Sturge-Weber Syndrome Brain Involvement Research Articles

Retrospective Analysis of Presymptomatic Treatment In Sturge-Weber Syndrome.

Ninety percent of infants with Sturge-Weber syndrome (SWS) brain involvement have seizure onset before 2 years of age; this is associated with worse neurologic outcome. Presymptomatic treatment before seizure onset may delay seizure onset and improve outcome, as has been shown in other conditions with a high-risk of developing epilepsy such as tuberous sclerosis complex. Electroencephalogram (EEG) may be a biomarker to predict seizure onset. This retrospective clinical data analysis aims to assess impact of presymptomatic treatment in SWS. This two-centered, IRB-approved, retrospective study analyzed records from patients with SWS brain involvement. Clinical data recorded included demographics, age of seizure onset (if present), brain involvement extent (unilateral versus bilateral), port-wine birthmark (PWB) extent, family history of seizure, presymptomatic treatment if received, neuroscore, and anti-seizure medication. EEG reports prior to seizure onset were analyzed. Ninety-two patients were included (48 females), and 32 received presymptomatic treatment outside of a formal protocol (5 aspirin, 16 aspirin and levetiracetam; 9 aspirin and oxcarbazepine, 2 valproic acid). Presymptomatically-treated patients were more likely to be seizure-free at 2 years (15 of 32; 47% versus 7 of 60; 12%; p<.001). A greater percentage of presymptomatically-treated patients had bilateral brain involvement (38% treated versus 17% untreated; p=.026). Median hemiparesis neuroscore at 2 years was better in presymptomatically-treated patients. In EEG reports prior to seizure onset, the presence of slowing, epileptiform discharges, or EEG-identified seizures was associated with seizure onset by 2 (p=.001). Presymptomatic treatment is a promising approach to children diagnosed with SWS prior to seizure onset. Further study is needed, including prospective drug trials, long-term neuropsychological outcome, and prospective EEG analysis to assess this approach and determine biomarkers for presymptomatic treatment.

Sturge–Weber syndrome: Updates in pathogenesis, diagnosis, and treatment

AbstractObjectivesWe summarize the current knowledge of Sturge–Weber syndrome (SWS) including genetic involvement, difficulties in diagnosis, symptoms caused by the vascular malformations, treatments, and future areas of research.MethodsPubMed searches were completed between October and December of 2022 including the following search terms: Sturge–Weber neuroimaging, Sturge–Weber ocular involvement, Sturge–Weber G‐protein alpha q subunit (GNAQ), Sturge–Weber presymptomatic treatment, and Sturge–Weber quantitative EEG. Clinically relevant articles and case reports were reviewed and summarized, with emphasis placed on reports from the last 20 years.ResultsLiterature suggests that early identification of brain involvement is essential for optimal medical care. Infants with a port‐wine birthmark on the forehead, temple, or eyelids are at risk for SWS brain and eye involvement. Neuroimaging findings include leptomeningeal enhancements, cortical calcifications, and brain atrophy, and diagnosis requires magnetic resonance imaging with and without contrast. Before 1 year of age, neuroimaging has low sensitivity and may underestimate the extent of involvement; imaging after 1 year of age is needed to exclude brain involvement. The most common underlying cause for SWS is a somatic mosaic mutation in GNAQ. Neurological symptoms include seizures, stroke or stroke‐like episodes, headaches, and cognitive deficits. Recommended treatment for SWS brain involvement includes aggressive seizure control with antiepileptic medications; low‐dose aspirin is also frequently but not universally utilized. Current literature suggests that children with SWS may benefit from presymptomatic treatment; further study of this approach is ongoing.ConclusionsSWS is a rare neurovascular disorder usually signaled by a facial port‐wine birthmark. Early diagnosis and appropriate treatment may improve outcomes.

Cannabidiol Treatment for Neurological, Cognitive, and Psychiatric Symptoms in Sturge-Weber Syndrome

BackgroundA prior drug trial of cannabidiol for treatment-resistant epilepsy in patients with Sturge-Weber syndrome (SWS), a rare neurovascular condition, implicated improvements in neurological, quality of life (QOL), neuropsychologic, psychiatric, and motor outcomes. MethodsTen subjects with SWS brain involvement, controlled seizures, and cognitive impairments received study drug in this Johns Hopkins institutional review board-approved, open-label, prospective drug trial. Oral cannabidiol was taken for six months (dose ranged from 5 to 20 mg/kg/day). SWS neuroscore, port-wine birthmark score, QOL, and adverse events were recorded every four to 12 weeks. Neuropsychologic, psychiatric, and motor assessments were administered at baseline and six months’ follow-up. Most evaluations were conducted virtually due to the coronavirus disease 2019 pandemic. ResultsCannabidiol was generally well tolerated. Six subjects reported mild to moderate side effects related to study drug and continued on drug; one subject withdrew early due to moderate side effects. No seizures were reported. Significant improvements in SWS neuroscore, patient-reported QOL, anxiety and emotional regulation, and report of bimanual ability use were noted. Migraine QOL scores were high at baseline in these subjects, and remained high. Neuropsychologic and other QOL and motor outcomes remained stable, with some within-subject improvements noted. ConclusionsFurther studies are needed to determine whether Epidiolex can improve quality of life and be beneficial for neurological, anxiety, and motor impairments in SWS independent of seizure control. Large multicentered studies are needed to extend these preliminary findings.

Quantitative EEG improves prediction of Sturge-Weber syndrome in infants with port-wine birthmark

ObjectivePort-wine birthmark (PWB) is a common occurrence in the newborn, and general pediatricians, dermatologists, and ophthalmologists are often called on to make an assessment of risk for Sturge-Weber syndrome (SWS) due to workforce shortages in pediatric neurologists and MRI’s low sensitivity for SWS brain involvement in infants. We therefore aimed to develop a quantitative EEG (qEEG) approach to safely screen young infants with PWB for SWS risk and optimal timing of diagnostic MRI. MethodsForty-eight infants (prior to first birthday) underwent EEG recording. Signal processing methods compared voltage between left and right sides using a previously defined pipeline and diagnostic threshold. In this test sample, we compared sensitivity/specificity of the qEEG metric against MRI performed after the first birthday. We also used likelihood ratio testing to determine whether qEEG adds incremental information beyond topographical extent of PWB, another risk marker of brain involvement. ResultsqEEG helped predict SWS risk in the first year of life (p = 0.031), with a sensitivity of 50% and a specificity of 81%. It added about 40% incremental information beyond PWB extent alone (p = 0.042). ConclusionqEEG adds information to risk prediction in infants with facial PWB. SignificanceqEEG can be used to help determine whether to obtain an MRI in the first year of life. The data collected can assist in developing a predictive model risk calculator that incorporates both PWB extent and qEEG results, which can be validated and then employed in the community.

Sirolimus Treatment in Sturge-Weber Syndrome

BackgroundSturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome. MethodsTen patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit. ResultsSirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus. ConclusionsSirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.

Cognitive and motor outcomes in children with unilateral Sturge–Weber syndrome: Effect of age at seizure onset and side of brain involvement

PurposeMost children with Sturge–Weber syndrome (SWS) develop seizures that may contribute to neurocognitive status. In this study, we tested the hypothesis that very early seizure onset has a particularly detrimental effect on the cognitive and/or motor outcomes of children with unilateral SWS. We also tested whether side of SWS brain involvement modulates the effect of seizure variables on the pattern of cognitive abnormalities. MethodsThirty-four children (22 girls; mean age 6.1years) with unilateral SWS and history of epilepsy in a longitudinal cohort underwent neurological and cognitive evaluations. Global intelligent quotient (GIQ), verbal intelligent quotient (VIQ), nonverbal intelligent quotient (IQ), and motor function were correlated with epilepsy variables, side and extent of brain involvement on magnetic resonance imaging (MRI). ResultsMean age at seizure onset was 1.3years (0.1–6years) and mean IQ at follow-up was 86 (45–118). Age at seizure onset showed a logarithmic association with IQ, with maximum impact of seizures starting before age 1year, both in uni- and multivariate regression analyses. In the left SWS group (N=20), age at seizure onset was a strong predictor of nonverbal IQ (p=0.001); while early seizure onset in the right-hemispheric group had a more global effect on cognitive functions (p=0.02). High seizure frequency and long epilepsy duration also contributed to poor outcome IQ independently in multivariate correlations. Children with motor involvement started to have seizures at/before 7months of age, while frontal lobe involvement was the strongest predictor of motor deficit in a multivariate analysis (p=0.017). ConclusionThese findings suggest that seizure onset prior to age 1year has a profound effect on severity of cognitive and motor dysfunction in children with SWS; however, the effect of seizures on the type of cognitive deficit is influenced by laterality of brain involvement.

Size of Facial Port-Wine Birthmark May Predict Neurologic Outcome in Sturge-Weber Syndrome

To determine whether the size of the birthmark in patients with Sturge-Weber syndrome (SWS) who have brain involvement can help predict neurologic disability. Fifty-one patients with SWS with facial birthmarks and brain involvement documented on magnetic resonance imaging were included in this retrospective chart review. A neuroradiologist, blinded to all clinical information, assigned a previously validated SWS neuroimaging score. A pediatric neurologist prospectively assigned previously validated neurologic severity scores, based on seizures, hemiparesis, visual field cut, and cognitive impairments. Three raters, blinded to clinical scores, independently graded the size of facial birthmark in each patient based on photographs. Their scores were averaged. Birthmark scores were compared with the imaging and neurologic severity results using nonparametric correlation analysis. Size of facial port-wine birthmark correlates with magnetic resonance imaging scores on the left and right sides (ρ = 0.57 and 0.66 [P < .001], respectively). Size is also positively associated with the neurologic severity rating for patients age 6 years and above (1-sided Fisher exact, P = .032). The size of facial port-wine birthmark in SWS brain involvement can be developed as a tool to predict neurologic severity of the disease.

GNAQ Mutation in the Venous Vascular Malformation and Underlying Brain Tissue in Sturge-Weber Syndrome.

AbstractThe recent identification of the somatic GNAQ mutation (c.548G &gt; A) provides insight into the pathogenesis of Sturge–Weber syndrome (SWS). Although the primary SWS brain pathology is the leptomeningeal angiomatosis (LMA), cerebral cortical and white matter abnormalities play a prominent role in the disease manifestations. In some cases, SWS brain involvement is present even without detectable LMA on magnetic resonance imaging (MRI). To expand our understanding of the etiology of SWS brain pathology, surgical SWS brain specimens from nine children (age: 0.8–7.5 years) were carefully separated into LMA and (non-LMA) brain tissue; the latter did not contain any vascular malformation. A custom Competitive Allele-Specific TaqMan PCR (castPCR) assay to detect the mutation in GNAQ was performed in these separated specimens. The mutation was present in all nine LMA and seven of the nine non-LMA brain tissues. LMA tissues were significantly enriched by the mutation, as compared with non-LMA brain (mean: 7.2 ± 2.1% and 1.2 ± 0.4%, respectively; p = 0.008). These results demonstrate that the somatic GNAQ mutation in SWS is not confined to the venous vascular malformation but can directly (although less severely) affect underlying brain parenchyma, not directly affected by LMA, and possibly contribute to SWS brain pathology. Future studies should identify the specific cell type(s) affected by the mutation in the SWS-affected brain parenchyma.

Reliability and Clinical Correlation of Transcranial Doppler Ultrasound in Sturge-Weber Syndrome

BackgroundThe reproducibility of transcranial Doppler (TCD) ultrasound measurements in Sturge-Weber syndrome (SWS) and TCD's ability to predict neurological progression is unknown. MethodsIn 14 individuals with SWS, TCD measured mean flow velocity, pulsatility index, peak systolic velocity, and end-diastolic velocity in the middle, posterior, and anterior cerebral arteries of the affected and unaffected hemisphere. TCD was performed either once (n = 5) or twice in one day (n = 9). We assessed the reproducibility of the measurements performed twice on the same day on subjects and compared the TCD measurements to previously published age-matched controls. Clinically obtained neuroimaging was scored for extent and severity of SWS brain involvement. Patients were prospectively assigned SWS neuroscores. ResultsMiddle cerebral artery velocity (r = 0.79, P = 0.04, n = 7), posterior cerebral artery velocity (r = 0.90, P = 0.04, n = 5), and anterior cerebral artery pulsatility index (r = 0.82, P = 0.02, n = 7) were reproducible TCD measurements comparing same-day percent side-to-side differences. In subjects with SWS, affected and unaffected mean peak systolic velocity and end-diastolic velocity in the middle, posterior, and anterior cerebral arteries were globally lower compared with age-matched control subjects. Subjects with the lowest affected middle cerebral artery velocity had the greatest worsening in the total neurological score between time 1 and 2 (r = −0.73, P = 0.04, n = 8) and the most severe magnetic resonance imaging involvement of the affected frontal lobe (r = −0.82, P = 0.007, n = 9). ConclusionsTCD may be a reliable measure with potential clinical value, indicating that blood flow may be globally decreased in SWS patients with unilateral brain involvement.

Cannabidiol Treatment for Refractory Seizures in Sturge-Weber Syndrome

BackgroundSturge-Weber syndrome results in leptomeningeal vascular malformations, medically refractory epilepsy, stroke(s), and cognitive impairments. Cannabidiol, a cannabinoid without psychoactive properties, has been demonstrated in preclinical models to possibly have anticonvulsant, antioxidant, and neuroprotective actions. MethodsFive subjects with Sturge-Weber syndrome brain involvement and treatment-resistant epilepsy were enrolled. Motor seizure frequency, quality of life, and adverse events were recorded from the eighth week of the pretreatment period, eight weeks after starting maintenance dose (week 14), and the most recent visit. ResultsFour subjects had data through week 14, one of whom initially withdrew for lack of efficacy but because of other benefits re-enrolled with a lower dose. Two subjects at week 14 and three subjects with bilateral brain involvement had at the last visit a greater than 50% seizure reduction, reported an improved quality of life, and remained on cannabidiol 63-80 weeks after starting the drug. Three subjects reported mild side effects considered related to cannabidiol. ConclusionThis study suggests that cannabidiol may be well tolerated as adjunctive medication for seizure management and provides initial data supporting further study of cannabidiol in individuals with Sturge-Weber syndrome.

Anticonvulsant Efficacy in Sturge-Weber Syndrome

ObjectiveWe analyzed individuals with epilepsy due to Sturge-Weber syndrome to determine which anticonvulsants provided optimal seizure control and which resulted in the fewest side effects. MethodsOne-hundred-eight records from a single center were retrospectively analyzed for Sturge-Weber syndrome brain involvement, epilepsy, Sturge-Weber syndrome neuroscores, and currently used anticonvulsants. ResultsOf the fourteen anticonvulsants that had been employed, the most often used agents were oxcarbazepine or carbamazepine, and levetiracetam. Individuals whose seizures at the most recent visit were fully controlled (seizure-free) for 6 months or longer were more likely to have ever tried, or currently used, oxcarbazepine or carbamazepine than those with uncontrolled seizures. Thirty-nine of 69 individuals (56.5%) were seizure-free with oxcarbazepine or carbamazepine history versus 11 of 35 individuals (31.4%) who had not taken these agents (P < 0.05); 38 of 62 patients (61.3%) were seizure-free while currently taking these anticonvulsants versus 12 of 42 (28.6%) not taking them (P < 0.01). Patients with seizure control for 6 months or longer were less likely to have ever tried, or to currently be taking, levetiracetam than those without control. Sixteen of 56 individuals (28.6%) were seizure-free with levetiracetam history versus 34 of 48 (70.8%) without it (P < 0.001); 14 of 43 individuals (32.6%) were seizure-free and currently taking levetiracetam versus 36 of 61 (59.0%) not taking it (P < 0.01). When topiramate was added as second-line medication, five of nine patients (55.6%) experienced decreased seizure severity, and worsening of glaucoma was not reported. ConclusionsCarbamazepine and oxcarbazepine were associated with better seizure control than levetiracetam in this Sturge-Weber syndrome cohort and so may be preferred as the initial therapy. When used as adjunctive therapy, topiramate was effective in this limited analysis without a clear increased incidence of glaucoma.

Use of quantitative EEG in infants with port-wine birthmark to assess for Sturge–Weber brain involvement

Many infants born with a facial port-wine (PW) birthmark will not develop brain involvement of Sturge-Weber syndrome (SWS). Previous studies have shown asymmetry in quantitative EEG (qEEG) correlates with degree of clinical impairment in children and adults with known SWS. We hope to determine if quantitative qEEG can be used as a method to predict which infants are most likely to develop SWS brain involvement on MRI. The current study looks at the ability of qEEG to differentiate between infants with radiographically demonstrated SWS and those without. We first performed an observational study of qEEG results on eight infants with facial PW birthmark (four had SWS brain involvement). We recorded standard clinical EEGs and then derived a measure of asymmetry. We subsequently validated this threshold through a study of an additional nine infants with PW birthmark (five with SWS brain involvement). Quantitative EEG correctly identified infants with SWS brain involvement in all cases in the Validation cohort. This technique was at least as good as a pediatric electroencephalographer with extensive experience reading SWS EEGs. This study demonstrates the ability for qEEG to discriminate between those infants with SWS brain involvement and those with neurologically asymptomatic PW birthmark. This study represents an important step toward the development of a qEEG technique able to predict which infants with PW birthmark will develop SWS brain involvement.