When Thirst Ceases to Exist: A Case Report and Literature Review of Adipsic Diabetes Insipidus Following Coil Embolization of a Ruptured Anterior Communicating Artery Aneurysm

Diabetes insipidus is a condition characterized by inappropriately dilute urine in the setting of serum hyperosmolality. The two predominant subtypes include central (from lack of vasopressin production) and nephrogenic diabetes insipidus (from renal resistance to circulating vasopressin). A common manifestation is the significant pursuant thirst from excessive polyuria. We present a case report and literature review of an infrequent variation of central diabetes insipidus known as adipsic (hypothalamic) diabetes insipidus, characterized by the absence of thirst, secondary to coiling of a ruptured anterior communicating artery aneurysm. Due to the loss of thirst, patients are at a heightened risk for hypernatremia and complications secondary to dehydration. Our patient's course was complicated by recurrent polyuria and hypernatremia, requiring a fixed-dose desmopressin regimen. On follow-up, only partial thirst sensation was restored. We provide a literature review to compare our case report to the scant literature available to broaden the awareness of this infrequent, perilous, manifestation.


Introduction
Thirst is defined as the strong desire for water and is integral to human survival, with the strongest stimuli for thirst being hyperosmolality and hypernatremia [1].Moreover, the desire for hydration can be an adverse effect of medications and may also be a clinical sign or symptom pertaining to an underlying pathological process.
Diabetes insipidus is one such pathology, characterized by excessive, dilute urine in the setting of serum hyperosmolality and has two predominant subtypes, either central (inadequate vasopressin production) or nephrogenic (renal resistance to vasopressin).Infrequently, during pregnancy, a third subtype can arise, whereby the placenta produces vasopressinase, which degrades vasopressin.Management of these conditions involves either replacement of the deficient hormone (administered as desmopressin, DDAVP), or enhancement of renal sensitivity to vasopressin.
We present a fourth subtype known as adipsic (hypothalamic) diabetes insipidus, which is akin to central diabetes insipidus with the caveat of impairment (or absence) of thirst sensation.Most commonly (as with our patient) this can occur following the management of a ruptured anterior communicating artery aneurysm and has been documented only a couple hundred times within the medical literature.We therefore provide a case report and review of the current literature to broaden the awareness of this phenomenon across all medical specialties.

Case Presentation
A 65-year-old gentleman with no significant past medical history was found unresponsive by his wife at home.Emergency medical services were contacted, and he was transported to the emergency department, where he was intubated for airway protection.He underwent a computed tomography angiography scan of his head and neck, demonstrating a ruptured 7 x 4 x 4 millimeter right anterior communicating artery aneurysm (incorporating origins of A 2 segments with antero-superior projection) leading to an acute right frontal parenchymal hematoma and subarachnoid hemorrhage (Figure 1).He was admitted to the neurosurgical unit and underwent an urgent coil embolization.During his admission, he was extubated; however, his course was complicated by dysphagia requiring the placement of a percutaneous endoscopic gastrostomy (PEG) tube, for which he received both water flushes and tube feeds.Additionally, he developed hydrocephalus requiring placement of a ventriculoperitoneal shunt (VPS), which failed, requiring subsequent placement of an external ventricular drain (EVD) and distal catheter revision of the VPS.His course was further complicated by an abdominal infection with ventriculitis requiring removal of the VPS hardware and EVD placement, with revision VPS.He improved following a course of antibiotic treatment and was transferred to acute inpatient rehabilitation three months following his initial presentation.

FIGURE 1: Computed Tomography Angiography of the Head and Neck (With Contrast) and Computed Tomography of the Head (Without Contrast)
A: Arrow is pointing to anterior communicating artery aneurysm, demonstrating its close proximity to the hypothalamus B: Subarachnoid hemorrhage with intraventricular hemorrhages At the acute inpatient rehabilitation, endocrinology was consulted due to the concern for diabetes insipidus.The day prior to being seen by endocrinology, the patient was polyuric with an output of three liters and was noted to have persistent sodium levels between 144 and 147 mEq/L, alongside a urine osmolality of 475 mOsm/kg in the setting of serum osmolality of 318 mOsm/kg (additionally demonstrated orthostatic hypotension during physical therapy).These results suggested an inadequate urine concentration (suggestive of partial diabetes insipidus).A water deprivation test was not pursued given his findings suggestive of (partial) diabetes insipidus, as well as his classic history of an anterior communicating artery aneurysm clipping, and hypotension.Peculiarly, the gentleman did not complain of thirst despite being polyuric and required repetitive reminders from the nursing staff to stay hydrated; he would frequently refuse oral hydration and tube flushes stating that he was not thirsty.
The patient was started on 0.1 milligrams (mg) of oral desmopressin nightly (oral desmopressin was easier to administer by the nursing staff), and his tube flushes were decreased in frequency from 400 mL every four hours to every six hours.When re-examined by Endocrinology, his sodium had increased to 147 mEq/L, with a urine osmolality of 327 mOsm/kg and documentation of around 800 mL of urine in a few hours (polyuric); this was suggestive of inappropriately dilute urine.His oral desmopressin was increased to 0.1 mg twice daily, and his tube flushes were reverted to every four hours.
Upon further follow-up, he remained hypernatremic, with intermittent polyuria (albeit not accurately documented) and frequent omission of tube flushes by the nursing staff.His oral desmopressin was frequently missed or taken near the timing of his tube feeds (likely impairing absorption), and he was switched to nasal desmopressin for improved absorption (one spray of 10 micrograms daily).At this time, the patient stated he had some thirst sensation return but required frequent reminders to hydrate throughout the day.His nasal demopressin was eventually increased to 20 micrograms twice daily as his PEG tube became dislodged and was no longer receiving free water flushes; in this regimen, he remained eunatremic with a stable sodium between 138 and 143 mEq/L and a decreased urine output.
Anterior pituitary hormone panels were performed at baseline on admission, and one week later.The results demonstrated secondary hypogonadism with low testosterone, likely from traumatic brain/pituitary injury.Testosterone was not initially commenced as this was a mildly low testosterone level with a recent injury, and it was decided to wait and repeat the level in a few months in case of recovery of the gonadal axis.Two months later, however, there was no improvement, and a discussion occurred between the patient, family, and the physical medicine and rehabilitation team, and a decision was reached to avoid testosterone supplementation (

Discussion
Our case report adds to the scant literature on adipsic diabetes insipidus, a rare encounter with no further than a couple hundred cases posed globally (Table 2).As demonstrated, our patient had impaired thirst sensation, with only partial improvement, and required a fixed regimen of desmopressin and controlled water intake for the management of his polyuria and hypernatremia.The case presented is unique compared to other case reports or series, as the patient had a prolonged stay in acute inpatient rehabilitation (seven months), for which, it was possible to observe his disease course in a controlled environment directly.1994 [54] Septo-Optic   1997 [20] Non  Adipsic diabetes insipidus occurs when there is significant damage in the hypothalamus at the areas that make vasopressin, and the thirst centres.Adipsic diabetes insipidus has been described following anterior communicating artery aneurysm repairs, intracranial tumors (craniopharyngioma, pinealoma, germinoma, pituitary tumors), head trauma, vascular malformations, infiltrative diseases, and congenital lesions among others; a full list is depicted in Table 3 [110].The most common cause of adipsic diabetes insipidus is following treatment of a ruptured anterior communicating artery aneurysm (responsible for around 40% of cases) [91].The risk of developing the condition following repair of an anterior communicating artery aneurysm is around 0.04% (with meta-analyses noting coiling associated with better outcomes over clipping) [16].Following aneurysmal ruptures, the next most common causes include craniopharyngiomas (13-30%) and congenital causes (5-20%) [62].As demonstrated in the study by Mavrakis and Tritos [6], patients with adipsic diabetes insipidus and a ruptured anterior communicating artery aneurysm are significantly likely to be older than those with craniopharyngiomas, germinomas, or congenital condition (age 39.8 +/-3.2 versus 23.1 +/-4.9 versus 13.3 +/-1.0 versus 5.5 +/-2.4 years, p < 0.001).

Causes of Adipsic Diabetes Insipidus
Repair

Pathophysiology
Water balance is maintained by vasopressin release and the sensation of thirst.Changes in osmolality are among the most powerful triggers for the production and release of vasopressin, alongside thirst, to control a tight osmolality of the serum between 285-295 mOsm/kg [110].As well as osmolality, baroreceptor response to both pressure and volume status are factors inducing the release of vasopressin [110].
Osmoreceptors are located within the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ and the anterior hypothalamus, with the nearby vasopressin-producing cells being located in the paraventricular and supraoptic nuclei of the hypothalamus (extending along axons into the pituicytes) (Figure 2).The osmoreceptors within the OVLT are close to the anterior wall of the third ventricle and are therefore readily able to detect such changes and respond appropriately [16].Following the release of vasopressin, it binds to V 2 receptors in the collecting duct of the renal tubule, leading to aquaporin-2 insertion within the luminal membrane, allowing for water permeation and reabsorption from urine into the blood, alongside stimulation of thirst centers within the hypothalamus.Due to such a tightly formed pathway, it is estimated that osmolality varies by no more than 2% in the setting of unrestricted access to water [111].

FIGURE 2: Nuclei of Water Balance
Obtained with Permission from [6] AP: Anterior Pituitary; OC: Optic Chiasm; OVLT: Organ Vasculosum of Lamina Terminalis; PA: Preoptic Area; PP: Posterior Pituitary; PVN: Paraventricular Nuclei; SON: Supraoptic Nucleus Blood supply of the OVLT is from four predominant sources, including superior branches of the anterior communicating artery, two lateral branches from the anterior cerebral arteries (itself branching from the anterior communicating arteries), and an inferior branch that ascends from below the optic chiasm [91].As a result, interventions such as clipping and coiling lead to downstream interruption and can result in adipsia and abnormalities in both vasopressin synthesis and release.
Postoperative diabetes insipidus is a common finding after pituitary surgery characterized by a triphasic response of hypothalamic dysfunction and early diabetes insipidus (with polyuria and hypernatremia), syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to release of pre-formed vasopressin from storage vesicles in the posterior pituitary, with a return to permanent diabetes insipidus due to depletion of these stores [110].With injury to the hypothalamic thirst centers, adipsia may remain alongside the central diabetes insipidus.Adipsic disorders are classified into four subtypes, A through D, with the patient described in the case report presenting with Type C Adipsia (Table 4) [62,112,113].

Subtype Description
Type A Also termed 'Essential Hypernatremia'.Occurs from reduced sensitivity of the osmoreceptors, leading to partial diabetes insipidus with concurrent subnormal sensation of thirst.It is characterized by an upward reset of the osmotic threshold for both thirst and vasopressin release (until osmolality has risen above the new threshold (often over 300 mOsm/Kg)).Patients are often protected from extremes of hypernatremia as a result.With water overload, thirst can be suppressed alongside vasopressin release, and hypotonic diuresis can develop.Underlying etiology is unknown as imaging of the pituitary is often unremarkable.

Type B
Subnormal vasopressin and thirst response to rising osmotic stimuli, with normal osmoregulatory point.Hypothesized to be a result of partial damage of the osmoreceptors.Described in patients with microcephaly and dysplastic corpora callosa.Baroreceptor-regulated vasopressin release is often intact, as is the release in response to insulin-provoked hypoglycemia and emesis.Appears to be increased renal sensitivity to vasopressin, and patients may retain capability of limiting free water excretion by concentrating the urine.

Type C
Described as the complete absence of thirst response and release of vasopressin with rising osmotic stimuli, caused from central impairment (such as clipping of anterior communicating artery aneurysm).Present with lack of thirst and polyuria.Often considered the most difficult subtype to manage, and patients are at risk for life-threatening hypernatremia.
Type D Thirst response is absent but osmoregulation of the release of vasopressin is maintained.Only a single case has been described in the literature.

Diagnosis
Adipsia is diagnosed when thirst is absent and spontaneous consumption of water does not occur with both hypernatremia (above 150 mEq/L) and hyperosmolality (above 310 mOsm/Kg) [110].Furthermore, water deprivation tests (or hypertonic stimuli such as saline infusions) can be performed, assessing consumption of water afterwards (lower consumption is consistent with adipsic diabetes insipidus [110]).A visual analog scale is frequently encountered in both clinical practice and research for a subjective assessment of thirst (Figure 3) [110].Crowley et al. [19] demonstrated significantly less water consumed (and less thirst sensation) in adipsic patients compared to controls, following the administration of a hypertonic saline infusion (p < 0.0017 and p < 0.001, respectively).The authors additionally note the depressed release of vasopressin following hypertonic saline solution administration compared to controls (p < 0.001).

FIGURE 3: Visual Analog Scale of Thirst
Obtained with Permission from [110] Although patients with adipsic diabetes insipidus have impaired vasopressin and thirst response to increasing osmolality, the response to hypotension and nausea can be varied, and appears to be dependent on the underlying cause (and likely extent of cerebral involvement).Notably, in patients following resection of a craniopharyngioma, the response to hypotension is absent, but usually preserved following coiling of a ruptured anterior communicating artery aneurysm.This was demonstrated by Smith et al. [17], whereby nine patients with adipsic diabetes insipidus were compared to controls.As expected, hypertonic saline infusion produced absent thirst and vasopressin response in the adipsic group compared to the control group (p < 0.001).Subsequently, trimetaphan was infused to produce a drop in the mean arterial pressure in both groups; none of craniopharyngioma patients (n = 3) demonstrated a significant rise in vasopressin (however, there was a significant rise in the remaining n = 6, p < 0.001).Mavrakis and Tritos [6] further parallel these findings in 13 out of 20 patients by assessing vasopressin response to baroreceptor-mediated challenges or emesis (from apomorphine), again demonstrating that patients with craniopharyngiomas were less likely to respond (p < 0.01).Crowley et al. [19] additionally demonstrated that trimetaphan failed to lead to vasopressin release in all craniopharyngioma patients (n =4) as well as one patient with a macroprolactinoma, but the response was preserved in the remaining patients with adipsic diabetes insipidus (n = 9) (p < 0.008).
Arima et al. [104] note a relative risk of 68 for hypernatremia (described as a serum sodium level of above 150 mEq/L) in patients with adipsic diabetes insipidus compared to those with central diabetes insipidus with intact thirst (p < 0.001).Whilst patients may be asymptomatic, the severity of the hypernatremia is often an indication for recurrent hospitalizations consisting of days to weeks, compared to those with an intact thirst sensation.Yang et al. [33] note that patients with adipsic diabetes insipidus are likely to have longer hospital durations compared to controls (9.6 days compared to 5.9 days, p = 0.000).Of note, however, as noted by Elamin et al. [62], such patients are often paradoxically at risk of hyponatremia due to the inability to appreciate fluid overload when adherent to oral hydration and desmopressin administration.
It is suggested that seizures are due to the presence of hypernatremia; however, eunatremic seizures are noted in around 50% of patients; in the study by Yang et al. [33], however, there was no significant difference in rates of seizures between adipsic patients and controls.While rhabdomyolysis can occur from seizures, more commonly, it is due to osmolar disturbances from fluid shifts (and subsequent muscle rupture), which can lead to acute kidney injury due to tubular injury from myoglobin.In addition to the rhabdomyolysis, patients are prone to acute kidney injury due to dehydration causing renal vasoconstriction; the study by Yang et al. [33] noted a significant risk of renal insufficiency compared to controls (12% versus 1%, p = 0.002).
Patients with adipsic diabetes insipidus compared to central diabetes insipidus have an odds ratio of 8.8 for the development of serious infections (p < 0.001), notably respiratory tract, reproductive systems and wounds along the abdomen; the causation is not readily known but appears to be related to recurrent hospitalizations [104].
Yang et al. [33] note higher rates of hyperglycemia, dyslipidemia and hyperuricemia in such patients; however, after multivariate logistic regression, only hyperglycemia appears to be significant with an odds ratio of 5.886 (p = 0.003).The authors further suggest a higher risk of venous thrombosis (14% versus 1%, p = 0.002), including the lower extremities and cerebral venous sinuses.This finding was first reported by Crowley et al. [19] and is likely related to the underlying state of dehydration, as large cohort studies note this is more frequent when thirst is not intact.Moreover, it is likely that the prolonged hospitalizations account for the heightened risk for deep venous thromboses due to related immobility.Another consideration is the treatment itself (desmopressin), which can lead to the release of factor VIII and von Willebrand factor from endothelial cells; however, it is noted that this would be clinically significant with a dose ten-fold of what is administered in such patients [110].A final consideration is the concomitant finding of sleep-disordered breathing in adipsic patients, whereby sleep apnea (present in more than 50% of patients in one case series) may contribute to polycythemia and predispose to a hypercoagulable state [19].
Sleep disordered breathing in patients with adipsic diabetes insipidus includes both obstructive and central sleep apnea, as well as obesity-related hypoventilation.It appears that patients with craniopharyngiomas have a higher obesity apnea-hypopnea index and demonstrate reductions in oxygen saturation overnight [110].Moreover, in patients with craniopharyngiomas, there is a greater chance of hypothalamic injury, which itself can be associated with sleep-disordered breathing.Adults with craniopharyngiomas have also been noted to have excessive daytime sleepiness, persisting even when matched for controls [110].
Cognitive dysfunction is a common finding associated with adipsic diabetes insipidus, including fatigue, short-term memory loss, and behaviour disturbances, which can lead to poor adherence with the respective treatment regimen.
Adipsic diabetes insipidus due to craniopharyngiomas is commonly associated with other hypothalamic disturbances, such as appetite disturbances (food cravings and over-eating), temperature instability, and behavioural misconduct [110].Notably, around 20-46% of patients with adipsic diabetes insipidus are either overweight or obese, most often described in the adult population [19,110].Additionally, as with our patient, anterior pituitary function can be compromised, ranging from single defects to panhypopituitarism.Mavrakis and Tritos [6] note 72% of their mixed cohort had deficits in anterior pituitary function, with 44% demonstrating panhypopituitarism, and 28% with partial defects in hormonal secretion; the authors, however, note this is significantly less likely in patients with anterior communicating artery aneurysm ruptures compared to craniopharyngiomas (p < 0.001).
Patients with adipsic diabetes insipidus also have a heightened premature death rate.Arima et al. [104] demonstrate an adjusted odds ratio of mortality for such patients to be 9.53 (95% CI 1.85-40.08,p = 0.007), most related to infection and respiratory failure (sleep-disordered breathing and venous thromboembolism).

Treatment
With the significant risks of comorbidities and mortality, as noted above, adherence to treatment is of utmost importance.Recommendations for treatment involve close monitoring of fluid intake (and documenting throughout the day), which is typically advised to be no more than 1.5-2 liters (titrated based on follow-up results).Patients are advised to pay close attention to insensible losses (such as from fever, diarrhea, exercise, warmer climates) which will require an increase in oral hydration [27].Patients are weighed when eunatremic to determine the target weight, followed by which they are weighed daily; if underweight, then the subtraction of the desired and current weight is added in oral hydration as liters.Over time, patients be prescribed a 'sliding scale' for oral hydration based on body weight [110].
Regular sodium monitoring is recommended, while there are no formal guidelines, Eisenberg and Frohman [110] recommend weekly sodium monitoring.Although primitive, home sodium capillary monitoring devices have been developed and trialed in both adults and children, accurately measuring sodium from capillary blood (r = 0.92 correlation between capillary and laboratory sodium), which can be incorporated into the customized oral hydration sliding scale [103,110].
Patients are furthermore prescribed desmopressin (DDAVP) to achieve a urine output of 1.5-2 liters daily.The dosage of desmopressin varies, as well as formulation (oral: 100-250 micrograms twice daily; intranasal 3-10 micrograms twice per day) [62,63].Oral absorption is often less preferable due to the significant variation with individuals and must be taken on an empty stomach [110].In neonates, some recommended injection therapy to minimize the absorption problems [110].Patients are often advised to avoid alcohol, due to the rapid and large shifts in fluid status that can occur [113].
Due to the correlation with memory deficits in certain patients with adipsic diabetes insipidus (which appears to be multifactorial), family-assisted reminders and prompts are beneficial.Behavioral modification, relying on scheduled hydration based on daily weights, urine output and laboratory monitoring, as well as reward systems, has proven successful [29].
Within the literature, anecdotal reports of chlorpropamide (a first-generation sulfonylurea medication) increasing awareness of thirst have been described, however, this is matched with the risk of hypoglycemia, hepatic injury, hematologic abnormalities and dermatological reactions [31].Similarly, limited reports note enhanced antidiuresis following the administration of clofibrate [21].These medications appear to induce SIADH and are not recommended due to the unpredictable side effects and variable responses.
Infrequently, patients may regain either partial, or complete recovery of thirst perception, months-to-years following the initial insult.Our patient appeared to regain partial thirst sensation approximately four months after the treatment of the ruptured aneurysm.Whilst thirst response may improve, the response of vasopressin to the increase in osmolality remains altered.

Conclusions
Adipsic diabetes insipidus is characterized by lack of vasopressin response to hyperosmolality and hypernatremia, with impairment of thirst sensation.While numerous causes in the literature have been depicted, the most common cause (as with our case report) is following coil embolization of a ruptured communicating artery aneurysm.Compared to central diabetes insipidus with preserved thirst sensation, adipsic patients are at heightened risk for comorbidities and mortality from the inability to appreciate thirst.Although some patients (as with our case report) may develop variable recovery in thirst sensation, it is not possible to predict which patient will regain this sensation.Treatment typically requires patient education, fixed desmopressin dosages, frequent osmolality monitoring, titration of urine output, and control of the amount of fluid intake (with corrections for insensible losses).This case report and literature review provide an overview of the typical presentation and management, alongside a review of the current literature pertaining to adipsic diabetes insipidus.

Reference Range Value on Admission to Acute Inpatient Rehab Value one Week Later Value Two Months Later Value Four Months
).