Cranial diabetes insipidus with pituitary stalk lesions

Cranial diabetes insipidus (CDI) is the deficiency of vasopressin. CDI is rarely resulted from a pituitary stalk lesion; these cases represent a clinical conundrum due to the differing clinical presentations and aetiologies. We present a series of three cases of CDI arising from pituitary stalk lesions/thickenings that highlight both the symptomatic features and multiple aetiologies of this condition. Vasopressin is an osmoregulatory hormone. It is synthesized in the hypothalamus whereupon it migrates to the posterior pituitary (neurohypophysis). Increased plasma osmolality above 280 mOsmol (milliosmol)/kg is detected by osmoreceptors within the anterior hypothalamus stimulating vasopressin release into the circulation. Vasopressin acts to achieve anti-diuresis through the nephron-mediated conservation of water. In cranial diabetes insipidus (CDI) there is a pathological deficiency in the secretion of vasopressin, resulting in failure to maintain optimal plasma osmolality.1 CDI has a prevalence of fewer than 1 per 25 000 population—up to 25% of these patients have cranial neoplasms or post-pituitary surgery CDI.1 Variant pathologies of the hypothalamus and pituitary including familial disorders such as neurohypophyseal diabetes insipidus and DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) syndrome result in CDI, which presents clinically with polyuria and polydipsia. CDI rarely occurs secondary to a pituitary stalk lesion. Anatomically the pituitary stalk, or infundibulum, is the connection between the hypothalamus and the posterior pituitary. The pituitary stalk contains axons, which carry both vasopressin and oxytocin from the hypothalamus to the posterior pituitary. The pituitary stalk measures between 1.9 and 3.5 mm; an increase in size of more than 2–3 mm upon MR imaging is indicative of enlargement secondary to a pituitary stalk lesion or from pituitary stalk thickening.2 Pituitary stalk lesions within adults are typically due to neoplastic conditions of the pituitary such as germinomas or seminomas. Stalk thickening also occurs with inflammatory, autoimmune or infiltrative granulomatous disorders.2 Interruption of both the neural pathways and pituitary portal vessels means that pituitary stalk lesions or thickening can present with a myriad of symptoms which reflect the loss of vasopressin and stimulatory factors from the anterior pituitary resulting in hypopituitarism and loss of inhibitory control on prolactin.3 With disparate clinical symptoms, CDI arising from a pituitary stalk lesion or pituitary stalk thickening remains a diagnostic challenge for physicians. Due to the pituitary stalk’s role in regulating several endocrine regulatory functions, the use of tissue biopsies to delineate the underlying cause represents an unsafe option due to the potential for residual endocrine abnormalities post-procedure. Clinicians face further challenges in the management of this condition due to the inability to differentiate the pathological cause of this condition and predict its’ behaviour. In this case series, we present three cases of CDI due to pituitary stalk lesions or pituitary stalk thickening which presented with differing features and underlying causes. By highlighting the commonalities associated with each case, we hope to provide clinicians with a novel aid when encountering this sparsely reported variation of CDI. (a) Case1 2006; Post-contrast coronal T1w images of the pituitary demonstrating swelling and homogenous enhancement of the infundibulum and the pituitary gland. (b) Case 1 2006; Post-contrast sagittal T1w images of the pituitary demonstrating swelling and homogenous enhancement of the infundibulum and the pituitary gland. (a) Case 1 2013: post-contrast coronal T1 weighted sequence and post-contrast sagittal T1 weighted sequence -normal enhancement of the infundibulum and normal appearance of pituitary gland. (b) Case 1 2013: post-contrast sagittal T1 weighted sequence and post-contrast sagittal T1 weighted sequence-normal enhancement of the infundibulum and normal appearance of pituitary gland. A 21-year old female presented with features of autoimmune thyrotoxicosis [thyroid stimulating hormone: <0.05 mU/l (normal: 0.30–6.00 mU/l), T4: 232 pmol/l (normal 10–22 mU/l), thyroid peroxidase antibodies: 1562 iU/ml (normal < 50 iU/l) and thyroid stimulating hormone receptor autoantibody: 229 U/l (normal: < 10 U/l)]. The patient experienced polyuria and polydipsia for two months. Initial investigations refuted diabetes mellitus, hypercalcaemia and psychogenic polydipsia. A water deprivation test confirmed CDI. Investigations noted no further endocrine abnormalities. Her pituitary MRI was reported to be normal. She was commenced on a course of desmopressin and carbimazole; within two months, the patient’s symptoms had resolved. Case 2 T1w coronal post-GAD 2006—large suprasellar mass with extension into the sella and to the floor of the third ventricle. Case 2 T1w coronal post-op post-GAD 2008—complete resection with decompression of the optic chiasm with normal appearances at the floor of the third ventricle. (a) Case 3 T1 coronal pre-gad 2008—demonstrates a homogenously enhancing lesion at the base of the infundibulum and the floor of the third ventricle. Normal appearance of the distal infundibulum and the floor of the pituitary gland. (b) Case 3 T1w coronal post-GAD 2008—demonstrates a homogenously enhancing lesion at the base of the infundibulum and the floor of the third ventricle. Normal appearance of the distal infundibulum and the floor of the pituitary gland. (a) Case 3 T1w coronal post-GAD 2015: resolution of the enhancing lesion with minimal residual enhancement at the third ventricle. Appearance consistent with an inflammatory process. (b) Case 3 T1w sagittal post-GAD 2015—demonstrates the resolution of the lesion noted in 2008. Normal appearance of the distal infundibulum and the floor of the pituitary gland. Neoplastic disorders have been reported as being the most prevalent cause of pituitary stalk disorders; congenital and both inflammatory and infectious (grouped together) disorders being noted to represent the second and third most common causes respectively.2 In children under ten years of age, congenital disorders and neoplasms remain prevalent.4,5 Pituitary stalk lesions amongst young adults (eleven to eighteen years) are commonly found to arise from an underlying meningioma or an infectious/inflammatory disorder.6 Pituitary stalk lesions present with a wide array of symptomatic features (Table 1) that reflect the vast array of diseases implicated with this condition. Our case series demonstrated that the clinical course of all three patients varied significantly, from a self-limiting disorder with minimal anterior pituitary function involvement to a rapidly growing pituitary stalk tumour with associated sight threatening pressure effect and rapid loss of pituitary function despite identical diagnoses. Advances in imaging technology have allowed for earlier recognition of pituitary stalk pathology. The actual incidence of pituitary stalk lesions in the general populations remains unknown. This article will concentrate on providing an overview of the common and potentially serious disorders implicated in pituitary stalk lesions and highlighting features which may aid clinicians to delineate diseases from one another. General features of pituitary stalk lesions2,7 General features of pituitary stalk lesions2,7 In children, germ cell tumours represent the most common cause of pituitary stalk thickening or a hypothalamic/pineal mass.1,4,5,8 Germ cell tumours present with symptomatic CDI or hypopituitarism and visual changes. Diagnosis of such lesions is confirmed by MRI/PET; relevant investigations include the identification of germ-cell secreted human chorionic gonadotropin (hCG) or alpha-fetoprotein (AFP) within the cerebrospinal fluid (CSF) and/or serum. Treatment involves adjuvant chemotherapy and radiotherapy as germ cell lesions are highly radio-sensitive.7 Pituitary stalk thickening can also be attributed to primary brain tumours such as gliomas, tanycytomas, pituicytomas and meningiomas.2,9,10 Consider the possibilities of underlying acute/chronic myeloid leukaemia and metastasis to the brain from primary breast and lung tumours in older patients.2 Congenital disorders resulting in pituitary stalk lesions are pituitary hypoplasia and septo-optic dysplasia. Pituitary hypoplasia occurs usually as a result of birth trauma, hypoxic pituitary injury during delivery or disordered embryogenesis. Children present with reduced consciousness, impaired vision, seizures, intellectual disability, slow growth and manifestations of hypopituitarism. Diagnosis is made through MRI revealing hypoplastic, absent or short thickened pituitary stalk, in addition to, an ectopic posterior pituitary signified by a high signal nodule in the area of the infundibular recess on the third ventricle. In apoplexy, surgical decompression is required. Supportive treatment and hormone replacement are advised.11 Septo-optic dysplasia refers to a congenital anomaly resulting in a triad of nerve hypoplasia, hypopituitarism and midline forebrain abnormalities.12 Children present with features reflective of anterior hormone deficiencies and are diagnosed via MRI following identification of an absent infundibulum. Patients are treated using hormone replacements and multi-disciplinary therapies.13 Inflammatory, infiltrative and infectious disorders have been identified as causes of pituitary stalk lesions. An example of this is lymphocytic hypophysitis (LH), whereby lymphocytes invade pituitary tissue, causing destruction of the pituitary gland and hypopituitarism. LH predominantly affects young women (male-to-female ratio of 1:8) and characteristically occurs in the post-partum period (∼60–70% of women affected).14,15 As delineated by case 1, patients with this condition typically present with headaches and features reflective of anterior pituitary dysfunction (Table 1) with the development of CDI occurring secondary to involvement of the pituitary infundibulum. Diagnosis of LH is made through MRI which reveals thickening of the pituitary stalk or enlargement of the neurohypophysis in addition to bright signal loss in the neurohypophysis; presence of enhancement in the infundibular tongue region on MRI indicates development of CDI.16 Treatment for LH itself is not always necessary with patient prognosis varying between cases—some patients will retain anterior pituitary function whereas others may not.17 Steroid therapy has been shown to be beneficial in reducing lesion size and increase the likelihood in preserving hormonal function; transphenoidal or gamma knife surgery may be necessary to remove rapidly growing lesions.18 Sarcoidosis can affect any organ within the body; the development of CDI reflects involvement of the hypothalamo-hypophyseal system. Diagnosis is made following clinical presentations secondary to cranial nerve lesions (such as impaired vision, visual field defects, impaired swallowing, facial movements and facial sensation) and MRI which identifies enlargement of the pituitary with corresponding thickening and enhancement of the pituitary stalk. The presence of periventricular lesions and enhancement in the lepto-meningeal region may aid differentiation of neurosarcoidosis from other pathologies.19 Other investigations warranted are levels of serum-ACE and soluble interleukin-2 receptor (IL-2R); the tests with the greatest specificity and sensitivity for sarcoidosis detection; a chest radiograph is necessary to identify the presence of pulmonary sarcoidosis.20 Steroid treatment has been shown to resolve the neurosarcoid-associated radiological but has shown to provide minimal improvement in endocrine function.21 Langerhans Cell Histiocytosis (LCH) is a rare granulomatous disorder of uncertain pathogenesis. When affecting the hypothalamic–pituitary axis, patients present with symptomatic features of either CDI or anterior pituitary deficiencies with signs of growth hormone deficiency. Diagnosis is through clinical identification of extra-cranial manifestations of LCH such as skin lesions, dyspnoea, spontaneous fractures, back pain, ulcers and chronic infections; but can also be made through biopsies. Treatment involves the use of chemotherapy with LCH-attributed hormonal deficiencies likely to be permanent.22 Wegener’s granulomatosis reflects a necrotizing granulomatous vasculitis which can involve the pituitary stalk. This condition is diagnosed by the presence of extra-cranial features such as granuloma formation leading to recurrent sinusitis, haemoptysis and haematuria and a positive cytoplasmic antineutrophil cytoplasmic antibody (cANCA) result. MRI will typically reveal an enlarged, thickened and enhanced pituitary that will often extend into the hypothalamus, plus reduced hyper-intensity within the posterior pituitary.23 Treatment with high dose steroids and cyclophosphamide has demonstrated resolution of the radiological changes and CDI occurring with this condition.24 Infective causes of pituitary stalk lesions include tuberculosis of the central nervous system which, presents with seizures, confusion, impaired vision and manifestations of hypopituitarism. CNS Tuberculosis is rare. Diagnosis is often made through a combination of cerebrospinal fluid analysis, which shows high protein, low glucose, a moderate number of lymphocytes, stain for acid-fast bacilli and have M.tuberculosis growing in culture, MRI of the pituitary gland, which will show a thickened stalk, with focal hypointense sections within/adjacent to the sella and confirmatory transphenoidal/transcranial biopsy. Treatment is via anti-tubercular agents and prognosis is generally good as anti-tuberculous agents are curative.25 Cranial diabetes insipidus with pituitary stalk lesion is a rare condition with variant possible underlying pathologies. We recommend serial MRI imaging guided by patient symptomology and 3–6 monthly biochemistry, to guide progress with treatment. The frequency of investigation can be reduced as symptoms resolve. With the existing lack of literature and evidence based guidelines on both the management and follow up of this uncommon condition, our case series raises awareness of the differing presentations of this clinical conundrum to aid physicians diagnose and treat this condition effectively and confidently. Conflict of interest: None declared.