AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

The Sturge-Weber syndrome (SWS), also called encephalotrigeminal angiomatosis, is a neurocutaneous disorder with angiomas involving the leptomeninges (leptomeningeal angiomas [LAs]) and skin of the face, typically in the ophthalmic (V1) and maxillary (V2) distributions of the trigeminal nerve. The cutaneous angioma is called a port-wine stain (PWS).

In the brain, LAs demonstrated by structural neuroimaging may be unilateral or bilateral; unilateral angiomas are more common. Functional neuroimaging may demonstrate a greater area of involvement than structural neuroimaging. This is called a structural versus functional mismatch.

The neurologic manifestations 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 angioma. These include seizures, which may be intractable; focal deficits, such as hemiparesis and hemianopsia, both of which may be transient, called "strokelike episodes"; headaches; and developmental disorders, including developmental delay, learning disorders, and mental retardation. Developmental disorders are more common when angiomas are bilateral. Seizure control is thought to improve the neurologic outcome, and epilepsy surgery may be beneficial for refractory seizures.

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. Cosmetic concerns are also important, and laser therapy is available for the PWS. Extracranial angiomas and soft-tissue overgrowth also may occur. Certain CNS malformations have been associated with the syndrome; other neurocutaneous disorders are included in the differential diagnosis.

SWS is referred to as complete when both CNS and facial angiomas are present and incomplete when only 1 area is affected without the other. The Roach Scale is used for classification, as follows:

• Type I - Both facial and leptomeningeal angiomas; may have glaucoma
• Type II - Facial angioma alone (no CNS involvement); may have glaucoma
• Type III - Isolated LA; usually no glaucoma

Pathophysiology

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.

Neurologic dysfunction results from secondary effects on surrounding brain tissue, which include hypoxia, ischemia, venous occlusion, thrombosis, infarction, or 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. Garcia et al and Gomez and Bebin reported that venous occlusion might actually cause the initial neurologic event, either a seizure, transient hemiparesis, or both, thereby beginning the process.

A "vascular steal phenomenon" may develop around the angioma, resulting in cortical ischemia. Therefore, 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.

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

Seizure control, aspirin therapy, and early surgical treatment may prevent neurologic deterioration.

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 unclear, although Huq et al reported evidence of somatic mosaicism in 4 patients with SWS. Two had skin biopsy from port-wine stains, and the other 2 had LAs from hemispherectomy. Inversion of chromosome arm 4q and trisomy 10 were seen in one patient each. Malformed cortical vessels in SWS have been reported to be innervated only by noradrenergic sympathetic nerve fibers, and increased endothelin-1 expression was also 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, 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.

Overall, in SWS, a somatic mutation appears to cause alterations in regulation of the structure and function of blood vessels, innervation of the blood vessels, as well as expression of extracellular matrix and vasoactive molecules.

Frequency

United States

According to Nelson's Textbook of Pediatrics, the incidence of SWS is estimated at 1 per 50,000. No regional differences have been identified. The inheritance is sporadic. The incidences of the major clinical manifestations of SWS are listed in Table 1.

Table 1. Clinical Manifestations of Sturge-Weber Syndrome

Mortality/Morbidity

• Neurologic and developmental morbidity includes seizures, weakness, strokes, headaches, hemianopsia, mental retardation, and developmental abnormalities. The development of seizures and the age of onset may correlate with the degree of neurologic involvement. Neurologic dysfunction increases with bilateral PWS. Patients may experience complications related to refractory seizures and anticonvulsants, visual loss and blindness from glaucoma, cosmetic deformities, and other manifestations of soft-tissue involvement.
• Of 60 patients in the combined series from Children's Hospital, Boston, 2 deaths (3.3%) have been reported (Erba and Cavazutti, 1990; Riviello et al, 1998). In earlier cases reported by Erba and Cavazutti, 1 death occurred in the postoperative period, after epilepsy surgery; in recent cases, 1 death occurred secondary to intractable seizures. Oakes reported 4 deaths in 30 patients (14%).

Race

No racial differences have been reported.

Sex

Both sexes are affected equally.

Age

• The typical patient presents at birth with facial angiomas; however, not all children with facial angiomas and PWS have SWS, which raises certain diagnostic and prognostic concerns.
• In the "incomplete" forms of SWS, CNS angiomas occur without cutaneous features (Type III, Roach Scale), and therefore, no suspicion of SWS arises until a seizure or other neurologic problem develops. Thus, the diagnosis of SWS is not always straightforward.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

The Sturge-Weber Foundation maintains a list of patients with SWS; its efforts have promoted clinical and scientific research, which have led to improvement in the treatment of SWS. This includes studies on the natural history of the disorder.

• Facial nevus, PWS
• • These 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. A PWS may be difficult to visualize in a patient with dark skin pigmentation.
  • Not all people with a PWS have SWS; the overall incidence of SWS has been reported to be 8-33% in those with a PWS. Several recent studies have evaluated this specifically.
  • Enjolras et al retrospectively studied 106 patients with a facial PWS, 12 of whom had SWS and 4 of whom had glaucoma without pial lesions. SWS occurred only when the PWS involved the V1 distribution of the trigeminal nerve. No patients with involvement of the V2 and/or mandibular (V3) area without V1 involvement had SWS. Patients considered "high risk" 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). They concluded that SWS occurred only when the PWS involved the V1 distribution.
  • Bioxeda et al studied 121 patients with PWS affecting the skin in the distribution of the trigeminal nerve. Facial PWS were distributed predominantly over the distribution of the V2 branch of the trigeminal nerve in 88%, either isolated to the V2 branch or also involving the V1 and/or V3 branches. An extrafacial PWS was more common when V3 was involved. The lesions were unilateral in 86% and bilateral in 14%. Glaucoma and epilepsy were present in 23 (17%) and 17 (14%) patients, respectively, all of whom had involvement of V1. The authors concluded that only those with V1 involvement are at risk of epilepsy or glaucoma.
  • In the largest study to date, Tallman et al reported on 310 patients with PWS; 85% had unilateral and 15% had bilateral involvement, and 68% had involvement of more than 1 dermatome. Only patients with PWS involving the distributions of the V1 and V2 branches of the trigeminal nerve had CNS or eye involvement. Overall, in those with trigeminal involvement, only 8% had CNS and eye involvement; 24% of those with bilateral lesions had eye or CNS involvement compared to only 6% with unilateral lesions. 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. None 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 PWS 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 PWS, with unilateral involvement in 83 (49%) and bilateral involvement in 86 (51%) patients.
  • Note that an extrafacial PWS may have associated intracranial abnormalities; for example, in Klippel-Trenaunay-Weber syndrome, neuroimaging may show findings similar to those of SWS, and a cervical PWS has been associated with occipital calcifications.
• Seizures, refractory seizures
• • The incidence of epilepsy in patients with SWS is 75-90%; seizures may be intractable. 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.
  • 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.
  • In a recent survey of cases identified by the Sturge-Weber Foundation, seizures occurred in 136 of 171 patients, with a median age of onset of 6 months, ranging from birth to 23 years. About 75% had onset during the first year of life, 86% before age 2 years, and 95% before 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 (72% with unilateral versus 93% with bilateral involvement), with median ages of onset of 8.5 months in patients with unilateral PWS and 4 months in patients with bilateral PWS.
  • Oakes reported seizures in 24 of 30 (80%) patients, with a mean age of onset of 6 months.
  • Pascual-Castroviejo et al reported seizures in 32 of 40 (80%) patients. Seizures began during a febrile illness in 10 (31%) patients (fever could be a precipitant at any age); 2 (6%) had infantile spasms.
• Focal versus generalized seizures
• • Since the lesion responsible for the epilepsy in SWS is focal, the majority of seizures are focal seizures.
  • Bebin and Gomez reported partial seizures in 35 of 76 (46%) patients, generalized in 15 (20%), and both in 26 (34%).
  • Pascual-Castroviejo et al reported seizures in 32 of 40 (80%) patients; 22 (69%) had focal seizures contralateral to the PWS, with subsequent generalization in 6; 8 (25%) had generalized seizures at onset, and IS occurred in 2 (6%).
  • 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.
  • According to Roach, the onset of seizures prior to age 2 suggests a greater chance of refractory epilepsy and mental retardation. Patients with refractory seizures are more likely to have mental retardation, since those with refractory seizures have more extensive brain involvement.
  • Bebin and Gomez reported an earlier onset of seizures in those with bilateral involvement (mean ages of seizure onset were 6 months with bilateral disease and 24 months with unilateral disease). Pascual-Castroviejo et al showed that those with more frequent seizures tended to have an earlier seizure onset (mean seizure onset at age 5-6 months compared to a mean onset at age 2 years in those with less severe involvement).
  • The largest series to address this issue is that reported by Sujansky and Conradi from data obtained through the Sturge-Weber Foundation. Overall developmental delay occurred in 97 of 168 (58%) patients; however, early developmental delay occurred in 71% of those with seizures and in only 6% of those without seizures. Those with a later seizure onset also had a lower incidence of developmental delay and fewer special education needs.
• 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.
• Hemiparesis: The incidence is approximately 33%, varying from 25-56%; it 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.
• Strokelike episodes: Transient episodes are referred to as strokelike episodes. These occurred in 14 of 20 patients described by Maria et al. Garcia et al reported recurrent thrombotic episodes. Stroke also may occur. The incidence of neurologic deficit is higher in adults; Sujansky and Conradi reported an occurrence in 34 of 52 (65%) patients, which also demonstrates the progressive nature of SWS.
• Hemianopsia: The mechanism is similar to that of hemiparesis and is dependent on the location of the lesions. Uram and Zullabigo reported hemianopsia in 11 of 25 (44%) patients.
• Developmental delay and mental retardation
• • These are related to the degree of neurologic involvement, occurring in 50-60% of patients; they are more likely in patients with bilateral involvement.
  • Bebin and Gomez reported normal mental functioning in only 8% of those with bilateral disease.
  • 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. Using a combination of CT scan, MRI, and functional imaging with single-photon emission computed tomography (SPECT), widespread abnormalities were found in 7 of 10 patients, a much higher incidence of bilateral involvement than detectable by any one diagnostic modality, accounting for the high incidence of developmental delay, mental retardation, and learning problems seen in this disorder.
  • Seizures are associated with a higher incidence of mental retardation, and regression also may be related to the frequency and severity of seizures.
• Headaches
• • These occur secondary to vascular disease, giving symptoms of a migraine headache, considered "symptomatic migraine."
  • In the study by the Sturge-Weber Foundation, headaches occurred in 132 of 171 (77%) patients of all ages and in 28 of 45 (62%) adults. In the reports by Maria et al, headaches occurred in 60%.
  • 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. Migraine headache occurred in 28%, and neurologic deficits occurred in 58% during the migraine. The prevalence of migraine in children younger than 10 years was 31% in children with SWS, much greater than the 5% prevalence in the general population.
• Ocular manifestations, glaucoma and blindness
• • Glaucoma typically occurs in SWS only when the PWS involves the eyelids. The incidence ranges from 30-71%. Glaucoma may be present at birth but can develop at any age, even in adults.
  • Treatment includes yearly examinations, looking for optic nerve damage (with measurement of IOP and visual fields) and corneal diameter and refractive changes in children.
  • Glaucoma usually occurs only with an ipsilateral facial PWS, although it 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. Of these, 36 (71%) had glaucoma, with onset before age 24 months in 26 patients; 35 (69%) had conjunctival or episcleral hemangiomas; and 28 had choroidal hemangiomas.
  • With time, choroidal hemangioma may cause other secondary changes such as retinal pigment epithelium degeneration, fibrous metaplasia, cystic retinal degeneration, and retinal detachment. Also retinal vascular tortuosity, iris heterochromia, optic disc coloboma, and cataracts have been seen in patients with SWS.
  • The Sturge-Weber Foundation data show that 82 of 171 (48%) patients had glaucoma; of these, 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.
  • 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.
• Buphthalmos (hydrophthalmia): Enlargement of the eye occurs from the same mechanisms as glaucoma.
• PWS, cosmetic problems, soft-tissue hypertrophy: The Sturge-Weber Foundation survey indicated that other abnormalities occurred in all 171 patients. These included other cutaneous lesions in all patients and body asymmetry in 164 of 171 patients, with soft-tissue hypertrophy in 38 of 164 patients and scoliosis in 11 patients. Basal cell carcinoma has been reported to occur within a PWS.
• 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. Seizures occurred in 83%, glaucoma in 60%, and a neurologic deficit in 65%, including stroke, paralysis, spasticity, or weakness. The age of onset of seizures ranged from 0-23 years, with a median of 6 months. Seizure outcome was known in 41 patients, with full control in 11 (27%), decreased seizures in 20 (49%), and no improvement in 10 (24%) patients. The morbid conditions associated with these seizures are listed in Table 2. About 39% of these individuals were financially self-sufficient and 55% would or could be married.
  • Headache occurred in 28 of 45 (62%) patients, the onset ranging from early childhood to age 38 years, with a median age of onset of 18 years. The headache frequency could be determined in 23 patients: daily in 9 (39%) patients, 1-4 times per week in 4 (17%), 1-2 times per month in 6 (26%) patients, and rare in 4 (17%).
  • Headaches were associated with increased discoloration of facial PWS, auras, nausea/vomiting, dysarthria, dizziness, and feelings of facial pulsation.
  • The age of onset of glaucoma ranged from 0-41 years, with a median of 5 years.

    Table 2. Developmental Morbidity Associated with Seizures in Adults with SWS
    
    

    	With Seizures (%)	Without Seizures (%)
    Developmental delay	45	0
    Emotional/behavioral problems	85	58
    Need for special education	71	0
    Employability	46	78

Physical

• PWS (see Picture 1)
• Macrocephaly
• Eye - Buphthalmos, heterochromia of iris, tomato-catsup color of the fundus (ipsilateral to the nevus flammeus) with glaucoma, possibility of choroidal angioma visible with an ophthalmoscope
• Soft-tissue hypertrophy
• Neurologic signs
  • Developmental delay/mental retardation
  
  
  • Learning problem
  • Attention deficit hyperactivity disorder
• Hemiparesis
• Visual loss
• Hemianopsia

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Headache, chronic
Vascular malformations and hematomas of the brain

PWS - May be isolated, occurring without SWS

Arteriovenous malformation - May calcify

Macrocephaly with SWS - Related to hydrocephalus or intracranial hypertension, secondary to the abnormal venous drainage

Cyst of the posterior fossa with partial cerebellar agenesis in association with facial angiomas - Angioma flat or tuberous, lies in the territory of the first division of the trigeminal nerve; may be familial

Epilepsy with bilateral occipital calcifications - Incomplete SWS versus celiac disease

Klippel-Trenaunay-Weber syndrome - Hemihypertrophy and hemangiomas; may occur with SWS; however, Klippel-Trenaunay-Weber associated with choroid plexus enhancement, atrophy, calcifications, and leptomeningeal enhancement

Rendu-Osler-Weber syndrome - Hereditary hemorrhagic telangiectasia

von Hippel-Lindau syndrome - Cerebellar or spinal hemangioma with retinal angioblastoma, pancreatic cysts, and renal cell carcinoma

Wyburn-Mason syndrome - Retinal arteriovenous angioma

Shapiro-Shulman syndrome - Bilateral facial nevi and abnormal venous drainage

Divry-van Bogaert syndrome - Leptomeningeal angioma (noncalcifying) with diffuse sclerosis, progressive neurologic disorder, and livedo reticularis

Bannayan-Zonna syndrome - Macrocephaly, lipomatosis, cutaneous hemangiomas

Cobb syndrome - Cutaneomeningospinal angiomatosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• 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.

Imaging Studies

• Neuroimaging studies: Besides the clinical examination, these have been the procedures of choice to establish the diagnosis. Historically these are skull radiograph, angiography, CT scan, MRI, MRI with gadolinium, and functional imaging with SPECT or positron emission tomography (PET).
• Skull radiograph
• • The skull x-ray may show the classical "tram-line," or "tram-track" or "trolley-track," calcifications considered pathognomonic for SWS in the era prior to modern neuroimaging; however, these 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; Borns and Rancier reported these in childhood leukemia.
• Angiography: Angiography does not show the angioma but demonstrates a lack of superficial cortical veins, nonfilling of dural sinuses, and abnormal, tortuous veins that course toward the vein of Galen.
• CT scan: CT scan may show calcifications in infants and even neonates; other findings include brain atrophy, ipsilateral choroid plexus enlargement, abnormal draining veins, and a breakdown of the blood-brain barrier with seizures. In a study of CT scans in 14 children with SWS by Terdjman et al, cortical calcifications were present in 12 patients (see Picture 2), localized atrophy in 10 patients, and enlargement of the choroid plexus and abnormal veins in 7 patients each.
• MRI
• • Although MRI does not show calcifications, gadolinium enhancement may show pial angioma; therefore, MRI may permit early diagnosis of SWS, even in the newborn with a facial PWS. Sugama et al reported that the most characteristic finding of SWS on MRI is enhancement of LAs following gadolinium, which may show an LA not seen on CT scan or angiography (see Picture 3); however, Fischbein reported that gadolinium enhancement may not be seen in every case.
  • Other MRI findings include accelerated myelination around the LA, a large choroid plexus whose size correlates with the extent of the LA, 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.
  • Bernal and Altman reported abnormal activation patterns in the occipital areas on functional MRI in patients with SWS.
  • Lin et al reported perfusion MRI findings compatible with impaired venous drainage in an early case of SWS with new-onset seizures. MR spectroscopy showed increased choline but no reduction in N-acetyl aspartate (NAA). Other reports of MR spectroscopy have shown decreased NAA; 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 diffuse MRI. Regarding the MR spectroscopy findings in these studies, the decreased NAA was considered as neuronal loss of dysfunction, and the elevated choline as a lack of normal development.
  • Mentzel et al reported that BOLD (blood-oxygen-level-dependent) MR venography may be sensitive in detecting early venous abnormalities in a case of SWS, earlier than conventional MRI sequences.
• Single-photon emission computed tomography
• • This measures cerebral blood flow, demonstrates underperfusion in the area of the pial angioma, and therefore may detect a latent angioma not seen with other studies (see Picture 4 and Picture 5). With SPECT, Reid et al demonstrated hypoperfusion before calcifications, anomalous drainage, or enhancement developed on either CT scan or MRI. Griffiths et al showed that MRI and SPECT together might reveal different areas of involvement.
  • Namer et al demonstrated a steal phenomenon during seizures, causing ischemia in remote areas, with subtraction ictal SPECT coregistered to MRI (SISCOM).
  • Pinton demonstrated that the cortex is hyperperfused during the first year of life before the first seizures, with the classic hypoperfusion appearing after 1 year of age, even in those without epilepsy.
  • Maria et al reported that enlargement of the choroid plexus correlates with abnormalities seen with SPECT.
• Positron emission tomography: In a pre-MRI study by PET scan, Chugani et al demonstrated metabolic abnormalities in the structurally affected hemisphere that extended beyond the anatomic abnormalities detected by CT scan. This result suggested that PET might help identify suitable candidates for hemispherectomy or focal cortical resection.
• Other modalities
• • Riela et al studied the xenon Xe 133 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. 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.
  • Recently, with quantitative proton magnetic resonance spectroscopy, Moore et al demonstrated an ipsilateral reduction of N-acetyl-aspartate, a neuronal marker, suggesting neuronal loss.
• Summary of neuroradiologic findings: The maximum extent of disease 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.

Other Tests

• EEG is used for evaluation of seizures and for 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 both the waking and sleep states, with activation procedures (hyperventilation and photic driving) decreased on the involved side. EEG findings predated calcifications. Epileptiform activity was limited to the involved hemisphere.
  • In a recent study, Sassower et al reported marked voltage attenuation in the region of the angioma in 13 of 14 patients; polymorphic delta activity (PDA) occurred in 12 of 14 patients; in those with PDA, it was unilateral in 6 and correlated with the angiomatosis, and none with unilateral PDA had mental retardation. In 6 with bilateral PDA, 4 had mental retardation 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.
  • Erba and Cavazzuti reported that late in the course of the syndrome, epileptiform activity might occur from the contralateral cortex.
  • In a study conducted at Toronto, 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 before and after diazepam administration in brain regions that structurally appeared intact; they suggested that diazepam-enhanced EEG may provide information on functional involvement and monitor progression of the disease.
• Findings in the work-up of SWS are summarized in Table 3.

  Table 3. Summary of Work-up Findings in Sturge-Weber Syndrome

  CSF analysis	Elevated protein
  Skull x-ray	Tram-track calcifications
  Angiography	Lack of superficial cortical veins Nonfilling dural sinuses Abnormal, tortuous vessels
  CT scan	Calcifications, tram-track calcifications Cortical atrophy Abnormal draining veins Enlarged choroid plexus Blood-brain barrier breakdown (during seizures) Contrast enhancement
  MRI	Gadolinium enhancement of LA Enlarged choroid plexus Sinovenous occlusion Cortical atrophy Accelerated myelination
  SPECT	Hyperperfusion, early Hypoperfusion, late
  PET	Hypometabolism
  EEG	Reduced background activity Polymorphic delta activity Epileptiform features

• Endocrinologic tests: The Sturge-Weber Foundation notes increasing use of growth hormone in its members. Some have developed a body habitus similar to that in Cushing syndrome. This has occurred around the time of puberty.

Histologic Findings

The leptomeninges 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, rarely, within neurons, and neuronal loss and gliosis occur. These pathologic abnormalities may occur at a distance from the actual vascular lesion.

Di Trapeni et al, from epilepsy surgery cases, reported a mucopolysaccharide substance with calcium in the connective tissue of the vessels early on, that later increases in size and migrates outside the vessels. They postulated that anoxia, necrosis, and variations in calcium concentrations act only as secondary factors.

Hoffman et al have shown aluminum within the calcium concretions.

Simonati et al have reported 4-layered microgyria below the angiomatosis.

In skin biopsies of the port-wine stain in SWS, dilated ecstatic 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 intra-trabecular spaces have been seen morphological abnormalities in the Schlemm canal. Hemangiomas in the trabecular meshwork are characteristic of SWS.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

This includes anticonvulsants for seizure control, symptomatic and prophylactic therapy for headache, glaucoma treatment to reduce the IOP, and laser therapy for PWS.

• Seizures: Since the seizures are typically focal, an anticonvulsant with efficacy in focal seizures is preferable (see anticonvulsant medications).
• Glaucoma: The goal of treatment is control of IOP to prevent optic nerve injury (please see the articles on glaucoma in eMedicine Ophthalmology journal). Medications either decrease the production of aqueous fluid or promote the outflow of aqueous fluid. Beta-antagonist eye drops reduce the production of aqueous fluid, adrenergic eye drops and miotic eye drops reduce IOP by promoting drainage, and carbonic anhydrase inhibitors decrease IOP by decreasing production of aqueous fluid.
• Headaches: Recurrent headaches can be treated with symptomatic and prophylactic medications (see Migraine Headache).
  • Kossoff et al recently evaluated 68 patients with SWS regarding headaches, identified through the Sturge-Weber Foundation. 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 to 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). The authors suggested that the headaches may be undertreated.
• Stroke-like events: Aspirin has been used for headaches and to prevent vascular disease, although it typically is used in patients who have had neurological progression or recurrent vascular events. Aspirin use needs to be with extreme caution in children, because of the concern about Reye syndrome, 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, and they also recommended varicella and yearly influenza immunizations, because of association of varicella and influenza infections in Reye syndrome. Maria et al reported a decreased incidence of stroke-like events in 20 patients who received aspirin; of 119 stroke-like 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.
• PWS: These need to be evaluated within the first week of life and differentiated from hemangioma.
• • PWS are treated with laser therapy, which should start as soon as possible, since multiple treatments are needed and earlier treatment may reduce the number needed. Also, the smaller the lesion initially, the fewer the laser flashes needed to remove the lesion.
  • Troilius et al reported on the potential psychological benefits from early treatment of PWS. In a survey of patients with PWS, 75% reported that the PWS had affected their lives negatively, 62% were convinced that their lives would improve if the PWS were removed, 47% suffered low self-esteem, and 28% said that the PWS made their school life and education more difficult. No persistent pigmentation changes or posttreatment scarring were reported after laser therapy.

Surgical Care

Surgery is desirable for refractory seizures, glaucoma, and specific problems related to various associated disorders, such as scoliosis.

• • Kossoff et al evaluated the outcome of hemispherectomy in 32 patients with SWS, using a questionnaire; these patients were identified through the Sturge-Weber Foundation.
    
    • Although this study was limited because of the volunteer basis of the returned questionnaires, still a larger number of patients were included to the previous studies. Patients had hemispherectomy between 1979 and 2001, and mean age of seizure onset was 4 months, median age of surgery was 1.2 years. Sixteen had anatomical hemispherectomy, 14 had functional hemispherectomy, and 2 had hemidecortications performed in 18 different centers throughout the world. Fifteen 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.
    • In this study, 81% became seizure free, with 53% off antiepileptic drugs. The type of surgery (anatomical hemispherectomy vs functional hemispherectomy vs hemidecortication) did not influence outcome. Age of seizure onset did not predict seizure freedom, while older age of surgery had a positive correlation. Postoperative hemiparesis was not worse compared with 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. They now perform a hemispherectomy, resulting in better neurologic recovery, even with some residual finger movement. Alternatively, if the patient is not a candidate for a limited resection or hemispherectomy, such as when disease is bilateral, corpus callosotomy can be done 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. In order to address these issues, the Sturge-Weber Foundation recruited a task force to evaluate epilepsy surgery in SWS. The following is a summary of recommendations for surgery in SWS, 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 both 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 who are not candidates for more definitive surgery.
    • Surgery should be done 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 done in those who are not candidates for other surgical procedures.
  • Summary: Data on the natural history of the disease are not yet sufficient to advocate hemispherectomy unless refractory seizures occur.
• Glaucoma surgery: If medications are unable to lower IOP, surgery may be beneficial. 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.

Consultations

Primary-care providers should be educated about SWS. Consultations are needed from a neurologist, an epileptologist (especially if seizures are intractable), a dermatologist, a plastic surgeon, a psychologist, a psychiatrist, a neuropsychologist, and a neuroendocrinologist.

Diet

No special diet is needed.

Activity

No restrictions are needed except as mandated by associated conditions.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Please refer to the various articles that describe anticonvulsant treatment of partial seizures.

Drug Category: Anticonvulsants

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

Drug Name	Carbamazepine (Tegretol)
Description	Anticonvulsant effective for treatment of complex partial seizures. Appears to act by reducing polysynaptic responses and blocking posttetanic potentiation. Major mechanism of action is reduction of sustained high-frequency repetitive neural firing.
Adult Dose	200 mg PO bid (100 mg qid of suspension); increase every wk by <200 mg/d PO tid/qid (bid with extended release) until best response obtained; not to exceed 1600 mg/d
Pediatric Dose	<6 years: 10-20 mg/kg/d PO bid/tid (qid with suspension); increase every wk to achieve optimal clinical response administered tid/qid 6-12 years: 100 mg PO bid (50 mg qid of suspension); increase every wk by adding 100 mg/d PO tid/qid (bid with extended release) until response obtained; not to exceed 1000 mg/d >12 years: Administer as in adults; not to exceed 1000 mg/d in children aged 12-15 years or 1200 mg/d if >15 years
Contraindications	Documented hypersensitivity; history of bone marrow depression; MAOIs within last 14 d
Interactions	Do not administer with MAOIs; danazol within last 30 d may increase serum levels significantly (avoid whenever possible); cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels)
Pregnancy	D - Unsafe in pregnancy
Precautions	Do not use to relieve minor aches or pains; caution with increased IOP; obtain CBCs and serum iron baseline level prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Drug Name	Phenytoin (Dilantin)
Description	Primary site of action of hydantoins, such as phenytoin, appears to be motor cortex, where may inhibit spread of seizure activity. May reduce maximal activity of brainstem centers responsible for tonic phase of grand mal seizures. Dosing should be individualized. If daily dosing cannot be divided equally, larger dose should be given before retiring. Phosphorylated formulation, fosphenytoin, available for parenteral use and may be given IM or IV.
Adult Dose	100 mg (125 mg suspension) PO/IV tid initially; maintenance dose 300-400 mg/d PO/IV divided tid, or qd/bid if using extended release; increase to 600 mg/d (625 mg/d suspension) may be necessary; not to exceed 1500 mg/24h
Pediatric Dose	<6 years: 5 mg/kg/d PO/IV divided bid/tid initially; maintenance dose 4-8 mg/kg PO/IV divided bid/tid >6 years may require minimum adult dose (300 mg/d); not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; sino-atrial block; sinus bradycardia; second- and third-degree AV block; Adams-Stokes syndrome
Interactions	Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity Barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several mo thereafter to monitor for blood dyscrasias; discontinue use if skin rash appears, and do not resume use if rash is exfoliative, bullous or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood sugars; discontinue use if hepatic dysfunction occurs

Drug Name	Valproic acid (Depakote, Depakene, Depacon)
Description	Chemically unrelated to other drugs used to treat seizure disorders. Although mechanism of action unknown, activity may be related to increased brain levels of GABA or enhanced GABA action. Also may potentiate postsynaptic GABA responses, affect potassium channels, or have direct membrane-stabilizing effect. For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% every 2 wk. This reduction may be started at initiation of therapy or delayed by 1-2 wk if 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 patient's regimen at dosage of 10-15 mg/kg/d. Dosage may be increased by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response achieved at daily doses <60 mg/kg/d.
Adult Dose	Monotherapy: 10-15 mg/kg/d PO qd or divided tid; increase by 5-10 mg/kg/wk until seizures controlled or adverse effects prevent further increases; if total daily dose >250 mg, give in divided doses; not to exceed 60 mg/kg/d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hepatic disease/dysfunction
Interactions	Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may reduce levels significantly; in pediatric patients, salicylates decrease protein binding and metabolism; may result in variable changes of carbamazepine concentrations with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels, while either may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
Pregnancy	D - Unsafe in pregnancy
Precautions	Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough plasma concentrations >110 mcg/mL in females and 135 mcg/mL in males; at periodic intervals and prior to surgery, determine platelet counts and bleeding time before initiating therapy; reduce dose or discontinue therapy if hemorrhage, bruising, or hemostasis/coagulation disorder occurs; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness

Drug Name	Gabapentin (Neurontin)
Description	Has properties in common with other anticonvulsants. However, exact mechanism of action unknown. Structurally related to GABA but does not interact with GABA receptors. Increases in daily dose are best tolerated when done slowly.
Adult Dose	100 mg PO tid or 300 mg PO hs on day 1; on day 2 increase dose to 400 mg PO tid; after 3 d at this dose, titrate prn; not to exceed 1200 mg
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids may significantly reduce bioavailability (administer > 2 h following antacids); may increase norethindrone levels significantly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe renal disease

Drug Name	Lamotrigine (Lamictal)
Description	Triazine derivative useful in treatment of both seizures and neuralgic pain. Inhibits release of glutamate and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membrane. Follow manufacturer's recommendation for dose adjustments.
Adult Dose	Adjunctive therapy with enzyme-inducing anticonvulsant: 50 mg/d PO first 2 wk, followed by 100 mg/d divided bid for 2 additional wk; for maintenance, may increase by 100 mg/d q1-2wk to 300-500 mg/d divided bid Adjunctive therapy with an anticonvulsant regimen containing valproate: 25 mg PO qod for first 2 wk, followed by 25 mg/d for 2 additional wk; for maintenance, may increase doses by 25-50 mg/d q1-2wk to 100-200 mg/d qd or divided bid Conversion from single enzyme-inducing anticonvulsant to lamotrigine monotherapy: 50 mg/d PO for first 2 wk, followed by 100 mg/d PO divided bid for 2 additional wk; for maintenance, may increase by 100 mg/d q1-2wk to 300-500 mg/d divided bid; enzyme-inducing anticonvulsant gradually withdrawn over 4-wk interval in 20% decrements per wk
Pediatric Dose	Adjunctive therapy with an enzyme-inducing anticonvulsant 2-12 years: 0.6 mg/kg/d PO divided bid, rounded down to nearest 5 mg for first 2 wk; followed by 1.2 mg/kg/d divided bid, rounded down to nearest 5 mg for 2 additional wk; for maintenance, increase by 1.2 mg/kg/d (round down to nearest 5 mg) q1-2wk and add this amount to previously administered daily dose; average maintenance 5-15 mg/kg/d; not to exceed 400 mg/d divided bid >12 years: 50 mg/d PO for first 2 wk, followed by 100 mg/d divided bid for 2 additional wk; for maintenance, increase dose by 100 mg/d q1-2wk; average maintenance dose 300-500 mg/d divided bid Concomitant therapy with valproic acid 2-12 years: 0.15 mg/kg/d PO qd or divided bid, rounded down to nearest 5 mg for first 2 wk; if initial calculated daily dose 2.5-5 mg, take 5 mg on alternate days for first 2 wk, followed by 0.3 mg/kg/d qd or divided bid, rounded down to nearest 5 mg for additional 2 wk; for maintenance, increase subsequent doses by 0.3 mg/kg/d q1-2wk, round down to nearest 5 mg, and add this amount to previously administered qd dose; average maintenance dose 1-5 mg/kg/d; not to exceed 200 mg/d qd or divided bid >12 years: 25 mg PO qod for first 2 wk, followed by 25 mg qd for 2 additional wk; for maintenance, increase by 25-50 mg/d q1-2wk; average maintenance dose 100-400 mg/d qd or divided bid
Contraindications	Documented hypersensitivity
Interactions	Acetaminophen increases renal clearance, decreasing effects; similarly, phenobarbital and phenytoin increase metabolism, causing decrease in levels; valproic acid increases half-life
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in impaired renal or hepatic function; associated with rash in 5% of patients; children who take lamotrigine with valproate have significantly increased risk of severe allergic drug reactions

Drug Name	Topiramate (Topamax)
Description	Sulfamate-substituted monosaccharide with broad spectrum of antiepileptic activity that may have state-dependent sodium channel– blocking action. Potentiates inhibitory activity of neurotransmitter GABA. May block glutamate activity. Not necessary to monitor plasma concentrations to optimize therapy. On occasion, addition to phenytoin may require adjustment of phenytoin dose to achieve optimal clinical outcome.
Adult Dose	50 mg/d PO; titrate by 50 mg/d at 1-wk intervals to target dose of 200 mg bid; not to exceed 1600 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Phenytoin, carbamazepine, and valproic acid can decrease levels significantly; reduces digoxin and norethindrone levels; carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; may have additive effects with CNS depressants in CNS depression, as well as other cognitive or neuropsychiatric adverse events
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Risk of developing kidney stone increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment

Drug Name	Tiagabine (Gabitril)
Description	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.
Adult Dose	4 mg PO qd in 2-4 divided doses; increase by 4-8 mg/wk until clinical response achieved or until total daily dose of 56 mg/d administered; effects of doses >56 mg/d have not been evaluated systematically in adequate well-controlled trials
Pediatric Dose	<12 years: Not established 12-18 years: 4 mg PO qd and increase by 4 mg after 2 wk; total daily dose may be increased by 4-8 mg/wk thereafter until clinical response achieved or 32 mg/d administered; >32 mg/d tolerated in small number of adolescent patients for relatively short duration
Contraindications	Documented hypersensitivity
Interactions	Cleared more rapidly in patients treated with carbamazepine, phenytoin, primidone, or phenobarbital than in patients who have not received these drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Patients receiving valproate monotherapy may require lower doses or slower dose titration of tiagabine for clinical response; moderately severe to incapacitating generalized weakness has been reported following administration of tiagabine in as many as 1% of patients with epilepsy; weakness may resolve after reduction in dose or discontinuation of tiagabine; should be withdrawn slowly to reduce potential for increased seizure frequency

Drug Name	Felbamate (Felbatol)
Description	Oral antiepileptic agent with weak inhibitory effects on GABA-receptor binding and benzodiazepine-receptor binding. Has little activity at MK-801 receptor-binding site of NMDA receptor-ionophore complex. However, is antagonist at strychnine-insensitive glycine-recognition site of NMDA receptor-ionophore complex. Not indicated as first-line antiepileptic treatment. Recommended for use only in patients whose epilepsy is so severe that benefits outweigh risks of aplastic anemia or liver failure. Most adverse effects during adjunctive therapy resolve as dosage of concomitant AEDs decreased.
Adult Dose	Monotherapy: 1200 mg/d PO divided tid/qid initially; titrate to 2400 mg/d with 600 mg increments q2wk and to 3600 mg/d if clinically indicated Conversion to monotherapy: 1200 mg/d divided PO tid/qid initially; reduce dosage of concomitant AEDs by one third at initiation of felbamate therapy; after first wk, increase dosage to 2400 mg/d while reducing dosage of other AEDs by additional one third of their original dosage; following wk 2, increase felbamate dosage up to 3600 mg/d and continue to reduce dosage of other AEDs prn Adjunctive therapy: 1200 mg/d PO; after first wk reduce dose of concomitant AEDs by one third; following first wk, administer 2400 mg/d and reduce original AED dose by another third; 3600 mg/d after third wk and reduce other AEDs as clinically indicated
Pediatric Dose	Monotherapy <14 years: Not established >14 years: Administer as in adults Adjunctive therapy 2-14 years: 15 mg/kg/d PO divided tid/qid; reduce other AEDs by 20%; titrate felbamate dose with 15 mg/kg/d increments qwk to 45 mg/kg/d >14 years: Administer as in adults
Contraindications	Documented hypersensitivity; blood dyscrasia; hepatic dysfunction
Interactions	May increase steady-state phenytoin levels (40% dose-reduction of phenytoin may be necessary in some patients); phenytoin may double clearance, resulting in more than 45% decrease in steady-state levels; may increase phenobarbital plasma concentrations; phenobarbital may reduce plasma levels; may decrease steady-state carbamazepine levels and increase steady-state carbamazepine metabolite levels; may increase steady-state valproic acid levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Associated with marked increase in incidence of aplastic anemia (monitor CBC periodically); marked increase in fatal hepatic failure—perform liver function testing (ALT, AST, bilirubin) before felbamate therapy and at 1- to 2-wk intervals during therapy; discontinue immediately if liver abnormalities detected during treatment

Drug Name	Phenobarbital (Luminal, Barbita)
Description	Exhibits anticonvulsant activity in anesthetic doses and can be administered orally. If IM route chosen, inject into large muscle such as gluteus maximus, vastus lateralis, or other areas where little risk of encountering nerve trunk or major artery. Injection into or near peripheral nerves may result in permanent neurological deficit. Restrict IV use to conditions in which other routes are not feasible, either because patient unconscious, as in cerebral hemorrhage, eclampsia, or status epilepticus, or because prompt action imperative.
Adult Dose	60-100 mg/d PO; alternatively, 200-320 mg IV/IM q6h prn
Pediatric Dose	3-6 mg/kg/d PO; alternatively, 4-6 mg/kg/d IV/IM for 7-10 d to blood level of 10-15 mcg/mL, maximum dose of 10-15 mg/kg/d
Contraindications	Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis
Interactions	May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may occur)
Pregnancy	D - Unsafe in pregnancy
Precautions	In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia since adverse reactions can occur; caution in myasthenia gravis and myxedema

Drug Name	Oxcarbazepine (Trileptal)
Description	Pharmacological activity primarily by 10-monohydroxy metabolite. Studies indicate that this drug may block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. This drug'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 <2 years have not been studied in controlled clinical trials.
Adult Dose	Monotherapy: 600 mg/d divided PO bid initially; increase dose by 300 mg/d q3d to 1200 mg/d; monitor patients for anticonvulsant adverse effects Conversion to monotherapy: 600 mg/d PO divided bid initially; gradually reduce dose of concomitant AEDs in about 3-6 wk and gradually increase oxcarbazepine dose in 2-4 wk; may increase oxcarbazepine dose as needed by maximum increment of 600 mg/d at weekly intervals; monitor patients closely during this transition phase for anticonvulsant adverse effects Adjunctive therapy: 600 mg/d PO divided bid initially; may increase by maximum of 600 mg/d at weekly intervals; recommended daily dose 1200 mg/d; monitor patients for anticonvulsant adverse effects
Pediatric Dose	Adjunctive therapy (age 4-16 years): 8-10 mg/kg/d PO divided bid, not to exceed 600 mg/d; gradually increase to target dose over 2 wk; target dose based on body weight as follows: 20-29 kg: 900 mg/d PO 29.1-39 kg: 1200 mg/d PO >39 kg: 1800 mg/d PO
Contraindications	Documented hypersensitivity
Interactions	May decrease levels of dihydropyridine calcium antagonists and oral contraceptives; can reduce serum concentrations of carbamazepine, phenobarbital, phenytoin, and valproic acid; when given in doses >1200 mg/d may increase phenytoin and phenobarbital serum concentrations significantly; can reduce serum concentrations of oral contraceptives and make oral contraceptives ineffective; can increase clearance of felodipine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Can cause cognitive adverse effects (eg, psychomotor slowing, impaired concentration, impaired speech, impaired language); decrease initiation dose by 50% with renal impairment (CrCl <30 mL/min) and increase dose more slowly; oxcarbazepine can cause hyponatremia (sodium <125 mmol/L); among persons with hypersensitivity to carbamazepine, 25-30% will have hypersensitivity to oxcarbazepine; rapid withdrawal of oxcarbazepine can cause exacerbation of seizures; observe for side effects and monitor plasma levels of concomitant anticonvulsants during dose titration

Drug Name	Zonisamide (Zonegran)
Description	Indicated for adjunct treatment of partial seizures with or without secondary generalization. Evidence that is effective in myoclonic and other generalized seizure types as well.
Adult Dose	100-600 mg/d PO effective dose 100 mg/d PO for 2 wk initial dose; increase 100 mg q2wk; >400 mg/d not shown to be of benefit
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase serum carbamazepine levels; carbamazepine may increase zonisamide concentrations; phenobarbital may decrease zonisamide levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause drowsiness, weight loss, ataxia, nausea, and slowing of mental activity; pediatric patients have an increased risk for oligohidrosis and hyperthermia

Drug Name	Levetiracetam (Keppra)
Description	Used as add-on therapy for partial seizures. Mechanism of action unknown. Has favorable adverse effect profile, with no life-threatening toxicity reported.
Adult Dose	500 mg PO bid initial dose; increase by 1000 mg q2wk; typical dose 1000-3000 mg
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal impairment; major side effects include somnolence, asthenia, incoordination, mild leukopenia (3%) and behavioral changes such as anxiety, hostility, emotional lability, depression and psychosis (1-2%), and depersonalization

Drug Name	Pregabalin (Lyrica)
Description	Structural derivative of GABA. Mechanism of action unknown. Binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.
Adult Dose	75 mg PO bid or 50 mg PO tid initially; if needed, may increase dose to maximum of 600 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain