Excerpt from Sturge-Weber Syndrome

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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

Risk of SWS with facial PWS	8%
SWS without facial nevus	13%
Bilateral cerebral involvement	15%
Seizures	72-93%
Hemiparesis	25-56%
Hemianopia	44%
Headaches	44-62%
Developmental delay and mental retardation	50-75%
Glaucoma	30-71%
Choroidal hemangioma	40%

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.

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