Disorders In Depth

Sturge-Weber Syndrome (SWS) - Leptomeningeal Angiomatosis

Sturge-Weber syndrome: Definition, epidemiology and pathology. Classically, Sturge-Weber Syndrome (SWS) is defined by a facial capillary malformation (port-wine birthmark/ PWB aka port-wine stain) in association with ipsilateral vascular malformations of the eye and/or the brain (Bodensteiner JB, 1999). The brain vascular malformation affects the leptomeninges, and is termed a leptomeningeal angioma. Variants exist where only one of these three structures is involved with the vascular malformation (Comi, 2003). SWS is a congenital syndrome that occurs almost exclusively sporadically, and not in families. Precise population-based data does not exist for the prevalence or incidence of SWS. However, port-wine stains occur in 3 per 1000 live births, and when a capillary malformation involves the forehead to one side and/or the upper eyelid, that individual is at risk for brain and/or eye involvement. The risk ranges between 10-35% depending on the size of the port-wine stain and whether it is unilateral or bilateral (Enjolras et al., 1985; Tallman et al., 1991). Prevalence data obtained from large dermatologic clinics (Enjolras et al., 1985; Tallman et al., 1991) suggests that about 5-10,000 individuals in the United States have SWS.

Port-wine birthmarks consist of ectatic (dilated) capillary-venous blood vessels in the dermis (Rydh et al., 1991). The capillary malformation is flat and pink at birth, lightens after birth, and then later in childhood or in adulthood frequently darkens and begins to thicken. Studies of the extracellular matrix found increased deposition of type IV collagen, laminin and fibronectin around the affected vessels (Mitsuhashi et al., 1988). The vascular malformation of the eye consists of enlarged, tortuous venous vessels that can affect the conjunctiva, episclera, retina and/or choroids. Glaucoma is the most frequent ophthalmologic complication, affects about 30-70% of individuals with SWS, and can result in optic atrophy and blindness. The vascular malformation of the brain in SWS consists of enlarged and tortuous leptomeningeal vessels and dilated deep venous vessels, most often involving the occipital cortex.

Impaired venous drainage from the involved brain regions results in reduced arterial perfusion to these regions (Lin et al., 2006). SPECT (Single Photon Emission Computed Tomography) studies in young infants with SWS have shown that cerebral perfusion goes from being generous in the very young infant to being deficient in the involved cortical region by end of the first year (Adamsbaum et al., 1996). The vessels of leptomeningeal angiomas are thin-walled venous structures, many of which are hugely dilated.  The vessels are innervated only by noradrenergic sympathetic nerve fibers (Cunha e Sa et al., 1997) and show increased endothelin-1 expression (Rhoten et al., 1997), suggesting that there may be increased vasoconstrictive tone in SWS. The impaired venous drainage through these vessels results in reduced microcirculation and hypoxia in the surrounding brain tissue. Microscopically, the cortical tissue underlying the angioma shows neuronal loss, calcium deposition, hypoplastic blood vessels, breakdown of the blood-brain barrier and gliosis (Comati et al., 2007). Changes are also seen in the underlying white matter: there is an early phase of hypermyelination, which is then followed by white matter loss (Juhasz et al., 2007).

The brain lesions in SWS are progressive, suggesting that there is ongoing angiogenesis in these lesions. Consistent with this idea, increased levels of endothelial proliferation and apoptosis were seen in leptomeningeal vessels from SWS patients relative to those of controls (Comati et al., 2007), as well as overexpression of fibronectin (Comi et al., 2005). The vessels also showed increased levels of expression of VEGF, VEGF receptors 1 and 2, neuropilin, Tie-2, and HIF-1α and HIF-2α (Comati et al., 2007). Thus, leptomeningeal angiomas in SWS appear not to be static lesions, but rather show evidence of ongoing vascular remodeling. Our preliminary findings of elevated levels of matrix metalloproteinases in the urine of SWS patients are also consistent with this hypothesis. It is unknown to what extent this remodeling contributes to the neurologic deterioration versus providing a compensatory mechanism to maintain blood flow.

Clinical context of SWS treatment. Most affected infants present with focal or complex partial/secondarily generalized seizures in the first year or two of life (Kramer et al., 2000).  Other common presentations in infants include early-handedness and the development of a gaze preference (evidence of a visual-field cut). Stroke-like episodes and migraines are also common (Dora and Balkan, 2001; Klapper, 1994). Migraines can lead to stroke-like episodes and seizures, and seizures can lead to migraines and stroke-like episodes. When episodes of seizures and/or stroke-like episodes are recurrent, the child frequently develops a permanent hemiparesis (weakness on one side of the body) and developmental delay. On the other hand, neurologic impairments including hemiparesis, visual field deficits and cognitive impairments can improve if the patient is seizure-free and clinically stable for a prolonged period (Lee et al., 2001). Severity of neurologic progression varies greatly, with some patients demonstrating stable and mild neurologic impairment but others having severe uncontrolled seizures, repeated strokes and loss of vision, strength and cognitive function. The only factors known to predict severity of neurologic progression and involvement are unilateral versus bilateral (worse) brain involvement and the age of seizure onset (Kramer et al., 2000). The clinical variability in presentation, severity and progression inherent in SWS, in addition to its rarity, has slowed efforts to identify effective biomarkers, to develop clinical tools and treatment guidelines, and to carry out high quality clinical/translational research.

Many important clinical questions about SWS remain unanswered or controversial. For example, how does family history of strokes, migraines, and endocrine, vascular or immune disorders impact the clinical manifestation of the individual affected by SWS? What pregnancy exposures or factors occur with increased frequency in individuals with SWS? Which patients would be best served by a hemispherectomy? What is the cognitive outcome after hemispherectomy versus medical management of seizures in SWS? Which patients should be treated with low-dose aspirin and what are the risks and side effects? How often does central hypothyroidism and growth hormone deficiency occur in patients with SWS? The answers to these and other questions will eventually be addressed with the aid of the consortium database.

Given the clinical variability inherent in SWS, another important goal is the development of safe, minimally invasive biomarkers and tools to monitor clinical status. Urine vascular biomarkers are a promising area of new investigation. Pioneered by Dr. Moses’ group, urine profiling of vascular biomarkers has previously been used successfully to profile different vascular disorders (infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation) and to separate progressive vascular lesions from stable lesions (Marler et al., 2005), thus providing proof-of-principle that this approach can be used to non-invasively differentiate vascular disorders, sub-group patients, and provide predictive information. A similar approach has proven successful using urine biomarkers to predict breast cancer risk (Pories et al., 2008). Published work with brain tumors also demonstrates that urinary biomarkers can be used to predict response to treatment (Smith et al., 2008). Hence, this method might also be a powerful means of rapid screening for potential vasculostatic drug effects in the context of a large, simple clinical trial.  This project will apply these biomarkers to predicting the neurologic course in SWS.

Etiology and pathogenesis of SWS. Sturge-Weber syndrome occurs almost entirely sporadically and with equal frequency in the sexes (Comi, 2003). The localized abnormalities of blood vessel development and function affecting the facial skin, eye and brain suggest a developmental disruption occurring in the first trimester of pregnancy. Since the abnormal blood vessels in SWS are usually localized to a single region on one side of the body, a somatic mutation (somatic mosaicism) model for the etiology of SWS has been proposed (Happle, 1987). During the first trimester of fetal development the primitive vascular plexus invades the adjacent developing brain, skin and eye in this region and a somatic mutation could prevent the normal maturation of these vessels. A report of typical bilateral Sturge-Weber syndrome in only one member of a pair of monozygotic twins reinforces the thought that any genetic basis for SWS is likely due to somatic, rather than germline mutation (Pedailles et al., 1993). We (Drs. Comi and Pevsner) have previously reported consistent differences in gene expression between affected and unaffected tissue from the same individual with SWS. Microarray and RT-PCR data revealed an increase in fibronectin expression in fibroblasts derived from the port-wine stains of subjects with Sturge-Weber syndrome compared to fibroblasts from the normal skin of the same subjects (Comi et al., 2003). Chromosomal abnormalities have also been noted in fibroblast cultures derived from affected regions (dilated leptomeningeal blood vessels in one case and port-wine derived skin tissue in the other) of two of four studied individuals with Sturge-Weber syndrome (Huq et al. 2002).  Research to better understand and treat SWS has been hindered by the lack of a firm understanding of the molecular pathogenesis of the syndrome. Identification of the causative somatic mutation(s) would determine the pathogenic pathways involved and provide clues to direct research into the prevention and treatment of SWS.


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