Cerebral Salt Wasting Syndrome

Etiology

The etiology of CSW is not fully understood; it is most frequently observed following central nervous (CNS) injury, with aneurysmal subarachnoid hemorrhage being the most commonly reported precipitating event. CSW occurs more often after aneurysmal subarachnoid hemorrhage than after traumatic subarachnoid hemorrhage or other CNS insults. The reason for the difference remains unexplained. Similarly, it is unclear why CSW is relatively uncommon in other CNS conditions, such as tuberculous meningitis, despite significant involvement of the CNS in these diseases.[2]

Epidemiology

Because CSW is an uncommon condition, its exact incidence and prevalence are difficult to determine. This condition most frequently occurs following aneurysmal subarachnoid hemorrhage, but can also result from other CNS injuries. CSW has been reported in a variety of other conditions, including postsurgical cases involving pituitary tumors or apoplexy, as well as in association with hypothalamic tumors, acoustic neuromas, gliomas, and metastatic carcinomas; it has also been observed after calvarial remodeling procedures, cranial trauma, and infections such as tuberculous and viral meningitis.[2][3]

Some clinicians estimate that CSW accounts for up to one-quarter of cases of severe hyponatremia following aneurysmal subarachnoid hemorrhage. In contrast, CSW resulting from other causes of CNS damage, such as pituitary apoplexy, is generally described only in case reports.[4] The incidence and prevalence of CSW in patients without CNS injury have not been reliably reported.

Pathophysiology

The true etiology of CSW remains an area of debate and ongoing investigation.[5] Some clinicians suggest that CSW is not a distinct entity but a variant of SIADH. Currently, 2 main theories have been proposed to explain the pathophysiology of CSW: one involves a circulating factor such as BNP, and the other centers on sympathetic nervous system dysfunction.[3] Both mechanisms are believed to lead to excessive renal sodium loss, resulting in hyponatremia and volume depletion.

According to the first theory, CNS injury prompts the brain to release brain natriuretic peptide (BNP), which enters systemic circulation through a disrupted blood-brain barrier. BNP acts on the collecting ducts of the renal tubules to inhibit sodium reabsorption and suppresses renin release, contributing to natriuresis and hyponatremia. The second theory suggests that damage to the sympathetic nervous system, such as may occur with hypothalamic tumor surgery, impairs sodium reabsorption and alters renin release.[3] The disruption in neurohormonal regulation may also contribute to the salt-wasting state. Despite these hypotheses, the exact mechanism of CSW remains unresolved and continues to be a subject of active research and debate.[5]

History and Physical

CSW is a condition characterized by hyponatremia and hypovolemia due to excessive renal sodium loss, typically occurring in patients with intracranial pathology such as subarachnoid hemorrhage, traumatic brain injury, or neurosurgical procedures. The most common cause of CSW is hyponatremia following aneurysmal subarachnoid hemorrhage.[6][7] Patients with CSW often present with symptoms related to hyponatremia and volume depletion. These may include nausea, vomiting, headache, lethargy, confusion, and in severe cases, seizures or coma. Symptoms usually occur within days to weeks following the inciting cerebral event. 

On physical examination, patients with CSW usually show clear signs of volume depletion. Blood pressure is often low, and a compensatory tachycardia may be present. Mucous membranes appear dry, and skin turgor is diminished. Neurologically, the spectrum ranges from mild confusion to profound encephalopathy, and seizures can occur in the setting of severe hyponatremia. 

Evaluation

Differentiating CSW from SIADH is crucial, as their treatments differ significantly. In CSW, patients exhibit hypovolemia and high urinary sodium excretion, whereas SIADH is characterized by euvolemia or hypervolemia with low urinary sodium excretion (see Table. Comparison of CSW and SIADH). Laboratory testing typically reveals marked hyponatremia accompanied by very high urinary sodium excretion, often exceeding 100 mmol/L.[8][9] Polyuria is also common, with daily urine volumes frequently surpassing 2.5 L.[8] These findings together support the diagnosis of CSW and differentiate it from other causes of hyponatremia.

SIADH presents with a laboratory profile similar to that of CSW, including hyponatremia and increased urine sodium levels; however, a key distinguishing feature is the patient’s volume status. In SIADH, patients are typically euvolemic or mildly hypervolemic due to retained free water, whereas in CSW, patients are hypovolemic compared to the hypovolemic picture of CSW.[10][11] Other potential causes of hyponatremia should also be sought, including polydipsia, renal disease, use of diuretics, heart failure, hypothyroidism, malignancies, hormone deficiency, and pseudohyponatremia. Many times, CSW becomes a diagnosis of exclusion after labs reveal serum hyponatremia with increased urine sodium levels.

Table. Comparison of CSW and SIADH

ADH, antidiuretic hormone; CNS, central nervous system

Treatment / Management

The treatments for CSW and SIADH are fundamentally different, making an accurate diagnosis essential before initiating therapy. Misclassification can lead to inappropriate management, potentially worsening the patient's clinical condition. CSW is most commonly associated with aneurysmal subarachnoid hemorrhage, so the initial management should focus on identifying and treating the underlying CNS insult. If the cause is aneurysmal, the aneurysm must be secured promptly.[7] Please see StatPearls' companion resource, "Subarachnoid Hemorrhage," for more information.[12]

Once the source of the CNS insult is managed, the next critical step is assessing and correcting the patient's volume status. In CSW, hypovolemia is a hallmark finding, and intravenous fluid replacement is necessary to restore intravascular volume and correct hyponatremia. Patients typically start on isotonic saline (0.9% sodium chloride), replenishing volume and raising serum sodium levels. 

In moderate to severe cases of hyponatremia, more aggressive sodium replacement may be required using 3% hypertonic saline. However, the correction rate should be carefully controlled, with the maximum increase in serum sodium limited to less than 8 mEq/L over 24 hours to avoid osmotic demyelination syndrome.[13] In high-risk individuals, intravenous desmopressin may be administered to prevent overly rapid correction of serum sodium levels.[14] Salt tabs (1 to 2 grams up to 3 times daily) can also be administered orally or via gastrostomy tube as an adjunct to correct hyponatremia. Additionally, some clinicians have advocated for fludrocortisone, a mineralocorticoid, to promote sodium retention and support volume status in patients with CSW.[11]

When correcting hyponatremia, serum sodium levels should be monitored frequently to ensure safe and effective management. Overcorrection can result in hypernatremia, which may lead to complications such as muscle twitching, lethargy, seizures, and even death. Equally important is avoiding overly rapid correction of hyponatremia, particularly in cases of chronic or long-standing hyponatremia. Rapid shifts in serum sodium can lead to osmotic demyelination syndrome, most notably central pontine myelinolysis. To minimize this risk, limit correction to no more than 10 mEq/L over 24 hours, or approximately 1 mEq/L every 2 hours.[15] (B3)

Hyponatremia in CSW may persist for weeks to months following the initial CNS event, necessitating ongoing monitoring and management. Throughout treatment, frequent assessment of the Glasgow Coma Score and neurological examination is critical to detect any signs of clinical deterioration. While most patients with CSW not caused by subarachnoid hemorrhage tend to have a favorable prognosis, some may continue to experience mild neurological deficits despite appropriate management.[16][17]

The most important clinical consideration is distinguishing between CSW and SIADH, which require different therapeutic approaches. SIADH is typically managed with fluid restriction, demeclocycline, or furosemide. Intravenous 0.9% saline should be avoided in treating SIADH due to the rapid and unpredictable fluctuation of serum sodium levels.[13]  In contrast, if a patient has true CSW, they are hypovolemic, and employing SIADH treatment modalities would worsen their condition by further exacerbating the hypovolemia.[2][14][18]

Differential Diagnosis

Distinguishing between CSW and SIADH is critical. Hyponatremia and an elevated urine sodium level, concentrated urine, and absence of edema characterize both conditions. The main distinguishing factor is the patient's volume status: in CSW, the patient is hypovolemic, whereas in SIADH, the patient is either euvolemic or hypervolemic.[10] The differential diagnosis for the etiology of CSW includes various CNS insults, such as:

• Head injury
• Brain tumor (hypothalamic or pituitary tumor)
• Stroke
• Intracranial surgery
• Aneurysmal subarachnoid hemorrhage
• Intracerebral hemorrhage
• Pituitary apoplexy
• Craniosynostosis repair
• Tuberculous meningitis

Prognosis

The prognosis for CSW can vary depending on the underlying cause and the timeliness and appropriateness of treatment. CSW is associated with significant morbidity and mortality, particularly in patients with severe neurological conditions such as traumatic brain injury and subarachnoid hemorrhage. Patients with CSW often experience increased complications, including prolonged hospitalizations, extended stays in intensive care units (ICUs), and a greater need for ventilator support.

Research results by Chendrasekhar et al demonstrated that individuals with traumatic brain injury who developed CSW had more severe injuries, spent more time in the hospital and ICU, and required longer ventilator support compared to those without CSW. Notably, survival to hospital discharge was lower in patients with CSW (88%) than those without the condition (99%).[19] Further, Tolunay et al found that the average duration required to correct hyponatremia in pediatric CSW cases was about 20 days. Of the 9 children evaluated, 1 did not survive.[20] CSW is being recognized more frequently in pediatric critical care settings. Although it is generally treatable with proper fluid and sodium management, it remains a significant clinical challenge. 

Ultimately, the outlook for patients with CSW is strongly influenced by the severity of the underlying neurological injury and how promptly and effectively treatment is initiated. Management strategies such as sodium supplementation, volume repletion, and—in some cases—using mineralocorticoids like fludrocortisone are essential for improving patient outcomes. Early diagnosis and tailored treatment are key to minimizing complications and enhancing recovery.[21]

Complications

CSW can lead to a range of complications, primarily due to the resulting hyponatremia and hypovolemia. These complications can significantly affect outcomes, especially in patients with preexisting neurological injuries or conditions. Prompt recognition and targeted management are essential to minimize risks and improve recovery.

Key complications associated with CSW include:

• Hyponatremia: Low serum sodium levels can result in neurological symptoms ranging from confusion and lethargy to seizures and coma if not promptly corrected.
• Hypovolemia: Loss of intravascular volume may lead to hypotension, reduced perfusion, and end-organ dysfunction.
• Increased morbidity and mortality: Patients with CSW often experience longer hospital and ICU stays, increased ventilator dependency, and a higher risk of adverse outcomes.
• Electrolyte imbalances: In addition to sodium loss, patients may develop disturbances in other electrolytes, further complicating management.
• Therapeutic challenges: Differentiating CSW from conditions like SIADH is critical, as mistreatment can exacerbate hypovolemia and worsen patient outcomes.

Early diagnosis and appropriate fluid and sodium replacement are crucial to reducing the impact of these complications and optimizing patient care. Delayed or incorrect treatment can lead to worsening neurological function, prolonged hospitalization, and potentially life-threatening outcomes.