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

Abstract

Objectives

We 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.

Methods

PubMed 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.

Results

Literature 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.

Conclusions

SWS is a rare neurovascular disorder usually signaled by a facial port‐wine birthmark. Early diagnosis and appropriate treatment may improve outcomes.

Introduction

Sturge–Weber syndrome (SWS) is a rare vascular malformation disorder that affects the skin, brain, and eyes at an estimated prevalence rate of about 1 in 20 000 to 1 in 50 000 live births. ¹ More recent reports have estimated as little as 0.19/100 000/year in a community in Minnesota ² and as much as 3.08/100 000/year in a population study in Korea. ³ SWS is caused by a somatic mosaic mutation during early fetal development and is typically associated with a facial port‐wine birthmark (PWB), leptomeningeal vascular malformation, and glaucoma. The venous‐capillary malformations typical of SWS brain involvement results in ischemic changes, calcification, and brain atrophy that varies in severity. Along with these structural abnormalities in the brain, individuals with SWS often present with seizures and stroke or stroke‐like episodes, usually beginning in infancy. These neurologic and ischemic episodes can cause motor, cognitive, behavioral, and learning or attention deficits.

Manifestations of SWS

Birthmark and symptoms

Skin involvement in SWS presents at birth as a pink or red, flat PWB on the midline forehead or on the upper face, either unilaterally or bilaterally (Figure 1). The location and extent of the cutaneous manifestation may predict brain involvement and severity of symptoms, ⁴ , ⁵ , ⁶ and the size of the PWB correlates positively with the extent of SWS brain involvement seen on magnetic resonance imaging (MRI). ⁴ This study in patients with SWS suggests the relationship between PWB location or extent and severity of neurological symptoms is limited by a small cohort size, and further studies are needed. The capillary malformation in SWS is also often associated with gradual hypertrophy of the underlying soft and bony tissue, leading to facial distortion involving the lip, jaw, and skull over the years. ⁷ , ⁸ PWB can involve other regions of the body ⁹ and can develop nodularity and superficial blebbing over time. ¹⁰ PWB in the head and neck can cause vision, breathing, and swallowing issues if left untreated. ¹¹

Figure 1.

Typical port‐wine birthmark in high‐risk area. (A) Image of facial port‐wine birthmark in the high‐risk area (forehead and eyelids) in infant with Sturge–Weber syndrome with brain and eye involvement. (B) Lateral view of facial port‐wine birthmark involvement in the temple area.

Glaucoma symptoms

Glaucoma develops in 25%–75% of patients with a facial PWB in the high‐risk area. ¹² , ¹³ , ¹⁴ , ¹⁵ The risk of glaucoma is highest when both eyelids are involved. ¹⁴ These issues result in increased eye pressure and risk injury to the optic nerve. Ophthalmic status in SWS requires close monitoring in infancy, as congenital glaucoma can cause buphthalmos (enlargement of the eye socket or cornea), vision loss, and, in extreme situations, loss of an eye. The conjunctiva of the eye can be affected by enlarged venous vessels producing a pinkish discoloration resulting from the hypervascularity. ¹⁶ Other symptoms of eye involvement can include increased tearing, eye pain, and change in the color of the iris. SWS eye involvement is particularly common in patients with a PWB that involves both the upper and the lower eyelids and can occur without SWS brain involvement. ¹⁴ While there is a high risk of glaucoma in infancy to early childhood, glaucoma in SWS can present or progress later in life, making close monitoring of ocular pressure and vision necessary through life. ¹⁷

Neurological symptoms

With the highest risk of SWS brain involvement associated with facial PWB on the forehead, upper eyelid, and temple area, ⁶ , ¹⁸ , ¹⁹ , ²⁰ at‐risk infants can be identified at birth. These infants must be evaluated and followed by appropriate specialists, at least until brain involvement can be excluded. About 10% of patients with SWS brain involvement present without a PWB; ²¹ , ²² these patients present with partial seizures and are diagnosed on contrast‐enhanced MRI of the brain. Some differences are reported in long‐term outcomes between patients with and without PWB. In a study of 140 patients by Powell et al., ²³ SWS associated with a PWB had higher likelihood of language disorders and intellectual disability. Patients without a PWB had fewer lobes affected by leptomeningeal angioma and were less likely to have bilateral involvement.

In SWS patients, seizures frequently present before 1 year of age, with earlier onset being associated with worse long‐term outcomes ¹⁴ , ²⁴ , ²⁵ and a family history of seizure making early onset seizures more likely. ⁵ These seizures are attributed to the structural brain abnormalities, including abnormal leptomeningeal blood vessels and flow, cortical calcification, and brain atrophy, as well as focal cortical dysplasia in surgical tissue samples. ²⁶ , ²⁷ , ²⁸ Severity of brain calcification positively correlates with seizure severity. ²⁹ Furthermore, the worsening of brain atrophy and calcification can cause an increase in seizure activity that can decrease blood flow in the cortex, thereby resulting in the progression of brain injury seen in many patients with SWS.

Prolonged seizure activity decreases adequate venous drainage and can result in a stroke‐like episode with transient neurological deficits, such as hemiparesis, visual field deficits, and speech impairment. ³⁰ , ³¹ , ³² These stroke‐like episodes have also been associated with minor head injuries, so families must be cautioned regarding the risk of head trauma in sports and other activities. ³¹ , ³³ The weakness and loss of function on one or both sides of the body associated with stroke‐like episodes may take days to months for a full recovery and can cause permanent hemiparesis. ³¹ Transient episodes of weakness and deficits without apparent seizure activity may be referred to as stroke like‐episodes. Deficits less than 24 hours that occur after seizures can be referred to as a Todd's paralysis when associated with seizure activity. More prolonged events, with or without seizures, can be referred to as prolonged stroke‐like episodes. When complete recovery does not happen, it can be referred to as a venous stroke, although evidence of venous infarction is often not detected on neuroimaging.

Over the lifetime of a patient with SWS, the neurological manifestations can progress in several phases (Figure 2) that vary over time. In the developmental phase, the somatic mutation occurs during fetal development. Typically, no concerns are suspected before birth and the PWB is noted at birth. During the neonatal period and early infancy, seizures or other neurological symptoms of SWS are unusual; this period is referred to as the presymptomatic phase. While the length of the presymptomatic phase can vary, symptoms of brain involvement typically manifest by 2 years of age. ¹⁴ Once seizures and symptoms occur, patients enter the symptomatic progressive phase, which is highly variable. In the early symptomatic phase, increased seizure activity further impairs cortical blood flow. Because the progressive phase usually coincides with substantial growth, it is important to adjust medication dosing to adjust for weight gain. By about age 5 years, neurological symptoms generally become more stable. While loss of seizure control may arise during puberty and breakthrough seizures can occur at any time, this phase is typically more stable than the symptomatic progressive stage. However, this timeline is variable and some patients with SWS may show stabilization with prolonged seizure control and development of deep draining vessels. Positive cognitive improvements have also been seen with prolonged seizure freedom, and a relationship with functional reorganization has been proposed. ²⁵ The last stage of SWS progression, the late progressive phase, occurs in a subset of patients who may present with seizure onset or stroke; further study of this stage is needed. ³⁴ , ³⁵ , ³⁶ , ³⁷ Further study of pregnancy in women with SWS is also needed, but minimum maintenance dosages of antiepileptics have been suggested ³⁸ throughout pregnancy. There have been several case reports of women with pregnancy complications, including recurrent seizures, hemiparesis, and headaches; ³⁹ , ⁴⁰ , ⁴¹ however, a recent review suggests that most pregnancies result in healthy children. ⁴¹

Figure 2.

Sturge–Weber syndrome progression over lifetime.

Headaches, with and without migraine complications, are also a common neurological finding in patients with SWS. Headache in SWS has been reported in the majority of SWS patients older than 6 years of age, with a prevalence of 39.4% overall. Headache in SWS can present at a younger age, with a median onset of 8 years of age. ⁵ A total of 49% of patients with SWS brain involvement and headaches reported that headaches presented a larger problem than seizures. ⁴² A family history of migraines is associated with headaches and migraines in patients with SWS, with 40.3% reporting headaches without a family history versus 68.6% in those with a family history of migraines. ⁵ Sleep problems are often reported in children with SWS, and recent literature suggests that 47% ⁴³ , ⁴⁴ of patients have difficulty with the early stages of sleep.

Hormone deficiencies are more likely to occur in patients with SWS ⁴⁵ , ⁴⁶ than in the general population; the precise mechanism is unknown. Vascular malformations may dysregulate the hypothalamus and pituitary gland, resulting in impaired hormone secretions. ⁴⁵ , ⁴⁶ Growth hormone deficiency presents with impaired growth in children with SWS, and central hypothyroidism presents with poor growth or with excessive sleepiness or weight gain. ⁴⁵ , ⁴⁶ Thyroxine levels during early childhood are especially important to monitor, as thyroxine is crucial for early neurocognitive development. ⁴⁷ Partial hypopituitarism has also been reported, and hormone levels should be checked when any of these symptoms are present, when cognitive impairment is worse than expected, and when pubertal issues are noted. ⁴⁸ , ⁴⁹

Functional Impairments in SWS

The neurological symptoms seen in patients with SWS include a wide array of functional impairments, including motor, cognitive, and behavioral deficits. The associated cognitive deficits commonly involve a range of language and visual‐spatial impairments, learning and attention problems, and reading or math disabilities; about 30%–50% are ultimately diagnosed with intellectual disability. ²³ , ⁵⁰ Language impairments occur more frequently when there is an earlier age of seizure onset and a higher frequency of seizure. ¹⁴ , ²³ Intellectual disability is more prevalent in patients with early onset and greater severity of seizures. ²³ , ²⁴ , ⁵⁰ , ⁵¹ These findings emphasize the importance of aggressive seizure control early on to mitigate the long‐term cognitive effects that poorly managed seizures can cause. ⁵² Location of neurological involvement and seizure activity correlates with intellectual disability, learning disabilities, and motor outcomes. ⁵ , ²⁵ SWS patients with frontal lobe involvement showed lower global IQ and verbal IQ scores than those without frontal lobe involvement. ²⁵

SWS has also been associated with autism spectrum disorder (ASD). ⁵³ In a recent study of 124 patients with SWS, 32% had a clinical diagnosis of autism. Additionally, 43% of individuals who were not diagnosed with autism had impaired social and communication skills ⁵³ ; the prevalence and association of autism in SWS requires confirmation. Generally, there has been discussion on the relationship between epilepsy, autism, and the development of social communication skills ⁵⁴ , ⁵⁵ ; prevalence of ASD in childhood epilepsy is higher in those children with intellectual disability. When all three occur together, ASD tends to be diagnosed at an older age, possibly due to symptoms being attributed to neuropathological comorbidities. In SWS, ASD was also diagnosed later (mean age of diagnosis 8 years 11 months). ⁵³ , ⁵⁶ Several studies have also reported that attention issues are frequently present in SWS patients, with attention‐deficient/hyperactivity disorder (ADHD) reported in up to 42% of SWS patients. ⁴³ , ⁵⁷ , ⁵⁸ As with epilepsy and ASD, there is a higher prevalence of ADHD in individuals with epilepsy. ⁵⁹

People with SWS may be at a higher risk of psychiatric symptoms such as mood disorder. One study suggested that anxiety symptoms are especially prevalent in younger patients. ⁴³ These anxiety and mood disorders may manifest as tantrums, sleep issues, school‐ or work‐related issues, or mood swings. People with SWS may also be at a higher risk of suicidal ideation compared with individuals with other neurological disorders, so it is important to screen patients regularly for suicidal ideation. ⁶⁰

Diagnosis of SWS

Newborns at risk of SWS have a facial PWB in one or more of the following skin regions: eyelids, temple, and forehead. The risk of SWS brain involvement is about 25% when PWB is located on the upper face. ⁶¹ It was previously thought that SWS brain involvement was associated with abnormal development of the first branch of the trigeminal nerve (V1). However, distribution in this upper face region is now known to be related to the development of embryonic placodes. ¹⁹

Diagnostic evidence of SWS brain involvement with neuroimaging includes the presence of leptomeningeal enhancement on contrast‐enhanced MRI of the brain. This is best seen on T1 postcontrast spin‐echo (Figure 3, Panel B) and T2 postcontrast flair sequences. ⁶² , ⁶³ Other abnormalities seen on neuroimaging include atrophy of the involved brain regions, increased deep draining vessels, cortical or subcortical calcification, and an enlarged choroid plexus; these secondary findings, however, are not diagnostic of SWS brain involvement and may be seen in other conditions. Very early in the first month or two of life, a feed and wrap nonsedated MRI can be done (usually without contrast) to screen for brain atrophy, choroid size, or signal changes; if concerning then MRI must be repeated with sedation and contrast to establish diagnosis. However, 75% of children with SWS brain involvement were missed on early neuroimaging. ⁶⁴ Therefore, early negative imaging does not exclude brain involvement and must be repeated after a year of age. We recommend doing a history, exam, and electroencephalogram (EEG). If any of these are concerning, we recommend proceeding with early neuroimaging. ⁶⁵ Early imaging with head computed tomography (CT) or MRI in the first months of life have low sensitivity for leptomeningeal enhancement and may result in false negative findings ⁶⁴ ; however, MRI of the brain with contrast after 1 year of age can exclude SWS brain involvement. ⁶⁶ Because SWS is a spectrum disorder, severity of brain involvement can vary. Recent studies have suggested that noncontrast brain MRI imaging can be used to screen for indirect signs of SWS, including choroid plexus enlargement, cerebral atrophy, and signal changes on apparent diffusion coefficient maps (Figure 3, Panel C), T1 sequences, or T2 sequences. ⁶³ , ⁶⁴ , ⁶⁷ , ⁶⁸ , ⁶⁹ These studies are limited by a small sample size, and caution is needed when implementing this screening approach; asymptomatic infants who do not have SWS brain involvement should not be started on seizure medications, low‐dose aspirin, or other medications. Arterial spin‐labeling perfusion imaging (ASL perfusion imaging) has also been used recently to visualize hypoperfusion in patients with SWS; ⁷⁰ however, further studies are needed to determine the efficacy of ASL perfusion imaging for diagnosis of SWS brain involvement.

Figure 3.

Neuroimaging in patient with Sturge–Weber syndrome. (A) Head CT showing calcification in the frontal lobe of the right hemisphere (asterisk). (B) Axial T1 MRI of the brain showing diffuse leptomeningeal enhancement over the right hemisphere (asterisk). (C) ADC MRI imaging of the brain with the decreased signal of affected tissue in frontal and parietal lobes, associated with calcification and decreased perfusion (asterisk). (D) SWI imaging of the brain showing calcification and increased deep draining vessels in the right hemisphere (asterisk). ADC, apparent diffusion coefficient; CT, computed tomography; MRI, magnetic resonance imaging; SWI, susceptibility‐weighted imaging.

EEG is also used for diagnosing or monitoring seizure activity in SWS. ⁷¹ , ⁷² Subclinical or subtle seizure activity can be diagnosed by overnight EEG and the seizures treated appropriately. Interictal EEG typically shows decreased amplitude and frequency in involved and dysfunctional brain regions. ⁷³ When the patient is doing well, however, with controlled seizures and near‐normal neurologic function, the clinical EEG is often normal; alternatively children with a plateau or decline in speech and development can have ictal, epileptiform, slowing, or other evidence of brain dysfunction on EEG.

To combat this diagnostic challenge, researchers developed a quantitative EEG (qEEG) biomarker to screen for patients who likely have SWS with brain involvement. ⁷⁴ Subsequent analysis in a larger group of infants indicated that this asymmetry of power analysis adds 40% more diagnostic information (above the information provided by the size and location of the PWB) to predict the risk of SWS brain involvement in infants. ⁷⁵ Use of presymptomatic EEG to screen for SWS brain involvement can aid early diagnosis. ⁷⁵ EEG may also help predict age of seizure onset; this is currently being studied. qEEG as an indirect measure of SWS brain involvement correlates with the extent of unilateral SWS brain involvement and severity of brain atrophy by MRI. ⁷⁶ This screening method also provides an objective measure of EEG asymmetry that was more strongly correlated with clinical severity and MRI asymmetry than a qualitative EEG reading. ⁷⁴ , ⁷⁵ , ⁷⁶ In the future, qEEG could prove beneficial where pediatric epileptologists are unavailable to read clinical EEGs in these infants. qEEG screening, along with neurologic history and exam, may allow some infants to avoid repeated unnecessary MRIs, with risks of exposure to repeated sedation and gadolinium contrast dye, and may enable clinicians to target infants who would benefit most for early imaging. Further study of qEEG as a biomarker for monitoring treatment response is needed.

Role of Neuroimaging in Clinical Care and Monitoring

Routine annual contrast‐enhanced MRI scanning is not recommended in children with SWS brain involvement due to risks of repeat exposure to sedation and contrast. Moreover, neuroimaging is likely to be stable especially in children who are doing well. MRI during the acute postictal stage or during a stroke‐like episode may identify transient perfusion abnormalities. Diffusion abnormalities can also be identified beyond involved cortical areas in the normal appearing white matter of patients with SWS. ⁷⁷ , ⁷⁸ Repeat imaging in these cases may be necessary to delineate transient vascular changes from the full extent of SWS involvement. ⁶⁶ , ⁷⁹ Routine imaging after full extent of brain involvement has been established (after 1 year of age) is not recommended, since the findings do not usually change in stable children and do not change treatment recommendations.

On first presentation with seizures, calcification on head CT (Figure 3, Panel A) can be misdiagnosed as cerebral hemorrhage; brain atrophy rather than edema of the involved brain regions, along with the PWB when present, points to the correct diagnosis. Repeated head CT to evaluate episodes of seizures and neurologic deficits should be avoided. Subdural hemorrhage in patients with SWS is very rare, and repetition of head CT carries the risk of excessive brain radiation. ⁸⁰ Instead, a rapid MRI of the brain can be done during a crisis. Increased calcification is associated with, and likely a consequence of, impaired perfusion in the affected area. Brain calcification is correlated with more severe seizure scores, longer seizure duration, earlier seizure onset, and more severe neurological symptoms. ²⁹ These cortical calcifications may be more progressive and involve a larger area of the brain in patients with an early onset epilepsy. ⁸¹ Calcified brain regions have decreased metabolic functionality, are associated with brain dysfunction, and may be a neuroimaging biomarker for the development of neurocognitive impairments. ⁸¹

MRI with susceptibility‐weighted imaging (Figure 3, Panel D) can demonstrate deep draining vessels that form as collaterals, which likely improve blood drainage from the involved cortex. ⁷⁷ , ⁸² Typically, the healthy cortex is drained by surface capillary/venous vessels. In SWS, however, there is impaired cortical venous blood drainage with abnormal, tortuous vessels on the brain surface. Abnormal leptomeningeal vessels impair drainage, thereby increasing venous pressure and diverting blood into subcortical deep draining vessels. The development of these collaterals, and the enlargement and/or increase of these deep vessels, may stabilize blood flow, seizures, and cognitive deficits. ⁸³ , ⁸⁴ While more research in this area is necessary, this postnatal compensatory mechanism to increase drainage vessels likely requires time to happen. Therefore, it may be important to delay the onset of seizures and stroke‐like episodes to allow time for these deep draining veins to develop. Further research to understand how enlarged deep draining vessels develop is needed; current understanding suggests that early onset of severe seizures and brain injury results in severe brain atrophy, while later seizure onset facilitates the development of deep draining vessels and less brain atrophy.

MRI‐ictal single‐photon emission computed tomographic (SPECT) imaging can be used to visualize the extent of SWS brain involvement and assess the impact of seizures on cerebral blood flow. Ictal hypoperfusion, or hyperperfusion of the affected region combined with hypoperfusion of surrounding areas, is seen on SPECT imaging, likely due to the venous abnormalities seen in SWS. ⁸⁵ , ⁸⁶ These studies indicate that prolonged seizures further impair cerebral blood flow to involved and other brain regions, a key observation that differentiates SWS from other causes of pediatric epilepsy. Prolonged seizure activity further impairs blood flow to the brain and can result in a stroke‐like episode, which can be associated with transient or permanent neurologic deficits likely due to the hypoperfused tissue in the brain. ³⁰ , ³¹ These observations serve as the current basis of conventional treatment, aggressive seizure management. ⁵²

Hyperperfusion is seen in infants before 1 year of age, but subsequently, the brain regions become hypoperfused in response to seizure activity and impaired cerebral blood flow. ⁸⁵ , ⁸⁷ , ⁸⁸ Hypoperfusion of brain regions is associated with more frequent seizure activity and longer seizure duration, as well as brain atrophy, emphasizing the connection between high seizure burden, impaired blood flow, and increased brain injury. ⁸⁹ Fluoro‐deoxy‐d‐glucose positron emission tomography (PET) is another tool used to visualize the extent of SWS brain involvement by measuring cortical glucose metabolism ⁹⁰ and can identify more extensive cortical dysfunction beyond the structures affected by leptomeningeal enhancements. ⁷⁷ , ⁹⁰ In one study of 14 patients, individuals with mild to severe hemiparesis showed extensive hypometabolism on PET scans, ⁹¹ highlighting the clinical characteristics associated with cortical metabolic abnormalities. Worsening of ischemic brain injury results from the coupling of hypoperfusion and excessive metabolic demand that is required during prolonged seizures. ⁸⁵ These studies can be important in making presurgical decisions as they indicate the central epileptogenic zone, ⁹² as well as regions of hypoperfusion and hypometabolism of the affected brain regions. ⁹³ , ⁹⁴ These abnormalities in cerebral blood flow and metabolism can be markers of seizure severity and cognitive impairments as the disorder progresses. ⁸⁹

Genetic Involvement in SWS

Both SWS and isolated PWB are caused by a somatic activating mutation of the G‐protein alpha q subunit (GNAQ) gene. Most SWS‐associated mutations occur postfertilization and account for the sporadic nature of SWS and PWB. This somatic mutation can be identified in the affected skin and brain tissues but is not appreciated in adjacent, unaffected tissues. It has been hypothesized that a germline mutation would be embryonic lethal, and that the timing of the SWS mutation during embryonic vascular development may lead to differences in phenotype, with earlier mutations being associated with syndromic SWS. ¹⁹ , ⁹⁵

About 90% of patients with SWS brain involvement have a somatic mosaic R183Q GNAQ subunit, with an amino acid substitution of Arg183Gln. ⁹⁵ , ⁹⁶ Less frequently, other mutations affecting GNAQ, GNB2, ⁹⁷ and GNA11 (a paralogue of GNAQ) have also been associated with SWS. ⁹⁸ , ⁹⁹ A difference in phenotype has been suggested between the R183Q GNAQ mutation and the R183Q GNA11 mutation (paralogue of GNAQ). The former typically presents as a pink/red confluent capillary malformation while the latter usually presents as a reticulated capillary malformation. These recently reported differences may be related to the direct vascular effects of these mutations. GNA11 mutations also may be associated with milder neurological symptoms related to SWS brain involvement. ¹⁰⁰ Early onset hypertension was recently identified in patients with either R183Q GNAQ or GNA11 variants, with 17% of 29 patients having a median diagnosis age of 15 years. All five patients with R183Q GNAQ/GNA11 and early onset hypertension (three of those five were diagnosed with SWS brain involvement; one with R183Q GNAQ and two with GNA11) had capillary malformations that involved the trunk and at least one extremity. ¹⁰¹ More genotype–phenotype studies are necessary to identify differences between the variants.

The venous‐capillary malformations that are associated with SWS caused by R183Q GNAQ affect the function of endothelial cells and likely increase activation of downstream targets. ¹⁰² , ¹⁰³ , ¹⁰⁴ Putative hyperactive downstream pathways are shown in Figure 4, including the RAS/MEK/ERK pathway, where abnormal activation influences gene expression and endothelial cell function. The RAS/MEK/ERK pathway acts on the mammalian target of rapamycin (mTOR) to dysregulate cell growth affecting skin, vessels, and tissue. Studies have reported increased mTOR activity in tissue sections from patients with SWS, as well as frequent expression of phospho‐S6 in abnormal leptomeningeal vessel endothelial cells ¹⁰⁴ and in skin vascular endothelial cells. ¹⁰⁵ The R183Q GNAQ mutation expressed in endothelial cells also upregulates the PLCβ effector protein and induces hyperactivity in downstream inflammatory mediators like angiopoietin‐2; these pathways are also implicated in the formation of capillary malformations. ¹⁰⁶

Figure 4.

Downstream pathways upregulated by genetic mutation in G‐protein alpha q subunit. Mutations in the alpha q subunit of the G‐protein (indicated by the yellow star) alter several downstream pathways that cause the dysregulation of endothelial cell function. Mutations in GNAQ can increase PKC signaling, affecting downstream targets like phosphorylated ERK that are elevated in leptomeningeal enhancements. This hyperactivation affects mTOR activity, leading to the abnormal growth and proliferation of endothelial cells. The PI3K/Akt pathway also affects mTOR activity as a mutation in PI3K can increase the conversion of PIP2 to PIP3 and lead to the activation of PI3K and other downstream targets, namely mTOR. Mutations in GNAQ can also increase the activation of the YAP/TAZ complex. The dysregulation of the targets affects endothelial cell growth, differentiation, and function and is implicated in the abnormal vasculature seen in SWS. Akt, protein kinase B; GNAQ, G‐protein alpha subunit q; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3‐kinase; SWS, Sturge–Weber syndrome.

The dysfunction in effectors downstream of G‐protein subunit alpha q results in abnormal vascular development, leading to the tortuous, abnormally innervated vessels observed in SWS. In the endothelial cells of leptomeningeal vessels, SWS samples showed increased expression of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR), as well as the angiotensin 1 (TIE2) receptor. We speculate that VEGF is induced by hypoxia‐inducible factor‐1α, which is elevated in the underlying brain tissue as a result of impaired blood flow to the brain. ¹⁰⁷ The VEGFR and TIE2 receptors have been identified as essential for normal vascular development.

Years before the identification of the underlying somatic mutation, upregulation of the RAS/MEK/ERK pathway was hypothesized to result in the abnormally increased VEGFR and TIE2 expression. More recent studies have suggested that phosphorylated extracellular signal‐regulated kinase (p‐ERK) expression is increased in the endothelial cells of leptomeningeal SWS vessel compared to epilepsy control tissue. ¹⁰³ , ¹⁰⁷ The mTOR pathway has also been hypothesized to be increased, indirectly as a result of increased p‐ERK. Studies in human PWB skin tissue and SWS brain tissue indicate mTOR activation.

Another pathway likely affected by the genetic mutations associated with SWS is the Hippo pathway (Figure 4), with data implicating a signaling role for the R183Q GNAQ mutation in uveal melanoma cells, ¹⁰⁸ and a recent study linking the GNB2 mutation reported in a patient with SWS to upregulation of Hippo/YAP. ⁹⁷ The Hippo pathway regulates transcriptional cofactors yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ). These cofactors form a complex that is dephosphorylated when the Hippo pathway is inactive. In this dephosphorylated state, the YAP–TAZ complex can move into the cell nucleus and transcribe proteins important for controlling cell proliferation, apoptosis, and cell fate. However, when the Hippo pathway is activated, the YAP–TAZ complex becomes phosphorylated and is sequestered in the cytoplasm, unable to regulate genes necessary for the appropriate proliferation, migration, and survival of endothelial cells. ¹⁰⁹

Treatments for SWS

Due to the multisystem nature of SWS, a multidisciplinary evaluation is important to assess dermatological, neurological, neuropsychological, and motor deficiencies and determine appropriate treatment methods. Because SWS is progressive, treatment and interventions should begin early with aggressive, appropriate care.

Treatment of PWB and glaucoma

For those born with the cutaneous manifestations of SWS, it important to intervene in early infancy when the birthmark is smaller. Most patients treated early show substantial improvement, and later hypertrophy of underlying soft tissue or bone is less likely when the birthmark is treated. Pulsed‐dye laser is the current standard of care for most young patients, and this technology continues to evolve. ¹¹⁰ , ¹¹¹ , ¹¹²

Standard treatment for glaucoma in SWS eye involvement involves eye drops that decrease eye pressure; ³³ , ⁶⁵ , ¹¹³ if this cannot counteract the increased pressure, surgical procedures such as a trabeculotomy or goniotomy may relieve pressure. ¹⁶ Eye pressure must be monitored closely, especially when the facial capillary malformation involves the eyelids. Ocular pressure can also initially be normal and then progress to glaucoma, with the periods of greatest risk during infancy and in young adulthood. ¹⁴ , ¹¹⁴ Retinal hemorrhages may occur in severely affected patients or as a complication of surgery and require the care of a retinal specialist.

Neurologic treatment

Standard anticonvulsant treatment is given for epilepsy due to SWS; most patients are initially treated with either oxcarbazepine or levetiracetam. Often these seizure medications are combined with low‐dose aspirin. ²² Oxcarbazepine is associated with better seizure control than levetiracetam, and patients with seizure control for six months or longer were less likely to have ever taken levetiracetam. ¹¹⁵ Topiramate also showed some efficacy when added as a second‐line treatment, with five of nine patients experiencing decreased seizure severity. Phenobarbital is another adjuvant seizure medication whose use is associated with concurrent use of levetiracetam, bilateral brain involvement, and younger age of seizure onset. ²² Other seizure medications used when needed include lamotrigine, clobazam, and lacosamide. ²²

Low‐dose aspirin has been utilized as an antiplatelet treatment in SWS. ¹¹⁶ , ¹¹⁷ , ¹¹⁸ By decreasing platelet accumulation, this treatment is thought to improve blood flow through malformed cortical veins and to decrease the likelihood of stroke or stroke‐like episodes. ¹¹⁹ Low‐dose aspirin can also decrease seizure frequency and duration. ¹¹⁶ , ¹¹⁸ , ¹¹⁹ Common side effects include increased bruising and excessive bleeding of the gums or nosebleeds, ¹¹⁸ , ¹²⁰ but with dose adjustments, most infants and children tolerate it well. Rarely subdural or intraparenchymal hemorrhage can occur, whether on or off low‐dose aspirin; ⁸⁰ anecdotal evidence (unpublished clinical experience) suggests an incidence of about 1 in 200 patients with SWS.

Neurosurgery is another viable treatment option for SWS patients with medically refractory seizures, especially those with unilateral brain involvement. If seizures are severe or frequent, surgery is also considered in bilaterally affected patients with limited involvement of the other hemisphere. Surgical options historically have ranged from anatomical (resective) hemispherectomy to more recent functional (disconnection) hemispheric and focal surgeries that target the epileptogenic region. ¹²¹ , ¹²² , ¹²³ These procedures are best done in the first several years of life to preserve cognitive function and allow neural reorganization in the immature brain to support postsurgical development. ¹²⁴ , ¹²⁵ Surgery performed in children younger than  one year of age may be more risky as the full extent of brain involvement may not be apparent, as discussed in previous sections. Of 11 children (ages 6–33 months) with SWS who underwent anatomical or functional hemispheric surgeries, eight became completely seizure‐ and aura‐free, and antiepileptics were discontinued in most of these children. ¹²⁶ In a study of 10 patients with SWS who underwent functional hemispherectomy, 80% of children became seizure‐free, and those who did not achieve seizure freedom had incomplete resection of epileptic regions. ¹²¹ , ¹²⁷ Functional lesional surgeries risk less postoperative developmental and motor deficits than hemispheric surgeries ¹²⁸ but are less likely to result in full seizure control, especially when ictal regions are not completely removed. ¹²⁹ , ¹³⁰ Vagus nerve stimulation may also aid seizure control in drug‐resistant epilepsy, but only anecdotal reports are available for SWS. ¹³¹ Corpus callosum disconnection is also a surgical option but is rarely used in patients with SWS and is associated with a risk of cognitive impairment. ¹³⁰ , ¹³²

The decision to treat refractory seizures with antiepileptics or with surgery in patients with SWS is complex. On the one hand, some patients with SWS can attain seizure freedom off of medications after being seizure‐free for several years, ¹³³ and surgery may worsen motor and cognitive impairments or visual field deficits. Other the other hand, delaying surgery beyond the first several years of life likely decreases the brain's ability to reorganize after the surgery and increases the duration of exposure to antiseizure medications, with attendant side effects and negative impact on development. Furthermore, patients with SWS frequently have seizures that cluster, with extended seizure‐free periods intervening, making the determination of medically refractory seizures challenging in many patients. As the safety of surgical interventions has improved, the role of surgery has gradually increased. Patients failing to respond to two or more seizure medications and low‐dose aspirin are considered for surgery. These surgeries are done at experienced centers with teams of experts to guide presurgical testing and decisions, perisurgical care, and rehabilitation. ¹³⁴

Another consideration for patients with SWS and seizures is the modified Atkins diet (MAD) or the ketogenic diet, particularly when surgery is not a good option. ¹³⁵ , ¹³⁶ The MAD does not restrict proteins, calories, or fluids, making it a potentially a safer option for children with SWS who are at a higher risk of stroke or stroke‐like episodes. The MAD can reduce seizure frequency and severity, with patients in one study experiencing a reduction of up to 75%–90% in a six‐month period. ¹³⁵ , ¹³⁶ The ketogenic diet can be helpful in infants with SWS and implemented with ketogenic formula. Patients and families frequently have difficulty sustaining these diets, however; children require close monitoring by an experienced nutritionist while on either the ketogenic or the MAD.

Vitamin D deficiency is common in patients with SWS on seizure medications, with 66% having abnormally low vitamin D levels. Low vitamin D levels are more frequently seen in Black patients and individuals with more severe brain involvement. ¹³⁷ A recent meta‐analysis found that insufficient circulating vitamin D levels are associated with an increased risk of stroke in healthy patients; however, vitamin D supplementation did not decrease stroke risk in these patients. Using vitamin D supplements as a treatment may improve neurological function and hemiparesis in patients with SWS, specifically in more severely affected individuals. ¹³⁷ Vitamin D supplementation may also improve seizure control ¹³⁸ generally.

For headache symptoms, recent research has supported the use of abortive and prophylactic therapies in SWS. ¹³⁹ , ¹⁴⁰ Many patients with SWS commonly use abortive medications for headache treatment ⁴² as opposed to prophylactic medications. Triptan use for headache prophylaxis was effective and safe in 22% of 74 patients with migraine headaches. ¹⁴¹ Further studies on the most appropriate treatment method for headaches in SWS are necessary. When hormone deficiencies are identified in patients with SWS, treatment to supplement the deficient hormone is usually indicated. When central hypothyroidism is treated, associated symptoms may improve, such as weight loss and improved energy levels. ⁴⁵ Growth hormone deficiency in SWS can be remedied by treatment with growth hormone; however, caution is required as growth hormone supplementation, in our clinical experience, can increase seizures in some patients with SWS.

Treatment for attention disorders in SWS includes stimulants, which are generally well‐tolerated and effective. ¹⁴² These patients and families should inform the treating physician of sleep issues due to the stimulant, as sleep impairment increases the risk of seizures. If intellectual or adaptive deficits are diagnosed, then accommodations, executive function supports, 504 plans, and individualized education program intervention are necessary to address the identified areas of difficulty. ⁵⁰

Treatment for motor impairments in SWS can include braces or splints on the affected limbs to allow flexion and stretching improve functional positioning of limbs, and manage spasticity. ⁵¹ Along with these bracing tools, occupational and physical therapy through early intervention programs is recommended to improve function over time, specifically in fine motor skills and increased involvement of the affected arm and hand in bilateral tasks. ⁵¹ Orthopedic evaluations and procedures may also be required in patients with significant motor impairments.

Future of SWS Research

Biomarker development

SWS is a highly variable disorder, and future research requires more longitudinal and prospective data. Multiple studies have suggested the utility of qEEG power analysis for screening and monitoring SWS brain involvement. ⁷⁴ , ⁷⁵ , ⁷⁶ A pilot study of sirolimus (discussed below) suggested that qEEG was treatment responsive in the subset of patients with a history of stroke‐like episodes. Urine vascular biomarker studies are also underway in SWS, with longitudinal urine biomarker data being analyzed along with clinical outcomes. Efforts are also underway to leverage neuroimaging data, using artificial intelligence to predict the age of seizure onset and clinical outcome. ¹⁴³ Further studies are also needed during acute decompensations and stroke‐like episodes to predict which patients will fully recover. A multicenter prospective study is inprogress to identify blood and imaging biomarkers in symptomatic patients with SWS (NCT04717427—longitudinal studies to identify biomarker for SWS).

Genetic testing and SWS

A total of 85%–90% of patients with SWS have an underlying somatic R183Q GNAQ mutation. Since the diagnosis of this most common somatic mutation does not aid in the diagnosis of brain or eye involvement and requires a skin biopsy from the face, genetic testing is not standard of care in most patients. However, recent studies have elucidated other causative mutations, and genotype/phenotype studies are needed. As more targeted treatments are studied, gene sequencing is likely to increase in importance.

Development of new symptomatic treatments

Cognitive impairments may improve with oral sirolimus, ¹⁴⁴ most notably in patients with SWS who have experienced stroke or stroke‐like episodes. ²² , ¹⁴⁵ Sirolimus functions as an inhibitor of mTOR, which is a downstream target likely upregulated by the mutated, hyperactive G‐protein (Figure 4). More research in this area is necessary to determine the role for sirolimus in patients with SWS, and a multicentered, prospective trial is in planning.

Cannabidiol (CBD) is also thought to inhibit the mTOR pathway. It has neuroprotective and anti‐inflammatory properties. ¹⁴⁶ CBD has shown potential for neuroprotection in ischemic stroke in several animal models, ¹⁴⁷ , ¹⁴⁸ and it has shown in several tumor studies to have antiproliferative effects and inhibit both ERK and PIK3/AKT pathways. ¹⁴⁹ The downregulation of angiogenic factors by CBD is also reported, suggesting that CBD treatment may decrease pathologic angiogenesis. ¹⁴⁹ There is also some evidence for CBD having benefit in stroke/stroke‐like episodes and ischemia ¹⁵⁰ ; further research for CBD's effect on stroke‐like episodes in SWS is necessary. In a pilot trial of CBD in patients with SWS and medically refractory epilepsy, seizures were decreased in the most severely affected patients, and CBD was associated with increased quality of life in patients with SWS. ¹⁵¹ In a recent study of 10 patients, nine showed improvements in the cognitive subscore of SWS neuroscore, suggesting some cognitive improvements in SWS due to CBD. The same study reported improvements in motor coordination and quality of life in most individuals. ¹⁵²

Development of effective presymptomatic treatment

Recent efforts have proposed presymptomatic treatment prior to the onset of seizures ⁵ in order to delay seizure onset, reduce early brain injury, and improve early neurocognitive development. Phenobarbital, valproic acid, low‐dose aspirin, and other commonly used seizure medications have been evaluated; ⁶⁹ , ¹⁵³ , ¹⁵⁴ however, many young children present with early seizures and neurologic deteriorations despite presymptomatic treatment. Presymptomatic treatment studies with other potentially more effective drugs are urgently needed.

Author Contributions

Chelsea B. Valery: Writing—original draft. Anne M. Comi: Writing—review and editing.