Sturge-Weber syndrome (SWS) is a sporadic neurocutaneous disorder characterized by a facial port-wine port-wine stain (PWS) and leptomeningeal angioma (LMA). SWS most often (85%) affects one hemisphere and has a progressive but variable clinical course, thus providing a unique clinical model to study the neurocognitive effects of an early, unilateral progressive brain lesion. 70-75% of children with unilateral SWS will develop seizures and neurological symptoms (motor deficit and visual field impairment). Currently, SWS has no cure or specific treatment. With NIH support and nationwide patient recruitment, we have built a clinical research program for children with SWS, in order to understand disease pathophysiology and find new treatment paradigms. In the first funding cycle, we have described the natural disease course and identified a critical age window (<4 years) when progressive brain damage most likely occurs. In the second funding cycle, we have identified two mechanisms, related to epileptogenesis and angiogenesis, as two potential drivers of early disease progression. In this resubmission renewal proposal we focus on developing novel treatment paradigms by targeting these mechanisms to alter early disease course.
In Aim 1, we will study young children with SWS, before onset of epilepsy, and will test glutamate (GLU, a major excitatory amino acid in the brain) MR spectroscopy and Diffusion Tensor Imaging for assessing risk for severe epilepsy, poor cognitive and motor functions and brain damage. The data will lead to a preventive antiepileptic drug trial and early motor intervention guided by advanced MRI.
In Aim 2, we will study the feasibility of a drug trial targeting abnormal angiogenesis detected in the LMA resected from children undergoing epilepsy surgery. The main goal is to study LMA and deep collateral vessels both by MR imaging and in resected brain tissues to compare their proliferative activity and angiogenetic potential. We will also localize the recently discovered activation somatic mutation in the GNAQ gene to the LMA. These data will provide critical information on the risk of potential adverse effects of antiangiogenic agents (such as propranolol, which has led to a recent paradigm shift in the treatment of infantile hemangiomas) before a clinical trial is designed. Finally, in Aim 3, we will use our prospectively collected clinical and imaging data in previously enrolled SWS children, demonstrating a non- linear (U-shaped) relation between the extent of unilateral brain damage (measured by glucose metabolism PET imaging) and cognitive functions (IQ). This suggested effective contralateral functional reorganization in those with extensive (>60% of the affected hemisphere) unilateral cortical damage. We will retest previously enrolled children with SWS, who continued antiepileptic drug treatment or underwent subsequent surgical resection (due to intractable seizures), and assess their long-term neurocognitive outcome to determine how surgical treatment altered long-term neurocognitive trajectory. These data will provide a much-needed guidance for future clinical decision-making in surgical patient selection using imaging and clinical variables to predict who will benefit most from surgery in terms of expected long-term cognitive outcome.
In this project we aim at developing new treatment paradigms to fundamentally alter neurocognitive outcome of children with Sturge-Weber syndrome (SWS), an often-progressive neurocutaneous disease with no cure or specific treatment currently. In this renewal resubmission application we will build upon results from the current funding period and collect data for a preventive antiepileptic treatment for SWS children who are at risk for severe epilepsy, guided by advanced magnetic resonance imaging. We will also study feasibility of a new treatment approach to block abnormal vessel proliferation in the affected intracranial vessels, while building upon surgical tissue data and the recent discovery of a somatic activating gene mutation in SWS. Finally, we will determine how surgical brain resection (currently applied in SWS children with intractable seizures) can alter long-term disease trajectory and improves neurocognitive outcome.
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