Our patient is the third reported pediatric patient who has experienced all three components of the SS triad. Hahn reported SS in a 16 year old female ; Muttikkal in a 9 year old girl . Delaney reported an 8 year old child who had BRAO and hearing loss, but no clinically evident encephalopathy . Of the approximately 80 cases of SS that have been reported in the international medical literature since Dr. Susac's first report in 1979, our patient represents only the second case of SS (adult or pediatric) reported in the rheumatologic literature . Although elevated VWF-Ag levels have not been reported in SS, one report has mentioned elevated Factor VIII levels . Thrombocytopenia has not been mentioned in any previous reports on SS.
Patients with SS often do not exhibit the complete triad at the beginning of their illness. Encephalopathy, BRAO, and hearing loss can each be the sole presenting manifestation of SS, with the other two components evolving later. Some patients with SS never develop clinical evidence of all 3 components of the triad.
Patients with SS are commonly mistakenly thought to have either "atypical multiple sclerosis (MS)" or "atypical ADEM." Several realizations can help the physician to distinguish SS from these two disorders : In MS and ADEM the callosal involvement is along the undersurface of the callosum at the septal interface; while in SS the central fibers of the corpus callosum are primarily affected. Leptomeningeal enhancement, which occurs in 33% of patients with SS, does not occur in MS or ADEM. Deep gray matter involvement is rare in MS, though common in pediatric ADEM. Deafness is rare in MS and has not been reported in ADEM. True BRAO is incompatible with a diagnosis of MS, and has not been reported in ADEM.
SS should also be considered when a patient presents with an enigmatic encephalopathy (including encephalopathy with a predominance of psychiatric manifestations), or visual disturbance, or hearing loss (or combinations of these three) and has a working diagnosis of "possible neuropsychiatric lupus," "possible primary angiitis of the CNS," "unusual Meniere's disease," "autoimmune inner ear disease (AIED)," "possible Cogan's syndrome," "possible CNS (or retinal) vasospasm," "possible CNS (or retinal) embolism/thrombosis," or "unexplained branch retinal artery occlusion."
When SS is a consideration, it is essential to obtain an MRI of the brain and focus on the corpus callosum. Early in the disease, the typical callosal lesions are best seen on thin-section sagittal FLAIR and sagittal T1 (with contrast) images of the corpus callosum. Even if the patient has no obvious hearing loss or visual symptoms, it is important to obtain an audiogram and to consult a neuro-ophthalmologist/retinal specialist. Even if a careful fundoscopic exam is normal, we strongly urge fluorescein retinal angiography to look for asymptomatic retinal vasculopathy. When the angiography is performed, it is particularly important to include a careful look at the retinal periphery.
Brain biopsies, anatomical observations, and responses to immunosuppressive therapy suggest that SS is a primary autoimmune microvascular endotheliopathy: Most reports on brain biopsies of patients with SS have emphasized the finding of small foci of necrosis (microinfarcts) within the cerebral cortex and white matter. Unfortunately, only a few reports have provided detailed information about the microvasculature [5–9]. Fox reported a microangiopathy characterized by adventitial thickening and endothelial swelling in precapillary arterioles, thickening of the basal lamina, and a perivascular infiltrate in small vessels . Heiskala reported that "the walls of several small arterioles were thickened and surrounded by an abnormal reticulin network and occasional lymphocytes; the normal capillary network was destroyed; and electron micrographs showed a remarkably thick basal lamina in many capillaries, both in the cerebral cortex and white matter ." Kaminska described "arteriolar wall proliferation with lymphocytic infiltration of the vessel wall ." Petty described "minimal perivascular lymphocytic infiltration without fibrinoid necrosis or necrotizing vasculitis ."
Petty performed muscle biopsies on 5 patients with SS and described "swollen endothelial cells and sparse periarteriolar inflammatory cells" in three . "The swollen endothelial cells nearly occluded some small arterioles." Similarly, in a muscle biopsy of a patient with SS, O'Halloran described "occluded endomysial capillaries" and "foci of C5b-9 within the walls of small arterioles ." None of these patients had clinical evidence of muscle disease. Petty and others have suggested that the same microvascular endotheliopathy that is occurring (subclinically) in the muscle of patients with SS is also occurring in the brain, retina, and inner ear .
The above-described histopathologic and electron microscopic findings in the microvasculature of the brain and muscle of patients with SS are quite reminiscent of the microvascular abnormalities seen in the skin and muscle of children with juvenile dermatomyositis (JDM). For example, documented characteristics of the microvascular endotheliopathy of JDM include: endothelial cell swelling, sometimes to the point of lumenal occlusion; endothelial cell degeneration and necrosis; capillary network destruction ("drop-out"); basement membrane thickening, reduplication, and lamellation; granular C5b-9 deposition in blood vessels; and perivascular lymphocytic infiltration [10–12]. Interestingly, in JDM, microvascular endotheliopathy has also been noted (rarely) in the brain and retina [20, 21]. For example, in JDM, the same endothelial cell swelling and endothelial cell necrosis that is seen in the muscle, skin, and GI tract has been noted (rarely) in the microvasculature of the brain . Spectacular multifocal branch retinal artery staining on fluorescein angiography has also been seen in JDM . And, transient retinal exudates and "cotton wool" spots, with temporary loss of vision, have been described in JDM .
In SS, the findings on fluorescein retinal angiography provide strong support for the notion that endothelial injury plays a central role in the pathogenesis of SS. The multifocal fluorescein staining/leakage localizes the site of immune attack to the endothelium of the precapillary arteriole (less than 100 microns), a site that consists primarily of endothelium and basement membrane. The elevated VWF-Ag and Factor VIII levels seen in our patient also provide evidence for endothelial cell perturbation in SS.
SS and JDM, therefore, have several characteristics in common. Both represent microvascular endotheliopathies that cause ischemic insult to a triad of tissues – primarily skin, muscle, and gastrointestinal tract in dermatomyositis; primarily brain, retina, and cochlea in SS. Both have biopsy findings characterized by endothelial cell injury in microvasculatures. Elevated VWF-Ag and Factor VIII levels have been detected in both diseases. Both follow variable courses [1, 2, 13, 23, 24]. In both cases, the disease may follow a 6–24 month duration monocyclic course (encephalopathic variety in SS), a polycyclic course (the recurrent BRAO/HL subset in SS), or a prolonged chronic continuous course (rare in SS). Both respond to immunosuppressive medication [1, 2, 13–15, 23, 24]. Finally, in SS, microvascular endotheliopathy can be found in muscle ; and, in JDM, microvascular endotheliopathy can be found in brain and retina [20, 21].
Because SS and JDM appear to have much in common, we suggest that lessons learned from study of the immunopathogenesis, clinical course and treatment of JDM may be applicable to SS. With this in mind, we treated our patient with an aggressive immunosuppressive approach [2, 14] that has been effective for severe JDM [13, 15].
Although we believe her treatment served her very well, the varied and only somewhat predictable natural history of SS makes it difficult to know exactly how much credit her treatment should be given for suppressing and maintaining control over her disease. To date, our knowledge of the natural history of SS and its responsiveness to treatment is based entirely on anecdotal case reports and retrospective analysis of short series of patients [1, 2, 5–9, 14, 16, 17, 23]. No controlled studies of treatment have been conducted.
Analysis of reported cases reveals that some patients with SS, despite receiving no immunosuppressive treatment, have experienced a monocyclic course that has remitted spontaneously and resulted in good clinical outcome. (Such cases initially suggested that SS might not be an autoimmune disorder.) Other patients have seemed to respond dramatically to corticosteroid therapy – strongly suggesting that SS is an autoimmune disorder. Others have failed to respond adequately to corticosteroid therapy, but have seemed to respond well to cyclophosphamide – suggesting that SS sometimes needs more than just corticosteroid therapy. Some patients have failed to respond to both corticosteroid and cyclophosphamide therapy – suggesting that some patients may have such severe disease that usual corticosteroid and cyclophosphamide therapy may be inadequate. Many patients have responded well to immunosuppressive therapy, but have relapsed (either spontaneously or when immunosuppressive therapy has been tapered too quickly), and have again responded to reinstitution or escalation of immunosuppression.
The above case reports are reminiscent of what is known about the natural history of JDM and the spectrum of responsiveness of JDM to various immunosuppressive therapies. It is wise to recall that in the pre-steroid era, a third of JDM patients recovered fully without any treatment, a third experienced chronic disability, and a third died. It is also important to realize that the prompt, aggressive, and sustained immunosuppressive treatment that children with JDM now receive has resulted in a marked improvement in outcome . At the current time, there is still a spectrum regarding how much immunosuppressive medication JDM requires (and for how long). The same is probably true for SS. Clearly, careful collaborative study of as large a number of patients as possible will be necessary to determine optimal treatment of SS.
In the meantime, we encourage prompt, aggressive, and sustained immunosuppressive treatment of SS. We think such treatment may prevent or minimize the feared sequelae of dementia, vision loss, and hearing loss. We suspect that, historically, encephalopathic SS has often been treated too late, with too little, and/or for too short a time. Historically, this was the case with JDM, too. We strongly encourage international collaborative study of SS to further test the hypothesis that the immunopathogenesis of SS is similar to that of JDM, and to determine optimal treatment. Our goal should be excellent outcome, not just good outcome. Until more is known, we offer the protocol depicted in Figure 3 and detailed elsewhere [2, 14] as a tentative model for treatment of encephalopathic SS. Finally, since SS appears to be an immune-mediated disease with immunohistopathologic characteristics similar to those seen in JDM and requires long-term immunosuppressive therapy, we urge the international rheumatology community to become more aware of SS, to view it as an autoimmune disease, and to become more involved in its diagnosis, treatment, and study.