Triphasic response of pituitary stalk injury following TBI: a relevant yet uncommonly recognised endocrine phenomenon

Abstract

The triphasic response of pituitary stalk injury has previously been described in a minority of patients following intracranial surgery, however, this phenomenon can also occur after traumatic brain injury. We present the case of a 20-year-old male who experienced the triphasic response of pituitary stalk injury (central diabetes insipidus, syndrome of inappropriate antidiuretic hormone and central diabetes insipidus again) after striking his head on a concrete curb. His history and presentation highlight the importance of recognising the distinctive symptoms of each individual stage of pituitary stalk injury, and using the appropriate diagnostic tools and therapies to guide further management.

Background

According to the Centers for Disease Control and Prevention, an estimated 1.7 million people sustain a traumatic brain injury (TBI) annually. Of these 1.7 million people, 275 000 are hospitalised and 52 000 die.¹ Falls result in the greatest number of TBI-related emergency department (ED) visits and hospitalisations. Although the importance of close monitoring of patients’ vitals and neurological function is well known, clinicians should also be aware of the clinical signs and symptoms that may reflect pituitary stalk injury after TBI. Previous literature describes this phenomenon following intracranial surgery but its development after TBI is less recognised.

Disorders of salt and water balance are common complications in the acute phase of TBI.² Unfortunately, patients with partial deficiency of arginine vasopressin (AVP) can be easily missed since they may have less severe symptoms initially, making their post-traumatic clinical course complicated by significant neurological and cognitive disabilities.³ Thus, patients with pituitary stalk injury require immediate recognition and careful successive monitoring of serum osmolality and urinary output, as the rapid fluctuations in homoeostasis can be life threatening. Timely diagnosis and administration of desmopressin (DDAVP) and/or hypertonic saline versus fluid restriction, depending on the clinical symptoms and phase of presentation, are critical for maintenance of sodium homoeostasis and symptom management.

Case presentation

A 20-year-old male with no significant medical history presented to the hospital with a severe, bifrontal headache. His headache started after he slipped on wet pavement and hit his head on a concrete curb five days prior to presentation. He did not experience any loss of consciousness and did not seek immediate medical attention after his fall. He presented for further evaluation after he started developing a worsening headache and dizziness two hours prior.

On presentation to the ED, CT head showed a subarachnoid haemorrhage, right parietal 3 mm subdural haematoma, and right non-displaced parietal and temporal bone fractures. Laboratory work revealed a normal serum sodium of 139 mEq/L and normal urine-specific gravity of 1.014. Neurosurgery recommended no surgical intervention, and the patient was admitted to general medicine for observation and further management.

On the second day of hospitalisation, the patient started complaining of increased thirst and his urinary output rapidly increased to 800 mL/hour. Laboratories revealed new-onset hypernatraemia with serum sodium of 153 mEq/L and urine-specific gravity of 1.005, both of which were concerning for diabetes insipidus (DI). He was started on maintenance intravenous fluids, treated with subcutaneous desmopressin and was allowed to drink to thirst. His sodium subsequently corrected from 153 mEq/L to 142 mEq/L over the next 24 hours with fluctuations in both his serum sodium and urine osmolality over the next 4 days (figure 1). MRI with contrast demonstrated a posterior pituitary lesion that lacked the expected high signal intensity (figure 2). Laboratory evaluation for anterior pituitary function was normal. He was transitioned to oral desmopressin two times a day with continued normalisation of his serum sodium and urine osmolality. On hospital day 5, the patient’s sodium was stable at 134 mEq/L and he was discharged home.

Figure 1.

Serum sodium and urine osmolality trend throughout hospitalisation. The first phase of the triphasic response (DI) started on day 2 of hospitalisation (sodium of 153 mEq/L and urine osmolality of 173 mOsm/kg), followed by the second phase of SIADH on day 7 (sodium of 125 mEq/L and urine osmolality of 680 mOsm/kg) and then final progression into the third phase (DI again) on day 11 (sodium of 137 mEq/L and urine osmolality of 113 mOsm/kg). DI, diabetes insipidus; SIADH, syndrome of inappropriate antidiuretic hormone.

Figure 2.

MRI brain with intravenous contrast. Absent posterior pituitary bright spot shown, confirming the diagnosis of diabetes insipidus.

The patient returned to the ED the next day with worsening headaches, vomiting and lethargy. He endorsed taking desmopressin only once since hospital discharge. Repeat CT head was unchanged from the patient’s previous CT. Laboratory work revealed new hyponatraemia with serum sodium of 125 mEq/L, urine sodium of 202 mEq/L and urine osmolality of 680 mOsmol/kg, all consistent with progression to the second phase of the triple phase response: hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone (SIADH). The patient was temporarily started on intravenous fluid, however, it was quickly discontinued after his repeat sodium worsened from 122 mEq/L to 120 mEq/L. He was upgraded to the intensive care unit, administered 3% hypertonic saline and started on a free water restriction of 1.5 L daily. His serum sodium subsequently improved to 130 mEq/L and hypertonic saline was discontinued.

The next day, the patient’s serum sodium abruptly increased back up to 137 mEq/L, urinary output increased from 120 mL/hour to 400 mL/hour and urine-specific gravity decreased to 1.004, all concerning for reversion to central DI (and the final phase of the triphasic response of pituitary stalk injury). His free water restriction was discontinued and he was allowed to drink to thirst. He was again treated with oral desmopressin two times daily with stable normalisation of his serum sodium levels, as well as improvement of his urinary output and urine-specific gravity. He was again discharged home on oral desmopressin two times daily.

Investigations

In addition to the laboratory evaluation of serum sodium, urine osmolality and urine-specific gravity, MRI with intravenous contrast is also used for the diagnosis of DI. When stored vasopressin is present in the neurosecretory granules of the posterior pituitary, T1-weighted images reveal a bright spot. Absence of the expected bright spot/high signal intensity is consistent with posterior pituitary dysfunction. Sometimes, persistent hyperintensity of the posterior pituitary can remain despite posterior pituitary dysfunction, but it is more rare in patients with central DI due to pituitary stalk injury.⁴

Differential diagnosis

Differential diagnosis for the patient’s initial presentation: DI (central or nephrogenic) or dehydration.

Differential diagnosis at the time of the patient’s readmission: SIADH, cortisol deficiency, DDAVP overdose, primary polydipsia, pseudohyponatraemia (hypothyroidism, hyperglycaemia or hypertriglyceridaemia) or cerebral salt wasting.

Outcome and follow-up

During outpatient follow-up, the patient endorsed polyuria, excessive thirst and headaches if he did not take his morning desmopressin and noted that he had to carry a water bottle with him throughout the day. Thus, it was recommended that he consistently take desmopressin both in the morning and in the evening. The severity of his headaches and excessive thirst improved with this therapy.

Discussion

The hypothalamus–pituitary–adrenal (HPA) axis helps regulate many physiological processes through direct actions and feedback mechanisms between the hypothalamus, anterior and posterior pituitary glands, and adrenal glands. The central nervous system plays in a vital role in the regulation of sodium and water homoeostasis, and disruption of the HPA axis can result in conditions of salt and water imbalance such as DI and SIADH. These two phenomena have been well studied and documented in the literature as potential risks after intracranial surgery, however, it is important to recognise that both can also occur after TBI.

Extensive reviews of fluid and electrolyte disturbances in TBI have been well documented in previous literature. These disturbances are either due to direct damage to the hypothalamic–pituitary axis or secondary to blood loss (with resulting salt and water retention to preserve intravascular volume and maintain end-organ perfusion). Additionally, increased vascular permeability in the setting of TBI can cause third-spacing distribution of fluid, and treatment of brain oedema may exacerbate sodium and water imbalances.⁵

Posterior pituitary dysfunction after head trauma is usually recognised during the early post-traumatic period, either as frank DI or as a decreased ability to excrete free water. This is in contrast to traumatic anterior hypopituitarism, which is usually diagnosed long after the injury, when clinical evidence of secondary end-organ failure has become evident.⁶ Post-traumatic DI may result from inflammatory oedema around the hypothalamus or posterior pituitary, with recovery as the swelling resolves.⁷ Although most patients with salt and water imbalances secondary to TBI usually recover, a minority of patients have chronic manifestations of DI even long after their TBI and require appropriate lifelong management in order to prevent severe long-term consequences. This mechanism of fluctuating salt and water balance results from hypothalamic-hypophyseal disruption after accidental pituitary stalk injury during either intracranial surgery or head trauma- and can be either transient, triphasic or permanent.⁸

The initial phase of the triphasic response of pituitary stalk injury after intracranial surgery or TBI consists of central DI due to ‘stunning’ of the AVP neurons and the severing of downstream nerve terminals in the posterior pituitary. Clinical symptoms of DI include dilute polyuria and polydipsia, with further workup revealing hypernatraemia, increased serum osmolality, decreased urine osmolality and decreased urine-specific gravity. This phase can last 5–7 days, as seen in our patient. Other causes of polyuria that can also result in increased urinary fluid losses post-TBI should be excluded, including hyperglycaemia, hyperosmolar fluid administration, diuretics, excessive fluid replacement or urea diuresis. In these cases, the solute diuresis results in increased urine osmolality, as opposed to the dilute urine seen in those with DI.⁹

Next is the second phase, which results in SIADH due to unregulated release of vasopressin, either from remaining degenerating neurons in the hypothalamus or from remaining nerve terminals in the posterior pituitary. Clinical symptoms of SIADH are more non-specific and depend on the degree of hyponatraemia, ranging from fatigue and vomiting to headache and seizures. By the time patients have progressed from the first phase to the second phase, intravenous fluids have usually been started to keep up with urinary losses from the initial DI. As seen in our patient, intravenous fluid can paradoxically worsen patients’ hyponatraemia and hypo-osmolality during the second phase and therefore fluid restriction is most appropriate. This phase can last 2–14 days.¹⁰

The third and final phase of pituitary stalk injury results again in DI since damaged neurons in the hypothalamus can no longer produce vasopressin and all the remaining AVP in the posterior pituitary gland gets released. The third phase with progression into permanent DI usually develops if >80%–90% of the AVP-secreting neuronal cell bodies in the hypothalamus have degenerated bilaterally.¹¹ As per Agha et al, in 102 patients with TBI, there was a 21% incidence of acutely post-traumatic DI, but only 6.9% of these patients had evidence of permanent DI several months after the injury.⁷

The patient described in our case was discharged with a serum sodium of 134 mEq/L and acutely presented again less than 24 hours later with hyponatraemia of 125 mEq/L. The single dose of DDAVP that he took at home cannot adequately explain this hyponatraemia. At the time of hospital discharge, the patient was likely transitioning from phase 1 (DI) to phase 2 (SIADH). Had the patient remained hospitalised for additional monitoring and recognition of the early signs of progression into the SIADH phase, he likely would have avoided the severe symptoms, need for intensive care unit admission and need for hypertonic saline administration.

The management and treatment of the triphasic response can be divided into the following: expectant monitoring, antidiuretic hormone therapy, maintenance of fluid balance, monitoring for resolution of transient DI or triphasic response and management of anterior pituitary insufficiency.¹² Strict surveillance of fluid intake and output with measurement of serum sodium, urine osmolality and urine-specific gravity every 6 hours is necessary. Vasopressin should be administered if there is polyuria (>200 mL/hour for more than 2 hours) with urine-specific gravity of <1.005 or urine osmolality <200 mOsm/kg. Patients should also be permitted to drink to thirst or given hypotonic intravenous fluid such as 5% dextrose in water or 5% dextrose in 0.45% saline if unable to maintain normal serum sodium levels during the DI phase.¹² Fluid restriction, on the other hand, should be used to maintain eunatraemia during the SIADH phase. Lastly, if there is concern for anterior pituitary hormonal deficits with resulting secondary adrenal insufficiency, corticosteroids should be administered.

DDAVP is a vasopressin V2 receptor-selective agonist, which increases cyclic adenosine monophosphate in the renal tubular cells with subsequent phosphorylation of aquaporin water channels.¹³ This leads to increased water permeability, resulting in decreased urine volume and increased urine concentration. Clinically, patients experience reduced urinary frequency and thirst after DDAVP administration. DDAVP can be given orally, intravenously, intranasally or subcutaneously.

The possibility of the triphasic response of pituitary stalk injury after TBI emphasises the importance of recognising the clinical manifestations of each individual phase, and the relevance of close long-term patient monitoring for future signs and symptoms of salt and water balance even after the initial acute presentation. Recognition of the neuroendocrine complications after TBI and routine follow-up with endocrinology specialists can prevent future morbidity and mortality.

Learning points.

• Recognise the possible signs and symptoms of the triphasic response of pituitary stalk injury following traumatic brain injury (TBI).

• Understand the workup and management of each phase of the triphasic response of pituitary stalk injury after TBI and initiate appropriate therapy accordingly.

• Emphasise the importance of closely monitoring patients for the appropriate time frame if there is concern for pituitary stalk injury after head trauma in order to prevent future morbidity and mortality.