Limbic encephalitis (LE) may occur as a paraneoplastic or autoimmune phenomenon and may be associated with syndrome of inappropriate anti-diuretic hormone secretion (SIADH). Ectopicantibody production can explain SIADH in paraneoplastic cases but the exact mechanism of hyponatremia in antibody-mediated LE, such as voltage gated potassium channel (VGKC), is unknown.

VGKC antibodies have been reported in association with several clinical syndromes involving the central and peripheral nervous systems [1,2]. However, only VGKC-LE has been found associated with hyponatremia with an incidence between 30-100% [3-5]. We present here a retrospective review of our cases of limbic encephalitis with a case series of VGKC-LE and its association of SIADH and review of literature discussing the possible mechanism.

We retrospectively reviewed medical charts of 848 adults from 2004-2010 who were clinically diagnosed with LE. Charts were reviewed for paraneoplastic panel, SIADH workup, basic metabolic panels, thyroid function tests, and neuroimaging. We then had a neuroradiologist blinded to the clinical data review the magnetic resonance images (MRI) for hypothalamic hyperintensities. A Pubmed search was performed reviewing the incidence of SIADH in VGKCLE and other autoimmune syndromes. This study was approved by the institutional IRB.

Paraneoplastic panel was resulted in 102 of the 848 patients. Six patients were positive for the VGKC antibody (mean age 62.5 years, 3 males). The mean time from clinical onset to diagnosis was 116 days (range 0 to 185 days). No evidence of malignancy on CT chest, abdomen, and pelvis was found in any of the six patients. Cerebrospinal fluid (CSF) results had an average white blood cell count of 4.0 cells/ mm³ (range 1 to 12 cells/mm³; normal 0 to 5 cells/mm³) and protein of 49.2 mg/dL (range 34 to 69 mg/dL; normal 15 to 60 mg/dL). The clinical features, VGKC titers and monitoring, and provided therapies are found in Table 1.

Table 1: Characteristics of patients with serology positive for VGKC antibodies.

Average admission sodium was 130.7 mmol/L (range 115 to 141 mmol/L). Three patients had admission sodium levels less than 130 mmol/L with an average of 122.7 mmol/L (range 115 to 128 nmol/L). In these three patients, average urine osmolality was 579.7 mosm/L (range 505 to 677 mosm/L) with urine sodium of 112.3 mmol/L (range 64 to 192 mmol/L). Two of these three patients had hypothalamic involvement with T2/FLAIR hyperintensity seen on MRI brain. Water restriction was instituted during hospitalization for all three hyponatremic patients. Their hyponatremia resolved completely or partially prior to discharge with average serum sodium upon discharge of 133.0 nmol/L (range 126 to 137 nmol/L). Basic metabolic workup and MRI findings can be seen in Table 2.

Table 2: Serum and urine laboratory findings.

Serology for other autoimmune antibodies was negative in five of the cases. One case had positive microsomal antibodies (138.6 IU/mL; normal <5 IU/mL) and thyroglobulin antibodies (1209 IU/mL; normal <10 IU/mL) but normal thyroid stimulating hormone (TSH) (4.63 uU/ mL; normal 0.4 to 5.5 uU/mL) and free T4 (1.2 ng/dL; normal 0.7 to 1.8 ng/dL). None had diabetes.

We present six cases of LE associated with the VGKC antibody. We found three of the six cases had SIADH consistent with the reported incidence in literature [1,3,5-9]. These cases responded completely or partially to the combination of immunomodulation and water restriction. Two of these three cases had hypothalamic involvement on MRI.

VGKC proteins constitute a diverse group of tetrameric signaling proteins present on the cell surface different tissue subtypes [1]. These proteins classically have a vital role in cellular action potential and recently have been shown to initiate paraneoplastic autoimmunity as autoantigens [1]. VGKC antibodies are seen in neuromyotonia, Morvan syndrome, epilepsy, and dysautonomic phenomena of hyperhidrosis and gastrointestinal dysmotility [1,2]. Interestingly, hyponatremia is not seen in these disorders [10]. Reports have postulated that the leucine-rich, glioma inactivated 1 (LGI-1) protein may be the target antigen of VGKC mediated LE whereas the contactin-associated protein 2 (CASPR-2) may be the antigen in Issaac’s and Morvan’s syndrome [9].

The mechanism of SIADH in patients with VGKC-LE is not completely understood. One possible mechanism is inflammation on the hypothalamic-pituitary neuraxis from direct extension. Two of the three hyponatremic patients in our series had hypothalamic hyperintensity on T2/FLAIR MRI. If that’s the case, all limbic encephalitis irrespective of the cause may have higher incidences of SIADH. Another possibility is involvement of the hypothalamic osmoreceptors regulating AVP release that are located in the lamina terminalis outside the blood brain barrier [8]. The predominant lack of an inflammatory response in CSF studies makes this mechanism less likely. The fact that most reports of hyponatremia improve with immunotherapy supports an antibody mediated mechanism with the target antigen either at the hypothalamus or perhaps at the Kv1.1 and/ or LGI-1 channels at the renal tubular epithelium, which could explain receptor sensitization and potentiating ADH-induced water transport [7].

Future areas of research should focus on detailed endocrinological evaluation of hyponatremia in patients with autoimmune encephalitis distinguishing SIADH from other causes of hyponatremia, such as cerebral salt wasting. Additionally, the histopathological query of hypothalamic and renal involvement in animal models of autoimmune encephalitis investigating VKGC as well as LGI-1 antibodies in hyponatremic animals would be beneficial to accurately define the causative protein for SIADH in VGKC-LE. The specificity of hyponatermia to VKGC-LE versus other causes of autoimmune encephalitis should also be explored. With the emerging VGKC subtypes and new antigen targets for VGKC antibody associated diseases, it is evident that the associations of LE and secondary features are complex. Our case series emphasizes the association and an early diagnosis of LE given the reversibility with a combination of water restriction and immunomodulation.

Dr. Surafel Gebreselassie, nephrology, for critical appraisal. Dr. Thinesh Sivapatham, neuroradiology, for reviewing MRI images.

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