Neuroinflammation-Induced SIADH in West Nile Virus Infection: An Uncommon Neurological and Endocrine Manifestation

Introduction

West Nile virus (WNV) is a vector-borne flavivirus that is typically transmitted by Aedes and Anopheles mosquitos and has become geographically heterogeneous over the decades, with its highest incidence in the western and midwestern United States [1]. WNV infection typically manifests with symptoms consistent with viral meningitis, which can include headache, altered mental status and extrapyramidal signs, along with more universal viral illness symptoms such as malaise and myalgias [2–5]. WNV infections are typically self-resolving, with symptoms lasting 3–10 days. Although uncommon, 30% of patients with positive findings of West Nile virus have hyponatremia, although the etiology is unclear [6,7]. It is speculated that because of the encephalitis, neuroinflammation may be involved in deterioration of adrenal signaling, leading to salt wasting, a condition sometimes associated with cerebral salt wasting. SIADH involves the inappropriate secretion of antidiuretic hormone (ADH), leading to water retention and hyponatremia. Etiologies include malignancies, medications, pulmonary pathologies, hormonal dysregulation, and acute stressors. Diagnostics include measuring serum and urine osmolality and sodium levels, with treatment involving fluid restriction and sodium supplementation [8]. On the other hand, cerebral salt wasting can present similarly with hyponatremia, but distinguishable with larger urine output leading to volume depletion which can be recognizable on clinical findings with dehydration [9]. We present the case of a 75-year-old man who presented with headache, neck pain, photophobia, and viral illness symptoms. He was ultimately found to be profoundly hyponatremic concerning for SIADH in the setting WNV infection.

Case Report

We present the case of a 75-year-old man with a past medical history significant for hypertension, who presented to the Emergency Department with headache, neck pain, photophobia, dyspnea, cough, and weakness, initially concerning for meningeal origins. He was moderately hyponatremic, with sodium 125 mmol/L, although clinically he appeared to be euvolemic. His vital signs were stable. Mucus membranes were moist and he had good skin turgor. Nephrology was consulted for further management of his ongoing hyponatremia. Rapid plasma reagin, HIV, cryptococcus, and coccidiodes were negative. A CSF meningitis/encephalitis panel was negative, and a subsequent lumbar puncture indicated WBCs 52/cumm, RBCs 70/cumm, PMN: 29%, lymphocytes 63%, and monocytes 8%. Due to hyponatremia, he was placed on observation by the hospitalist team and received 4–5 L of IV fluid on admission. On the second hospital day, his sodium fell to 117 mmol/L and he then became lethargic and confused, suggesting severe hyponatremia. He continued to remain euvolemic, as indicated by continued moist mucus membranes, good skin turgor, and stable vital signs. At that time, serum osmolality was 248 mOsm/kg, urine sodium was 137 mmol/L, and urine osmolality was 614 mOsm/kg, consistent with SIADH. CT head did not indicate acute intracranial pathology. He was subsequently admitted to the ICU for observation and was given 50 mL of 3% saline bolus for rapid correction, but without improvement. His sodium level initially continued to fall despite fluid restriction with 1000 mL/h and salt tablets, 2 g, 3 times daily and 3% NaCl. There was consideration of tolvaptan for his hyponatremia; however, given his hepatic steatosis, this was not possible. UreNa 15 g twice daily was also added to the regimen. MRI head and CT of the chest, abdomen, and pelvis were also ordered to search for a source of the malignancy; however, all were negative except for suggestions of a negative posterior pituitary bright spot, which is sometimes noted in patients with SIADH (Figure 1). His copeptin level was 21.7 pmol/L, suggesting this was caused by elevated ADH. Serum anti-aquaporin 4 antibodies were normal. Subsequently, Neurology recommended a paraneoplastic panel to assess for alternative causes for elevated ADH. This panel was also negative, although the results were not received until well after discharge. His initial CSF titers collected on admission for West Nile virus returned on the day just before discharge and were quite remarkable, showing IgM 9.94 g/L and IgG 1.41 g/L. On further questioning, it was discovered that the patient frequently spent time outside on his patio, while his lawn sprinklers were on, with occasional open bodies of water. He stated that he may have received a few mosquito bites over the past few weeks prior to admission, but they had healed. He continued outpatient follow-up with Nephrology after discharge, with instructions to continue taking salt tablets. With each additional follow-up, his sodium level improved with continued tapering of the sodium tablets, without the need for UreNa. His sodium level has since normalized. He still retains some neurological deficits, including balance issues, although they are much improved compared to his admission status.

Discussion

WNV infection typically manifests itself with symptoms consistent with viral meningitis, which include fever, headache, and meningeal signs. Ultimately, West Nile virus and other mosquito-borne infections contribute to pathologic changes in the brain, which can include but are not limited to perivascular lymphocytic infiltrates, cellular nodules and neuronal degeneration and/or inflammation, which can affect multiple cerebral entities [3,4]. West Nile virus was previously endemic to Africa but has spread to North America, Europe, and Asia since the 1990s. It is now present across the world, with infected individuals experiencing neurologic problems due to encephalitis [10]. This case highlights the diagnostic complexity of WNV-associated SIADH/hyponatremia and the challenges of managing severe hyponatremia of unknown etiology in conjunction with symptoms concerning for encephalitis. When faced with a patient with these concerns, it is crucial to consider viral diseases beyond West Nile virus during the initial workup due to their potential for significant electrolyte imbalances. Hyponatremia is well-documented in various viral infections ranging from HIV, influenza, and coronaviruses to arbovirus-related infections, including La Crosse virus and St. Louis Encephalitis virus. SIADH has been noted when considering arbovirus infections, although the etiology remains unclear [11,12]. The association between WNV infection and SIADH resulting in hyponatremia adds a new dimension to our understanding of the neurological consequences of mosquito-borne illnesses. It is important to note that copeptin levels in a hyponatremic patient are variable and the use of this parameter in diagnosing hyponatremia is still controversial [13,14]. However, the clinical presentation of our patient, elevated copeptin levels, MRI imaging showing the loss of the pituitary bright spot collectively suggest SIADH as the underlying cause of hyponatremia. Further, the absence of paraneoplastic origins in our patient, along with the established pathophysiology of WNV encephalitis infection, suggests SIADH because of neuroinflammation and subsequent neuroendocrine pathway alteration [15,16]. This can be distinguished from cerebral salt wasting syndrome in that supplementation with salt tablets and fluid restriction eventually improved his sodium level. It can be speculated that this method did not lead to immediate correction of sodium because of the need for fluid redistribution as his body adjusted to new fluid and sodium levels, leading to a delayed response [17]. There is no clear role for specific medical treatments such as corticosteroids vs IV immunoglobulins. Supportive care is recommended for those testing positive for West Nile virus. Data are conflicting regarding the risks and benefits of these agents and treatment is determined on a case-by-case basis. Acyclovir and ribavirin do not appear to play a role in the treatment of West Nile virus given the reported lack of efficacy [18]. This case underscores the intricate interplay between WNV infection, neuro-inflammation, and hormonal dysregulation, emphasizing the diagnostic complexity and management challenges in this and similar clinical scenarios.

Conclusions

West Nile virus presents a unique challenge to providers due to its difficult diagnosis and association with hyponatremia. Clinicians should consider the possibility of viral infections such as West Nile virus in patients living in endemic areas who present with unexplained hyponatremia, cognitive symptoms, and relevant history, especially as it relates to their outdoor activities and potential exposures to mosquito bites. This case highlights the importance of thorough patient history-taking in identifying potential sources of infection and guiding appropriate clinical investigations and management.