Sturge-Weber Syndrome

Sturge-Weber syndrome (SWS), also called encephalotrigeminal angiomatosis, is a neurocutaneous disorder with angiomas that involve the leptomeninges (leptomeningeal angiomas [LAs]) and the skin of the face, typically in the ophthalmic (V1) and maxillary (V2) distributions of the trigeminal nerve. Extracranial angiomas and soft-tissue overgrowth also may occur in SWS. (See Pathophysiology, Etiology, and Clinical Presentation.)

Cutaneous manifestations

The hallmark of SWS is a facial cutaneous venous dilation, also referred to as a nevus flammeus or port-wine birthmark (PWB), which is present in as many as 96% of patients and is visible at birth (see the image below). The facial venous dilation appears as 1 or several dull red patches of irregular outline that are situated along, but are not limited to, the distribution of 1 or more divisions of the trigeminal nerve.[6, 7, 8] SWS belongs to a group of disorders collectively known as the phakomatoses ("mother-spot" diseases). (See Pathophysiology and Clinical Presentation.)

Laser therapy is available for the PWB. Although concerns have been raised that laser therapy to treat PWB might cause or worsen glaucoma or ocular hypertension; a 2009 retrospective review did not reveal evidence to support this. (See Treatment.)[2]

Neurological manifestations

In the brain, LAs demonstrated by structural neuroimaging may be unilateral or bilateral[9] ; unilateral angiomas are more common. Functional neuroimaging may demonstrate a greater area of involvement than structural neuroimaging.[10] This is called a structural-versus-functional mismatch. (See Workup.)

The neurological manifestations of SWS vary, depending on the location of the LAs (which most commonly are located in the parietal and occipital regions) and the secondary effects of the angiomas. These neurological morbidities include the following:

• Seizures - May be intractable

• Focal deficits - Including hemiparesis and hemianopsia, both of which may be transient (called "strokelike episodes")

• Headaches

• Developmental disorders - Including developmental delay, learning disorders, and intellectual disability; more common when angiomas are bilateral

Focal or generalized motor seizures usually begin in the first year of life. Profound seizure activity sometimes may be observed, with resultant further neurological and developmental deterioration.[11] Seizure control is thought to improve the neurological outcome, and epilepsy surgery may be beneficial for refractory seizures. Therefore, diagnosing and treating the disease early, before permanent damage to the brain occurs, is preferable. (See Prognosis and Treatment.)

Progressive, characteristic calcifications in the external layers of the cerebral cortex underlying the angiomatosis associated with ipsilateral cortical atrophy frequently develop and progress with age, occasionally extending anteriorly to the frontal and temporal lobes. (See Pathophysiology and Etiology.)

Certain CNS malformations have been associated with SWS; other neurocutaneous disorders are included in the differential diagnosis.

Ophthalmic manifestations

The primary complications involving the ipsilateral eye are buphthalmos and glaucoma, with treatment aimed at controlling the intraocular pressure (IOP) and preventing progressive visual loss and blindness.

Classification

SWS is referred to as complete when both CNS and facial angiomas are present, and incomplete when only the face or CNS is affected. The Roach Scale is used for classification, as follows:[12]

• Type I - Facial and leptomeningeal angiomas; patient may have glaucoma

• Type II - Facial angioma alone (no CNS involvement); patient may have glaucoma

• Type III - Isolated LA; usually no glaucoma

Examples of ocular manifestations of SWS are shown in the images below.

SWS is caused by residual embryonal blood vessels and their secondary effects on surrounding brain tissue. A vascular plexus develops around the cephalic portion of the neural tube, under ectoderm destined to become facial skin. Normally, this vascular plexus forms in the sixth week and regresses around the ninth week of gestation. Failure of this normal regression results in residual vascular tissue, which forms the angiomata of the leptomeninges, face, and ipsilateral eye.[13]

Neurologic dysfunction results from secondary effects on surrounding brain tissue, which include the following[14, 15] :

• Hypoxia

• Ischemia

• Venous occlusion

• Thrombosis

• Infarction

• Vasomotor phenomenon

From a review of pathologic specimens, Norman and Schoene thought that blood flow abnormalities in the LA caused increased capillary permeability, stasis, and anoxia.[16] Garcia et al and Gomez and Bebin reported that venous occlusion may actually cause the initial neurologic event, either a seizure, transient hemiparesis, or both, thereby beginning the process.[17, 18]

A "vascular steal phenomenon" may develop around the angioma, resulting in cortical ischemia. Recurrent seizures, status epilepticus, intractable seizures, and recurrent vascular events may aggravate this steal further, with an increase in cortical ischemia, resulting in progressive calcification, gliosis, and atrophy, which in turn increase the chance of seizures and neurologic deterioration.[19, 20]

Disease progression and neurological deterioration may occur in SWS. Although the actual LA is typically a static anatomic lesion, Maria et al, Reid et al, and Sujansky and Conradi have clearly documented the progressive nature of SWS.[21, 22, 23]

Udani et al followed the natural disease course and magnetic resonance imaging (MRI) findings of 9 patients with SWS. They found that earlier onset seizures correlated with more residual neurologic deficits and worse focal cerebral atrophy and that in most cases the course stabilized after age 5 years.[24]

Seizure control, aspirin therapy, and early surgical treatment may prevent neurological deterioration.[1]

The main ocular manifestations (ie, buphthalmos, glaucoma) occur secondary to increased IOP with mechanical obstruction of the angle of the eye, elevated episcleral venous pressure, or increased secretion of aqueous fluid.

The etiology of SWS is primarily likely associated with somatic mosaicism. Huq et al reported evidence of somatic mosaicism in 4 patients with SWS.[25, 26] Tissue samples were via skin biopsy from port-wine stains in 2 patients, and LAs from hemispherectomy in the other 2 patients. Inversion of chromosome arm 4q and trisomy 10 were seen in one patient each. Shirley et al identified a somatic activating c.548G->A mutation in GNAQ (on chromosome 9q21) in samples of affected tissues, in 23 out of 26 study participants with SWS.[27]

Malformed cortical vessels in SWS have been reported to be innervated only by noradrenergic sympathetic nerve fibers,[28] and increased endothelin-1 expression has also been seen in malformed intracranial vessels. These findings may suggest increased vasoconstriction in these abnormal blood vessels, as endothelin-1 is a peptide associated with vasoconstriction.

Fibronectin is a molecule important in regulating angiogenesis, maintenance of the blood-brain barrier, and blood vessel structure and function, as well as brain tissue responses to seizures. Comi et al reported that, in patients with SWS, decreased expression of fibronectin was noted in the leptomeningeal blood vessels, while increased expression was noted in the parenchymal vessels. The leptomeningeal blood vessel circumference was decreased, while blood vessel density was increased in SWS.[29]

Overall, in SWS, an activating somatic mutation in the GNAQ gene (p.Arg183Gln), seen in most cases[27] on chromosome 9 (at 9q21.2), appears to cause alterations in regulation of the structure and function of blood vessels, innervation of the blood vessels, and expression of extracellular matrix and vasoactive molecules.

Glaucoma

Glaucoma in SWS is produced by mechanical obstruction of the angle of the eye, elevated episcleral venous pressure, or hypersecretion of fluid by either the choroidal hemangioma or ciliary body. The anterior chamber angle abnormality is consistently seen in the infantile glaucoma cases in SWS, while increased episcleral venous pressure may have a key role in late-onset glaucoma cases in SWS. Decreased vision and blindness result from untreated glaucoma, with increased IOP leading to optic nerve damage. An acceptable range of IOP is 10-22 mm Hg. Enlargement of the eye occurs from the same mechanisms as glaucoma.

Occurrence in the United States

According to the National Organization of Rare Disorders, Sturge-Weber Syndrome (SWS) occurs in one of every estimated 20,000 to 50,000 live births.[30]  The inheritance is sporadic, and no regional differences in incidence have been identified. The incidences of the major clinical manifestations of SWS are listed in Table 1.

Table 1. Clinical Manifestations of Sturge-Weber Syndrome (Open Table in a new window)

International occurrence

Sturge-Weber syndrome is found worldwide. Generally, the condition is easily diagnosed at birth or in early infancy based on the external clinical signs alone. However, the development of morbidity from secondary changes and complications occurs throughout life.

The typical patient presents at birth with facial angiomas; however, not all children with facial angiomas and port-wine birthmark (PWB) have SWS, which raises certain diagnostic and prognostic concerns.[31]

In incomplete SWS (type III, Roach Scale), CNS angiomas occur without cutaneous features; therefore, no suspicion of SWS arises until a seizure or other neurologic problem develops. Thus, the diagnosis of SWS is not always straightforward.

Secondary glaucoma may present at any age, although early onset is the rule, with approximately 60% of glaucomas presenting at birth or in early infancy and another 30% presenting during childhood. The median ages reported for onset of visual symptoms related to secondary retinal changes range from age 8-20 years.

Neurologic and developmental morbidities in Sturge-Weber syndrome (SWS) include the following:

• Seizures

• Weakness

• Strokes

• Haeadaches

• Hemianopsia

• Intellectual disability

• Developmental abnormalities

The development of seizures and their age of onset may correlate with the degree of neurologic involvement. Neurologic dysfunction increases with bilateral port-wine birthmark (PWB). Patients may experience complications related to refractory seizures and anticonvulsants, they may suffer visual loss and blindness from glaucoma, and they may display cosmetic deformities and other manifestations of soft-tissue involvement.

The glaucoma associated with SWS is a significant cause of morbidity because of its early onset and resistance to conventional forms of treatment. Glaucoma has been estimated to occur in 30-71% of patients with Sturge-Weber syndrome.

Prognostic factors

Factors predicting a poor outcome (or indicating potential need for surgery) in SWS include the following:

• Early seizure onset

• Extensive leptomeningeal angioma (LA)

• Medically refractive seizures

• Relapsing or permanent motor deficits

• Headaches or mild trauma associated with transient motor deficits

• Evidence of progressive neurologic damage

• Focal seizures with subsequent generalization

• Increasing seizure frequency and duration

• Increasing duration of postictal deficits

• Increasing focal or diffuse atrophy

• Progressive atrophy or calcifications

• Development of hemiparesis

• Deterioration in cognitive functioning (loss of intellectual abilities)

Port-wine stain

Facial nevi are congenital macular lesions that can be progressive; they may be a light pink color initially and then progress to a dark red or purple nodular lesion. These may be isolated to the skin, associated with lesions in the choroidal vessels of the eye or the leptomeningeal vessels of the brain, or even located on other body areas.[32] A facial nevus, or PWB may be difficult to visualize in a patient with dark skin pigmentation.

Not all people with a PWB have SWS; the overall incidence of SWS has been reported to be 8-33% in individuals with a PWB. Several studies have evaluated this specifically.

A study by Enjolras et al indicated that in patients with a PWB, SWS occurs only when the nevus involves the V1 (ophthalmic) distribution of the trigeminal nerve. In their retrospective review, the investigators studied data from 106 patients with a facial PWB, 12 of whom had SWS and 4 of whom had glaucoma without pial lesions. No patients who had involvement of the V2 (maxillary) and/or V3 (mandibular) area without V1 involvement had SWS.[31]

Patients in the study who were considered to be at high risk for SWS were those with involvement of the entire V1 area; 11 of 25 patients with full V1 involvement had SWS. Patients with only partial involvement of V1 were at low risk (only 1 of 17 patients had SWS).

In a study of 121 patients with facial nevi affecting the skin in the distribution of the trigeminal nerve, Bioxeda et al concluded that only those persons with V1 involvement were at risk for epilepsy or glaucoma. The investigators found that glaucoma and epilepsy were present in 23 (17%) and 17 (14%) patients, respectively, with V1 involvement occurring in all 40 of these individuals.[33]

The investigators also found that the facial nevi were located predominantly over the distribution of the V2 branch of the trigeminal nerve in 88% of these individuals, either isolated to the V2 branch or also involving the V1 and/or V3 branches. An extrafacial PWB was more common when V3 was involved. The lesions were unilateral in 86% of patients, and bilateral in 14% of them.

In a similar, but larger, study, Tallman et al found that only patients with a PWB involving the distributions of the V1 and V2 branches of the trigeminal nerve had CNS or eye involvement. The investigators reported on 310 patients with facial nevi, 85% of who had unilateral involvement, 15% of whom had bilateral involvement, and 68% of who had involvement of more than 1 dermatome. Overall, in patients with trigeminal involvement, only 8% had CNS and eye involvement; 24% of those with bilateral lesions had eye or CNS involvement, compared with only 6% of patients with unilateral lesions.[34]

Tallman and colleagues also found that all patients with eye or CNS involvement had lesions on the eyelids; 91% of these had both upper and lower eyelid involvement, whereas 9% had only lower eyelid involvement. No patients with upper eyelid involvement alone had eye or CNS involvement. Three of 16 patients with involvement of V1, V2, and V3 had eye and/or CNS involvement. The authors recommended screening for glaucoma and CNS involvement when the PWB involved the eyelids, with unilateral V1, V2, and V3 lesions, or with bilateral lesions.

Patients identified by the Sturge-Weber Foundation had a different pattern of involvement—170 of 171 patients had a craniofacial PWB, with unilateral involvement in 83 patients (49%) and bilateral involvement in 86 patients (51%).

Note that an extrafacial PWB may have associated intracranial abnormalities; for example, in Klippel-Trenaunay-Weber syndrome, neuroimaging may show findings similar to those of SWS,[35] and a cervical PWB has been associated with occipital calcifications.[32]

Seizures

The incidence of epilepsy in patients with SWS is 75-90%. Seizures result from cortical irritability caused by cerebral angioma, through mechanisms of hypoxia, ischemia, and gliosis. Dual pathology, such as microgyria, also may be present, which also contributes to epileptogenesis. Seizures may be intractable in some patients.

Garcia et al reported that a child with SWS could have an early normal neurologic course, with a seizure as the presenting manifestation of a neurologic problem.[17]

In a survey of cases identified by the Sturge-Weber Foundation,[8] seizures occurred in 136 of 171 patients, with the age of onset ranging from birth to 23 years and the median age of onset being 6 months. About 75% of the patients had onset during the first year of life; 86%, before age 2 years; and 95%, before age 5 years. Seizures occurred in 71% of those with unilateral and 87% of those with bilateral disease.

Bebin and Gomez, from the Mayo Clinic, reported that seizures occurred in 80% of patients with SWS (72% with unilateral involvement vs 93% with bilateral involvement), with the median age of onset being 8.5 months in patients with unilateral PWB and 4 months in patients with bilateral PWB.[36]

Oakes reported seizures in 24 (80%) of 30 patients with SWS, with a mean age of onset of 6 months.[37]

Bebin and Gomez reported an earlier onset of seizures in patients with bilateral involvement (mean ages of seizure onset were 6 months with bilateral disease and 24 months with unilateral disease).[36] Pascual-Castroviejo et al showed that patients with more frequent seizures tended to have an earlier seizure onset (mean seizure onset at age 5-6 months compared with a mean onset at age 2 years in those with less severe involvement).[38]

Pascual-Castroviejo et al reported seizures in 32 (80%) of 40 patients. Seizures began during a febrile illness in 10 patients (31%; fever could be a precipitant at any age), while infantile spasms occurred in 2 patients (6%).[38]

Developmental delay

In the patients reported by the Sturge-Weber Foundation, 50% had complete control and 39% had partial control of seizures with medications. Those with a later age of seizure onset had a lower incidence of developmental delay and fewer special educational needs.

The onset of seizures prior to age 2 may suggest a greater chance of refractory epilepsy and intellectual disability.[1] Patients with refractory seizures are more likely to have intellectual disability, since those individuals have more extensive brain involvement.

In a report by Sujansky and Conradi, using data obtained through the Sturge-Weber Foundation,[23] overall developmental delay occurred in 97 (58%) of 168 patients with SWS. Early developmental delay, however, occurred in 71% of patients with seizures and in only 6% of those without seizures. Patients with a later seizure onset also had a lower incidence of developmental delay and fewer special education needs.

However, even with seizure onset within the first year, Erba and Cavazzuti reported satisfactory control in 50% of patients, with 30% of patients being seizure free for at least 2 years. Among the other patients, 17% had an average of 1 seizure per month, and 33% were considered to have poorly controlled seizures, defined as greater than 1 seizure per week.[39] Therefore, early seizures may not predict either the severity of subsequent epilepsy or severe intellectual disability.

Maria et al divided their patients into 2 groups by age for a longitudinal study—those aged 1-3 years versus those aged 10-22 years—and found no difference in clinical outcomes with early onset seizures.[21]

Focal versus generalized seizures

Since the lesion responsible for epilepsy in SWS is focal, the majority of seizures are focal seizures. In a study of 76 patients, Bebin and Gomez reported partial seizures in 35 patients (46%), generalized seizures in 15 of them (20%), and both in 26 of them (34%).[36]

Pascual-Castroviejo et al reported seizures in 32 (80%) of 40 patients with SWS; 22 (69%) of them had focal seizures contralateral to the PWB, with subsequent generalization in 6 patients; 8 patients (25%) had generalized seizures at onset, and infantile spasms occurred in 2 patients (6%).[38]

Status epilepticus

Prolonged seizures cause neurologic injury secondary to metabolic disturbances such as hypoxemia, hypoglycemia, hypotension, ischemia, and hyperthermia.

In an already compromised vascular system, such as a vascular steal from the angioma, seizures are more likely to cause injury, even when short. Episodes of status epilepticus are, therefore, especially dangerous in SWS.[40]

Strokelike episodes

Transient episodes are referred to as strokelike episodes. These occurred in 14 (70%) of 20 patients described by Maria et al.[21] Garcia et al reported recurrent thrombotic episodes.[17] Stroke also may occur. The incidence of neurologic deficit is higher in adults; Sujansky and Conradi reported an occurrence in 34 (65%) of 52 patients,[41] results that demonstrated the progressive nature of SWS.

Hemiparesis

The incidence of hemiparesis is approximately 33% in patients with SWS, varying from 25-56%. The disorder occurs secondary to ischemia with venous occlusion and thrombosis. Commonly, transient weakness may occur with seizures and may increase with recurrent seizures. Transient hemiplegia may be accompanied by migraine headache, suggesting a vascular mechanism. However, Jung et al reported a case of a woman with headache and left hemiparesis but no neuroimaging evidence of acute thrombosis formation or recent vascular event.[42]

Hemianopsia

The mechanism for hemianopsia is similar to that for hemiparesis and is dependent on the location of the lesions. Uram and Zullabigo reported hemianopsia in 11 (44%) of 25 patients.[43] In 2009, Shimakawa et al reported a rare case of recurrent homonymous hemianopsia that became permanent.[44]

Developmental delay and intellectual disability

Related to the degree of neurologic involvement, developmental delay and intellectual disability occur in 50-60% of patients with SWS; they are more likely to exist in patients with bilateral involvement.[9] Bebin and Gomez reported normal mental functioning in only 8% of patients with bilateral SWS.[36]

In a detailed study of 10 patients with SWS, Maria et al found developmental delay and learning problems in all 10 and attention deficit hyperactivity disorder in 3.[45] Using a combination of computed tomography (CT) scanning, MRI, and functional imaging with single-photon emission CT (SPECT) scanning, abnormalities were found bilaterally the majority of patients, including extensive abnormalities in glucose metabolism and cerebral perfusion. These results may account for the high incidence of developmental delay, intellectual disability, and learning problems seen in SWS.

Seizures are also associated with a higher incidence of intellectual disability, and regression may be related to the frequency and severity of seizures as well.

Alkonyi et al reported on 14 patients with bilateral SWS who had an asymmetrical pattern on positron-emission tomography (PET) scanning and found that bilateral frontal and temporal hypometabolism was associated with poor developmental outcome. Good seizure control and only mild to moderate developmental impairment was seen in about 50% of the patients with bilateral SWS.[46]

Headaches

Occurring secondary to vascular disease, these have the symptoms of a migraine headache and are considered "symptomatic migraines."

In the aforementioned study by the Sturge-Weber Foundation, headaches occurred in 132 (77%) of 171 of patients of all ages and in 28 (62%) of 45 adults. In reports by Maria et al, headaches occurred in 60% of patients.[21, 45, 1]

In a specific study of headaches in SWS reported by Klapper, 71 patients identified by the Sturge-Weber Foundation responded to a questionnaire about headaches.[47] Migraine headache occurred in 28% of patients, and neurologic deficits occurred in 58% of these patients during the migraine. The prevalence of migraine was 31% in children younger than 10 years, much greater than the 5% prevalence in the general population.

Ocular manifestations

Glaucoma typically occurs in SWS only when the PWB involves the eyelids. The incidence ranges from 30-71%. Glaucoma may be present at birth but can develop at any age, even in adults.[48, 49]

Treatment includes yearly examinations to look for optic nerve damage (with measurement of IOP and visual fields) and for corneal diameter and refractive changes in children.

Glaucoma usually occurs only with an ipsilateral facial PWB, although the glaucoma may be bilateral when facial involvement is bilateral. Contralateral glaucoma may develop, although rarely. Glaucoma also may occur without neurologic involvement (Type II, Roach Scale).

Sullivan et al reviewed ocular abnormalities in 51 patients with SWS.[50] Of these, 36 patients (71%) had glaucoma, with onset before age 24 months in 26 (51%) patients; 35 (69%) patients had conjunctival or episcleral hemangiomas; and 28 (55%) patients had choroidal hemangiomas.

With time, choroidal hemangioma may cause other secondary changes, including the following:

• Retinal pigment epithelium degeneration

• Fibrous metaplasia

• Cystic retinal degeneration

• Retinal detachment

Retinal vascular tortuosity, iris heterochromia, optic disc coloboma, and cataracts have also been seen in patients with SWS.

The Sturge-Weber Foundation data show that 82 (48%) of 171 patients had glaucoma. Of these patients, 61% developed glaucoma during the first year of life; a second peak occurred in children aged 5-9 years, when it developed in another 11 (15%) patients.

Endocrine problems

An increased rate of growth hormone deficiency was found in SWS, as identified from a registry of 1653 patients.[51] Comi et al found central hypothyroidism in 2 children out of 83 (2.4%) with SWS and brain involvement, indicating that central hypothyroidism is much more prevalent in such patients than it is in the general population.[52]

Additional morbidities

The Sturge-Weber Foundation survey indicated that other abnormalities occurred in all 171 patients in the study. These included other cutaneous lesions in all patients and body asymmetry in 164 (96%) of 171 patients, with soft-tissue hypertrophy occurring in 38 (23%) of the 164 patients and scoliosis existing in 11 (6.7%) of the 164 patients. Basal cell carcinoma has been reported to occur within a PWB.[53]

Adults with SWS

Few data are available on adults with SWS. Sujansky and Conradi studied the outcomes in 52 adults older than 18 years who had SWS and were identified by the Sturge-Weber Foundation.[41] The age of onset of glaucoma ranged from 0-41 years, with a median of 5 years.

Seizures occurred in 83% of the patients, glaucoma in 60%, and a neurologic deficit—such as stroke, paralysis, spasticity, or weakness—in 65%. The age of onset of seizures ranged from 0-23 years, with a median of 6 months.

Seizure outcome was known in 41 patients in the study, with full control attained in 11 (27%) patients, a decrease in seizures achieved in (49%) 20 patients, and no improvement found in 10 (24%) patients. The morbid conditions associated with these seizures are listed in Table 2, below.

Headache occurred in 28 (62%) of 45 patients, with age of onset ranging from early childhood to age 38 years and with a median age of onset of 18 years. The headache frequency could be determined in 23 patients: daily in 9 patients (39%), 1-4 times per week in 4 (17%), 1-2 times per month in 6 (26%) patients, and rare in 4 patients (17%).

Headaches were associated with increased discoloration of facial PWB, auras, nausea/vomiting, dysarthria, dizziness, and feelings of facial pulsation.

Table 2. Developmental Morbidity Associated with Seizures in Adults with SWS (Open Table in a new window)

Counseling may assist with treatment.[54]  Support groups for persons with Sturge-Weber syndrome include The Sturge-Weber Foundation, PO Box 418, Mount Freedom, NJ, 07970-0418.

Sturge-Weber syndrome (SWS) is generally diagnosed on clinical grounds by the association of the typical cutaneous, CNS, and ocular abnormalities. Neurological signs include the following:

• Developmental delay/intellectual disability

• Learning problems

• Attention deficit-hyperactivity disorder

Children with bisymptomatic or trisymptomatic SWS may, however, initially seem neurologically normal and have no symptoms of glaucoma or other ocular manifestations. In some instances, therefore, the diagnosis may not become clear for an extended period of time.

Progressive neurological injury

Factors suggesting a progressive course of cortical injury in SWS include the following:

• Initial focal seizures progressing to frequent, secondarily generalized seizures

• Increasing seizure frequency and duration despite the use of antiepileptic drugs (AEDs)

• Increasing duration of a transient postictal deficit

• Increase in focal or diffuse atrophy determined by serial neuroimaging

• Progressive increase in calcifications

• Development of hemiparesis

• Deterioration in cognitive functioning

Physical signs of Sturge-Weber syndrome (SWS) are as follows:

• Port-wine birthmark (PWB; see the image below)

  A child with Sturge-Weber syndrome with bilateral facial port-wine stain.

• Macrocephaly

• Ocular manifestations

• Soft-tissue hypertrophy

• Hemiparesis

• Visual loss

• Hemianopsia

When a typical facial vascular skin lesion is found in a newborn, it should alert the physician to perform a complete ophthalmic and systemic assessment for the potentially serious associated disorders.

Cutaneous lesions

The cutaneous venous facial lesion is usually the first component of the syndrome to be observed, because it is visible at birth. It may be very pale at first, but it usually becomes darker with age. However, the lesion does not increase in extent. PWB is not a medically threatening condition, but because it is a cosmetic deformity, it may carry a psychological impact.

Ocular changes

Ocular involvement in SWS may include the following signs:

• Hemangiomalike, superficial changes (which on histology demonstrate only venous dilation) in the eyelid

• Buphthalmos

• Glaucoma

• Tomato-catsup color of the fundus (ipsilateral to the nevus flammeus) with glaucoma

• Conjunctival and episcleral hemangiomas

• Diffuse choroidal hemangiomas

• Heterochromia of the irides

• Tortuous retinal vessels with occasional arteriovenous communications

• Ocular signs that may indicate the presence of infantile glaucoma include the following:

• Corneal diameter of more than 12 mm during the first year of life

• Corneal edema

• Tears in the Descemet membrane (Haab striae)

• Unilateral or bilateral myopic shift

• Optic nerve cupping greater than 0.3

• Any cup asymmetry associated with intraocular pressure above the high teens

• Optic nerve damage resulting in myopia, anisometropia, amblyopia, strabismus, and visual field defects

Increased conjunctival vascularity can be seen on slit lamp examination or can be viewed by the naked eye as a pinkish discoloration. The abnormal plexus of episcleral vessels may be hidden by the overlying tissue of the Tenon capsule in infancy and only appreciated clinically in later childhood.

Prominent, tortuous conjunctival and episcleral vascular plexuses affect as many as 70% of patients with SWS and often correlate with increased episcleral venous pressure, probably resulting from arteriovenous shunts within the episcleral hemangiomas. The overlying retinal vessels may be affected, demonstrating dilation and tortuosity, as well as peripheral arteriovenous communications.

Iris heterochromia occurs in approximately 10% of patients with SWS. The more deeply pigmented iris usually is ipsilateral to the PWB, signifying an increase in melanocyte number or activity.

The diagnosis of diffuse choroidal hemangioma is based on tumor appearance on indirect binocular ophthalmoscopy.

Several possible mechanisms may be responsible for decrease in visual function in patients with SWS. As soon as the syndrome is first suspected or documented, a complete ophthalmic evaluation is essential to rule out glaucoma, since the infant's eye is damaged quickly by increased intraocular pressure. The earlier glaucoma is documented and the more effectively it is controlled, the less likely secondary glaucomatous changes will occur.

Amblyopia

Amblyopia is an important cause of poor vision in patients with infantile glaucoma. Amblyopia usually is anisometropic from glaucoma-induced myopia or secondary to unilateral or bilateral pattern deprivation caused by cloudy corneas. Even when glaucomatous optic nerve damage is present, amblyopia may be superimposed on the organic damage. Therefore, a trial of amblyopia therapy is indicated.

Choroidal hemangioma

Diffuse choroidal hemangioma is present in as many as 40-50% of patients with SWS. A circumscribed, isolated form occurs in otherwise normal adults. It is almost always unilateral and ipsilateral to the PWI, but bilateral cases associated with bilateral nevus flammeus have been described. (See the image below.)

Choroidal hemangiomas are flat, commonly covering over one half of the fundus, involving the posterior pole, and extending into the equatorial zone. Diffuse involvement of the entire uvea may be seen. In some cases, the extent and character of the pathognomonic choroidal vascular lesion results in a striking reddish glow, to which the descriptive term tomato-catsup fundus has been applied (see the images below). Some patients have a focal area (often paramacular) where the angioma is more thickened and elevated.

The choroidal angiomatosis grows slowly and usually remains asymptomatic in childhood. During adolescence or adulthood, marked thickening of the choroid sometimes becomes evident with secondary changes to overlying ocular structures.

Retinal changes

Changes in the overlying retinal pigment epithelium overlying the choroidal hemangioma range from mild atrophy to focal proliferation with drusen formation to severe fibrous transformation and focal ossification. The retina over the hemangioma may be attached and well preserved, attached and degenerated, or detached.

Degenerative changes in the overlying retina include focal chorioretinal adhesions, loss of photoreceptors, severe cystoid degeneration of the outer layers, and marked gliosis. Widespread serous detachment, retinal leakage, and edema may occur. In its early stages, the choroidal thickening and elevation of the retina may produce an increasing ipsilateral hyperopia. With progression of secondary changes, visual loss and visual field defects may develop. Subretinal fibrosis in the macular area and cystoid macular edema are associated with the most severe visual loss.

Glaucoma

Glaucoma is almost always unilateral and ipsilateral to the PWB, although contralateral or bilateral glaucoma with unilateral cutaneous lesions has been reported. The occurrence of glaucoma has been especially noted when the facial skin changes involve the upper and lower eyelids.

Glaucomatous damage, as well as degenerative changes in the outer retinal layers and vascular abnormalities in the occipital lobe, may cause visual field defects. Careful visual field perimetry is indicated.

As soon as Sturge-Weber syndrome (SWS) is first suspected or documented, a complete ophthalmologic evaluation is essential to rule out glaucoma, since the infant's eye is damaged quickly by increased intraocular pressure (IOP).

In young patients, examination under anesthesia or deep sedation is necessary to confirm the diagnosis of glaucoma. Careful assessment in each eye of IOP, corneal diameter, cycloplegic refraction, axial length, and optic nerve cupping, as well as gonioscopic examination, is mandatory.

Cerebrospinal fluid (CSF) protein may be elevated, presumably secondary to microhemorrhage. Note that a major intracranial hemorrhage itself is rare in SWS, although microhemorrhage may be common.

Besides the clinical examination, the following have historically been the procedures of choice to establish the diagnosis (see Table 3, below)[1] :

• Skull radiography

• Angiography

• CT scanning

• MRI

• MRI with gadolinium

• Functional imaging - With SPECT or PET scanning

Table 3. Summary of Work-up Findings in Sturge-Weber Syndrome (Open Table in a new window)

Free thyroxine assay

A study by Siddique et al indicated that in patients with SWS who are taking anticonvulsants (which can cause abnormal results on thyroid function tests), a free thyroxine equilibrium dialysis assay is a more accurate means of diagnosing true hypothyroidism than is thyroid function testing. The investigators found that out of 5 children with SWS who were taking anticonvulsants and had been diagnosed with hypothyroidism using thyroid function testing, only 2 were revealed to have true hypothyroidism when tested with a free thyroxine equilibrium dialysis assay.[58]

Skull radiographs may show the classic double-lined gyriform pattern of calcifications paralleling cerebral convolutions referred to as “tram-track” (also called tramline, trolley-track, or railroad track) calcifications. These were considered pathognomonic for SWS in the era prior to modern neuroimaging, but they are often a late finding and may not be present initially.

Wilms et al reported tram-track calcifications in tuberous sclerosis with calcification located in extensive cortical tubers[59] ; Borns and Rancier reported these in childhood leukemia.[60]

Angiography does not show the angioma but instead demonstrates a lack of superficial cortical veins, nonfilling of dural sinuses, and abnormal, tortuous veins that course toward the vein of Galen.

Fluorescein angiography has become a useful complementary examination in SWS. Angiography may reveal only an exaggerated background choroidal fluorescence early in the disease, widespread and irregular areas of hyperfluorescence secondary to diffuse leakage of dye from the surface of the tumor during the later stages of angiography, or even a diffuse, multiloculated pattern of fluorescein accumulation in the outer retina characteristic of polycystic degeneration and edema in more advanced disease.

Diffuse choroidal hemangioma may be overlooked easily on ophthalmoscopic examination because the color of the hemangioma resembles that of normal fundus, and the elevation may be minimal, especially in children.

Comparison of the red reflex in the eye being examined with that in the normal opposite eye can be helpful in confirming the diagnosis of a diffuse choroidal hemangioma; the normal eye may appear less orange.

CT scans may show calcifications in infants and even in neonates, with Sturge-Weber syndrome (SWS); other findings include the following:

• Brain atrophy

• Ipsilateral choroid plexus enlargement

• Abnormal draining veins

• Breakdown of the blood-brain barrier with seizures

CT scanning is more sensitive than skull radiography and MRI in the detection subcortical calcifications, and detection is sometimes possible in patients younger than 2 years.[61]

In a study of CT scans in 14 children with SWS, conducted by Terdjman et al, cortical calcifications were present in 12 patients (see the image below), localized atrophy had occurred in 10 patients, and enlargement of the choroid plexus and abnormal veins were found in 7 patients each.[62]

Neuroimaging can confirm central nervous system (CNS) involvement. MRI has been reported to be superior to CT scanning in detecting the malformations affecting the CNS in Sturge-Weber syndrome (SWS). However, the diagnosis is often obvious on plain skull radiography.

A retrspective study of 60 patients with SWS reported the presence of asymmetric cavernous sinus (CS) enlargement in 11.6% of patients. A finding of asymmetric CS enlargement, along with brain atrophy and deep venous dilatation, was associated with neurologic deficits.[63]

MRI allows recognition of abnormalities, including abnormal venous drainage and abnormal pial contrast enhancement, associated with the SWS angiomatous malformation that can confirm the diagnosis, even in very young children.

MRI also demonstrates cerebral volume reduction and ipsilateral choroid plexus enlargement. In addition, intravenous contrast can demonstrate the curvilinear posterior contrast enhancement of ocular choroidal angiomas. (See the images below.)

On the other hand, CT scanning is superior to MRI in detecting tram-track calcifications. However, these calcifications are usually not detectable before age 1 year and may not be seen for several years.

MRI with gadolinium enhancement

Although MRI does not show calcifications, gadolinium enhancement may show pial angioma; therefore, MRI may permit early diagnosis of SWS, even in newborns with a facial PWS.[64] Sugama et al reported that the most characteristic finding of SWS on MRI with gadolinium is enhancement of leptomeningeal angiomas (LAs).[65] LAs may be seen that did not appear on CT or angiographic images. MRI with gadolinium may also delineate the extent of the LA. Fischbein, however, reported that gadolinium enhancement may not be seen in every case.[66]

Hu et al reported that MR susceptibility-weighted imaging (SWI) may complement gadolinium-enhanced, T1-weighted MRI in characterizing abnormalities in SWS.[67]

MR spectroscopy and diffusion-weighted MRI

MR spectroscopy has shown increased choline but no reduction in the neuronal marker N- acetyl aspartate (NAA) in SWS, although in other reports, MR spectroscopy has shown decreased NAA.[68] Cakirer et al showed decreased NAA and increased choline in a patient with SWS, while the abnormal area also showed increased apparent diffusion coefficient (ADC) on diffusion-weighted MRI.[69, 70]

Regarding the MR spectroscopy findings in these studies, the decreased NAA was considered to represent neuronal loss, and the elevated choline was believed to demonstrate a lack of normal development.

BOLD MR venography

Mentzel et al reported that blood-oxygen-level-dependent (BOLD) MR venography may be sensitive in detecting early venous abnormalities in a case of SWS (earlier than conventional MRI sequences).[71]

MRI with DTI

Sivaswamy et al reported diffusion tensor imaging (DTI) abnormalities in the corticospinal tract of the affected hemisphere, which were seen before severe motor deficits developed.[72] In this study, the authors found lower fraction anisotropy (FA) values and higher ADC values of the cortical spinal tract in the affected hemisphere in 16 children with SWS (aged 1.5-12.3 y).

Interestingly, Moritani et al reported increased FA and decreased ADC in the subcortical white matter adjacent to the LAs in a term neonate aged 7 days with SWS.[73] As there are such varied findings on DTI and ADC, further studies are necessary to clarify the nature of DTI and ADC changes in SWS. It is likely that these changes are influenced by multiple factors, such as age and the stage of SWS.

Additional findings

Other MRI findings include accelerated myelination around the LA;[74]  a large choroid plexus, the size of which correlates with the extent of the LA[75] ; and progressive sinovenous occlusion on MR venography. Of note, Benedikt et al reported pial angiomatosis with adjacent cortical atrophy on MRI in 4 patients in whom unenhanced MRI or CT scan was normal or showed only nonspecific findings.[76]

Juhasz et al reported that cerebral hemisphere white matter volume ipsilateral to the angioma was an independent predictor of IQ, and that loss of such white matter volume may play a significant role in cognitive impairment in children with SWS.[77]

Bernal and Altman reported abnormal activation patterns in the occipital areas on functional MRI in patients with SWS.[78]

Lin et al reported perfusion MRI findings compatible with impaired venous drainage in an early case of SWS with new-onset seizures.[79]

SPECT scanning

This modality measures cerebral blood flow and demonstrates underperfusion in the area of the pial angioma; it may therefore detect a latent angioma not seen in other studies (see the image below). Using SPECT scanning, Reid et al demonstrated the presence of hypoperfusion before calcifications, anomalous drainage, or enhancement developed on either CT or MRI scans.[22] Griffiths et al showed that MRI and SPECT scanning together may reveal different areas of involvement.[80]

Namer et al demonstrated a steal phenomenon during seizures, causing ischemia in remote areas, with subtraction ictal SPECT co-registered to MRI (SISCOM).[81]

Pinton et al demonstrated that in infants with SWS, the cortex is hyperperfused during the first year of life before the first seizures occur. Classic hypoperfusion appears after 1 year of age, even in patients without epilepsy.[82]

Maria et al reported that enlargement of the choroid plexus correlates with abnormalities seen with SPECT scanning.[1]

PET scanning

In a pre-MRI study by PET scanning of children with Sturge-Weber syndrome (SWS), Chugani et al demonstrated metabolic abnormalities in structurally affected hemispheres that extended beyond the anatomic abnormalities detected by CT scanning.[83] This result suggested that PET scanning might help to identify suitable candidates for hemispherectomy or focal cortical resection.

In the diagnosis of diffuse choroidal hemangioma, A-scan and B-scan ultrasonography may be useful diagnostic aids. B-scan ultrasonography characteristically shows a solid, echogenic mass, whereas A-scan ultrasonography demonstrates high internal reflectivity. (See the ultrasonograms below.)

Jordan et al reported the use of transcranial Doppler ultrasonography in 8 children with SWS. Decreased arterial blood flow velocity and increased pulsatility were found in the middle and posterior cerebral arteries, suggesting high resistance. These results may reflect high venous stasis, potentially contributing to chronic hypoperfusion.[84]

Riela et al studied the xenon-133 (133 Xe) inhalation technique in 4 patients with SWS and demonstrated decreased regional perfusion in the area of the LA, with impaired vasomotor reactivity documented in 2 patients.[85] Decreased flow was prominent in 2 younger patients with normal neurologic status, suggesting that the blood flow abnormality may actually precede neurologic symptoms and may therefore cause or at least contribute to the deterioration.

Determining the maximum extent of disease in patients with Sturge-Weber syndrome (SWS) may require a combination of structural and functional neuroimaging, since a mismatch may exist among neuroimaging modalities. Each modality may demonstrate abnormalities not detected by the other. This is especially important in the identification of the epileptogenic region when considering surgery for refractory seizures. A combination of modalities may also demonstrate a larger area of functional abnormality affected by SWS and potentially provide more information on prognosis.

Juhász et al studied 13 children with SWS using susceptibility-weighted images and DTI, in conjunction with PET scanning. SWI detected cortical abnormalities and deep transmedullary veins in the white matter adjacent to the hypometabolic regions. DTI detected abnormalities in the hypometabolic cortex and the adjacent white matter with collateral veins.[86]

Alkonyi et al reported 20 unilateral SWS patients with DTI and fluorodeoxyglucose (FDG)-PET scanning, measuring the diffusion parameters and FDG uptake in the thalami. Severe asymmetries of glucose metabolism and diffusion were strong predictors for low IQ.[87]

Electroencephalography (EEG) is used for the evaluation of seizures and for the localization of seizure activity in refractory seizures when epilepsy surgery is considered.

Brenner and Sharbrough reported unilateral reduction of background amplitude as the most consistent finding in the waking and sleep states, with activation procedures (hyperventilation and photic driving) decreased on the involved side.[88] EEG findings predated calcifications. Epileptiform activity was limited to the involved hemisphere.

In a study of children with Sturge-Weber syndrome (SWS) and epilepsy, Sassower et al reported marked voltage attenuation in the region of angioma in 13 of 14 patients; polymorphic delta activity (PDA) occurred in 12 of 14 patients. The PDA was unilateral in 6 of the dozen patients and correlated with the angiomatosis. None of the patients with unilateral PDA had intellectual disability. In the 6 patients with bilateral PDA, 4 had intellectual disability despite a unilateral angioma. Interictal spikes occurred in only 2 patients and were bilateral in 1 patient with unilateral disease. Seizures were recorded in 4 patients, and the ictal activity came from the periphery of the lesion. The seizures were refractory to treatment in 6 of 14 patients.[89]

Erba and Cavazzuti reported that late in the course of SWS, epileptiform activity might occur from the contralateral cortex.[39]

In a Canadian study, the EEG was normal in only 4%, background suppression occurred in 74% (unilateral in 64% and bilateral in 10%), and epileptiform discharges occurred in 22%.

Jansen et al reported asymmetry in beta activity in SWS, before and after diazepam administration in brain regions that structurally appeared intact.[90] The investigators suggested that diazepam-enhanced EEG may provide information on functional involvement and monitor progression of the disease.

The leptomeninges in Sturge-Weber syndrome (SWS) appear thickened and discolored by the LA, which fills the subarachnoid space, and abnormal venous structures are seen. Biopsies typically are not performed in SWS. However, pathologic specimens, such as those examined by Norman and Schoene, show calcium deposits in the cerebral vessel walls, in perivascular tissue, and, in rare cases, within neurons, as well as neuronal loss and gliosis.[16] These pathological abnormalities may occur at a distance from the actual vascular lesion.

Di Trapeni et al reported a mucopolysaccharide substance with calcium in the connective tissue of the vessels early on in SWS. This substance was found to increase in size and migrate outside the vessels. The investigators postulated that anoxia, necrosis, and variations in calcium concentrations act only as secondary factors.[91]

Hoffman et al have showed that aluminum was present within the calcium concretions,[92] and Simonati et al reported 4-layered microgyria below the angiomatosis.[93]

In skin biopsies of the PWS in patients with SWS, dilated, thin-walled vessels are seen in the superficial vascular plexus, but with no increase in the number of blood vessels.

In trabeculectomy specimens in patients with SWS, abnormal collagen depositions and abundant vessels in the intratrabecular spaces have been seen with morphologic abnormalities in the Schlemm canal. Hemangiomas in the trabecular meshwork are characteristic of SWS.

Medical care in Sturge-Weber syndrome (SWS) includes antiepileptic medications for seizure control, symptomatic and prophylactic therapy for headache, glaucoma treatment to reduce the intraocular pressure (IOP), and laser therapy for port-wine birthmark (PWB).

Surgery is desirable in patients with SWS for refractory seizures, glaucoma, and specific problems related to various SWS-associated disorders, such as scoliosis.[3]

Medical treatment of glaucoma in SWS usually fails with time, so most ophthalmologists consider surgical therapy to be the mainstay of treatment for SWS-associated glaucoma.[94]

Because seizures in Sturge-Weber syndrome (SWS) are typically focal, an antiepileptic medication with efficacy in focal seizures is preferable. Antiepileptic medications include the following:

• Oxcarbazepine (Trileptal)

• Carbamazepine (Tegretol)

• Phenytoin (Dilantin)

• Lamotrigine (Lamictal)

• Levetiracetam (Keppra)

• Valproic acid (Depakote, Depakene, Depacon)

• Zonisamide (Zonegran)

• Topiramate (Topamax)

• Lorazepam (Ativan)

• Phenobarbital (Luminal, Barbita)

• Gabapentin (Neurontin)

• Pregabalin (Lyrica)

• Tiagabine (Gabitril)

• Diazepam (Valium)

• Felbamate (Felbatol)

• Lacosamide (Vimpat)

• Clonazepam (Klonopin)

The modified Atkins diet was reported as safe and effective in reducing seizure frequency in 5 children with SWS.[95]

The chance of achieving seizure control with medical therapy in SWS varies. Depending on the series, complete seizure control has been achieved in 10-50% of patients, and refractory seizures occur in 11-83% (see Table 4, below). Results vary by the patient population seen at different centers, with a higher incidence of medical failures reported by surgical centers. However, according to Arizmanoglou, even data from the surgical centers indicate that good seizure control is achieved in one third to one half of the patients seen at these centers.[96]

Table 4. Seizure Control in Sturge-Weber Syndrome (Open Table in a new window)

The goal of treatment is control of intraocular pressure (IOP) to prevent optic nerve injury. This can be achieved with the following agents:

• Beta-antagonist eye drops - Decrease the production of aqueous fluid

• Carbonic anhydrase inhibitors - Also decrease production of aqueous fluid

• Adrenergic eye drops and miotic eye drops - Promote drainage of aqueous fluid

Although medical treatment of SWS glaucoma usually fails with time, it may be tried initially. This is because a significant reduction in IOP may be seen, at least temporarily, and may be helpful in clearing the cornea, thus facilitating surgical therapy. Moreover, it can be used to delay filtration surgery in younger patients. This is especially important, because the technical difficulties of operating on a smaller eye are excessive, and there is an increased tendency for scarring at the site of the scleral flap in the younger patient, reducing the chances for long-term surgical success.

Medical therapy can also be used as an adjunct to surgery. Topical antiglaucoma therapy for extended periods of time is sometimes helpful postoperatively to further reduce borderline IOP elevations without the need for reoperation. Initial medical therapy with a topical beta blocker, followed sequentially with the addition of a carbonic anhydrase inhibitor (systemic in infants and topical in older children) and topical prostaglandin (latanoprost [Xalatan]), is a reasonable protocol in patients with SWS.

Recurrent headaches can be treated with symptomatic and prophylactic medications. Kossoff et al found evidence that headaches in Sturge-Weber syndrome (SWS) may be undertreated. The investigators evaluated 68 patients with SWS regarding headaches, identified through the Sturge-Weber Foundation.[99] Mean onset of the headaches was 8 years. Fifty-five of the 68 patients had epilepsy as well. Twenty-two of these patients perceived that the headaches were a more significant problem compared with their epilepsy. A positive family history of headaches was seen in 37 of these patients.

Most of the patients were using only abortive treatment, mainly acetaminophen and ibuprofen, while only 15 were tried on preventative agents, including gabapentin, valproate, and amitriptyline (none were on beta-adrenergic blockers).

Kossoff et al also reported that in SWS, triptans and preventative agents appear to be effective for headaches. In the study, 104 patients with SWS and migraine headaches self-reported treatment patterns through a questionnaire.[100]

Aspirin has been used for headaches and to prevent vascular disease, although it typically is used in patients who have had neurologic progression or recurrent vascular events.[101] Aspirin needs to be used with extreme caution in children because of the risk that Reye syndrome could develop, and the risks and benefits need to be carefully weighed.

Thomas-Sohl, Vaslow, and Maria have recommended 3-5 mg/kg/day of aspirin for stroke-like events. They also recommended varicella and yearly influenza immunizations because of the association of varicella and influenza infections with Reye syndrome.[1]

Maria et al reported a decreased incidence of strokelike events in 20 patients with Sturge-Weber syndrome (SWS) who received aspirin. Of 119 strokelike events, 31 occurred in patients treated with aspirin, whereas 88 of these events occurred in those not treated with aspirin. The authors suggested further investigation of aspirin treatment in SWS.[21]

Using data from a survey on aspirin use in 34 SWS patients, Bay et al reported a reduction of strokelike episodes from 1.1 to 0.3 per month and a reduction of seizures from 3 to 1 per month. The investigators found that 39% of patients had complications of predominantly bruising or gum/nose bleeding, although none were reported to have discontinued aspirin due to adverse effects.[102]

Lance et al, in a review of 58 patients with SWS on aspirin, found that 49 had no significant adverse effects, while the remaining 9 had allergic reactions or minimal to significant bleeding while on aspirin. Reasonable seizure control was seen in 91% of the patients, no or mild hemiparesis occurred in 57% of them, no vision impairment was found in 71% of patients, and no or mild cognitive impairment was seen in 80% of them. The authors suggested that these data support the use of low-dose aspirin for optimizing neurodevelopmental outcome in SWS.[103]

The port-wine birthmark (PWB) needs to be evaluated within the first week of life and differentiated from hemangioma.

Treatment of the cutaneous PWB with dye laser photocoagulation has been helpful in reducing the cosmetic blemish from the cutaneous vascular dilatation.[2] The therapy should start as soon as possible, since multiple treatments are needed and earlier treatment may reduce the number of sessions required. Also, the smaller the lesion is initially, the lower the number of flashes that will be required to remove it.[104, 105]

In a survey of patients with PWB that examined the potential psychological benefits from early treatment of the lesion, Troilius et al found that 75% of the patients reported that the PWB had affected their lives negatively, 62% of them were convinced that their lives would improve if the PWB were removed, 47% of them suffered low self-esteem, and 28% of the patients said that the PWB made their school life and education more difficult. No persistent pigmentation changes or posttreatment scarring were reported after laser therapy.[106]

Surgical options are available for seizures refractory to medical treatment, especially for focal seizures.[107] Erba and Cavazzuti estimated that 40% of patients with SWS could become epilepsy surgery candidates, excluding those with either good seizure control or bilateral disease.[39]

Surgical procedures include focal cortical resection, hemispherectomy, corpus callosotomy, and vagal nerve stimulation (VNS).[4] SWS is considered one of the catastrophic epilepsies, which, according to Holmes, result in poor seizure control and developmental outcome if not controlled early. However, criteria for medical intractability should be fulfilled before considering surgery.[108]

Early surgery has been advocated specifically in SWS to improve outcome and prevent refractory seizures, developmental delay, and hemiparesis. In the era prior to modern neuroimaging, Alexander and Norman suggested exploratory craniotomy and lobectomy if the diagnosis was confirmed, even before seizures started, because they believed that early onset seizures were associated with intellectual disability.[109]

Hoffman et al and Ogunmegan et al later advocated early hemispherectomy for seizures.[98, 110]

Erba and Cavazzuti recommended surgery when seizures, as well as other neurologic events, such as headaches or mild head trauma, are associated with functional neurologic deficits. The presence of such deficits indicates an impairment in cortical perfusion.[39]

Arzimanoglou and Aicardi preferred to treat seizures initially with antiepileptic drugs (AEDs), no matter what the age of onset, and recommended surgery when seizures are intractable or when evidence of progressive cortical damage is noted. The appropriate surgical procedure would be determined individually by clinical course, EEG, and neuroimaging.[96, 111]

Overall, while some variations exist in the criteria, most studies recommend early surgery with difficult-to-control seizures and a progressive clinical course, determined on an individual basis, as noted above.

Outcome of epilepsy surgery in SWS

Three centers have reported surgery outcomes involving groups of more than 10 patients, including Hoffman et al, from Toronto; Arzimanoglou and Aicardi, from Paris; and the authors' series, from Children's Hospital, Boston (see Table 5, below). Of the 32 patients from these groups who had limited resection, 18 became seizure free, 10 experienced improvement, and 4 had no improvement. Of the 26 patients who were treated with hemispherectomy, 24 became seizure free.

The Toronto researchers found that, in terms of developmental outcome, surgical treatment was preferable to medical therapy. They compared the ultimate developmental outcome (determined by intelligence quotient [IQ] score) of medical and surgical therapies in 50 patients, 17 of whom underwent surgery and 33 of whom were given medical therapy. Normal or borderline functioning was more common after surgical treatment (10 of 17 patients [58.8%]) than after medical therapy (11 of 33 patients [33.3%]).[92]

When surgery is considered, the choice of appropriate procedure must be the main consideration. The epileptogenic region is located in the cortex adjacent to the angioma, and electrocorticography (ECOG) may be needed. However, the LA usually covers the entire hemisphere, and even areas without angioma may be epileptogenic and therefore need resection to achieve seizure control.

Focal cortical resection

A focal cortical resection (a more limited resection) is performed when the LA and, therefore, the epileptogenic region is smaller and more localized. This can be demonstrated preoperatively by localizing the area of seizure onset, either with surface EEG or ECOG (if invasive monitoring has been done), with a combination of structural and functional neuroimaging, and with intraoperative ECOG.

A hemispherectomy is performed when an extensive, unilateral epileptogenic region exists. When the epileptogenic region is smaller, a focal cortical resection (ie, a more limited resection) is preferable, since it is less likely to cause a neurological deficit. Hoffman reported that focal disease responds well to resection, ECOG identifies adjacent epileptogenic cortex, and hemispherectomy produces a significant improvement in outcome, leading to normal intelligence and a greater than 90% chance of becoming seizure free.

Residual seizures, however, are more likely to occur after a more limited resection than they are following hemispherectomy. Gilly et al reported a 30% failure rate after limited resection,[97] and in the combined data from 3 surgical centers, 12.5% of those patients who underwent a limited resection had no improvement. (See Table 5, below.)

Table 5. Surgical Results of Hemispherectomy and Limited Resection from 3 Centers (Open Table in a new window)

In a study of hemispherectomy outcomes in cases of SWS, 81% of patients were found to be seizure free, with 53% off antiepileptic drugs; the type of surgery (anatomic hemispherectomy vs functional hemispherectomy vs hemidecortication) did not influence outcome. In the report, Kossoff et al evaluated the results of hemispherectomy in 32 patients with SWS, using a questionnaire; these patients were identified through the Sturge-Weber Foundation.[112]

Although this study was limited because of the volunteer basis of the returned questionnaires, it nonetheless included a larger number of patients were involved in previous studies. Patients had hemispherectomy between 1979 and 2001; the mean age of seizure onset was 4 months, and the median age of surgery was 1.2 years.

Sixteen patients in the study had anatomic hemispherectomy, 14 had functional hemispherectomy, and 2 had hemidecortications, with the surgeries performed in 18 different centers throughout the world. Fifteen patients had complications in the immediate postoperative period, including hemorrhage, infection, and severe headaches, and they underwent reoperation due to persistent seizures, shunting, or hypertension. No deaths occurred.

Age of seizure onset did not predict seizure freedom. Older age, however, had a positive correlation with surgical outcome. Postoperative hemiparesis was not worse than it was before the surgery. Cognitive outcome was not related to age at surgery, side of surgery, or seizure freedom.

The Toronto group suggested that hemispherectomy is more successful if done during infancy, since earlier seizure control helps to preserve the function of the normal hemisphere.[92, 98]

Alternatively, if the patient is not a candidate for a limited resection or hemispherectomy, such as when disease is bilateral, corpus callosotomy can be performed or VNS can be administered. VNS has been shown to be effective for focal seizures; its mechanism of action is a putative increase in CNS inhibitory activity.

Surgical recommendations

The Sturge-Weber Foundation recruited a task force to evaluate epilepsy surgery in SWS. The following is a summary of recommendations for such surgery, modified to include VNS:

• Hemispherectomy should not be done in every patient with SWS solely because of the emphasis on increasingly early surgery; surgery is appropriate only for medically refractory seizures

• Patients with intractable seizures and very localized lesions should have a limited resection that preserves as much normal tissue as possible

• Video EEG and structural and functional neuroimaging should be used to define the extent of the lesion and the site of seizure origin

• Corpus callosotomy is reserved for patients with intractable atonic or tonic seizures leading to secondary injury, if the patients are not candidates for more definitive surgery

• Surgery should be performed only in a center with an ongoing pediatric epilepsy surgery program

• Although the benefit of surgery for refractory seizures is accepted generally, additional work is needed to evaluate the natural history of the syndrome and the potential benefits and risks of surgery

• VNS can be performed in patients who are not candidates for other surgical procedures

Data on the natural history of SWS are not yet sufficient to advocate hemispherectomy unless refractory seizures occur.

Management of affected eyes emphasizes the reduction of subretinal fluid as the main therapeutic aim in an attempt to stabilize or reverse, if possible, visual impairment caused by nonrhegmatogenous retinal detachment.

However, no reliable treatment of the retinal detachment that develops in these patients has been found, and even in the exceptional case in which the retina can be reattached, fibrous metaplasia of the retinal pigment epithelium and cystoid degeneration of the retina overlying the choroidal hemangioma prevent good visual result. Many such eyes eventually become blind and painful and must be enucleated.

Attempts at repairing the nonrhegmatogenous retinal detachment variously involve cryotherapy and diathermy, xenon arc or argon laser photocoagulation, subretinal fluid drainage, and radiation therapy. A critical factor in a successful outcome appears to be the early initiation of treatment.

Laser photocoagulation

In laser photocoagulation, which is generally considered to be the preferred therapeutic intervention, placement of light photocoagulation scars over the entire tumor is completed in an attempt to strengthen the adhesion between the retina and the underlying pigment epithelium and, thus, to prevent the spread of the retinal detachment. This form of treatment has afforded limited success. However, retinal detachment often recurs even after photocoagulation therapy, and in some patients, complete reattachment of the retina is not possible. Furthermore, treatment success with large hemangiomas, as well as with diffuse, infiltrating tumors of the macula, is limited.

Radiation therapy

A few patients with diffuse choroidal hemangiomas associated with a bullous, nonrhegmatogenous retinal detachment have been treated with radiation therapy (such as brachytherapy or external beam irradiation). Preliminary reports on this treatment suggest that radiation therapy for diffuse choroidal hemangiomas may be a reasonable alternative to photocoagulation, the currently preferred therapy, in selected patients. However, the ultimate risk-to-benefit ratio for this form of treatment is still unknown. Furthermore, the precise indications and contraindications for such treatment currently are unknown.

Drainage

External drainage of subretinal fluid with or without scleral buckling in conjunction with xenon photocoagulation has been used to treat diffuse choroidal hemangiomas associated with large, exudative retinal detachments in SWS.

Pars plana vitrectomy, endolaser, and internal drainage of subretinal fluid can be performed. Cryotherapy and penetrating diathermy are of limited use because of the posterior location of the tumor.

Most ophthalmologists consider surgical therapy to be the mainstay of glaucoma therapy in patients with Sturge-Weber syndrome,[94] with antiglaucoma medications primarily useful as treatment adjuncts. However, the selection of surgical technique remains controversial.[113] Surgical options in SWS glaucoma include the following:

• Goniotomy

• Trabeculotomy

• Full-thickness filtration surgery

• Partial-thickness filtration surgery (trabeculectomy)

• Combined trabeculotomy-trabeculectomy

• Argon laser trabeculoplasty

• Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser goniotomy

• Seton procedures

Trabeculectomy increases the release of aqueous fluid from the anterior chamber and opens the outflow pathway. Goniotomy is similar but is done through the eye. A Molteno valve can be placed (similar to a shunt), and cyclodestructive procedures with either freezing or laser decrease the production of aqueous fluid.[48]

The long-term results of SWS glaucoma surgery are often disappointing, as they are associated with a high failure rate compared with the same procedure performed for primary infantile glaucoma.

Because SWS glaucoma is relatively rare, no controlled series of cases comparing one intervention to another have been published, nor are standard treatment guidelines available. The objective of therapy is rapid and permanent lowering of the IOP into the normal range (generally < 20 mm Hg) or to a level slightly higher but without progression of other signs, such as corneal enlargement, increased myopia, or increased optic nerve cupping.

The anesthesiologist should be aware that the patient has SWS, because the presence of a spinal cord or brain hemangioma may increase the risk of intracerebral bleeding or disseminated intravascular coagulation with anesthesia. In addition, an anesthesia protocol should be planned to prevent the development of hypertension, which could result in hemorrhage.

Goniotomy and trabeculotomy

Goniotomy or trabeculotomy is believed by some to be the treatment of choice in early onset glaucoma in infancy when the probable mechanism for pressure elevation is an abnormal outflow angle. These procedures are often unsuccessful in infants with SWS or are successful only after being repeated several times and with the addition of adjunctive medical therapy. Nevertheless, some authors prefer to perform these procedures initially, because they are sometimes successful and goniotomy also is thought to be less likely to cause complications (especially expulsive choroidal hemorrhage or choroidal effusion) that are associated with a precipitous drop in intraocular pressure.

Filtration surgery

With glaucoma onset in the older age group, when the outflow angle appears clinically normal, glaucoma filtration surgery, either full thickness or partial thickness (trabeculectomy), is more likely to be successful, because it bypasses any component of the glaucoma possibly caused by elevated episcleral venous pressure. Combined trabeculotomy-trabeculectomy may be a reasonable compromise in the older patient with Sturge-Weber syndrome in view of the possible combination of angle abnormality and raised episcleral pressure in glaucoma.

Adjunctive antimetabolites used in conjunction with a filtration surgery may create a more satisfactory degree of intraocular pressure control in this patient population, by slowing wound healing and scar formation. The most commonly used clinical agents are 5-fluorouracil (5-FU) and mitomycin-C. 5-FU usually is given as a series of subconjunctival injections postoperatively. Mitomycin-C is usually applied intraoperatively, using a sponge saturated with mitomycin solution.

Postoperative subconjunctival injections usually are impossible in very young patients; thus, intraoperative application of mitomycin-C most frequently is required in these patients. Mitomycin-C and 5-FU are associated with thinner, more cystic blebs and may carry a higher rate of complications, such as wound leaks, chronic hypotony, and, possibly, late endophthalmitis.

Corticosteroids should be used after filtration surgery to diminish postoperative inflammation and scarring of the bleb. A sub-Tenon injection of a short-acting corticosteroid (eg, dexamethasone, triamcinolone) at the completion of surgery and the use of topical corticosteroid drops or ointment after surgery are recommended.

Cyclocryotherapy

Cyclocryotherapy is difficult to control and has a high complication rate. Therefore, it should be used only when all other procedures have failed or are not feasible, to save useful vision or to prevent or relieve severe pain. New types of cyclodestructive procedures, such as Nd:YAG transscleral laser and therapeutic ultrasonic cyclodestructive procedures, have had only limited trial in pediatric and SWS glaucoma, and their potential for long-term success, as well as for complications, in young patients is not fully understood.

Seton procedures

Seton devices are being used when routine filtration surgery has failed. Encouraging initial results have been reported using various posterior tube shunt implant devices, but long-term follow-up results are not yet available.

Laser surgery

Nd:YAG laser goniotomy and argon laser trabeculoplasty have been used to a limited extent in pediatric glaucoma, and favorable results in some patients with SWS have been reported.

Complications in glaucoma surgery

Management of secondary open-angle glaucoma in patients with SWS, using filtration surgery and seton procedures, bears an increased risk for a number of surgical complications. The most vision threatening and feared of these are expulsive choroidal hemorrhage and intraoperative massive choroidal effusion.

Choroidal hemorrhage and effusion

Sudden change in the IOP gradient when the eye is opened may result in expulsive choroidal hemorrhage from the choroidal hemangioma. Treatment involves rapid closure of all scleral incisions, with restoration of IOP. Transscleral drainage of suprachoroidal blood may also be indicated.

The intraoperative formation of a massive choroidal effusion without hemorrhage occurs frequently during filtration surgery in patients with SWS. Increased episcleral venous pressure in these patients is assumed to cause a similar increase in the venous pressure within the ciliary body and choroid.

Choroidal and retinal detachment

During surgery, when the eye is opened and the IOP falls, rapid transudation of fluid from the intravascular to the extravascular space results. The extravasation of fluid can be massive enough to instantly cause choroidal detachment and, later, serous retinal detachment. Although the mechanism is probably similar to that for the more commonly seen benign postoperative choroidal detachment, the degree and the speed of fluid extravasation during surgery make this entity more serious.

This intraoperative event can mimic an expulsive suprachoroidal hemorrhage because of rapid fluid accumulation after the commencement of surgery. It differs, however, because, if the suprachoroidal space is evacuated, clear, copious amounts of yellow fluid are found and the eye can be decompressed transiently.

It seems that once the intraoperative effusion is treated with immediate drainage, the postoperative prognosis becomes excellent despite the persistence of some degree of choroidal and serous retinal detachment. Smaller, postoperative serous choroidal detachment is another possible complication in SWS.

Serous retinal detachment often occurs in association with choroidal effusion and hypotony. A choroidal effusion may temporarily interfere with the metabolic transport systems of the retinal pigment epithelium. These serous retinal detachments usually resolve spontaneously as the IOP normalizes.

Prevention of complications

Various preoperative and perioperative prophylactic measures to counteract or prevent the above complications have been suggested, including the use of hyperosmotics, maximum preoperative antiglaucoma therapy, prophylactic posterior sclerotomy, prophylactic radiotherapy or laser photocoagulation of the choroidal hemangioma, and electrocautery of the anterior episcleral vascular anomaly.

Eibschitz-Tsimhoni and colleagues demonstrated minimal risk of subchoroidal hemorrhage or effusion in a large case series of patients with SWS undergoing filtration surgery using modern surgical techniques.[114] The authors questioned the need for prophylactic posterior sclerotomy in patients with SWS.

Suggested steps to minimize the intraoperative and postoperative hypotony include the following:

• Preplacement of scleral flap sutures

• Injection of a viscoelastic prior to excision of the trabecular meshwork

• Tight suturing of the scleral flap with releasable sutures that can be lysed after surgery with argon laser, removed at the slit lamp or at the time of examination under anesthesia

Any recent intraocular surgery predisposes the eye to the risk of bacterial endophthalmitis. Patients with filtering blebs, especially the thin, avascular blebs seen with the use of mitomycin-C, are at increased risk for developing bacterial endophthalmitis months, or even years, after surgery. Because this risk is increased further by contact lens wear, the use of any type of contact lens in these patients is discouraged. Other potential sources of infection include normal conjunctival flora, episodes of bacterial conjunctivitis, and contaminated medicine dropper bottle tips.

For small degrees of anisometropia in SWS, full optical correction of both eyes or at least full correction of the refractive difference between the eyes is desirable. In higher degrees of anisometropia or in children who develop strabismus, measures to prevent amblyopia and treat strabismus should be initiated. Anisometropic amblyopia may require occlusion therapy along with correction of the refractive error. In some patients, a contact lens may be required to treat fusion difficulty due to aniseikonia.

Any significant strabismus that is still present after the completion of amblyopia therapy, refractive lens correction, and orthoptics is treated best with eye muscle surgery. Avoiding or carefully cauterizing the dilated subconjunctival and episcleral vessels during strabismus surgery is important to prevent bleeding and scarring, so that the conjunctiva and anterior sclera are preserved for future glaucoma procedures.

Primary-care providers should be educated about SWS. Consultations are needed from the following clinicians:

• Neurologist

• Epileptologist - Especially if seizures are intractable

• Dermatologist

• Plastic surgeon

• Psychologist

• Psychiatrist

• Neuropsychologist

• Neuroendocrinologist

Postoperative care frequently requires repeated examination under anesthesia in infants and young children to assess surgical success. If continued borderline IOP elevation is found, then a trial of adjunctive medical therapy with close follow-up care may be continued safely as long as no evidence of progression of glaucoma damage is observed. However, if the IOP remains clearly elevated or evidence of progressive glaucomatous damage is detected, then repeat glaucoma surgery should be performed.

All patients with SWS must have regular ophthalmologic examinations for life, even when no ocular abnormalities are detected initially, to avoid later loss of vision secondary to late-onset glaucoma.

American Academy of Dermatology

In 2021, the American Academy of Dermatology (AAD) released a consensus statement for the management and treatment of port-wine birthmarks (PWBs) in Sturge-Weber syndrome (SWS). The AAD recommends treating PWBs at an early age to minimize the psychosocial impact and diminish nodularity and potentially tissue hypertrophy. In the United States, pulsed dye laser is the standard for all PWBs regardless of the lesion size, location, or color. When performed by experienced physicians, laser treatment can be safe for patients of all ages. The choice of using general anesthesia in young patients is a complex decision that must be considered on a case-by-case basis.[115]

The Sturge Weber Foundation

A panel of 13 national peer-recognized experts in neurology, radiology, and ophthalmology with experience treating patients with SWS, supported by the Sturge Weber Foundation, developed clinical recommendations for the management and treatment of SWS. The panel found that children with a high-risk PWB should be referred to a pediatric neurologist and a pediatric ophthalmologist for baseline evaluation and periodic follow-up. In newborns and infants with a high-risk PWB and no history of seizures or neurological symptoms, routine screening for brain involvement is not recommended, but brain imaging can be performed in select cases. Routine follow-up neuroimaging is not recommended in children with SWS and stable neurocognitive symptoms. The treatment of ophthalmologic complications, such as glaucoma, differs based on the age and clinical presentation of the patient.[116]

Medical therapy in patients with Sturge-Weber syndrome (SWS) involves many agents, including beta-blockers, carbonic anhydrase inhibitors, and prostaglandin analogues, that can be used to lower the intraocular pressure (IOP). Medical therapy can be used as an initial treatment, especially in late-onset glaucoma, but surgical therapy is the initial therapy in early onset cases.

Aqueous suppressants are typically used for initial medical therapy. Prostaglandin analogues may not be as effective in these patients, because the episcleral venous pressure is often elevated by dilated, tortuous episcleral veins. Corticosteroids are used to reduce inflammation.

Class Summary

These agents are used to terminate clinical and electrical seizure activity as rapidly as possible and prevent seizure recurrence.

Lorazepam (Ativan)

Lorazepam is a sedative hypnotic with a short onset of effects and a relatively long half-life.

By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS, including the limbic system and reticular formation.

It is important to monitor the patient's blood pressure after administering a dose. Adjust the dosage as necessary.

Carbamazepine (Tegretol, Epitol, Carbatrol)

Carbamazepine is effective for the treatment of complex partial seizures. It appears to act by reducing polysynaptic responses and blocking posttetanic potentiation. The drug's major mechanism of action is reduction of sustained, high-frequency, repetitive neural firing.

Phenytoin (Dilantin, Phenytek)

The primary site of action for phenytoin (and other hydantoins) appears to be the motor cortex, where this agent may inhibit the spread of seizure activity. Phenytoin may reduce maximal activity of brainstem centers responsible for the tonic phase of grand mal seizures. Dosing should be individualized. If daily dosing cannot be divided equally, larger dose should be given before retiring. A phosphorylated formulation, fosphenytoin, is available for parenteral use and may be given intramuscularly or intravenously.

Diazepam (Diastat, Valium)

Diazepam is an extremely lipid-soluble agent that enters the brain very quickly in the first pass and often stops seizures in 1-2 minutes. It modulates the postsynaptic effects of GABA-A transmission, resulting in an increase in presynaptic inhibition. Diazepam appears to act on part of the limbic system, the thalamus, and the hypothalamus, to induce a calming effect. It has also been found to be an effective adjunct for the relief of skeletal muscle spasm caused by upper motor neuron disorders.

Diazepam rapidly distributes to other body fat stores. Twenty minutes after initial IV infusion, the serum concentration drops to 20% of Cmax. Individualize the dosage and increase cautiously to avoid adverse effects.

Oxcarbazepine (Trileptal, Oxtellar XR)

Oxcarbazepine's pharmacologic activity comes primarily from its 10-monohydroxy metabolite. Studies indicate that this drug may block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. Oxcarbazepine's anticonvulsant effect may occur by affecting potassium conductance and high-voltage activated calcium channels. Drug pharmacokinetics are similar in older children (>8 y) and adults. Young children (< 8 y) have 30-40% increased clearance compared with older children and adults. Children under 2 years have not been studied in controlled clinical trials.

Clonazepam (Klonopin)

Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces the monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. Clonazepam has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). It reaches peak plasma concentration at 2-4 hours after oral or rectal administration.

Lamotrigine (Lamictal)

This agent is a triazine derivative that is useful in the treatment of seizures and neuralgic pain. It inhibits the release of glutamate and also inhibits voltage-sensitive sodium channels, which stabilizes the neuronal membrane. Follow the manufacturer's recommendation for dose adjustments.

Levetiracetam (Keppra, Keppra XR)

Levetiracetam is used as add-on therapy for partial seizures. Its mechanism of action is unknown, but it has a favorable adverse effect profile, with no life-threatening toxicity reported.

Valproic acid (Stavzor, Depakene, Depacon)

Valproic acid is chemically unrelated to other drugs used to treat seizure disorders. Although its mechanism of action is unknown, its activity may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. Valproic acid also may potentiate postsynaptic GABA responses, affect potassium channels, or have a direct membrane-stabilizing effect.

For conversion to monotherapy, concomitant antiepileptic drug (AED) dosage ordinarily can be reduced by approximately 25% every 2 weeks. This reduction may be started at the initiation of therapy or delayed by 1-2 weeks if there is concern that seizures are likely to occur with reduction. Monitor patients closely during this period for increased seizure frequency. As adjunctive therapy, divalproex sodium may be added to the patient's regimen at a dosage of 10-15 mg/kg/day. Dosage may be increased by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses of under 60 mg/kg/day.

Zonisamide (Zonegran)

Zonisamide is indicated for the adjunct treatment of partial seizures with or without secondary generalization. There is evidence that is effective in myoclonic and other generalized seizure types as well.

Topiramate (Topamax)

Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic activity; it may have state-dependent sodium channel–blocking action. The drug potentiates inhibitory activity of the neurotransmitter GABA and may block glutamate activity. It is not necessary to monitor topiramate's plasma concentrations to optimize therapy. On occasion, the addition to phenytoin may require adjustment of the phenytoin dose to achieve optimal clinical outcome.

Phenobarbital

Phenobarbital exhibits anticonvulsant activity in anesthetic doses and can be administered orally. If the intramuscular (IM) route is chosen, inject phenobarbital into a large muscle, such as the gluteus maximus, the vastus lateralis, or other areas where there is little risk of encountering a nerve trunk or major artery. Injection into or near peripheral nerves may result in permanent neurologic deficit. Restrict intravenous (IV) use to conditions in which other routes are not feasible, either because the patient is unconscious, as in cerebral hemorrhage, eclampsia, or status epilepticus, or because prompt action is imperative.

Gabapentin (Neurontin, Gralise)

This agent has properties in common with other anticonvulsants. However, its exact mechanism of action is unknown. Gabapentin is structurally related to GABA but does not interact with GABA receptors. Increases in the daily dose are best tolerated when done slowly.

Pregabalin (Lyrica)

Pregabalin is a structural derivative of GABA. Its mechanism of action is unknown. Pregabalin binds with high affinity to the alpha2-delta site (a calcium channel subunit). In vitro, it reduces the calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. Pregabalin has been approved by the US Food and Drug Administration (FDA) for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.

Tiagabine (Gabitril)

Mechanism of action in antiseizure effect unknown. However, believed to be related to its ability to enhance activity of GABA, major inhibitory neurotransmitter in CNS. May block GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on surfaces of postsynaptic cells and possibly prevents propagation of neural impulses that contribute to seizures by GABA-ergic action. Dosing modification of concomitant AEDs not necessary unless clinically indicated.

Felbamate (Felbatol)

Felbamate is an oral antiepileptic agent with weak inhibitory effects on GABA- and benzodiazepine-receptor binding. It has little activity at the MK-801 receptor-binding site of the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. However, it is an antagonist at the strychnine-insensitive glycine-recognition site of the NMDA receptor-ionophore complex. Felbamate is not indicated as a first-line antiepileptic treatment. It is recommended for use only in patients whose epilepsy is so severe that the benefits outweigh the risks of aplastic anemia or liver failure. Most adverse effects during adjunctive therapy resolve as the dosage of concomitant AEDs is decreased.

Lacosamide (Vimpat)

This agent selectively enhances the slow inactivation of voltage-gated sodium channels, resulting in the stabilization of hyperexcitable neuronal membranes and the inhibition of repetitive neuronal firing. Lacosamide is indicated for adjunctive therapy for partial-onset seizures.

Class Summary

These agents lower IOP by decreasing the production of aqueous humor.

Levobunolol (AKBeta, Betagan)

This is a nonselective beta-adrenergic blocking agent that lowers IOP by reducing aqueous humor production

Class Summary

These agents lower IOP by decreasing aqueous production.

Dorzolamide (Trusopt)

Dorzolamide inhibits carbonic anhydrase in the ciliary processes, which decreases aqueous humor formation.

Brinzolamide 1% (Azopt)

Brinzolamide inhibits carbonic anhydrase in the ciliary processes, which decreases aqueous humor formation.

Class Summary

These agents lower IOP by increasing aqueous outflow through the uveoscleral pathway.

Latanoprost 0.005% (Xalatan)

Latanoprost may decrease IOP by increasing the outflow of aqueous humor.

Class Summary

These medications are used to treat ocular inflammation.

Prednisolone acetate 1% (Pred Forte, Pred Mild, Omnipred)

This agent inhibits the edema, fibrin deposition, capillary dilation, and phagocytic migration of the acute inflammatory response, as well as capillary proliferation. It causes the induction of phospholipase A2 inhibitory proteins.

Dexamethasone ophthalmic (Maxidex, Ozurdex)

Dexamethasone ophthalmic decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability.

Triamcinolone (Triesence)

Triamcinolone is used to treat inflammatory reactions that are responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

Class Summary

These agents inhibit cell growth and proliferation.

Fluorouracil (Efudex)

Fluorouracil interferes with deoxyribonucleic acid (DNA) synthesis by blocking the methylation of deoxyuridylic acid, inhibiting thymidylate synthetase and, subsequently, cell proliferation.

Mitomycin (Mitosol, Carac)

Mitomycin interferes with DNA synthesis by alkylation and by cross-linking the strands of DNA.