disorders 18 1 GH: growth hormone, H-P: hypothalamic-pituitary, MRI: magnetic resonance imaging, RT: cranial radiotherapy In our study, there were five patients with papilledema the GH was not prescribed by the Paediatric Endocrinology (1.7%), a higher incidence compared with the expected Department. However, we have conducted a retrospective incidence in the general paediatric population (8,9,11,13). study of these patients with renal disease on GH treatment All of them had GH deficiency. Other indications for GH during the same time period and have also detected a higher treatment did not appear to cause papilledema in this incidence of papilledema, as described in the literature. series, although these results may be biased due the small The association between the dose of GH and the risk of PTCS populations with these other indications. is not clearly established. Malozowski et al (15) reported that As all the patients with papilledema were found to have GH higher doses and increased frequency of administration deficiency, we analysed this group, classifying patients into since the introduction of recombinant human GH in 1985 three subgroups (Table 2): may be contributing to the development of PTCS in some 1. Isolated GH deficiency (no other associated hormone patients. However, Reeves and Doyle found no relationship deficiencies) with normal hypothalamic-pituitary axis between the GH dose and PTCS development (8). One anatomy on MRI. of our patients received GH at the usual dose without complications, later on it was withdrawn due to lack of 2. Isolated GH deficiency or associated with other hormone therapeutic effect. Interestingly, papilledema appeared three deficiencies with altered hypothalamic-pituitary axis months after restarting GH at a higher dose. Patients with anatomy on MRI and/or past history of cerebral radiotherapy. PWS and mutations in the SHOX gene, who received higher 3. GH deficiency in patients with genetic or chromosomal doses of GH did not present with papilledema, although diseases. these subgroups were small in this study. Even though there is no evidence that the GH dose is directly related with When considering patients who presented with papilledema, this complication, we recommend starting at lower dose three completed criteria for subgroup 2, presenting with and increasing it progressively, in order to minimize this hypothalamic-pituitary axis abnormalities and external complication. radiotherapy treatment in one case for a suprasellar tumour. These three patients in subgroup 2 had an intracranial Patients with a previous history of PTCS may experience hypertension, but not technically a PTCS, because the brain recurrence at rates reported to vary between 6-22% MRI was not normal. One other patient was classified as (4,17,18,19). There is usually a triggering factor, such as subgroup 3 for a non-specific genetic disease. Only one weight gain or the introduction of known medications patient presented with an isolated GH deficiency with associated with secondary PTCS (20). In our series, the only normal cerebral MRI, however this patient had had primary patient with a previous history of PTCS, presented with PTCS five years earlier. The patient with a suprasellar tumour papilledema. This patient was obese, which could have been also had a ventriculoperitoneal shunt, suggesting that the a further risk factor for primary PTCS recurrence, however his presence of a shunt is not protective against a rise in ICP weight had remained stable prior to starting GH treatment, induced by GH therapy. at one month and at two months of treatment, when papilledema was diagnosed. For this reason, we believe it For each GH indication, the incidence of this adverse effect is important to identify patients initiating GH therapy with a can vary. Reeves and Doyle (8), reported higher incidences previous history of PTCS because of the risk of recurrence. in patients with renal failure and Turner syndrome. Souza Also, consideration should be taken for starting treatment and Collet-Solberg (11), also detected a higher incidence in at a lower dose with progressive increases, accompanied by patients with chronic kidney disease. Darendeliler et al (16) with careful follow-up including fundus examination during proposed that patients with Turner syndrome, organic GH the first months of treatment. deficiency, PWS and chronic renal insufficiency might be more prone to develop papilledema when receiving GH. Headache is a common symptom in the general paediatric In our study, patients with renal disease were excluded, as population, and is also relatively frequent in patients on GH 149 Martín-Begué N et al. J Clin Res Pediatr Endocrinol Growth Hormone and Papilledema 2021;13(2):146-151 therapy, being the third most prevalent side effect described Informed Consent: All subjects (or their parents or in KIGS (Pfizer International Growth study database) (16). guardians) gave their written informed consent. On the other hand, headache is the main manifestation Peer-review: Externally peer-reviewed. of intracranial hypertension at any age. However, in the paediatric population, headache is less common and Authorship Contributions 33% of children with PTCS may be totally asymptomatic Surgical and Medical Practices: Nieves Martín-Begué, (21,22), and diagnosis is only made on the observation Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, of papilledema on fundus examination. It is important to highlight that papilledema is a cause of visual morbidity, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, including irreversible vision loss, independent of the patient Diego Yeste, Concept/Design: Nieves Martín-Begué, symptoms. In our series, all patients with papilledema were Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, asymptomatic, whereas no patients examined urgently for María Clemente, Ariadna Campos-Martorell, Ana Fábregas, headache presented with papilledema. Diego Yeste, Data Collection or Processing: Nieves Martín- Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Stopping GH is usually enough to treat this complication. Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Once papilledema has resolved GH can be reintroduced at Fábregas, Diego Yeste, Analysis or Interpretation: Nieves a lower dose and progressively increased until the required Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia dose is achieved to prevent recurrence and optimum growth. Alarcón, María Clemente, Ariadna Campos-Martorell, Ana In the four patients where GH was reintroduced there were Fábregas, Diego Yeste, Literature Search: Nieves Martín- no recurrences of papilledema. Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Study Limitations Diego Yeste, Writing: Nieves Martín-Begué, Eduard Mogas, The strengths of our study are the prospective design and Charlotte Wolley Dod, Silvia Alarcón, María Clemente, the number of patients included in it. As children may Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste. be asymptomatic, prospective studies are the only way to establish the real incidence of this complication. The Financial Disclosure: The authors declared that this study main limitation of our study is that patients with kidney received no financial support. diseases were not included and this group of patients has been reported to be at greatest risk of this complication in References a different series. 1. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology Conclusion 2013;81:1159-1165. Epub 2013 Aug 21 2. Rangwala LM, Liu GT. Pediatric Idiopathic Intracranial Hypertension. In this study, we have shown that GH therapy is a risk factor Surv Ophthalmol 2007;52:597-617. for intracranial hypertension and the at-risk group were 3. 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