Newly discovered Pituitary Adenoma in the Emergency Center during the COVID-19 Pandemic in Serbia: Treatment and Early Postoperative Outcome (preprint)

Introduction:Pituitary tumors represent 10-15% of all intracranial tumors. Clinical manifestations depend on the size of the tumor such as microadenoma, macroadenoma or giant adenoma, and type of the tumor (secreting or non-secreting). Surgical treatment of pituitary adenoma can be managed via transcranial or transsphenoidal approach. Depending on the approach, there is a possibillity of postoperative complications such as meningitis, pneumocephalus, liquorrhea, transient diabetes insipidus and ect. Aim:The aim of this study was to establish the frequency of newly discovered pituitary tumors in the Emergency Center, University Clinical Center Of Serbia, during the COVID-19 pandemic in Serbia, and early postoperative complications in patients treated with an endoscopic and microscope transsphenoidal approach. Material and methods: During the time period during the pandemic, the study contains 119 patients, from January 1, 2020 to March 1, 2023, of which 64 are male (53.8%) and 55 are female (46.2%), age range is 14 to 85 years with a mean of 52.10. As for statistical analysis, assessment of frequency rate and relative numbers were used as methods of descriptive statistics. Results:Macroadenoma was present in 95 patients (79.83%), microadenoma in 22 patients (18.49%), and giant adenoma in 2 patients (1.69%). Transient DI developed postoperatively in 11 patients (9.24%). The average duration of hospitalization after surgery was 8 days. Conclusion: The duration of hospitalization depends on numerous factors where the COVID-19 pandemic can serve as an example for future similar crisis situations so that better organization and preoperative preparation of patients can be implemented.

AVP deficiency (central diabetes insipidus) following immunization with anti-COVID-19 BNT162b2 Comirnaty vaccine in adolescents: A case report.

Introduction: The coronavirus disease 19 (COVID-19) pandemic has prompted the development of new vaccines to reduce the morbidity and mortality associated with this disease. Recognition and report of potential adverse effects of these novel vaccines (especially the urgent and life-threatening ones) is therefore essential. Case presentation: A 16-year-old boy presented to the Paediatric Emergency Department with polyuria, polydipsia and weight loss over the last four months. His past medical history was unremarkable. Onset of symptoms was referred to be few days after first dose of anti-COVID-19 BNT162b2 Comirnaty vaccine and then worsened after the second dose. The physical exam was normal, without neurological abnormalities. Auxological parameters were within normal limits. Daily fluid balance monitoring confirmed polyuria and polydipsia. Biochemistry laboratory analysis and urine culture were normal. Serum osmolality was 297 mOsm/Kg H2O (285-305), whereas urine osmolality was 80 mOsm/Kg H2O (100-1100), suggesting diabetes insipidus. Anterior pituitary function was preserved. Since parents refused to give consent to water deprivation test, treatment with Desmopressin was administered and confirmed ex juvantibus diagnosis of AVP deficiency (or central diabetes insipidus). Brain MRI revealed pituitary stalk thickening (4 mm) with contrast enhancement, and loss of posterior pituitary bright spot on T1 weighted imaging. Those signs were consistent with neuroinfundibulohypophysitis. Immunoglobulin levels were normal. Low doses of oral Desmopressin were sufficient to control patient's symptoms, normalizing serum and urinary osmolality values and daily fluid balance at discharge. Brain MRI after 2 months showed stable thicken pituitary stalk and still undetectable posterior pituitary. Due to persistence of polyuria and polydipsia, therapy with Desmopressin was adjusted by increasing dosage and number of daily administrations. Clinical and neuroradiological follow-up is still ongoing. Conclusion: Hypophysitis is a rare disorder characterized by lymphocytic, granulomatous, plasmacytic, or xanthomatous infiltration of the pituitary gland and stalk. Common manifestations are headache, hypopituitarism, and diabetes insipidus. To date, only time correlation between SARS-CoV-2 infection and development of hypophysitis and subsequent hypopituitarism has been reported. Further studies will be needed to deepen a possible causal link between anti-COVID-19 vaccine and AVP deficiency.

New developments and concepts in the diagnosis and management of diabetes insipidus (AVP-deficiency and resistance).

Diabetes insipidus (DI) is a disorder characterised by the excretion of large amounts of hypotonic urine, with a prevalence of 1 per 25,000 population. Central DI (CDI), better now referred to as arginine vasopressin (AVP)-deficiency, is the most common form of DI resulting from deficiency of the hormone AVP from the pituitary. The less common nephrogenic DI (NDI) or AVP-resistance develops secondary to AVP resistance in the kidneys. The majority of causes of DI are acquired, with CDI developing when more than 80% of AVP-secreting neurons are damaged. Inherited/familial CDI causes account for approximately 1% of cases. Although the pathogenesis of NDI is unclear, more than 280 disease-causing mutations affecting the AVP2 protein or AVP V2 receptor, as well as in aquaporin 2 (AQP2), have been described. Although the cAMP/protein kinase A pathway remains the major regulatory pathway of AVP/AQP2 action, in vitro data have also revealed additional cAMP independent pathways of NDI pathogenesis. Diagnosing partial forms of DI, and distinguishing them from primary polydipsia, can be challenging, previously necessitating the use of the water deprivation test. However, measurements of circulating copeptin levels, especially after stimulation, are increasingly replacing the classical tests in clinical practice because of their ease of use and high sensitivity and specificity. The treatment of CDI relies on desmopressin administration, whereas NDI requires the management of any underlying diseases, removal of offending drugs and, in some cases, administration of diuretics. A better understanding of the pathophysiology of DI has led to novel evolving therapeutic agents that are under clinical trial.

Transient diabetes insipidus in critically ill COVID19 patients.

PURPOSE: Vasopressin has become an important vasopressor drug while treating a critically ill patient to maintain adequate mean arterial pressure. Diabetes insipidus (DI) is a rare syndrome characterized by the excretion of a large volume of diluted urine, inappropriate for water homeostasis. We noticed that several COVID19 patients developed excessive polyuria suggestive of DI, with a concomitant plasma sodium-level increase and/or low urine osmolality. We noticed a temporal relationship between vasopressin treatment cessation and polyuria periods. We reviewed those cases to better describe this phenomenon. METHODS: We retrospectively collected COVID19 ECMO patients' (from July 6, 2020, to November 30, 2021) data from the electronic medical records. By examining urine output, urine osmolality (if applicable), plasma sodium level, and plasma osmolality, we set DI diagnosis. We described the clinical course of DI episodes and compared baseline characteristics between patients who developed DI and those who did not. RESULTS: Out of 37 patients, 12 had 18 episodes of DI. These patients were 7 years younger and had lower severity scores (APACHE-II and SOFA). Mortality difference was not seen between groups. 17 episodes occurred after vasopressin discontinuation; 14 episodes were treated with vasopressin reinstitution. DI lasted for a median of 21 h, with a median increase of 14 mEq/L of sodium. CONCLUSIONS: Temporary DI prevalence after vasopressin discontinuation in COVID19 ECMO patients might be higher than previously described for vasopressin-treated patients.

Infection with SARS-CoV-2 may alter the half-life of desmopressin (DDAVP) in patients with central diabetes insipidus.

We present a 9-year-old boy with diabetes insipidus. The boy is treated with desmopressin (DDAVP) therapy. Under this therapy, the drinking quantity and the laboratory parameters were normal. No nocturia occurred any more. In the context of a clinically mild infection with SARS-CoV-2, the duration of action of DDAVP was significantly prolonged (approximately +50%). The original dosage was then reintroduced and was still sufficient until months later. A possible connection to the infection with SARS-CoV-2 can be suspected. Our case report should make physicians who care for patients with diabetes insipidus aware of such a possible prolongation of the effect of DDAVP. More frequent monitoring may be needed in such patients to assess the risk of symptomatic dilutional hyponatremia.

[Update on the diagnosis and management of SIADH and Diabetes insipidus]. / SIADH & Diabetes insipidus: Neues zu Diagnosestellung und Therapie.

Dysnatremia is a common occurrence in patients with COVID-19 and is associated with higher mortality and risk for septic conditions. The pathomechanisms are probably multifaceted, but severe hyponatremia may also occur as a result of underlying SIADH or hypocortisolism. Patients with preexisting AVP dysfunction, like SIADH or diabetes insipidus, are at high risk for severe electrolyte imbalances in the event of a COVID-19 infection.The recently growing use of immune checkpoint inhibitors in oncology is associated with a spectrum of endocrine immune-related adverse events (endocrine irAEs). These AEs usually occur unpredictably and may even manifest after discontinuation of the anticancer therapy. Hyponatremia is a common factor of several endocrine irAEs and may serve as a red flag biomarker for possibly underlying endocrine irAEs such as hypophysitis or adrenalitis. New-onset hyponatremia should always prompt a comprehensive diagnostic workup and exclusion of endocrine irAEs before the diagnosis of SIADH is made.Hyponatremia with severe symptoms should be treated with hypertonic (3 %) saline solution to resolve the cerebral edema and prevent from detrimental neurological sequelae. Both rapid intermittent bolus (RIB) therapy and continuous infusion therapy have now been reported to be safe and equally effective. The RIB therapy limits the risk of overcorrection and requires less often re-lowering treatment than continuous infusion therapy.Fluid restriction has long been considered as first-line treatment of chronic hyponatremia due to SIADH. Additional treatment with Furosemid and/or oral NaCl tablets does not improve efficacy but reduces tolerance to therapy.Copeptin-based dynamic tests show higher diagnostic accuracy in the differential diagnosis of patients with hypotonic polyuria polydipsia syndrome than the indirect water deprivation test.

Vasopressin and Its Analogues: From Natural Hormones to Multitasking Peptides.

Human neurohormone vasopressin (AVP) is synthesized in overlapping regions in the hypothalamus. It is mainly known for its vasoconstricting abilities, and it is responsible for the regulation of plasma osmolality by maintaining fluid homeostasis. Over years, many attempts have been made to modify this hormone and find AVP analogues with different pharmacological profiles that could overcome its limitations. Non-peptide AVP analogues with low molecular weight presented good affinity to AVP receptors. Natural peptide counterparts, found in animals, are successfully applied as therapeutics; for instance, lypressin used in treatment of diabetes insipidus. Synthetic peptide analogues compensate for the shortcomings of AVP. Desmopressin is more resistant to proteolysis and presents mainly antidiuretic effects, while terlipressin is a long-acting AVP analogue and a drug recommended in the treatment of varicose bleeding in patients with liver cirrhosis. Recently published results on diverse applications of AVP analogues in medicinal practice, including potential lypressin, terlipressin and ornipressin in the treatment of SARS-CoV-2, are discussed.

ENDOCRINOLOGY IN THE TIME OF COVID-19-2021 UPDATES: The management of diabetes insipidus and hyponatraemia.

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counselling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of postoperative SIAD. They should know hyponatraemia symptoms. Hyponatraemia in COVID-19 is common with a prevalence of 20-30% and is mostly due to SIAD or hypovolaemia. It mirrors disease severity and is an early predictor of mortality. Hypernatraemia may also develop in COVID-19 patients, with a prevalence of 3-5%, especially in ICU, and derives from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.

Central adrenal insufficiency and diabetes insipidus as potential endocrine manifestations of COVID-19 infection: a case report.

SARS-CoV-2 infection, responsible for the coronavirus disease-2019 (COVID-19) has rapidly spread, causing a global pandemic. COVID-19 can affect any organ system in the body due to overwhelming dysregulated immune response and long-term effects of the disease is still unknown. Endocrine complications associated with COVID-19 is exceedingly rare. Here we present a unique case of a 44-year-old female who developed adrenal insufficiency and central diabetes insipidus following COVID-19 infection.

Case Report: SARS-CoV-2 Infection in a Child With Suprasellar Tumor and Hypothalamic-Pituitary Failure.

In early 2020, a novel coronavirus leading to potentially death was discovered. Since then, the 2019 coronavirus disease (COVID-19) has spread to become a worldwide pandemic. Beyond the risks strictly related to the infection, concerns have been expressed for the endocrinological impact that COVID-19 may have, especially in vulnerable individuals with pre-existing endocrinological health conditions. To date new information is emerging regarding severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in children but the literature is still scarce concerning this infection in patients with intracranial malignant neoplasms. We report a 9-year-old child infected with SARS-CoV-2 and recent diagnosis of suprasellar non-germinomatous germ cell tumor also suffering from diabetes insipidus and hypothalamic-pituitary failure (hypothyroidism, adrenal insufficiency, hypothalamic obesity and growth hormone deficiency) and its clinical course. The patient remained asymptomatic for the duration of the infection without requiring any change in the replacement therapeutic dosages taken before the infection. We then discuss the proposed approach to treat a pediatric patient with SARS-CoV-2 infection and hypothalamic-pituitary failure and we include a review of the literature. Our report suggests that SARS-CoV-2 infection is usually mild and self-limiting in children even those immunocompromised and with multiple endocrinological deficits. Patients are advised to keep any scheduled appointments unless informed otherwise.

Diabetes Insipidus and Concomitant Myocarditis: A Late Sequelae of COVID-19 Infection.

Severe acute respiratory syndrome coronavirus 2 causes coronavirus disease 2019 (COVID-19), which has become a global pandemic. Apart from the mild features of the disease, long-term complications involve many systems including both endocrine and cardiovascular systems. Myocarditis, secondary to COVID-19, has become a well-known complication of the disease. However, endocrine complications are generally not common, particularly isolated pituitary abnormalities. There is one other report of diabetes insipidus developing as a late sequela of COVID-19. In this article, we report a case of a young male who presented with features of myocarditis but developed diabetes insipidus on day 7 of admission as a long-term complication after recovery from COVID-19 infection. His laboratory test results at the time of developing the complication revealed a high serum sodium level and low urine osmolality. The patient recovered on administration of desmopressin and was discharged after 16 days of hospitalization.

Diabetes or endocrinopathy admitted in the COVID-19 ward.

The Covid-19 pandemic confronted us with unknown clinical pictures, also in diabetology and endocrinology. Sharing clinical experiences is therefore of enormous importance. Actually, information about the care given in the Covid-19 ward (in contrast to that provided in the Emergency Room/ICU) is still sparse. The last weeks we built experience and gathered knowledge while giving hospital care to patients who had a pre-existent endocrine disease (and diabetes; most patients suffered from a type two diabetes). In our contribution we presented our insights obtained from this intensive period obtained in the Covid-19 ward.

ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of diabetes insipidus and hyponatraemia.

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counseling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of the postoperative syndrome of inappropriate antidiuresis (SIAD). They should know hyponatraemia symptoms. The prevalence of hyponatraemia in patients with pneumonia due to COVID-19 is not yet known, but seems to be low. In contrast, hypernatraemia may develop in COVID-19 patients in ICU, from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.