A novel association of osmotic demyelination in Sjögren's syndrome prompts revisiting role of aquaporins in CNS demyelinating diseases: A literature review

Abstract

Background: Primary Sjögren's syndrome (SS) is a chronic systemic autoimmune disease with varied neurological manifestations. SS is associated with anti-aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD), a demyelinating autoimmune disorder of the central nervous system (CNS). Intriguingly, there are reports of osmotic demyelinating syndrome (ODS), a supposedly non-inflammatory disorder, in the context of SS and renal tubular acidosis (RTA), both of which are not yet established risk factors for ODS.

Methods: A literature search was undertaken to identify case reports of ODS in patients with SS. Details of the clinical and laboratory features of these patients were compiled. Additionally, we searched for NMOSD in patients with SS. We looked for co-existing RTA in patients with SS-ODS as well as SS-NMOSD. We also screened for reports of ODS in RTA without underlying SS.

Results & discussion: We identified 15 patients (all women, median age 40 years) with ODS in SS, and all of these patients had comorbid RTA. There were only three reported cases of ODS in RTA without underlying SS. We identified a total of 67 patients with SS-NMOSD, of whom only 3 (4.5%) had RTA. Hence, unlike NMOSD, the development of ODS in SS requires a prolonged osmotic or electrolyte abnormality caused by the comorbid RTA. The 15 patients with ODS and SS -RTA, showed heterogeneous clinical manifestations and outcomes. The most common symptom was quadriparesis, seen in 14 of the 15 patients. Eleven of the 15 patients had one of the following features, either alone or in combination: worsening of the sensorium, extensor plantar response, dysphagia/dysarthria, and facial palsy. The latter four manifestations were present at the onset in 7 patients and later in the course of the illness in the remaining 4 patients. Ocular palsy was seen in only four of the 15 patients and was a late manifestation. One patient who had extensive long-segment myelitis and subsequent ODS died, but most patients recovered without significant sequelae. None had hyponatremia, while all patients had hypokalemia and/or hypernatremia. Hypokalemia causing nephrogenic diabetes insipidus (NDI) followed by rapid rise in sodium and the resultant osmotic stress could potentially explain the occurrence of ODS in SS-RTA. Aquaporin (AQP) in astrocytes is implicated in ODS, and renal AQP is downregulated in NDI. Antibodies against AQPs are present in some patients with SS. Defective AQP is therefore a common link underlying all the connected diseases, namely SS, NDI, and ODS, raising the possibility of immune-mediated AQP dysfunction in the pathogenesis.

Conclusion: The hitherto unreported association between SS-RTA and ODS may implicate SS and/or RTA in the development of ODS. In the setting of SS-RTA, ODS must be suspected when a patient with flaccid quadriparesis does not respond to the correction of potassium or develops additional neurological features along with a rise in sodium. Defective functions of AQPs may be a possible mechanism linking demyelinating CNS lesions, SS, and RTA. Studies evaluating AQP functions and serum antibodies against AQPs in these conditions are warranted.

Keywords: Aquaporin; Central pontine myelinolysis; Sjogren's syndrome; hypokalemia; neuromyelitis optica spectrum disorders; renal tubular acidosis.