Sturge-Weber syndrome

INTRODUCTION — Sturge-Weber syndrome (SWS) is a rare congenital vascular disorder characterized by facial capillary malformation (port wine stain) and associated capillary-venous malformations affecting the brain and eye. It is not a heritable disorder. Thus, recurrence is unlikely.

GENETICS AND PATHOGENESIS

●GNAQ pathogenic variants – The main cause of SWS is somatic mosaic GNAQ pathogenic variants, as identified in a study that performed whole-genome sequencing of affected and normal tissue samples from three patients with SWS [1]. This process identified a GNAQ single-nucleotide variant (c.548G→A, p.Arg183Gln) shared by affected tissue from all three patients. The variant was also found in samples of affected tissue from 23 of 26 study participants (88 percent) with SWS and 12 of 13 participants (92 percent) with nonsyndromic (isolated) port wine stains, but in none of four participants with other cerebrovascular malformations and in none of six controls. The prevalence of the variant in affected tissues ranged from 1 to 18 percent. These findings confirm the longstanding hypothesis that the capillary-venous malformations of SWS, historically called angiomata, result from somatic pathogenic variants in fetal ectodermal tissues that cause inappropriate control or maturation of capillary blood vessel formation [2,3].

The GNAQ gene encodes a guanine nucleotide binding protein, G protein subunit alpha q, that functions to regulate intracellular signaling pathways. The p.Arg183Gln somatic GNAQ pathogenic variant activates a set of signaling pathways that are thought to result in either nonsyndromic port wine stains or SWS, depending upon what stage of embryonic development is affected [1]. Somatic pathogenic variants in GNAQ occurring at a later stage in embryogenesis may affect only precursors of vascular endothelial cells and lead to nonsyndromic port wine stains, while those occurring at an earlier stage may affect a greater variety of precursor cells and lead to SWS.

●GNA11 pathogenic variants – Atypical SWS associated with pathogenic variants in GNA11 has been reported in a small number of patients [4].

GNA11 also encodes a guanine nucleotide binding protein, G protein subunit alpha 11, which has an approximately 90 percent amino acid sequence identity with G protein subunit alpha q [5].

●Neurologic injury – The reasons for neurologic involvement and progression in SWS are uncertain. A possible mechanism is hypoxic-ischemic injury to tissue adjacent to the leptomeningeal capillary-venous malformation. This is supported by findings in some patients of reduced cellular glucose metabolism, possibly resulting from decreased cerebral blood flow [2,6-8]. Other proposed mechanisms are venous occlusion and increased venous pressure.

CLINICAL FEATURES — SWS is characterized by a facial capillary malformation, also known as a port wine stain (picture 1), and an associated leptomeningeal capillary-venous malformation (leptomeningeal angioma) involving the brain and eye [9]. These vascular malformations are associated with specific neurologic and ocular abnormalities.

The neurologic features of SWS may be progressive and include seizures, focal neurologic deficits, and intellectual disability. Visual field defects are common when the occipital cortex is affected. These manifestations occur with variable severity. Hydrocephalus also may occur [10]. This complication is thought to result from increased venous pressure caused by thrombosis of the deep venous channels or extensive arteriovenous anastomoses. A small proportion of patients have no neurologic abnormalities. The neurologic manifestations of SWS associated with GNA11 pathogenic variants may be milder than typical SWS caused by GNAQ pathogenic variants [11]. (See 'Genetics and pathogenesis' above.)

Ocular features of SWS include glaucoma and capillary-venous vascular malformations of the conjunctiva, episclera, choroid, and retina [12,13].

Port wine stain — Cutaneous port wine stain (capillary malformation) is the most common type of vascular malformation, occurring in 0.3 percent of newborn infants (picture 1). However, only a small proportion of children with port wine stains have SWS. (See "Capillary malformations (port wine birthmarks) and associated syndromes".)

In SWS, the port wine stain typically is present on the forehead and upper eyelid, primarily in the distribution of the first or second division of the trigeminal nerve [14]. In one report, 274 patients had port wine stains located in the distribution of the trigeminal nerve, and involvement of the eye or central nervous system was noted in 22 (8 percent) [15]. All 22 patients of these patients had a port wine stain in the first or second division of the trigeminal nerve. Although overlapping the trigeminal distribution, the pattern of capillary malformations in SWS may actually reflect the embryonic vascular supply of the face [16]. Although traditionally considered important in determining meningeal involvement risk, the location of the capillary malformation (port wine stain) on the face is not a good indicator of the risk of an underlying meningeal capillary malformation. Extension of the skin lesion to both sides of the face and the trunk and extremities is common.

The skin lesion usually is obvious at birth. However, its appearance changes with age and its size increases as the patient grows. In the newborn, the lesion is flat and usually light pink in color. It typically darkens with age to a deep red, port wine appearance, and vascular ectasias may develop (picture 2). The vascular ectasias produce nodularity and superficial blebbing, which lead to overgrowth of the underlying soft tissues and sometimes the bone. Dental abnormalities may occur as a result of gingival thickening if this area is affected. By the fifth decade, 65 percent of patients with a facial port wine stain have hypertrophy and nodularity within the lesion [17].

Leptomeningeal vascular malformation — A leptomeningeal capillary-venous malformation (LCVM), historically referred to as leptomeningeal angioma, occurs in 10 to 20 percent of cases when a typical facial lesion is present. The intracerebral capillary-venous malformation usually occurs on the same side as the port wine stain. The parietal and occipital areas are affected most commonly, although any portion of the cerebrum can be involved. LCVM seldom occurs without an accompanying facial capillary malformation [18].

The pathologic appearance of the leptomeninges includes thickening and discoloration caused by the increased vascularity. The LCVM typically fills the subarachnoid space in the sulci, and large tortuous venous structures most commonly drain into the deep venous system, but they may also drain into superficial veins. The underlying parenchyma may be atrophic and contain multiple calcific granular deposits (image 1). The intraparenchymal calcification is the result of chronic tissue ischemia caused by venous stasis, a phenomenon known as dystrophic calcification.

There is evidence that the LCVM in SWS are not static lesions but rather undergo angiogenic remodeling. In one study, the abnormal tissue vessels showed an increased expression of vascular endothelial growth factor (VEGF), VEGF receptors, and angiopoietin receptor TIE2 [19]. These findings may lead to the development of new therapeutic strategies in SWS.

Seizures and epilepsy — In a series of 171 patients with SWS, seizures occurred in 80 percent [20]. Several reports have found that bilateral port wine stains are associated with an increased risk of epilepsy [20-22]. As an example, in the series of 171 subjects with SWS, seizures were more common with bilateral than unilateral port wine stains (87 versus 71 percent) [20]. In another report, seizures occurred in 93 percent of patients with bilateral leptomeningeal lesions [21]. In one case series of six patients with SWS who underwent epilepsy surgery, pathologic examination in all patients revealed a cortical malformation (polymicrogyria, cortical dysplasia) [23].

Seizures in SWS may develop at any age, although they usually start in early childhood [20,24,25]. In the study of 171 patients with SWS, seizures began by one, two, and five years of age in 75, 86, and 95 percent of affected patients, respectively [20]. In another report of 77 children and adults with SWS and at least one witnessed seizure, the median age of seizure onset was six months [24]. A pattern of severe seizures occurring in clusters was noted in 30 patients (39 percent). In patients with this pattern, seizures occurred in clusters of 1 to 21 (median 5) over a period of 1 to 10 days (median 2).

Seizures are often the first symptom of SWS. They may occur in the setting of an acute illness and may be associated with the acute onset of hemiparesis. (See 'Hemiparesis and stroke-like events' below.)

Initially, seizures are typically focal, but they often become generalized tonic-clonic. Less often, infantile spasms or myoclonic or atonic seizures are seen.

The success of controlling seizures with antiseizure medication is variable and unpredictable. Some patients have long intervals without seizures, even without medication, while others have frequent or prolonged seizures despite high doses of multiple medications. (See 'Epilepsy' below.)

Hemiparesis and stroke-like events — Hemiparesis often develops acutely in conjunction with the onset of seizures [9]. The deficit occurs contralateral to the intracranial lesion. The paretic extremity usually does not grow at a normal rate, resulting in hemiatrophy.

Some affected children have progressive loss of motor function or have a series of stroke-like events. The mechanism for this deterioration is uncertain. Possible mechanisms include a cumulative effect of repeated thrombotic events within the LCVM or chronic disturbance of blood flow and oxygen delivery to the involved tissues.

Intellectual disability — Children with SWS typically develop normally for several months after birth, after which they manifest developmental delay. However, the course of cognitive change in children with SWS is highly variable, including both increases and decreases in intelligence quotient (IQ) over time. Factors associated with a lower IQ at follow-up in one longitudinal study included baseline abnormalities on electroencephalography (EEG), high seizure frequency, and early frontal lobe involvement on brain MRI [26]. Cognitive impairment can be obvious soon after birth, especially in infants with extensive brain involvement.

In one report, intellectual disability was present in 60 percent of patients and was severe in 33 percent [27]. In another study, intellectual disability was present in approximately one-half of affected adults [28].

Cognitive function is poorest in patients with bilateral intracerebral lesions. In one report of 122 patients with SWS, only 8 percent of patients with bilateral LCVMs had average intelligence [21].

Behavioral problems — Behavioral problems are more common in children with SWS than in their unaffected siblings [29]. The risk for behavioral problems is associated with poorer cognitive function and the presence of epilepsy [29,30]. However, behavioral problems can occur in patients with normal intelligence. Autism spectrum disorder and social communication difficulties are also associated with SWS [31]. The results of one small retrospective study suggested that patients with SWS may be at increased risk of suicidal thoughts or behaviors compared with patients with other neurologic conditions [32].

Visual field defects — Many patients have visual field defects, typically a homonymous hemianopia. This is due to the presence of a LCVM affecting one or both occipital lobes and optic tracts. (See "Homonymous hemianopia".)

Glaucoma — The predominant ocular abnormality of SWS is glaucoma (increased intraocular pressure), which occurs in approximately one-half of affected patients. Therefore, we suggest ophthalmology referral and follow-up for all patients presenting with SWS and for all infants and children presenting with a capillary malformation involving the upper and lower eyelids and/or extensive lesions in the frontotemporal region (V1 and V2 segments).

The risk of glaucoma is highest in the first decade. Congenital glaucoma is seen in approximately one-half of patients with SWS and presents in newborns with enlargement of the globe (buphthalmos). Occasional patients develop glaucoma as adults. Thus, continued vigilance is needed, even in patients with initially normal intraocular pressure. (See "Overview of glaucoma in infants and children", section on 'Sturge-Weber syndrome'.)

Other ophthalmologic findings — Other ophthalmologic complications include vascular anomalies, heterochromia of the iris, and visual field defects [12].

●Capillary-venous malformation of the choroid (also known as choroidal hemangioma) occurs in 30 to 40 percent of patients with SWS and can lead to increased intraocular pressure [12,33,34]. These lesions may be diffuse or localized within the retina (picture 3).

●Episcleral and conjunctival lesions include anomalous vessels or capillary-venous malformations [35]. In a series of 51 children with SWS, episcleral or conjunctival hemangiomas occurred in 69 percent [12].

●Heterochromia of the iris originally was noted by Weber. The more deeply pigmented iris usually is ipsilateral to the facial angioma. The pigmentation is caused by aggregated melanocytic hamartomata on the anterior surface of the iris.

Neuroendocrine aspects — The incidence of growth hormone deficiency in SWS is increased up to 18-fold compared with the general population [36]. Growth hormone deficiency occurs without neuroimaging evidence of pituitary or hypothalamic abnormalities. Central hypothyroidism has also been reported in SWS [37]. Since both of these conditions can be effectively treated, appropriate screening tests should be obtained if indicated.

DIAGNOSIS — The diagnosis of SWS is based upon demonstration of the facial capillary malformations and leptomeningeal capillary-venous malformations. Occasional patients who have the leptomeningeal lesion but no facial lesion are identified when neurologic problems develop. These patients also may have glaucoma or other ocular features of the disorder.

SWS should be distinguished from Klippel-Trenaunay syndrome. In the latter, extensive capillary malformations associated with dysplastic veins involve the limbs and trunk, often with hypertrophy of the affected extremity.

NEUROIMAGING — The preferred neuroimaging technique for the diagnosis of SWS is brain MRI with gadolinium contrast, which demonstrates the presence of the leptomeningeal capillary-venous malformation and the extent of involvement with brain structures (image 1 and image 2) [38,39]. There is a general consensus among experts that a negative brain MRI with gadolinium at one year of age can reliably exclude the presence of a leptomeningeal lesion. If MRI is not available, cranial computed tomography can identify brain calcification and provide some anatomic information (image 1 and image 2).

Earlier imaging during infancy is generally not indicated. In some cases, leptomeningeal involvement may not be detected by neuroimaging during infancy and becomes apparent later [2]. Thus, SWS cannot be ruled out by a normal brain MRI in the first few months of life. In addition, approximately 90 percent of infants with facial port wine stains do not have an intracranial lesion and would be expected to develop normally. Given these data, and the need to sedate infants for MRI, it is reasonable to perform imaging in infancy only if specific ocular and neurologic abnormalities (glaucoma, seizures, or hemiparesis) are present.

Limited retrospective data suggest that neuroimaging with CT or MRI has a low yield for patients with SWS who develop acute neurologic symptoms. In a single-center study of 136 patients with SWS who presented to the emergency department (mainly with seizures, stroke-like episodes, and/or headaches), 73 had neuroimaging but none of the imaging studies revealed acute ischemic stroke or intracranial hemorrhage [40].

MANAGEMENT — No specific treatment exists for SWS. The cutaneous, ocular, and neurologic manifestations are treated with mixed success.

Epilepsy — Management of seizures in SWS often is difficult. In one report, adequate control was accomplished with antiseizure medications in approximately 40 percent of cases [41]. Antiseizure medications are standard first-line therapy for patients with epilepsy related to SWS [24,42], though the optimal regimen is unknown. In a retrospective, single center report that analyzed a database of 108 subjects with SWS and one or more prior seizures, carbamazepine and oxcarbazepine were associated with better seizure control than levetiracetam, but no drug was clearly superior [43]. The strength of these observations is limited by the small sample size and retrospective nature of the study.

In refractory cases, hemispherectomy or more limited surgical resection of epileptogenic tissue may be beneficial, although data are limited [25,44-47]. Most studies suggest that focal resections are less likely to result in good seizure control than hemispherectomy:

●In a survey of 70 patients identified by the Sturge-Weber Foundation who had a hemispherectomy between 1979 and 2001, 81 percent of the 32 who responded were free of seizures and 53 percent were off anticonvulsants [46].

●In a retrospective review of 27 children with SWS who had surgery for medically resistant epilepsy, functional or anatomic hemispherectomy was followed by complete resolution of seizures in eight of eight patients; with focal resection, seizure-free outcome was reported of 11 of 19 (58 percent) [47].

Thus, some experts recommend surgery with hemispherectomy, lobectomy or transection of the corpus callosum for patients with SWS and medically resistant epilepsy (eg, poor seizure control despite treatment for six months with a minimum of two anticonvulsants), particularly when associated with clinically significant hemiparesis, visual field loss, and developmental delay [48].

Cutaneous lesions — Port wine stains can be treated by selective photothermolysis using a pulsed dye laser. This is discussed in detail separately. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Capillary malformations (port wine birthmarks)'.)

Glaucoma — The development of topical medications has improved the medical management of glaucoma in SWS [13]. However, topical treatment often is ineffective in normalizing intraocular pressure [49]. In these cases, the surgical treatment depends upon the etiology of the glaucoma. (See "Overview of glaucoma in infants and children", section on 'Sturge-Weber syndrome'.)

Low-dose aspirin — For all children diagnosed with SWS, we suggest treatment with low-dose aspirin (3 to 5 mg/kg per day) beginning in infancy [50]. There is increasing agreement among experienced clinicians that low dose aspirin may be beneficial, with the rationale that antithrombotic therapy may prevent the progression of impaired cerebral blood flow and hypoxic-ischemic neuronal injury [8,51-53]. Limited observational data suggest that low-dose aspirin may reduce the frequency and severity of seizures and stroke-like events [6,54,55]. However, no controlled studies exist. There is no increased risk of intracranial hemorrhage in patients with SWS whether on aspirin or not.

PROGNOSIS — The prognosis for SWS depends upon the extent of brain and skin involvement, and the age of seizure onset. In a study of 277 participants (two months to 66 years of age) with SWS, the extent of the port-wine birthmark was associated with an increased risk of epilepsy and of glaucoma surgery, while the presence of bilateral leptomeningeal capillary-venous malformations (LCVMs) was associated with both learning disorder and intellectual disability [56]. Similarly, a report of 112 patients with SWS found that the extent of LCVM was associated with seizure severity [57].

The occurrence of seizures, the age at seizure onset, and the response to treatment also affect prognosis. Earlier onset of seizures (eg, before one year) and poor response to anticonvulsant therapy are associated with a greater likelihood of cognitive and motor impairment [20,56,58].

Neurologic function may deteriorate with age. As a result, approximately one-half of affected adults are impaired, including those who initially were normal.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sturge-Weber syndrome".)

SUMMARY AND RECOMMENDATIONS

●Sturge-Weber syndrome (SWS) is a rare congenital vascular disorder that affects capillary size blood vessels. SWS is caused by somatic mosaic pathogenic variants in the GNAQ gene. It is not a heritable disorder. (See 'Genetics and pathogenesis' above.)

●SWS is characterized by facial capillary malformation (port wine stain) and associated capillary-venous malformations affecting the brain and eye. These vascular malformations are associated with specific ocular and neurologic abnormalities. (See 'Clinical features' above.)

●Cutaneous port wine stain is the most common type of vascular malformation, occurring in 0.3 percent of newborn infants (picture 1). However, only a small proportion of children with port wine stains have SWS. The port wine stain of SWS typically is present on the forehead and upper eyelid, primarily in the distribution of the first or second division of the trigeminal nerve. Although traditionally considered important in determining meningeal involvement risk, the location of the port wine stain on the face is not a good indicator of the risk of an underlying meningeal capillary malformation. (See 'Port wine stain' above.)

●A leptomeningeal capillary-venous malformation (LCVM; angioma) occurs in 10 to 20 percent of cases when a typical facial lesion is present. The intracerebral lesion usually occurs on the same side as the port wine stain. The parietal and occipital areas are affected most commonly. (See 'Leptomeningeal vascular malformation' above.)

●Ocular features of SWS include glaucoma, vascular malformations of the conjunctiva, episclera, choroid (picture 3) and retina, and heterochromia of the iris. (See 'Glaucoma' above and 'Other ophthalmologic findings' above.)

●The neurologic features of SWS may be progressive and include seizures, focal neurologic deficits, visual field defects, and intellectual disability. These problems occur with variable severity. A small proportion of patients have no neurologic abnormalities. Seizures in SWS may develop at any age, although they usually start in early childhood. Hemiparesis often develops acutely in conjunction with the onset of seizures. Some affected children have progressive loss of motor function or have a series of stroke-like events. (See 'Seizures and epilepsy' above and 'Hemiparesis and stroke-like events' above and 'Intellectual disability' above and 'Behavioral problems' above and 'Visual field defects' above.)

●The diagnosis of SWS is based upon demonstration of the facial and leptomeningeal vascular malformations. Occasional patients who have the LCVM but no facial lesion are identified when neurologic problems develop. SWS should be distinguished from Klippel-Trenaunay-Weber syndrome in which extensive capillary angiomata associated with dysplastic veins involve the limbs and trunk, often with hypertrophy of the affected extremity. (See 'Diagnosis' above.)

●The preferred diagnostic neuroimaging technique for SWS is brain MRI with gadolinium contrast, which demonstrates the presence of the LCVM and the extent of involvement with brain structures (image 1 and image 2). A negative brain MRI with gadolinium at one year of age can reliably exclude the presence of leptomeningeal lesion. (See 'Neuroimaging' above.)

●No specific treatment exists for SWS. The cutaneous, ocular, and neurologic manifestations are managed with mixed success. Observational data suggest that low-dose aspirin may be beneficial. Therefore, for all children diagnosed with SWS, we suggest treatment with low-dose aspirin (3 to 5 mg/kg per day) beginning in infancy (Grade 2C). There is no increased risk of intracranial hemorrhage in patients with SWS whether on aspirin or not. (See 'Management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John B Bodensteiner, MD, who contributed to an earlier version of this topic review.