The pathogenesis of SCLS remains unclear. Cytokines, leukotrienes, vascular endothelial growth factor (VEGF), and complement have been implicated. A substantial increase in the interleukin 2 receptor–positive peripheral blood M-cell count has been noted during episodes of hyperpermeability.24
Proteins with weights up to 900 kDa can extravasate, but the exact cause of hyperpermeability remains unknown. Endothelial microvesicular body and bleb formation during attacks is suggestive of endothelial apoptosis; however, attempts to directly link M protein to endothelial damage have been unsuccessful.25,26
The appearance of this syndrome in a 17-day-old infant in our series suggests the possibility of intrauterine transfer of soluble mediators or an inherited disorder.
Our cohort included only patients who had spontaneous attacks without a clear etiology. Another term, secondary SCLS
, has been coined for similar attacks of generalized vascular hyperpermeability in which the causative factor of SCLS is known. Tumor necrosis factor, interferon-α and β, acitretin, epoprostenol, gemcitabine, interleukin 2, denileukin diftitox, and filgrastim have been implicated in secondary SCLS.27-31
Hepatitis C infection and malignancies have also been reported as etiological factors, but none of the patients in our cohort had such illnesses concurrently at the time of initial evaluation.32-35
Similarities in age and sex distribution were noted between our cohort and that by Amoura et al.19
The poor representation of African Americans was likely a reflection of referral bias. Only a few cases have been reported in the pediatric age group thus far, and our study adds another 2, suggesting the rarity of this disease in children.36-39
To increase awareness of this disorder, a report on SCLS was recently added to the National Organization of Rare Disorders database. A patient-support Web site (http://www.rareshare.org) has also included SCLS. An increase in the reported cases of SCLS in the past decade could perhaps be attributed to greater awareness among clinicians rather than an increase in its incidence.3
As underscored by many illustrative cases, delayed diagnosis and misdiagnosis increase patient morbidity and may adversely affect outcome. Protracted lag time (median, 13.5 months) between the onset of symptoms and the establishment of the correct diagnosis was a noteworthy finding in our study.
We used stringent criteria to define patients with SCLS in this series. Coexisting MGUS, warning signs, triggering factors, oliguria with onset of an attack, pulmonary edema, and polyuria in the recruitment phase followed by spontaneous resolution of symptoms are typical features but are not mandatory for making a formal diagnosis.
Although most patients were able to recognize the onset of an attack because of symptom recurrence and similar, if not identical, triggering factors, the severity of the attack was less predictable, making it important for the patient to promptly seek urgent care at the onset of an attack regardless of its severity.
Except for an isolated case of a newborn to a patient with SCLS, family history was noncontributory, a finding that compares well with previous reports. The frequency of attacks varied widely. As in a previously reported case, a subset of patients (8%) was diagnosed as having chronic hyperpermeability, characterized by stable blood pressure, persisting edema (albeit to a lesser degree between the acute flares), and, on occasion, serous effusions.40
In Clarkson's patient, a clear temporal relationship to the menstrual cycle was established. In our series, only 1 patient had menses-related crises and, unlike previous reports, no attacks were observed in the peripartum period.41
Preservation of mentation is not uncommon during an SCLS attack. In this series, only 2 patients presented with seizures during crisis, 1 of whom had cerebral edema, a well-documented finding in SCLS.42
Cerebral hypoperfusion resulted in a stroke in 1 patient. Acute renal failure, noted in nearly half of patients, is a common complication and a consequence of hypotension-related reduced kidney perfusion, acute tubular necrosis, and rhabdomyolysis-related pigmenturia.43-45
Tissue salvage (decompression) therapy was required by 3 of the 5 patients who had developed compartment syndrome, a grave complication of SCLS due to massive fluid leakage into the muscle tissue.46-48
Acute deep venous thrombosis, which occurred in 8% of patients, perhaps resulted from attack-induced activation of the components of the Virchow triad.
The detection of M protein in most patients (n=19; 76%) may be attributed to the selection bias of the patients referred to our dysproteinemia clinic. However, the results are similar to those of the French study by Amoura et al,19
wherein all 13 cases reported MGUS (11 of the κ type), and a subsequent review, in which 39 of 50 cases had MGUS (28 of the κ type).3
It is important to reiterate that the absence of an M-spike does not exclude SCLS.49,50
Unlike other PC disorders such as POEMS syndrome (p
onoclonal gammopathy, and s
kin changes), which is almost always associated with IgG-λ or IgA-λ, and Schnitzler syndrome (chronic urticarial rash, monoclonal gammopathy, fever, arthralgia, bone pain, and lymphadenopathy), which is associated with IgM monoclonal gammopathy, patients with Clarkson's disease predominantly have IgG-κ or IgA-κ monoclonal gammopathy.51,52
In contrast to Schnitzler and POEMS syndromes, the M component does not appear to be a major criterion required for diagnosis of SCLS.51,52
The evolution to MM, plasma cell leukemia, and, rarely, systemic amyloidosis has been reported.2,6,53
In our cohort, the rate of transformation was 0.7% per person-year of follow-up, which is comparable to 1% per year reported in MGUS.54
Surveillance for MM is therefore necessary. Recurrence (or severity) of attacks did not correlate with the size of the M-spike.
This disorder, particularly the unpredictability of recurrent life-threatening episodes as well as of adverse effects of treatment, took an emotional toll on most patients, some of whom also exhibited overt signs of major depression.
Much has been learned through delineating the distinct “phases” of an attack. During the initial leak phase, cautious volume expansion and central venous pressure monitoring can aid in maintaining adequate perfusion of vital organs.18
Overaggressive hydration can precipitate pulmonary edema. Corticosteroid therapy can be beneficial during an attack16,33,55
because cytokine-mediated endothelial damage has been implicated.56
In addition, plasmapheresis16,19,57,58
and intravenous γ-globulin19,50,59
have proved to be successful in the acute phase. In our study, 1 patient received intravenous immunoglobulin at an outside institution due to IgG2 deficiency before the diagnosis of SCLS was established, and only 1 underwent plasmapheresis.
To date, terbutaline and aminophylline-mediated prophylaxis17
that increases cyclic adenosine monophosphate or inhibits the intracellular Rho kinase pathway60
has had the most effect on the maintenance of quiescent periods.18
and thalidomide (which possibly acts through tumor necrosis factor α inhibition in M cells)57
have been used. Endothelial targets such as VEGF have also been exploited. Therapies involving monoclonal antibodies, such as bevacizumab (anti-VEGF) and infliximab (anti–tumor necrosis factor α), have been used with varying success.63,64
Institution of antimyeloma therapy in patients with SCLS and concomitant MM has reportedly abated subsequent SCLS attacks.19
However, this observation could not be verified in our cohort because the single patient with both SCLS and MM died shortly after the latter was diagnosed.
The 5-year OS rate of 76% in our cohort reflects an improvement in mortality when compared with previous studies,16,19
but the factor that contributes most to this improved outcome has not been definitively identified.
The constraints of studying the natural history and clinical course of a rare disorder are well known. Our study has the usual limitations of a retrospective analysis of selected patients from a tertiary care center with limited follow-up.