Since the pathophysiology of SCLS is unknown and there are no validated criteria for diagnosis, we stress the importance of demonstrating hypotension, hemoconcentration and hypoalbuminemia in patients with recurrent episodes of edema to establish the diagnosis. It is unclear whether or not patients with chronic SCLS, who often lack cyclical leak/post leak phases, frank hypotensive episodes, and a serum monoclonal paraprotein, have a distinct pathophysiologic basis for their symptoms. In either case, secondary causes of edema must be rigorously excluded until unique diagnostic indicators of SCLS are discovered.
We also emphasize the need for prospective therapeutic studies for SCLS outside of the time-honored regimen of theophylline and terbutaline. Investigation of newer evidence-based therapeutic modalities may be warranted given the fatal nature of SCLS and the persistent difficulty in treating acute, grave attacks. Targeting other endothelial signal transduction pathways may be possible for SCLS. For example, statins may ameliorate vascular permeability (72
) and could diminish symptoms in patients with chronic SCLS or reduce severity of acute flare-ups. Src and abl tyrosine kinases mediate permeability pathways induced by growth factors such as VEGF (76
), and kinase inhibitors such as dasatinib or imatinib, which have been used safely for the treatment of leukemias and solid tumors (78
), may stabilize endothelial barrier function while preserving angiogenesis (80
If the plasma cell clone mediates disease pathology by producing a toxic paraprotein (a link yet to be established), more aggressive, potentially curative, hematological intervention might be considered for SCLS. In POEMS, high dose chemotherapy followed by autologous peripheral blood stem cell transplantation (auto PBST) has been successful (81
). A single patient with SCLS and plasma cell leukemia saw complete resolution of capillary leak symptoms after auto PBST even when the leukemia relapsed (51
). Thus, given the similarity of SCLS to POEMS on many fronts, we propose that auto PBST be considered for the treatment of patients with frequent, life-threatening SCLS episodes refractory to standard therapy.
Since little progress has been made in treatment of SCLS, we feel that it is time for this disease to be reexamined, particularly because it shares many phenotypic similarities with other “shock” syndromes such as sepsis, anaphylaxis, and angioedema. The endothelial dysfunction seen in SCLS as also typifies a diverse group of disorders including diabetic retinopathy (83
), lupus nephritis (84
), and infection with malaria and Ebola/Marburg viruses (85
). Clarification of the unique features of SCLS will further our understanding of both the immune system and endothelial cell biology.