Discussion
Our initial care for this patient focused on diagnosing the cause of her hyponatremia. This patient was clinically euvolemic with a hypo-osmolar hyponatremia in the presence of inappropriately concentrated urine and elevated urine sodium. This identifies that, despite progressive hyponatremia, the patient's expected suppression of antidiuretic hormone had not occurred and was, therefore, inappropriately high, confirming the diagnosis of SIADH.[1]
After diagnosing SIADH, we initiated early measures to correct her hyponatremia, including restriction of fluid intake. This patient did not have signs of significant neurologic sequelae of hyponatremia (including seizure or coma) requiring the administration of hypertonic intravenous saline. Identifying and treating the underlying cause of this syndrome is its ultimate cure, and we next sought to determine the process driving the development of SIADH in this patient.
SIADH has many causes, malignancy being the most common etiology. Small cell carcinoma of the lung accounts for many of these cases and has been shown to occur in 15% of patients with this malignancy.[2] This probably represents a paraneoplastic process through the production of ectopic antidiuretic hormone. Other malignancies associated with the syndrome include other forms of lung cancer, thymoma, and cancers of the head and neck, pancreas, bladder, small bowel, and prostate.[2] Several medications can induce the syndrome, including carbamazepine, oxycarbazepine, fluoxetine, paroxetine, and cyclophosphamide.[3,4,5,6] Nonmalignant pulmonary diseases such as infection, chronic obstructive pulmonary disease, and acute respiratory failure can cause SIADH as well; the mechanism for this process is poorly understood. And finally, disorders involving the central nervous system (CNS), including head trauma, brain tumors, subarachnoid hemorrhage, and infection, can cause SIADH.[2]
CNS infection is a rare but established cause of SIADH. Specific infections implicated include tuberculous, bacterial, and enteroviral meningitis, as well as herpes simplex, St. Louis encephalitis, and California-La Crosse encephalitis.[7,8,9,10,11,12] The mechanism of this phenomenon remains unclear. Patwari and colleagues[13] described a positive correlation between the degree of meningeal inflammation and incidence of SIADH in children with acute bacterial meningitis. Additionally, Weller and colleagues[14] discovered elevations of the inflammatory cytokine interleukin-6 within the serum and cerebrospinal fluid of patients with LNB, and Mastorakos[15] demonstrated that this cytokine induces antidiuretic hormone release. This evidence suggests that perhaps CNS inflammation mediates the development and severity of SIADH. When this process is responsible for SIADH, the syndrome will nearly uniformly resolve after successful treatment of the CNS infection.[2]
With our patient, we were able to rule out many of the causes of SIADH on the basis of her history, physical, and initial medical work-up. However, on the basis of her change in mental status and other neurologic signs and symptoms, we could not rule out primary CNS process. MRI and lumbar puncture were performed. This patient's marked lymphocytic pleocytosis and elevated CSF protein suggested that she was suffering from a CNS infection and that this inflammatory process was likely the pathophysiologic drive for her development of SIADH. Furthermore, given her recent history of rash and opportunity for tick exposure, we felt that this infectious process was suggestive of early LNB. CSF and serologic testing for this disease confirmed our suspicion.
Lyme disease usually presents as 3 distinct syndromes. The first is an early localized disease, characterized by erythema migrans (EM) rash and, possibly, associated flu-like symptoms including myalgias, arthralgias, headache, stiff neck, and fever, in 80% of cases.[16] After this syndrome, the patient may experience relief from symptoms, but will then progress to an early disseminated form of the disease. Fifteen percent of patients who enter this phase will suffer from nervous system involvement, or early LNB, characterized by any combination of several neurologic sequelae.[16] This will typically occur between 3 weeks and 3 months from the time of infection.[17] If left untreated, patients may progress to late disseminated disease, characterized by chronic and subtle encephalopathy, polyradiculoneuropathy, and recurrent bouts of arthralgia and arthritis.[16]
The diagnosis of early LNB is mainly clinical and should be considered in patients with opportunity for tick exposure in an endemic region, who develop an EM rash within weeks of exposure, and then suffer any combination of lymphocytic meningitis, cranial neuropathy, radiculoneuropathy, ataxia, or encephalitis, without any other identifiable cause.[17] Serologic and CSF evidence of antibody response to Borrelia burgdorferi, the causative agent, are helpful to confirm the diagnosis, but should not be used in the absence of a recent and suggestive history for Lyme disease. The most widely used serologic test, the 2-tiered ELISA and Western immunoblot, is only 83% sensitive at the onset of early LNB.[17] Additionally, the ELISA has a high false-positive rate and both tests may remain positive long after treatment of Lyme disease, further invalidating their use as diagnostic tests in patients without a proper history.[17] Tests to identify CSF antibody are specific for early LNB, but these tests are not standardized and also remain positive after successful treatment.[17]
The first-line treatment for LNB is intravenous ceftriaxone for 2 to 4 weeks. Alternative regimens include intravenous cefotaxime or penicillin G and, in cases of allergy to these medications, doxycycline.[18] After starting treatment, most patients will experience complete relief from neurologic signs and symptoms within a few weeks.[16]
Our patient presented with SIADH. Because treating the cause of SIADH is its definitive therapy, our care then focused on finding the etiology of this syndrome. Resolution of the patient's hyponatremia occurred after the ultimate discovery and successful treatment of Lyme neuroborreliosis. SIADH has recently been associated with Lyme neuroborreliosis in 2 patients.[19] Our case also demonstrates this clinical course and adds to a growing body of evidence for this phenomenon. This case specifically stresses the importance that clinicians should recognize Lyme neuroborreliosis as a potential cause for patients who present with SIADH.
Note: The views expressed in this case report are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or US Government.
