Sturge-Weber Syndrome (SWS) - Leptomeningeal Angiomatosis
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. 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 1,000 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. Choroidal thickness can now be monitored in SWS patients with the use of spectral-domain optical coherence tomography in order to discover abnormalities that were previously undetectable (Arora et al., 2013). Glaucoma is the most frequent ophthalmologic complication, affecting 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).
Clinical studies have shown that the vascular malformation of the skin and eye progress at variable rates, with increased dilation and tortuosity of the vessels over time. However, many questions remain regarding the relationship between the port-wine birthmark, the eye involvement, and the neurologic involvement of SWS. The vascular malformation of the brain in SWS consists of enlarged and tortuous, leptomeningeal, vessels, and dilated deep venous vessels. Impaired venous draining from the involved brain regions results in reduced arterial perfusion to these regions (Lin, Barker, Kraut, & Comi, 2003). Susceptibility-weighted imaging and post-contrast T1-weighted MRI scans in children with SWS have demonstrated that some individuals will develop deep draining vessels and venous angiomas over time.
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 vascular malformations 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. A new project within the BVMC will be investigating the extent to which 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). Infants presenting with seizures onset at 6 months of age or younger have been found to have greater hemiparesis than those presenting at older ages, and are more likely to have clusters of seizures followed by prolonged seizure-free periods (Kossoff et al., 2009). Whatever the age of seizure onset time, EEGs have been found to progress in most patients from relatively normal to abnormal, involving more epileptiform activity over time (Kossoff et al., 2014), so it is possible that younger onset is related to further progression at a younger age. These studies suggested, however, that neither early onset, nor clustering (Kossoff et al., 2009), nor more advanced EEG progression (Kossoff et al., 2014) were related to an increase in seizure frequency. At older ages, some patients with SWS begin to present with psychiatric and behavioral issues, including learning and attention issues, problems with sleep and mood, as well as substance abuse (Turin et al., 2010). 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.
Some important clinical questions about SWS have been addressed only with case series and limited cohorts due to the rarity of the disease, and so controversies and further questions remain. There is data that suggests low-dose aspirin can control seizures and decrease stroke-like episodes; leading to stabilization or even improvement in clinical outcomes with relatively few side effects. However, clinicians are still conflicted about aspirin’s use and more research is needed (Lance et al., 2013). A higher prevalence of central hypothyroidism has been noted in SWS patients than in the general population, but the small number of subjects available for this single-center study prevents a more precise accounting of overall prevalence in SWS at this time (Comi et al., 2008). Many questions remain completely unanswered. For example, how does a family history of stroke, migraine, endocrine, vascular, or immune disorders impact the clinical manifestations 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? The answers to these and other questions will eventually be addressed with the aid of the consortium database, which allows for the creation of larger cohorts.
One study has explored the use of stimulants in the treatment of attentional difficulties in Sturge-Weber syndrome (Lance, Lanier, Zabel, & Comi, 2014). All 12 of the study patients had SWS brain involvement and suffered from seizures. Most of the SWS patients had comorbid diagnoses, such as, epilepsy (n=12), hemiparesis (n=8), vision deficits (n=6), and headaches (n=8). Eight out of twelve patients reported appetite suppression and/or headaches as side effects. The majority reported benefits and seven patients remained on the stimulant medication at the time of the retrospective review.
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). More recently, Dr. Moses's and Dr. Comi's groups examined urinary biomarkers in individuals with and without SWS. They found that the matrix metalloproteinases MMP-2 and MMP-9 are present much more often in the urine of those with SWS than in those without it, and higher levels of these biomarkers have been correlated with poorer clinical status at the time of biomarker measurement. (Sreenivasan et al., 2013). Research into the potential of these biomarkers to predict and measure long-term outcomes is part of ongoing research through the BVMC.
Etiology and pathogenesis of SWS:
SWS 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. Recently, whole Genome Sequencing of DNA samples from affected and unaffected skin or brain samples of individuals with SWS have been carried out. From these analyses, and subsequent studies, it was determined that SWS is caused by an activating somatic mutation in GNAQ, which likely occurs early in fetal development (Shirley et al., 2013).
The somatic mutation in GNAQ is hyper-activating and impacts the function of GPCRs known to be critical to angiogenesis, vascular function, and vascular remodeling. Gαq (encoded by the GNAQ gene) is a G protein subunit that modulates a wide spectrum of downstream signaling pathways, depending on the biochemical and cellular context (Kimple, Bosch, Giguere, & Siderovski, 2011). In a recent study, the phosphorylation status of several downstream effectors of Gαq after transfection of the R183Q mutation and controls were accessed (Shirley et al., 2013). The R183Q mutants demonstrated moderate constitutive hyper-phosphorylation of ERK and a trend for a similar increase in phosphorylation of JNK. Gαq is associated with GPCRs such as endothelin 1, angiotensin, and serotonin that can all impact vascular development, remodeling, and function (Kimple, Bosch, Giguere, & Siderovski, 2011). The discovery of the precise somatic mosaic mutation causing SWS has catapulted research to investigate the downstream protein signaling pathways involved in the molecular etiology of SWS.
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