Persistent hypernatremia secondary to adipsic central diabetes insipidus in a patient with herpes-induced meningoencephalitis and COVID-19 infection: a case report

Abstract

Central diabetes insipidus (CDI) typically manifests as a polyuria–polydipsia syndrome, in which normonatremia is generally maintained through the polydipsia. A 53-year-old woman presented with diabetic ketosis and hyperosmolar hyperglycemic syndrome. Her medical history included herpes meningoencephalitis, which was associated with confusion and amnesia. On physical examination, she was apyretic, confused, and had signs of extracellular dehydration. Her capillary glucose concentration was high and her urine was positive for ketones. Laboratory investigations revealed severe hyperglycemia, hypernatremia (plasma hyperosmolarity of 393.6 mOsm/L), and mild acute renal failure. In addition, she had a paucisymptomatic COVID-19 infection. Intravenous rehydration with isotonic saline solution and insulin therapy were effective at controlling the ketosis and ameliorating the hyperglycemia, but failed to normalize the hypernatremia and hyperosmolarity. She was not thirsty and had a urine output of 1 L/day, with urinary hypotonicity. Desmopressin administration reduced the hypernatremia and hyperosmolarity to within their normal ranges, and the patient’s urinary osmolarity increased to 743 mOsm/L. Therefore, adipsic CDI was diagnosed. Endocrine investigations revealed isolated central hypothyroidism. The results of pituitary magnetic resonance imaging were normal. Thus, patients with impaired thirst may have an atypical presentation of CDI. In addition, the diagnosis of adipsic CDI is particularly challenging.

Introduction

Central diabetes insipidus (CDI) is a rare condition caused by low or absent production of arginine vasopressin (AVP), the antidiuretic hormone. ¹ CDI can be either idiopathic or develop secondary to traumatic, neoplastic, or autoimmune lesions of the AVP-secreting neurons. ² It typically manifests as a polyuria–polydipsia syndrome. The polyuria is usually compensated for by an increase in water intake that aims to maintain the serum osmolarity within its normal range. ¹ Rarely, patients present with hypodipsia or adipsia. ³ Adipsia is a rare disorder that is defined by a lack of thirst and is the result of damage to the thirst center, which is located in the hypothalamus. Patients with adipsia are particularly vulnerable to dehydration, hypernatremia, and thromboembolic complications.^1,3

Here, we report the case of a woman who presented for the first time with diabetic ketosis, hyperosmolar hyperglycemic syndrome, and COVID-19 infection, and who had persistent hypernatremia reflecting the presence of adipsic CDI.

Case presentation

A 53-year-old woman was admitted to the Department of Endocrinology because of the development of diabetic ketosis and hyperosmolar hyperglycemic syndrome. Her medical history included herpes meningoencephalitis, which occurred 3 years previously and caused persistent confusion, amnesia, and adipsia. There was no known individual or family history of autoimmune or neoplastic disease.

The patient presented with asthenia and weight loss. On physical examination, she was confused (Glasgow coma scale score: 13 to 14/15); and had a body mass of 73 kg, a height of 1.51 m, a body mass index of 32.0 kg/m², a blood pressure of 130/80 mmHg, a heart rate of 100 beats/minute, a respiratory rate of 18 breaths/minute, and signs of extracellular dehydration. Her body temperature was normal. A breast examination revealed no abnormalities.

The patient’s capillary glucose concentration was >33 mmol/L and a urine sample was positive for ketones (++). Further laboratory investigations revealed severe hyperglycemia, hypernatremia (plasma hyperosmolarity of 393.6 mOsm/L), and mild acute renal failure (Table 1). Her arterial blood gas parameters were normal. A COVID-19 infection was diagnosed using a reverse transcription polymerase chain reaction (PCR) assay. A chest x-ray revealed no abnormalities.

Table 1.

Laboratory data.

	Result	Normal range
Glucose (mmol/L)	55.1	3.88–5.55
HbA1c (%)	>14	<5.7
Sodium (mmol/L)	159	135–145
Potassium (mmol/L)	5	3.5–5.0
Creatinine (µmol/L)	62.5	53–97
Urea (mmol/L)	10.5	2.5–7.5
C-reactive protein (nmol/L)	152.4	<47.6
Calcium (mmol/L)	2.3	2.2–2.6
White blood cell count (elements/μL)	6,100	4,000–10,000
Lymphocyte count (elements/μL)	1,630	1,500–4,000
pH	7.34	7.35–7.45
${\text{HCO}}_3^{-}$ (mmol/L)	27.1	21–28
8-hour cortisol (nmol/L)	546	110.36–551.80
FT4 (pmol/L)	8.23	9.01–19.30
TSH (mIU/L)	1.92	0.35–4.94
LH (IU/L)	20	2.0–9.0
FSH (IU/L)	39.5	1.8–11.2
Prolactin (ng/mL)	12.6	0–20
Glutamic acid decarboxylase antibodies	Negative
Islet-cell antibodies	Negative
Thyroperoxidase antibodies	Negative

FSH: follicle-stimulating hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone, FT4: free thyroxine.

The patient underwent rehydration with intravenous isotonic saline solution, potassium supplementation, and insulin therapy, which controlled her ketosis and hyperglycemia. However, her hypernatremia persisted (serum sodium concentration of 148 to 158 mmol/L), along with her plasma hyperosmolarity (321 to 336 mOsm/L). Her urine output was 1 L/day and her urine osmolarity was 139.8 mOsm/L, indicating hypotonicity. Despite her high serum sodium concentration, the patient was not thirsty (fluid intake <1 L/day), and intravenous rehydration with 5% dextrose failed to normalize the hypernatremia. Owing to the presence of a combination of persistent hypernatremia, plasma hyperosmolarity, and inappropriate urinary hypotonicity, in the absence of an increase in thirst, the presence of adipsic CDI was suspected. Therefore, therapeutic testing was performed by the sublingual administration of 240 μg of desmopressin (four tablets of 60 µg each) followed by close monitoring of clinical signs and blood and urine parameters for 24 hours (Table 2). Desmopressin administration reduced the serum sodium concentration and plasma osmolarity to within their normal ranges (145 mmol/L and 309 mOsm/L, respectively), and the patient’s urine osmolarity increased to 743 mOsm/L. Endocrine investigations of anterior pituitary gland function revealed isolated central hypothyroidism (Table 1). In addition, brain magnetic resonance imaging (MRI) revealed large porencephalic temporo-insular lesions relating to the patient’s herpes encephalitis, but her anterior pituitary gland was normal. The posterior pituitary bright spot was present and the pituitary stalk had a median location and was thin.

Table 2.

Desmopressin test results.

	T0	T4H	T12H	T24H
Serum
Sodium (mmol/L)	157	153	151	145
Potassium (mmol/L)	3.6	3.9	3.4	3.6
Glycemia (mmol/L)	8.9	6.3	8.2	6.2
Urea (mmol/L)	4.6	5.5	4.7	5.6
Osmolarity (mOsm/L)	334.7	325.6	321.7	309
Urine
Sodium (mmol/L)	54	90	128	121
Potassium (mmol/L)	13	48	82	41
Urea (mmol/L)	71	238	380	419
Osmolarity (mOsm/L)	205	514	800	743

T0: before desmopressin administration. T4H, T12H, T24H: after 4 hours, 12 hours, and 24 hours of desmopressin administration, respectively.

The patient was subsequently treated with desmopressin tablets (60 µg twice daily) and levothyroxine. Her insulin was discontinued because of recurrent hypoglycemia, and instead she was treated with metformin. Her family members received appropriate information and were involved to ensure compliance with the treatment and regular fluid intake. The patient regularly attended our outpatient clinic and remained asymptomatic. After 3 months, her urine output had increased to 1.5 L/day, her serum sodium concentration was 140 mmol/L, her fasting blood glucose concentration was 7.26 mmol/l, her HbA1c was 6.8%, and her serum free thyroxine concentration was 10.55 pmol/L. The concentrations of the other pituitary hormones remained normal over the follow-up period.

The reporting of this case conforms to the CARE guidelines. ⁴ Written informed consent was obtained from the patient for her treatment and for the publication of this case report. The requirement for ethics approval for this case report was waived because of the retrospective nature of the study.

Discussion

The maintenance of water homeostasis and normal plasma sodium concentration and osmolarity require a balance between water intake, induced by thirst, and the antidiuretic effect of AVP on the distal collecting ducts of the kidney.^5,6

CDI is a complex condition that is defined by AVP deficiency. In the absence of AVP secretion, patients with CDI depend entirely on their thirst to stimulate adequate water intake to compensate for the polyuria and maintain plasma osmolarity within the normal range. However, some patients have abnormal thirst perception, which leads to hypodipsia, or in extreme cases, to adipsia, a condition that is referred as adipsic CDI.^7,8 This is an extremely rare disorder, with only a few cases having been reported.^3,6,9–11 Because of osmoreceptor dysfunction, these patients are unable to experience thirst and to respond to an increase in osmolarity by an increase in fluid intake. ⁸ The osmoreceptors are located in the organum vasculosum of the lamina terminalis in the anterior hypothalamus. They detect an increase in plasma sodium concentration and osmolarity, which causes an increase in thirst,^11,12 and the destruction of these receptors leads to adipsia.

Patients with adipsic CDI are particularly vulnerable to hypernatremia, dehydration, and venous thromboembolism.^1,3 Arima et al. ¹ performed a retrospective study of 149 patients with CDI (23 with adipsia and 126 without adipsia) which showed that the incidences of hypernatremia and infection and the risk of death are significantly higher in patients with adipsia than in those without.

Adipsic CDI should be suspected in the presence of hypernatremia, plasma hyperosmolarity, and inappropriately dilute urine, in the absence of thirst. The diagnosis can be confirmed by the normalization of these abnormalities by desmopressin administration, as in the present patient.^11,13

CDI is commonly caused by neoplastic or infiltrative hypothalamic lesions, traumatic brain injury, neurosurgery, or autoimmune destruction of the posterior lobe of the pituitary.^2,14–16

Pituitary MRI is used for the diagnosis and to determine the etiology of CDI. The loss of the posterior pituitary bright spot is the classic MRI finding in patients with CDI,^16,17 but the presence of a T1 posterior pituitary hypersignal does not rule out a diagnosis of CDI,^17,18 and this signal may disappear during the course of the disease. The etiology of the CDI in the present patient was not clear; it may have been caused by the herpes infection or the COVID-19 infection, a viral infection of the central nervous system has rarely been reported as an etiologic factor. ¹⁹ A few cases of CDI associated with COVID-19 infection have recently been reported,^20,21 but no explanation of this association has been identified. The principal hypotheses are inflammatory lesions induced by viral hypophysitis and delayed autoimmune hypohysitis. ²¹ The hypothalamus–pituitary axis is affected by COVID-19 infection because it expresses both angiotensin-converting enzyme 2 and the transmembrane protease serine 2, which are potential receptors for SARS-CoV-2.^21,22 CDI has been reported as a late complication of COVID-19 infection in the majority of cases. ²⁰ The present patient had adipsic CDI that was probably the result of a combination of adipsia caused by herpes meningoencephalitis and the loss of ADH secretion secondary to recent inflammatory hypothalamic or pituitary lesions induced by COVID-19 infection, diagnosed using reverse transcription PCR. However, this test cannot determine the exact timing of an infection because a considerable number of patients are positive on PCR for long periods of time following their recovery. ²³ The present patient had no symptoms of a viral infection during her hospitalization.

The management of adipsic CDI is particularly challenging, especially in the presence of cognitive impairment that affects fluid intake and compliance with medication. Therefore, family education is crucial. The pillars of adipsic CDI management are adequate fluid intake and desmopressin administration. Desmopressin is a synthetic analogue of AVP that is administered intranasally or sublingually at a daily dose that is titrated on an individual basis to avoid hyponatremia and hypernatremia. ²⁴ In addition, the appropriate daily water intake should be carefully determined on the basis of regular weighing and the determination of serum sodium concentration.^11,25 Patients with amnesic disorders or behavioral issues need a caregiver to ensure their correct fluid intake and the administration of desmopressin.

Conclusion

Adipsic CDI is a rare condition that may be life-threatening. Both its diagnosis and management are particularly challenging. The condition should be suspected in the presence of hypernatremia and high plasma osmolarity, alongside inappropriately diluted urine. The management of adipsic CDI involves adequate fluid intake and the administration of desmopressin.