Advances in Sturge-Weber syndrome

PURPOSE OF REVIEW: Recent neuroimaging, clinical and molecular neuropathologic studies have provided new insights into the neurologic aspects of Sturge-Weber syndrome and are summarized here. RECENT FINDINGS: Molecular studies suggest that abnormal brain blood vessel vasoactive and extracellular matrix molecule expression, as well as aberrant brain vascular innervation, contribute to the vascular malformation and its consequences. New magnetic resonance sequences may be useful for the early diagnosis of Sturge-Weber syndrome and perfusion magnetic resonance imaging, single photon emission computed tomography imaging, and positron emission tomography imaging studies are suggesting that decreased brain blood flow combined with altered hemodynamics during prolonged seizures may contribute to the neurologic declines in Sturge-Weber syndrome. SUMMARY: Recent advances in our understanding of the neurologic issues offer promise for preventing brain injury in Sturge-Weber syndrome. More research is needed to translate advances in molecular research and neuroimaging advances into new treatment strategies for the disease.     

Clinical outcomes in bilateral Sturge-Weber syndrome

Approximately 15% of patients with Sturge-Weber syndrome demonstrate bilateral intracranial involvement, and the prognosis of these patients is considered particularly unfavorable. We reviewed the clinical and neuroimaging features of patients with Sturge-Weber syndrome and bilateral intracranial involvement. Seizure variables, the presence of hemiparesis, and the degree of developmental impairment at most recent follow-up were compared with imaging abnormalities. Of 110 Sturge-Weber syndrome patients, 14 demonstrated bilateral brain involvement, with an asymmetric pattern on glucose metabolism positron emission tomography. Although most patients manifested frequent seizures initially, associated with frontal hypometabolism on positron emission tomography, six (43%) had achieved good seizure control during follow-up. Bilateral frontal hypometabolism was associated with severe developmental impairment. Two children with bitemporal hypometabolism exhibited autistic features. Hemiparesis was associated with superior frontal (motor cortex) hypometabolism. Three patients underwent resective surgery, resulting in improved seizure control and developmental outcomes. The severity of neurologic complications and clinical course depend on the extent of cortical dysfunction in bilateral Sturge-Weber syndrome. Bilateral frontal and temporal hypometabolism is associated with poor developmental outcomes. Good seizure control and only mild/moderate developmental impairment can be achieved in about 50% of patients with bilateral Sturge-Weber syndrome, with or without resective surgery.     

Detection of Cerebral Hyperperfusion Syndrome after Carotid Endarterectomy with CT Perfusion

We present the case of a 60‐year‐old female patient, who developed symptomatic internal carotid artery stenosis and subsequently underwent carotid endarterectomy. Four days after an uneventful surgery the patient developed confusion, seizures, and was admitted to the ICU. CT perfusion revealed reduced ispilateral time‐to‐peak and mean‐transient‐time and increased cerebral blood volume and cerebral blood flow, confirming the diagnosis of cerebral hyperperfusion syndrome. We thus propose CT perfusion as a diagnostic means for cerebral hyperperfusion syndrome, a syndrome that remains underdiagnosed.     

Pathophysiology of Sturge-Weber syndrome

Sturge-Weber syndrome is a neurocutaneous disorder classically presenting with a facial port-wine stain, vascular eye abnormalities, and an ipsilateral occipital leptomeningeal angioma. Children with Sturge-Weber syndrome often develop progressive neurologic problems. Data on the pathophysiology of Sturge-Weber syndrome are briefly reviewed. The embryologic, genetic, and pathologic considerations are discussed, as are theories regarding the mechanisms of the degenerative brain changes. Sturge-Weber syndrome likely results from an early embryologic malformation of vascular development affecting the development of the nearby skin, eye, and brain structures. Studies suggest that complex molecular interactions contribute to the abnormal development and function of blood vessels in Sturge-Weber syndrome. Neurologic deterioration in Sturge-Weber syndrome is likely secondary to impaired blood flow to the brain and is worsened by the presence of seizures. Insights from related areas are discussed, and future research studies are suggested.     

Sturge-Weber disease: operative indications and surgical results

Patients with Sturge-Weber disease with epilepsy refractory to medical therapy have been reported to develop slowly progressive neurological deficits and ultimately become moderately or severely disabled. We studied six patients with Sturge-Weber syndrome including its incomplete form. Three out of six patients with Sturge-Weber syndrome revealed evolution of calcified angioma on computed tomography. All of the three cases developed medically intractable seizures. Total and/or subtotal hemispherectomy was performed for these three cases. The surgery was effective for controlling seizures in all three cases except one with infantile spasm with hypsarrythmia on electroencephalogram who is still on anticonvulsant. Although the unremitting deterioration in mental retardation and hemiparesis was not effectively prevented by the surgery possibly because the timing of surgery was delayed in one case, the surgery not only stopped the frequent medically-intractable seizures, but also dramatically prevented the psychomotor deterioration in the other case. Although the role of surgical treatment for the patients with Sturge-Weber syndrome remains poorly defined, one can expect excellent results if the indications for surgery are carefully analyzed and hemispherectomy is performed on an individual basis.     

Single photon emission computerized tomography during and between seizures

Summary In three patients, patterns of brain activity were measured by ^99mTc-hexamethyl-propyleneamineoxime (^99mTc-HM-PAO) brain SPECT (single photon emission computerized tomography) in ictal and interictal states. Increased relative blood flow indicated the focus of partial seizures, its spreading to adjacent cortical regions and to distant brain structures via neuronal pathways. Ictal patterns of regional cerebral blood flow (rCBF) were in agreement with clinical symptomatology. Successive SPECT studies were performed after 3–7 days in the absence of electroencephalographic and clinical signs of seizures but still revealed increased relative blood flow in the focus of the seizures. SPECT studies, performed 2–6 weeks after the last clinically observable seizures, demonstrated the transition from increased to decreased relative blood flow in the focus of the seizures. In one patient, the EEG was complementary to and corresponded with the rCBF patterns in the ictal state. However, the dynamics of interictal changes could only be assessed by brain SPECT.     

Study of the cerebral blood flow in partial epilepsy of childhood using the SPECT method

Cerebral functional imaging methods provide information on the location of the epileptic focus in partial epilepsy of adults. We report our experience of one of these methods, single photon emission computed tomography (SPECT), in epilepsy of children. SPECT enables the regional cerebral blood flow (rCBF) to be measured, after inhalation or injection of 133-Xenon, on 5 contiguous, 20 mm thick axial sections, with a 14 mm resolution and negligible brain irradiation. In Sturge-Weber syndrome (13 patients aged 9 months to 18 years) the rCBF was reduced in the same territory as CT abnormalities suggesting ischaemia of the brain tissue lying below the pial angioma; the SPECT image facilitated the diagnosis in 3 patients with atypical CT. In hemimegalencephaly (6 patients aged 1 month to 10 years) the rCBF was extremely low in the hypertrophic hemisphere and in 1 case the SPECT image was determinant in the decision to perform hemispherectomy. In partial epilepsy with normal CT and/or MRI (42 children aged 1 to 15 years) the rCBF was abnormal in 83% of the patients, and its abnormality was located in the same area as the EEG focus in three quarters of the cases. Between seizures, the rCBF was low in 3 out of 4 cases and abnormality decreased after the seizures had ceased (6 patients explored twice); it was high in 1 out of 4 cases. Thus, in children as in adults, cerebral functional imaging provides new data which contribute to the localization and follow-up of epileptic foci.     

Decompressive hemicraniectomy in a new cat model. Methodological description of the PET study protocol

Positron emission tomography (PET) is increasingly used to quantify regional hemodynamic and metabolic changes in different animal models. Most of these (multitracer) studies provided important early data on already functionally altered brain tissue, indicating selective vulnerability by a large variability in the functional blood flow threshold of individual neurons. To fill the gap between experimental studies at early time points and rather late clinical studies at well-defined but singular time points, we repeatedly measured cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction rate and cerebral metabolic rate of glucose (CMRglc) in three cats before and up to 28 h after decompressive hemicraniectomy on normal brain tissue. Decompressive hemicraniectomy in the cat decreased CBF, and to a lesser extent CMRO2 and CMRglc 2 h after surgical intervention in normal brain tissue that last for at least 1 day. CBF significantly decreased (p < 0.01) and oxygen extraction fraction (OEF) (p < 0.05) significantly increased. CMRO2 and CMRglc decreased only in regions with most severe CBF reduction. These effects remained for at least a day irrespective of corrective sustaining cranioplasty. The method and data analysis is decreased and discussed in detail in the presented protocol. In conclusion, serial positron emission tomography studies are best suited to repeatedly and non-invasively demonstrate circulatory and biochemical changes by surgical interventions in normal brain tissue for at least one day. The transition of normal brain tissue into misery-perfused or non-viable regions can be followed over time. Such state-of-the-art imaging modalities as sequential high-resolution positron emission tomography provide insight into the dynamic of regional pathophysiology and may thus further justify the development of rational therapeutic strategies for decompressive hemicraniectomy, especially for disease with focal disturbances in cerebral blood flow.     

Effects of acetazolamide on cerebral blood flow, blood volume, and oxygen metabolism: a positron emission tomography study with healthy volunteers.

To evaluate changes in cerebral hemodynamics and metabolism induced by acetazolamide in healthy subjects, positron emission tomography studies for measurement of cerebral perfusion and oxygen consumption were performed. Sixteen healthy volunteers underwent positron emission tomography studies with 15O-gas and water before and after intravenous administration of acetazolamide. Dynamic positron emission tomography data were acquired after bolus injection of H2[15O] and bolus inhalation of 15O2. Cerebral blood flow, metabolic rate of oxygen, and arterial-to-capillary blood volume images were calculated using the three-weighted integral method. The images of cerebral blood volume were calculated using the bolus inhalation technique of C[15O]. The scans for cerebral blood flow and volume and metabolic rate of oxygen after acetazolamide challenge were performed at 10, 20, and 30 minutes after drug injection. The parametric images obtained under the two conditions at baseline and after acetazolamide administration were compared. The global and regional values for cerebral blood flow and volume and arterial-to-capillary blood volume increased significantly after acetazolamide administration compared with the baseline condition, whereas no difference in metabolic rate of oxygen was observed. Acetazolamide-induced increases in both blood flow and volume in the normal brain occurred as a vasodilatory reaction of functioning vessels. The increase in arterial-to-capillary blood volume made the major contribution to the cerebral blood volume increase, indicating that the raise in cerebral blood flow during the acetazolamide challenge is closely related to arterial-to-capillary vasomotor responsiveness.     

Cerebral blood volume, endarterectomy and SPECT

Cerebral blood flow and cerebral blood volume were measured and quantified using single photon emission computed tomography before and after unilateral endarterectomy in 3 patients with bilateral severe lesions of the internal carotid artery. These parameters were measured using an intravenous injection of 133 Xenon and 99m Technetium respectively. Before endarterectomy cerebral blood volume was high in all patients suggesting a focal vasodilatation in response to a reduced cerebral perfusion pressure. After endarterectomy a decrease of cerebral blood volume and an increase of cerebral blood flow were observed. These preliminary results confirm that the hemodynamic adaptative mechanisms secondary to carotid occlusion are reversible when the stenosis is removed and demonstrate that these changes can be accurately measured using single photon emission computed tomography. Positron emission tomography was previously considered to be the only method able to quantify cerebral blood volume in man. Single photon emission computed tomography can also be considered a reliable technique to measure both cerebral blood flow and cerebral blood volume. This technique can then be used to assess individual cerebral vascular adaptative states and to evaluate the influence of cerebral hemodynamic changes on stroke occurrence in large longitudinal studies.     

Cerebral haemodynamic changes after extracranial-intracranial bypass surgery.

Regional cerebral blood flow, oxygen utilisation, fractional oxygen extraction, and cerebral blood volume were measured by positron emission tomography in twelve patients with carotid artery occlusion. Follow-up studies were carried out at a mean interval of eleven weeks after extracranial-intracranial bypass surgery. Clinical improvement was observed in three patients who had presented with frequent transient ischaemic attacks. One patient with multiple vascular occlusions suffered a stroke at the time of surgery. Follow-up studies showed an increase of regional cerebral blood flow in only two of the twelve patients. In the group as a whole, there was no significant change of cerebral blood flow, oxygen consumption or fractional oxygen extraction after bypass surgery. The most consistent post-operative change, observed in eleven of the twelve patients, was a fall of cerebral blood volume in the cortical territory of the bypassed carotid artery (p less than 0.01). This effect was most marked in patients with bilateral carotid occlusion, in whom there was often an accompanying fall of blood volume in the contralateral hemisphere. The post-operative findings were consistent with an increase of regional cerebral perfusion pressure as a result of the bypass procedure. Although this effect is potentially of value, those patients with most to gain from bypass surgery may also run the highest risk of peri-operative cerebral ischaemia.     

Autism with facial port-wine stain: a new syndrome?

The hallmark of Sturge-Weber syndrome is leptomeningeal angiomatosis. Over 15 years, four children were identified (2 boys, age 2.9-6 years) with unilateral facial port-wine stain, referred for presumable Sturge-Weber syndrome but who were also autistic. Computed tomography and magnetic resonance imaging scans failed to show evidence of leptomeningeal angioma in all four children. Three of the children had a history of seizures. Detailed neuropsychologic testing of three children revealed a similar presentation, characterized by developmental disturbance, particularly involving delayed onset of language, and early-emerging social atypicality. Positron emission tomography scanning of cerebral glucose metabolism revealed hypometabolism in the bilateral medial temporal regions, anterior cingulate gyrus, frontal cortex, right temporal cortex, and cerebellum. The pattern of glucose hypometabolism differed from that of 12 children with infantile autism (age 2.7-7.9 years) who had mild left medial temporal but more severe right temporal cortical hypometabolism and showed a reversal of normal frontotemporal asymmetry of glucose metabolism. Unilateral facial port-wine stain and autism with no intracranial angioma on conventional imaging may represent a rare clinical entity distinct from both infantile autism and previously described variants of Sturge-Weber syndrome.     

Physiological responses to focal cerebral ischemia in humans

Positron emission tomography (PET) was used to investigate the regional hemodynamic and metabolic changes that accompany focal reductions in cerebral blood flow to ischemic but uninfarcted regions of the brain. Studies were performed on 7 patients chosen from a larger group of subjects with transient ischemic attacks and normal computed tomographic findings, specifically because their PET studies showed decreased blood flow to the symptomatic hemisphere rather than symmetrical flow to the two hemispheres. In regions with decreased blood flow, the cerebral metabolic rate for oxygen was also decreased, but to a lesser degree. Cerebral blood volume, vascular mean transit time, and fractional extraction of oxygen from blood were all increased. These findings indicate that cerebral oxygen metabolism was maintained in the face of decreased blood flow by local compensatory mechanisms that included dilation of intraparenchymal blood vessels and increased transfer of oxygen from blood to tissue. Such knowledge of the physiological characteristics of ischemic, uninfarcted brain is important if PET is to be used clinically to differentiate reversible cerebral ischemia from irreversible infarction.     

Regional cerebral blood flow by SPECT imaging in Sturge-Weber disease: an aid for diagnosis.

Regional cerebral blood flow (rCBF) was studied using SPECT (single photon emission computed tomography) with 133-Xenon in 13 patients with confirmed Sturge-Weber disease, aged 9 months to 18 years. CT scan, performed at the same time, showed evident cerebral angioma in 10 but not in three. A marked hypoperfused area was found in all patients, ranging from -32% to -72% and of the same location as the CT signs. The hypoperfusion seems to result from post ictal phenomenon as well as from chronic ischaemia. SPECT imaging is therefore a sensitive method for visualising intracranial angioma in Sturge-Weber disease and it provides an aid for diagnosis when a CT scan is not reliable.     

Regional cerebral blood flow characteristics of the Sturge-Weber syndrome

Four patients with the Sturge-Weber syndrome were studied using the non-invasive Xenon-133 inhalation technique. All four patients had decreased regional cerebral blood flow in the area of their lesion, and in two patients who were subsequently tested with 5% carbon dioxide inhalation, impaired vasomotor reactivity was documented. Diminished regional cerebral blood flow is consistent with previously described nuclide flow studies which demonstrated a delay in the initial perfusion blush in the region of the abnormal vasculature. The focal decrease in blood flow was greatest in the most severely affected patient, but was also prominent in the two younger patients, both of whom have excellent neurologic function. These studies suggest that localized decrease in blood flow and vasomotor dysfunction in Sturge-Weber syndrome can precede the occurrence of severe neurologic impairment and extensive cerebral atrophy and possibly be a major contributing factor in progressive dysfunction. A secondary observation was that the blood flow in the unaffected hemisphere was significantly greater in two children compared to the two adults and was similar to the age-related differences reported for normal children and adults.     

Corpus callosum section in the treatment of intractable seizures in the Sturge-Weber syndrome

The Sturge-Weber syndrome includes unilateral cerebral cortical angiomatosis, which often leads to progressive cerebral dysfunction and epileptic seizures that are medically difficult to control. Cerebral resections and hemispherectomy have been successfully performed in the past in intractable epileptic cases. Two children with medically unresponsive generalized seizure activity secondary to the Sturge-Weber syndrome have been surgically treated by dividing their corpus callosum. Cessation of generalized epilepsy was achieved in both cases. Corpus callosotomy is presented as a less destructive and safer procedure in dealing with intractable seizures in the Sturge-Weber syndrome.     

Changes in brain volume 2 years after extracranial-intracranial bypass surgery: A preliminary subanalysis of the Japanese EC-IC trial

BACKGROUND AND METHODS: We studied changes in brain volume on magnetic resonance imaging in 10 patients with and without extracranial-intracranial (EC-IC) bypass surgery who met the inclusion criteria for the Japanese EC-IC Bypass Trial, a multicenter, randomized, prospective study of patients with hemodynamic brain ischemia due to cerebral artery occlusive disease. We also examined the association of cerebral hemodynamics on single-photon emission computed tomography with the changes in brain volume. RESULTS: The affected/unaffected ratio of the percent brain volume declined in patients without EC-IC bypass surgery (p < 0.02, n = 4), and the affected/unaffected percent regional cerebral blood flow ratio increased in patients with the surgery (p < 0.03, n = 6). Acetazolamide reactivity increased in the affected hemisphere of patients with surgery (p < 0.01). Two-year increase (decrease) in acetazolamide reactivity of the affected hemisphere showed a significant positive correlation with 2-year changes in the affected/unaffected percent brain volume ratio (R2 = 0.737, p = 0.0007). CONCLUSIONS: Change in acetazolamide reactivity might be a good predictor for brain atrophy in cerebral artery occlusive disease.     

Changes in cerebral glucose metabolism in newborn infants with cerebral infarction

Cerebral infarction in infants is not uncommon, and it differs in many important ways from cerebral infarction in older children and adults. Computed tomography, ultrasound, and conventional and diffusion-weighted magnetic resonance imaging are useful for diagnosing cerebral infarction, but these imaging techniques cannot be used to measure cerebral blood flow and metabolic activity. Abnormality in those parameters seems to follow a different pattern and time course than those in older patients. In this study, the rapid changes in regional cerebral blood flow and metabolic rate of glucose were estimated by single-photon emission computed tomography and positron emission tomography during the acute and subacute phases of neonatal infarction. Subacute increases in blood flow and metabolic rate in the infarcted area of a term infant with multiple apneic episodes within 2 days after birth were observed, as well as acute increases in both in the infarcted area of a term infant with acute clonic seizures within 24 hours after birth. Follow-up studies at 4 months for the first infant and at 10 days for the second infant demonstrated that both the blood flow and metabolic rate in the infarcted region decreased. The results of this study should contribute to an understanding of the relationship between blood flow and metabolic rate changes after neonatal infarction as well as to improvement of diagnosis of neurologic impairments in neonates.     

Postictal switch in blood flow distribution and temporal lobe seizures.

The ictal increase of regional cerebral blood flow has yet to be fully utilised in the investigation of focal seizures. Although single photon emission tomography (SPECT) is being increasingly used in the localisation of epileptic foci, the evolution and time courses of the peri-ictal perfusion changes have yet to be clarified. We performed serial SPECT studies in the interictal, ictal and immediate postictal states in 12 patients with refractory temporal lobe epilepsy to define the patterns and duration of peri-ictal cerebral blood flow changes. Visual analysis showed a constant pattern of unilateral global increases in temporal lobe perfusion during seizures which suddenly switched to a pattern of relative mesial temporal (hippocampal) hyperperfusion and lateral temporal hypoperfusion in the immediate postictal period. Quantitative analysis confirmed the visual assessment. Lateral temporal cortex ictal/normal side to side ratios were increased by mean 35.1% (95% confidence interval 21.8% to 48.4%) more in the ictal studies than in the interictal studies and mesial temporal cortex ratios increased by mean 30.8% (22.4% to 39.2%). In the postictal state, however, lateral temporal ratios were reduced by mean 7.7% (-15.8% to 0.4%) compared with interictal values, whereas mesial temporal perfusion was maintained compared with the interictal studies. These observations provide critical information for interpreting scans which can be used in the localisation of epileptic foci. This postictal switch in blood flow patterns may reflect the underlying metabolic processes of neuronal activation and recovery and have implications for understanding the neurobiology of human epileptic seizures.     

Positron emission tomography in Rasmussen's encephalitis

This report presents unusual positron emission tomography findings in an 11-year-old male with Rasmussen's encephalitis. This patient underwent fluorine-18 fluorodeoxyglucose positron emission tomography to localize his ictal focus before surgical consideration. Positron emission tomography disclosed marked hypermetabolism in the left cerebral hemisphere and basal ganglia with subnormal right cerebral activity and crossed cerebellar diaschisis. The heterogeneous distribution of metabolism suggests a combination of areas in different stages of ictal and postictal involvement. The hypermetabolic region in the left hemisphere was larger in size and extent (now including the left frontoparietal lobe) than the sole hypermetabolic left temporal lobe on his positron emission tomography from 2 years ago. While this positron emission tomography pattern of progression appears most commonly in Rasmussen's encephalitis case studies, few serial reports exist. The complex positron emission tomography findings of this case emphasize the importance of knowing the history of recent seizures, seizure type, clinical status at time of injection, and electroencephalographic correlation before interpreting functional neuroimaging studies. Finally, positron emission tomography studies can help clarify whether patients with Rasmussen's encephalitis with dominant hemisphere involvement are appropriate candidates for surgery or not.