A RARE CASE OF ADIPSIC DIABETES INSIPIDUS ASSOCIATED WITH LANGERHANS CELL HISTIOCYTOSIS

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1 Case Report A RARE CASE OF ADIPSIC DIABETES INSIPIDUS ASSOCIATED WITH LANGERHANS CELL HISTIOCYTOSIS Shejil Kumar, MBBS (Hons) 1 ; Peter Rohl, MBBS, FRACP 2 ; Terrence Diamond, MBBCh, MRCP, FRACP 2 ABSTRACT Objective: We describe a case of adipsic diabetes insipidus, hypopituitarism, and cognitive impairment in a patient with a hypothalamic mass diagnosed with Langerhans cell histiocytosis. We aim to highlight the difficult and complex management of such a rare case. Methods: We report the initial presentation, laboratory results, imaging, management, complications, and outcome of a patient with adipsic diabetes insipidus. We conducted a literature search to review the reported cases of adipsic diabetes insipidus. Results: A previously well 36-year-old woman presented with amenorrhea, headaches, polyuria, polydipsia, and cognitive decline. Initial investigations demonstrated serum hypernatremia (156 mmol/l), hyperosmolality (322 mmol/kg), and inappropriate hypotonic polyuria (urine osmolality 100 mmol/kg, urine output 500 ml/hour). Pituitary investigations showed hyperprolactinemia and secondary hypothyroidism, hypocortisolemia, and hypogonadism. Magnetic resonance imaging brain scan revealed a cm enhancing hypothalamic mass. She displayed an appropriate renal response to desmopressin (urine osmolality 400 to 500 mmol/kg, urine output <100 ml/hour) and thus was diagnosed with Submitted for publication January 14, 2018 Accepted for publication March 20, 2018 From the 1 St. George Public Hospital, Kogarah, New South Wales, Australia, and 2 Endocrinology, St. George Public Hospital, Kogarah, New South Wales, Australia. Address correspondence to Shejil Kumar, 106 Boundary Road, Mortdale, NSW, Australia, shejil_kumar@hotmail.com. DOI: /ACCR To purchase reprints of this article, please visit: Copyright 2018 AACE. central diabetes insipidus. Histopathology from partial tumor resection confirmed Langerhans cell histiocytosis. During her course, she developed adipsia and worsening cognitive impairment, resulting in chronic hypernatremia (average sodium 152 mmol/l reaching up to 180 mmol/l) due to poor compliance with desmopressin, strict fluid balance, and prescribed fluid intake. She died at 9 months after initial presentation without ever completing her chemoradiotherapy. Conclusion: Adipsic diabetes insipidus is a rare and dangerous condition and especially difficult to manage when combined with cognitive dysfunction. We urge clinicians to consider the diagnosis of Langerhans cell histiocytosis in patients presenting with a hypothalamic mass, diabetes insipidus, hypopituitarism, and cognitive impairment. (AACE Clinical Case Rep. 2018;4:e388-e393) Abbreviations: ADH = antidiuretic hormone; DI = diabetes insipidus; IV = intravenous; LCH = Langerhans cell histiocytosis CASE REPORT A 36-year-old woman presented with 6 months of amenorrhea and intermittent headaches, 3 months of polyuria and polydipsia (both approaching 6 L/day), and 2 months of cognitive decline and drowsiness. She had no significant past medical history, no regular medications, and an unremarkable social history. On admission, she was confused and disoriented (Glasgow Coma Scale 14/15), had no focal neurologic deficit, and was dehydrated. Initial biochemistry demonstrated hypernatremia (sodium 156 mmol/l), normokalemia (potassium 4.4 mmol/l), and mild acute kidney injury (creatinine 94 µmol/l). Anterior pituitary investigations (Table 1) showed hypopituitarism (hypothyroidism, hypocortisolemia, e388 AACE CLINICAL CASE REPORTS Vol 4 No. 5 September/October 2018 Copyright 2018 AACE

2 Copyright 2018 AACE Rare Case of Adipsic Diabetes Insipidus, AACE Clinical Case Rep. 2018;4(No. 5) e389 hypogonadism) and hyperprolactinemia. In addition, she had hypernatremia (156 mmol/l), hyperosmolality (322 mmol/kg), and inappropriate hypotonic polyuria (urine osmolality 100 mmol/kg and output 500 ml/hour), indicating the diagnosis of diabetes insipidus (DI). Computed tomography (CT) brain scan showed an enhancing hypothalamic cm mass which appeared separate from the pituitary gland. Magnetic resonance imaging (MRI) brain scan with gadolinium confirmed a cm homogenous enhancing mass in the hypothalamic region, with slight extension into the infundibulum (Fig. 1). Following regular desmopressin administration, her urine osmolality rose to 400 to 500 mmol/kg and urine output fell to <100 ml/hour. Our patient s hypothalamic lesion and her appropriate renal response to desmopressin therapy indicated a diagnosis of central DI. She underwent craniotomy and partial tumor resection, with histopathology (Fig. 2) confirming Langerhans cell histiocytosis (LCH) based on characteristic inflammatory infiltration with positive staining for cluster of differentiation (CD)1a, CD68, and S100. Unfortunately, surgery resulted in right frontal and temporal brain injury. She had no suspicious cutaneous lesions, and investigations were negative for systemic disease, including skeletal survey, CT chest/abdomen/pelvis, liver biopsy, and bone marrow aspiration. Her LCH was promptly managed with cytarabine chemotherapy, which was ceased before the third cycle due to febrile neutropenia. Radiotherapy was subsequently initiated but then ceased before the fourth fraction due to severe agitation. Despite incomplete treatment, the hypothalamic mass shrunk considerably (Fig. 3) without improvement in her endocrine dysfunction. During her course, she developed worsening behavioral issues and cognitive impairment. Formal neuropsychologic assessment revealed perseveration, impulsivity, and poor orientation, memory, language, reasoning, visuospatial skills, and insight into her condition. She was diagnosed with global cognitive decline and marked frontal lobe dysfunction. Due to her cognitive deficits and frontal disinhibition, managing her central DI became more difficult despite desmopressin, drinking to thirst, and hypotonic 5% dextrose intravenous (IV) fluid. She would often refuse desmopressin and pull out IV lines and indwelling urinary catheters. She then developed adipsia 4 to 5 weeks after presentation, whereby, when conscious, even with serum sodium >150 mmol/l and plasma osmolality >310 mmol/kg, she demonstrated no thirst response and only consumed up to 300 ml of water per day. In addition to the above treatment, a daily fluid prescription was unsuccessful. She developed moderate chronic hypernatremia with severe exacerbations up to 180 mmol/l due to poor compliance with desmopressin, strict fluid balance, and prescribed fluid intake (Fig. 4). She displayed further evidence of hypothalamic dysfunction with significant polyphagia and obesity (body mass index >40 kg/m 2 ), recurrent hypothermia (33 to 34 C), abnormal sleep/wake patterns, and seizures. She died at 9 months after her initial presentation, without ever completing her chemotherapy or fractionated radiotherapy. DISCUSSION Following a literature research, this is the fourth reported case of adipsic DI in association with LCH. Table 1 Anterior Pituitary Investigations at Initial Presentation Showing Hypopituitarism (Hypothyroidism, Hypocortisolemia) and Hyperprolactinemia Hormone Concentration Reference range a Interpretation TSH mu/l Normal ft pmol/l Low ACTH pg/ml Low Cortisol nmol/l Low FSH miu/ml b Low LH < µg/l b Low Estradiol < pmol/l b Low Progesterone < nmol/l b Low IGF nmol/l b Normal Prolactin 2, mu/l High Abbreviations: ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; ft4 = free thyroxine; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; TSH = thyroid-stimulating hormone. a As supplied by SEALS (South Eastern Area Laboratory Services) Pathology, St. George Hospital, Sydney, NSW, Australia. b Values specific for a postmenopausal state.

3 e390 Rare Case of Adipsic Diabetes Insipidus, AACE Clinical Case Rep. 2018;4(No. 5) Copyright 2018 AACE Adipsic DI is an extremely rare condition from any cause ( 100 reported cases) (1) and develops in patients with central DI who have subnormal thirst responses to rising serum osmolality (1,2). Patients with adipsic DI due to a hypothalamic lesion affecting both antidiuretic hormone (ADH) synthesis and thirst osmoreceptors are unable to respond to rising serum osmolality by increasing ADH release and maintaining an appropriate water intake (1-4). These patients are at high risk of hypernatremia and dehydration (1-4). Arima et al (3) recently demonstrated in a retrospective study of 149 patients the importance of the thirst mechanism in central DI. The authors showed that the frequency of sodium measurements 150 mmol/l over a 5-year period was 25% (n = 23) in adipsic patients and A B Fig. 1. Initial sagittal view pituitary magnetic resonance imaging (MRI) with gadolinium showing hypothalamic mass (A), and coronal view pituitary MRI with gadolinium showing mild extension of mass into the infundibulum (B). A B C D Fig. 2. Histopathology (obtained from partial tumor resection) with hematoxylin and eosin staining (A) showing irregular, large pathologic histiocytes (red arrow), surrounded by mixed inflammatory infiltrates of particularly eosinophils (black arrow) and neutrophils (green arrow). Strong positive staining of the large pathologic histiocytes for CD1a (B), CD68 (C), and S100 (D) are also shown. Images provided courtesy of Dr. Zaid Househ, Anatomical Pathology Department, St. George Public Hospital, NSW, Australia.

4 Copyright 2018 AACE Rare Case of Adipsic Diabetes Insipidus, AACE Clinical Case Rep. 2018;4(No. 5) e391 A B C Fig. 3. Coronal view pituitary magnetic resonance imaging with gadolinium showing size of hypothalamic mass pre-operatively (A), postoperatively (B), and postchemotherapy (C). Fig. 4. Blue line represents the trend of the 259 sodium concentrations over the 9-month period from our patient s initial presentation to shortly before her death. The red dotted lines symbolize the upper and lower limits of normal sodium concentrations. Results are courtesy of SEALS (South Eastern Area Laboratory Services) Pathology, St. George Public Hospital, Sydney, NSW, Australia. 0.4% (n = 126) in nonadipsic patients. From our patient s 259 serum sodium measurements over a 9-month period, the average sodium concentration was 152 mmol/l (range, 130 to 180 mmol/l), and 58.3% of results were 150 mmol/l, reflecting the difficulty of her management. She also demonstrated other clinical features associated with hypothalamic adipsic DI, including obesity, hypopituitarism, sleep and temperature disturbance, emotional lability, and cognitive dysfunction (1,2). Adipsic DI was diagnosed clinically in our patient based on evidence of central DI, with conscious adipsia despite serum hypernatremia >150 mmol/l and hyperosmolality >310 mmol/kg (1,2). The diagnosis of adipsic DI is usually confirmed after a hypertonic saline infusion test demonstrates subnormal ADH and thirst responses to serum hyperosmolality (1,5). However, this test may be difficult to perform and potentially dangerous, especially in patients with cognitive dysfunction, and there is no general consensus that this test is essential for the diagnosis of adipsic DI (1). Management of adipsic DI is inherently difficult, particularly in patients with cognitive impairment. On

5 e392 Rare Case of Adipsic Diabetes Insipidus, AACE Clinical Case Rep. 2018;4(No. 5) Copyright 2018 AACE account of its rarity, evidence guiding management for clinicians is limited to expert opinion and case series (1). General recommendations include a fixed daily desmopressin dose with dynamic daily fluid prescription based on regular weights and sodium concentrations, whereby a rise in serum sodium and reduction in weight would warrant an increase in the fluid prescription (1). Fluid prescription was near impossible in our patient due to her cognitive and behavioral issues. Among the other causes of adipsic DI (for example, craniopharyngioma, anterior communicating artery aneurysm rupture or clipping, traumatic brain injury), there are only three reported cases due to LCH (1). Central DI was presumably caused by LCH in our case; however, it is unclear whether her adipsia was due to LCH or neurosurgical intervention, given it developed a few weeks after hypothalamic biopsy. LCH is a rare, inflammatory, neoplastic condition whereby pathologic dendritic cells, resembling epidermal Langerhans cells, form infiltrations in single or multiple organs (6). The most common organs involved in adults include bone, skin, lung, and the hypothalamic-pituitary system (6). Central DI occurs in 25 to 30%, and anterior pituitary dysfunction in 15 to 20% of patients (6). Approximately 30% of patients may demonstrate radiologic improvement of lesions after chemotherapy and/or radiotherapy. Nevertheless, the endocrine complications rarely respond and are generally permanent (6-9). Our patient similarly did not recover from central DI or hypopituitarism despite marked reduction in the size of the initial hypothalamic mass after neurosurgical intervention and chemotherapy (Fig. 3). There are few studies reporting neuropsychiatric deficits in patients with multisystem LCH involving the hypothalamus (10-14), including impairments in memory, learning, behavior, and executive function. Only Fahrner et al (11) have explored reversibility with a retrospective analysis showing chemotherapy or radiotherapy could not reverse neuropsychiatric symptoms in 5 patients with hypothalamic LCH. The Histiocyte Society, however, is currently conducting the LCH-IV trial to prospectively determine the effectiveness of cytarabine and cladribine in reversing LCH-related cognitive impairments (15), both of which are recommended by expert international groups in treatment of pediatric hypothalamic LCH (15) and in adults (6). Hypothalamic lesions from any cause are known to produce socio-emotional and executive dysfunction, and there is a growing body of evidence these could be due to disrupted hypothalamic connections with the prefrontal cortex, cingulate cortex, and thalamus (16,17). We hypothesize our patient developed severe cognitive impairment and frontal lobe dysfunction secondary to the hypothalamic lesion itself, which was not reversible despite mass regression. However, postsurgical frontal cortex injury and metabolic encephalopathy caused by fluctuating serum sodium and osmolality were likely contributing factors to her cognitive and behavioral decline. The presentation of central DI, infundibular thickening, and a hypothalamic mass can be explained by various pathologies, including LCH, germinoma, and lymphocytic hypophysitis (18,19). Accurate diagnosis should be obtained promptly in order to initiate timely and targeted therapy. Although MRI is highly sensitive in characterizing these lesions, findings are nonspecific, and histopathologic diagnosis is ultimately required (18-20). Extracranial LCH manifestations (for example skin, bone, and lung) are common in patients with central DI due to LCH and can be utilized to avoid a potentially hazardous intracranial biopsy (20). In a retrospective study by Prosch et al (20) of patients with central DI as the presenting feature of LCH, 49/54 patients (91%) had LCH diagnosed on biopsy of extracranial lesions, with 10/54 patients (18%) having extracranial manifestations already present at time of diagnosis of central DI. In our case, it can be argued we should have investigated for potential extracranial manifestations before performing hypothalamic biopsy, especially given the subsequent postsurgical complication of frontal cortical injury. However, these investigations were negative shortly after diagnosis of LCH, and so regardless, we would not have been able to avoid an intracranial biopsy. CONCLUSION Adipsic DI is associated with poor outcomes and carries a high risk of premature death (1,3), which is unsurprising given dangerous potential complications and difficulties with management. Reported causes of death include respiratory failure due to sleep apnea or venous thromboembolism, infection, and fluctuating serum hypernatremia and hyperosmolality (1,3). Death in our patient was likely the result of one or more of these factors. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Eisenberg Y, Frohman LA. Adipsic diabetes insipidus: a review. Endocr Pract. 2016;22: Mavrakis AN, Tritos NA. Diabetes insipidus with deficient thirst: report of a patient and review of the literature. Am J Kidney Dis. 2008;51: Arima H, Wakabayashi T, Nagatani T, et al. Adipsia increases risk of death in patients with central diabetes insipidus. Endocr J. 2014;61: Cuesta M, Hannon MJ, Thompson CJ. Adipsic diabetes insipidus in adult patients. 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