63–year–old male with history of hypertension and dyslipidemia presented to the hospital with a 5 month history of fatigue, 40 lbs. weight loss, diaphoresis, insomnia, short–term memory loss, and hyponatremia secondary to presumed syndrome of inappropriate antidiuretic hormone secretion (SIADH). His exam was notable for normal vitals, dry mucus membranes, fine tremor, and a mini–mental status score of 29. Laboratory measures were consistent with sodium: 133 mmol/L, creatinine: 2.6 mg/dL, BUN: 53 mg/dL, otherwise unremarkable. He was given intravenous saline and his creatinine normalized. Despite attaining a euvolemic state with continuous intravenous hydration, his sodium dropped to a nadir of 126 with urine sodium: 57 mmol/L and osmolality: 586 mOsm/kg confirming SIADH. HIV screen and RPR were negative, TSH: 1.99 mclU/mL, morning cortisol: 14.7 mcg/dL, with negative serum and protein electrophoresis and anti–nuclear antibody. Electromyography was normal. Magnetic resonance imaging of brain and whole body positron emission tomography scan were only consistent with an old cerebellar infarct and no pathologic hypermetabolic activity. Patient continued to have intermittent confusion associated with visual hallucinations, hyperhydrosis, and fatigue despite near normal sodium levels with fluid restriction. His plasma and urine normetanephrine and dopamine levels were mildly elevated; however, a normal adrenal scan excluded an occult pheochromocytoma. Serotonin syndrome also was excluded with a normal 24–h urinary 5–hydroxyindoleacetic acid level. Urinary heavy metal screen was negative and serum ceruloplasmin level was normal. An electroencephalogram was performed which did not reveal an epileptiform foci. A paraneoplastic workup was consistent with elevated antibody levels to voltage–gated K and calcium channels (Table) strongly suggestive of limbic encephalitis (LE).
LE is an inflammation of the limbic system associated with features of limbic dysfunction such as behavioral and psychiatric symptoms, cognitive decline, short–term memory loss, and complex–partial seizures. Hypothalamic and autonomic dysfunction can occur in the form of hyperthermia, somnolence, and endocrine abnormalities. Imaging studies can be nonspecific, the cerebrospinal fluid commonly is bland, and hyponatremia is usually present. LE can be secondary to both auto–immune and paraneoplastic encephalitides. Extensive serologic exam is required to establish the diagnosis. In case of associated malignant process, the diagnosis of the primary tumor may have a lag with the clinical syndrome.
Internists should consider LE and perform a paraneoplastic workup in any patient with progressive cognitive decline, behavioral symptoms, seizure, and hyponatremia with an otherwise unapparent etiology.
Table 1Serologic Evaluation for LE
|N–Methyl d–Aspartic Acid (NMDA) antibody||Negative|
|Antineuronal nuclear antibody 1 (ANNA–1)||Negative|
|Anti–Glial Nuclear Antibody||Negative|
|Anti–Purkinje Cell Cytoplasm Antibody||Negative|
|Anti P/Q type calcium channel||0.05 nmol/L (normal high < 0.02)|
|Anti N type calcium channel||Negative|
|Anti–Ganglionic Neuronal Ach receptor antibody||Negative|
|Anti–Voltage gated K channel||0.69 nmol/L (normal high < 0.02)|