Sturge-Weber Syndrome Center: Completed Research Studies

Our past research has had three main goals: 1) to better understand how to diagnose and treat the complications of Sturge-Weber syndrome (SWS), 2) to develop better safe and non-invasive tools to diagnose and monitor disease progression, and 3) to improve our understanding of the underlying abnormalities in SWS (pathogenesis). From the beginning, on of the purposes of the Center has been to bring the different experts together so that they can learn from each other, find new ways to collaborate, and develop both new research questions and new treatment strategies. Another mandate upon all members of the Center is to publish their clinical experience and research so that patients and physicians who not here can benefit from this work.

Read about our studies to:

• Improve Clinical Care of Sturge-Weber syndrome.
• Improve Diagnosis and Monitoring of Sturge-Weber syndrome.
• Understand the Pathogenesis of Sturge-Weber syndrome.

Studies to Improve Clinical Care of Sturge-Weber Syndrome

• Aspirin use in Sturge-Weber syndrome: side effects and clinical outcomes. Lance EI, Sreenivasan AK, Zabel TA, Kossoff EH, Comi AM. J Child Neurol. . 2013
  Feb;28(2):213-8. doi: 10.1177/0883073812463607. Epub 2012 Oct 30.
  • This study summarized our experience with the side effects and outcomes of low-dose aspirin usage in a large number of children with Sturge-Weber syndrome suggesting that low-dose aspirin is generally safe and useful in the treatment of patients with SWS.

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• Importance of utilizing a sensitive free thyroxine assay in Sturge-Weber syndrome. Siddique L, Sreenivasan A, Comi AM, Germain-Lee EL. J Child Neurol. 2013
  Feb;28(2):269-74. doi: 10.1177/0883073812463606. Epub 2012 Oct 30.
  • This study described 5 children with Sturge-Weber syndrome on anticonvulsants suspected to have hypothyroidism and the importance of using the free T4 assay in order to accurately diagnose hypothyroidism.

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• A pilot study of the modified Atkins diet for Sturge-Weber syndrome. Kossoff EH, Borsage JL, Comi AM. Epilepsy Res. 2010 Dec;92(2-3):240-3.
  • Studied how a modified Atkins diet (MAD) as a dietary treatment for epilepsy in patients with Sturge-Weber syndrome. Theoretically is safer than the ketogenic diet for children with SWS. All children had urinary ketosis and seizure improvement, including 3 with > 50% seizure reduction.

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• Survey of aspirin use in Sturge-Weber syndrome. Bay MJ, Kossoff EH, Lehmann CU,Zabel TA, Comi AM. J Child Neurol. 2011 Jun;26(6):692-702.
  • Study showed a significant relative reduction in both self-reported seizure frequency and stroke-like episodes after starting aspirin. It also suggests that low-dose aspirin can be safely used in these patients.

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• Effect of a single application of pulsed dye laser treatment of port-wine birthmarks on intraocular pressure. Quan SY, Comi AM, Parsa CF, Irving ND, Krakowski AC, Cohen BA. Arch Dermatol. 2010 Sep;146(9):1015-8.
  • Study examined optimal timing and use of laser in the treatment of patients with or at-risk for Sturge-Weber syndrome. No evidence of worsening of eye pressures was noted immediately after laser treatments compared to just prior to the laser eye treatment.

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• Sturge-Weber syndrome with cerebellar involvement. Smith PM, Abdalla WM, Lin DD, Comi AM, Boltshauser E, Gailloud P, Huisman TA. J Neuroradiol. 2008. Aug 20. [Epub ahead of print]
  • Divisions of Interventional Neuroradiology, Johns Hopkins Hospital, Baltimore, USA.
  • The importance of this study is that it highlights the occurrence of lesser known cerebellar brain involvement in SWS so that this is aspect is not overlooked in patients.
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    Sturge-Weber syndrome is a rare neurocutaneous disorder that typically presents with angiomas involving the face, ocular choroid and ipsilateral supratentorial leptomeninges. Posterior fossa involvement is extremely rare. We present two patients with simultaneous supra- and infratentorial involvement. Magnetic resonance imaging (MRI) and digital subtracted angiography (DSA) findings are discussed.

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• Central hypothyroidism and Sturge-Weber syndrome. Comi AM, Bellamkonda S, Ferenc LM, Cohen BA, Germain-Lee EL. Pediatr Neurol. 2008 Jul; 39(1):58-62.
  • Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA. comi@kennedykrieger.org
  • This paper stresses the need to test thyroid function in patients with SWS and treat deficiency if present. This problem was not previously described in the context of SWS.
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    Sturge-Weber syndrome is a rare disorder manifesting with a facial port-wine birthmark and a vascular malformation of the brain. Infants and children present with seizures and stroke-like episodes with focal neurologic deficits. Our previous investigations revealed that growth-hormone deficiency occurs with an increased prevalence in Sturge-Weber syndrome, presumably secondary to involvement of the hypothalamic-pituitary axis. We have continued to screen for hormonal abnormalities in patients with Sturge-Weber syndrome, specifically those from our multidisciplinary center for patients with this condition. We describe 2 children out of 83 (2.4%) with Sturge-Weber syndrome and brain involvement who were evaluated at our center and diagnosed with central hypothyroidism, based on clinical signs and laboratory findings. This prevalence is much higher than that of central hypothyroidism in the general population. Although it is well-known that anticonvulsants can lead to abnormalities in thyroid function tests, including central hypothyroidism, patients with Sturge-Weber syndrome carry the additional risk of developing hypothalamic-pituitary dysfunction, secondary to their central nervous system dysfunction. Therefore, it is important that patients with Sturge-Weber syndrome undergo routine thyroid-function testing, especially in the face of any clinical manifestations.

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• Sturge-Weber syndrome and epilepsy: an argument for aggressive seizure management in these patients. Comi AM. Expert Rev Neurother. 2007 Aug; 7(8):951-6.
  • Department of Neurology, Kennedy Krieger Institute & Johns Hopkins Medicine, Baltimore, MD, USA. comi@kennedykrieger.org
  • This paper argues, based on the literature, our research, and our clinical experience that early aggressive seizure management is important to the longterm neurodevelopmental outcome in SWS.
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    Sturge-Weber syndrome (SWS) involves vascular malformations of the skin (facial port-wine stain), eye (glaucoma) and the brain (leptomeningeal angioma). Children born with a port-wine stain on the upper part of the face are also at risk for brain involvement. These infants and young children often develop seizures and other neurologic impairments. Progression in neurologic deficits does occur in some patients, but this is quite variable. A diagnosis of brain involvement is made with head computed tomography and contrast-enhanced MRI, but the sensitivity of standard imaging in young asymptomatic infants is low. Seizures occur in more than 75% of affected individuals. Clinical course and functional imaging suggest a role for both cerebral perfusion impairments and seizures in the development of neurologic deficits. Several controversies exist in the management of seizures and other neurologic impairments in SWS. Continued efforts are needed to develop a multicentered network for SWS clinical trials. Future research should be focused on this goal and on studies to improve our understanding of the cause(s) and molecular neuropathology of SWS.

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• Self-reported treatment patterns in patients with Sturge-Weber syndrome and migraines. Kossoff EH, Balasta M, Hatfield LM, Lehmann CU, Comi AM. J Child Neuro. 2007 Jun; 22(6):720-6.
  • Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. ekossoff@jhmi.edu
  • This research highlighted several important findings including the underuse of migraine prophylactic medications and the safe effective use of triptans for migraines in some patients with SWS.
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    Migraine is common in patients with Sturge-Weber syndrome, yet treatment options are poorly described. An Internet-based questionnaire was completed anonymously by 104 Sturge-Weber syndrome patients, 74 of whom reported experiencing migraines (median age, 25 years; range, 3-64 years). Sixteen (22%) subjects self-reported trying triptans. Five of 12 (42%) describing triptan response believed they were very efficacious (median time of onset of 26 minutes), compared to 13 of 65 (20%) using over-the-counter analgesics (P = .08). Eighty-eight percent (14/16) of triptan users self-reported that when they do not use medications, migraines had a moderate to severe impact on their quality of life; however, while taking triptans, only 50% (7/14) of users reported such an impact (P = .03). Two patients using triptans reported transient unilateral weakness. Of the 26 patients (35%) who received daily preventative medications, 80% experienced improved quality of life. In addition, only 10 of 24 (42%) reported a significant negative impact of migraines on quality of life with daily preventative use, compared to 22 of 26 (85%) without their use (P = .002). Sturge-Weber syndrome patients with migraines are using triptans and preventative agents and self-reporting good efficacy. The small sample size precludes any safety analysis, however, and future prospective trials of both treatment options are needed.

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• Update on Sturge-Weber syndrome: diagnostic, treatment, quantitative measures, and controversies. Comi AM. Lymphat Res Biol. 2007; 5(4):257-64.
  • Neurology and Developmental Medicine, Kennedy Krieger Institute, Department of Neurology and Pediatrics, Johns Hopkins School of Medicine; Baltimore, MD 21205, USA. comi@kennedykrieger.org
  • This review summarized the recent and evolving literature on the current and needed tools for diagnosis and monitoring in SWS, treatment trends, and highlighted key research questions and directions.
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    Sturge-Weber syndrome (SWS) is defined by the association of a facial capillary malformation (port-wine stain), with a vascular malformation of the eye, and/or vascular malformation of the brain (leptomeningeal angioma). Variants exist where only one of these three structures is involved with the vascular malformation. SWS occurs sporadically and is congenital. Port-wine stains occur in 3 per 1000 live births. No good population-based data exist for how many people have Sturge-Weber syndrome, however, estimates range between one in 20-50,000 live births. This review summarizes literature regarding the main features and pathophysiology of Sturge-Weber syndrome, however the cause of this syndrome remains obscure. Recent advances in neuroimaging have provided important insights into the progression of neurologic injury that occurs as a result of impaired blood flow. Important limitations exist, however, as currently the early diagnosis and exclusion of Sturge-Weber syndrome is impaired by the poor sensitivity of imaging in the newborn period and early infancy. Several important controversies complicate our ability to care for these patients and include the questions of ideal timing of surgery, whether seizures themselves contribute to the neurologic injury, and what the role of low-dose aspirin should be. This review will summarize several recent advances in our understanding of the mechanisms of brain injury in SWS, new measures for quantifying the neurologic involvement and new approaches and controversies in the management of the neurologic complications.

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• Myoclonic-astatic epilepsy in a child with Sturge-Weber syndrome. Ewen JB, Comi AM, Kossoff EH. Pediatr Neurol. 2007 Feb; 36(2):115-7.
  • Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. ewen@kennedykrieger.org
  • This paper highlights the importance of being aware that patients with SWS can have generalized drop seizures that worsen with some anticonvulsants and need to be properly diagnosed with EEG and properly treated with an anticonvulsant that covers both focal and generalized seizures.
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    A child with Sturge-Weber syndrome and a left occipital leptomeningeal angioma developed focal seizures at 6 years of age that responded initially to oxcarbazepine. After 7 months of seizure freedom, the patient developed typical myoclonic-astatic seizures associated with generalized electrographic discharges, which worsened as oxcarbazepine was increased. The seizures and electroencephalogram improved dramatically in 3 weeks as the oxcarbazepine was withdrawn and valproic acid was initiated. This case demonstrates the importance of recognizing that children with epilepsy due to focal lesions can develop secondary bilateral synchrony that can be aggravated by medications that are effective for partial seizures. In such cases, treatment with a broad-spectrum antiepileptic may be advantageous.

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• Oromaxillofacial osseous abnormality in Sturge-Weber syndrome: case report and review of the literature. Lin DD, Gailloud P, McCarthy EF, Comi AM. AJNR Am J Neuroradiol. 2006 Feb; 27(2): 274-7.
  • Division of Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • This paper reported an unusual bony tumor of the upper jaw associated with SWS so that if this situation occurs again doctors know what to do.
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    We report a case of a 17-month-old child affected by Sturge-Weber syndrome who had unusually rapid overgrowth of the left frontal, temporal, orbital, and maxillary regions. CT angiography illustrated osteohypertrophy with periostitis and associated soft tissue hypertrophy directly corresponding to the distribution of the cutaneous port-wine stain. Extended maxillectomy was performed because of rapid growth and clinical debilitation, with surgical pathology revealing juvenile ossifying fibroma.

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• Advances in Sturge-Weber syndrome. Comi AM. Curr Opin Neurol. 2006; 19(2):124-8.
  • Neurology and Pediatrics, Kennedy Krieger Institute and Johns Hopkins Medicine, 707 N. Broadway, Baltimore, MD 21205, USA. comi@kennedykrieger.org
  • This review article summarized recent advances in diagnosis and treatment of SWS.
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    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.

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• Growth hormone deficiency in children with Sturge-Weber syndrome. Miller RS, Ball KL, Comi AM, Germain-Lee EL. Arch Dis Child. 2006 Apr;91(4):340-1
  • Division of Pediatric Endocrinology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • This research demonstrated for the first time that growth hormone deficiency occurs in SWS with greatly increased prevalence compared to the general population and requires treatment.
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    Sturge-Weber syndrome (SWS) is a disorder involving central nervous system abnormalities that may increase the risk of hypothalamic-pituitary dysfunction. Records of 19 patients with suspected growth hormone deficiency (GHD), identified from a registry of 1653 patients with SWS, were reviewed; nine patients with GHD were found.

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• Comorbidity of headaches and epilepsy in patients with Sturge-Weber syndrome. Kossoff EH, Hatfield LA, Ball KL, Comi AM. J Child Neurol. 2005 Aug;20(8):678-82.
  • Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. ekossoff@jhmi.edu
  • This research showed that in older children and adults with SWS headaches are an important and undertreated neurologic problem requiring additional study and new treatment options.
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    Sturge-Weber syndrome is associated with leptomeningeal angioma, trigeminal port-wine stain, epilepsy, and glaucoma. Clinically, many patients with Sturge-Weber syndrome are observed to have both seizures and headaches, but this has never been described in the literature. A questionnaire was mailed to 190 patients with reported comorbid epilepsy and headache as identified by the Sturge-Weber Foundation. Sixty-eight surveys were returned anonymously; 55 reported both seizures and headaches. The median age at headache onset was 8 years, with a median of three headaches per month. Fifty-eight percent felt that headaches were an equal or greater problem. Ibuprofen and acetaminophen were the most frequently tried abortive medications; 22% had tried sumatriptan. Only 22% reported a neurologist suggesting the use of an anticonvulsant as a preventive agent. Subjects with a family history of headaches had an earlier age at headache onset (7.5 vs 11 years; P = .02), and those with a family history of seizures were more likely to report behavior problems (69% vs 33%; P = .02). Subjects reporting learning problems or hemiparesis had an earlier age at seizure onset. Migraine-like headaches can be as significant a problem as epilepsy for patients with Sturge-Weber syndrome. Despite this, triptans and prophylactic medications (including anticonvulsants) were used in less than half of the patients. Correlations of family history with both age at symptom onset and behavior problems suggest that genetic substrate could be one factor determining the variable neurologic manifestations seen in Sturge-Weber syndrome.

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• Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide. Kossoff EH, Buck C, Freeman JM. Neurology. 2002 Dec 10;59(11):1735-8.
  • This research indicated that hemispherectomy was effective in controlling seizures in SWS but this study did not indicate that early hemispherectomy significantly improved longterm functional outcome compared with later surgery.
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    BACKGROUND: Epilepsy affects 80% of patients with Sturge-Weber syndrome; the majority of seizures begin before the age of 1. When seizures are intractable to medications and unihemispheric, hemispherectomy is often advised. OBJECTIVE: To examine the natural history of patients who underwent hemispherectomy and identify the outcomes in terms of seizure reduction, cognition, and motor deficits. METHODS: A questionnaire was mailed to the parents of patients identified by the Sturge-Weber Foundation as having had a hemispherectomy between 1979 and 2001. Forty-six percent (32/70) of the parents responded. RESULTS: The mean age at onset of seizures was 4 months, and the median age at surgery was 1.2 years. Children had failed to respond to 3.7 anticonvulsants prior to surgery and averaged 387 seizures/month. Forty-seven percent had complications (e.g., hemorrhage and hypertension) in the perioperative period; however, 81% are currently seizure-free, with 53% off anticonvulsants. Hemispherectomy type (anatomic versus functional versus hemidecortication) did not influence outcome. Age at onset of seizures did not predict seizure freedom; however, an older age at hemispherectomy was positively correlated. Postoperative hemiparesis was not more severe than before surgery. Cognitive outcome was not related to the age at operation, side of operation, or seizure freedom. CONCLUSIONS: Children undergoing hemispherectomy presented at a young age and had frequent seizures for approximately 1 year but are now mostly seizure-free. Age at surgery did not have an adverse effect on either seizure or cognitive outcomes.

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• Sturge-Weber syndrome. Comi AM. In: Gilman, S, editor. MedLink Neurology. San Diego: MedLink Corporation. Available at MedLink 2004.
  • This review updated annually summarizes information on eitiology, diagnosis, treatment and monitoring of patients with SWS.
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    Dr. Anne Comi explains that Sturge-Weber syndrome is a neurocutaneous disorder presenting with a facial capillary malformation (port-wine birthmark), abnormal blood vessels on the surface of the brain (leptomeningeal angioma) and glaucoma. These patients frequently develop seizures, focal neurologic impairments, visual problems, and cognitive deficits. Her updated chapter summarizes recent research into the pathophysiology of this unique disorder and explains the diagnosis and treatment approaches utilized at the Sturge-Weber Syndrome Clinical Center of Excellence.

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Studies to Improve the Diagnosis and Monitoring of Sturge-Weber Syndrome

• Case Report of Subdural Hematoma in a Patient With Sturge-Weber Syndrome and Literature Review: Questions and Implications for Therapy. Lopez J, Yeom KW, Comi A, Van Haren K. J Child Neurol. 2012 Jul 17.
  • Authors present a toddler with Sturge-Weber syndrome who developed a subdural hematoma in the setting of a mechanical fall with minor head trauma. This paper discusses the possible role of aspirin in contributing to, or perhaps protecting against, intracranial hemorrhage in patients with Sturge-Weber syndrome.

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• Neuropsychological features and risk factors in children with Sturge-Weber syndrome: four case reports. Zabel TA, Reesman J, Wodka EL, Gray R, Suskauer SJ, Turin E, Ferenc LM, Lin DD, Kossoff EH, Comi AM. Clin Neuropsychol. 2010;24(5):841-59. doi: 10.1080/13854046.2010.485133.
  • Four cases presented here (ages 8-9, two females) illustrate the broad range of physiologic involvement and associated neuropsychological functioning in SWS. Findings argue against the idea of a "typical" SWS neuropsychological presentation. Report highlights a preliminary collection of disease status/severity factors thought to impact neuropsychological presentation in SWS.

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• Physiatric findings in individuals with Sturge-Weber syndrome. Suskauer SJ, Trovato MK, Zabel TA, Comi AM. Am J Phys Med Rehabil. 2010 Apr;89(4):323-30.
  • Retrospective chart review of physiatric evaluation of 30 individuals, aged 4 mos to 55 yrs (median age, 2.4 yrs), with Sturge-Weber syndrome with brain involvement. Study summarized physiatric findings and recommendations in this cohort.

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• Behavioral and psychiatric features of Sturge-Weber syndrome. Turin E, Grados MA, Tierney E, Ferenc LM, Zabel A, Comi AM. J Nerv Ment Dis. 2010 Dec;198(12):905-13.
  • Studied a small group of outpatients (N = 16, age, 3-34 years) with Sturge-Weber syndrome seeking medical services to report their behavioral and psychiatric features.

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• Use of quantitative EEG in infants with port-wine birthmark to assess for Sturge-Weber brain involvement. Ewen JB, Kossoff EH, Crone NE, Lin DD, Lakshmanan BM, Ferenc LM, Comi AM. Clin Neurophysiol. 2009 Aug;120(8):1433-40.
  • Performed an observational study of qEEG results on eight infants with facial PW birthmark (four had SWS brain involvement). Recorded standard clinical EEGs and then derived a measure of asymmetry. Validated this threshold through a study of an additional nine infants with PW birthmark (five with SWS brain involvement). Quantitative EEG was able to distinguish between those infants with and those without brain involvement and should be further developed as a biomarker for the early screening of SWS brain involvement in at risk infants.

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• An infantile-onset, severe, yet sporadic seizure pattern is common in Sturge-Weber syndrome. Kossoff EH, Ferenc L, Comi AM. Epilepsia. 2009 Sep;50(9):2154-7.
  • The young age of onset and frequently intractable nature of seizures associated with Sturge-Weber syndrome (SWS) have been well-reported in large studies. However, many clinicians also anecdotally describe prolonged but sporadic seizure clusters. We analyzed data over a 5-year period from 77 children and adults with SWS in relation to sporadic seizure clusters. Sporadic seizure clusters were common and complicate the management of these patients.

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• Hemiparesis is a clinical correlate of general adaptive dysfunction in children and adolescents with Sturge-Weber syndrome. Reesman J, Gray R, Suskauer SJ, Ferenc LM, Kossoff EH, Lin DD, Turin E, Comi AM, Brice PJ, Zabel TA. J Child Neurol. 2009 Jun;24(6):701-8.
  • Study sought to identify neurologic correlates of adaptive functioning in individuals with Sturge-Weber syndrome. Hemiparesis identified on neurologic exam correlated with the presence if impaired general adaptive dysfunction suggesting that hemiparesis when noted on clinical exam should trigger neuropsychological evaluation to address more global functional needs.

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• Sturge-Weber syndrome: ear, nose, and throat issues and neurologic status. Irving ND, Lim JH, Cohen B, Ferenc LM, Comi AM. Pediatr Neurol. 2010 Oct;43(4):241-4.
  • This study determined what types of ENT issues most affect patients with Sturge-Weber syndrome and identified symptoms and issues that should be screened for and evaluated in order to optimize neurologic outcome.

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• Transcranial Doppler ultrasound in children with Sturge-Weber syndrome. Jordan LC, Wityk RJ, Dowling MM, DeJong MR, Comi AM. J Child Neurol. 2008 Feb; 23(2):137-43.
  • Department of Neurology, The Johns Hopkins University School of Medicine, USA.
  • This research found that transcranial doppler is a safe way to measure blood flow abnormalities in SWS suggesting that it may be useful for tracking response to treatment in a clinical trial or monitoring progression in SWS.
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    Transcranial Doppler ultrasound is a noninvasive vascular assessment technique proved useful in the management of pediatric disorders predisposed to stroke and may have similar utility for Sturge-Weber syndrome. Eight children with Sturge-Weber syndrome had velocities measured in the major cerebral arteries via the Stroke Prevention Trial in Sickle Cell Anemia methodology. Velocities and pulsatility indexes were compared between the unaffected and affected sides. All subjects had reduced velocity on the affected side; the mean middle cerebral artery percentage difference was 20% (95% CI, 15%-25%). Pulsatility index was increased on the affected side; mean middle cerebral artery pulsatility index percentage difference, 34% (95% CI, 15%-53%). Six subjects also had reduced posterior cerebral artery velocity on the affected side. Side-to-side differences in middle cerebral artery and posterior cerebral artery velocities correlated with severity of MRI asymmetry (Spearman rho = 0.88, P = .02). Decreased arterial flow velocity and increased pulsatility index in the middle cerebral artery and posterior cerebral artery suggests a high resistance pattern that may reflect venous stasis and may contribute to chronic hypoperfusion of brain tissue. Further study of Transcranial Doppler in children with Sturge-Weber syndrome is indicated.
    

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• Quantitative EEG asymmetry correlates with clinical severity in unilateral Sturge-Weber syndrome. Hatfield LA, Crone NE, Kossoff EH, Pyzik PL, Lin DDM, Kelley TM, Comi AM. Epilepsia. 2007 Jan;48(1):191-5.
  • Department of Neurology, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
  • This novel research found that decreased power by quantitative EEG analysis on the affected brain side of patients with SWS correlated with the severity of neurologic involvement. These findings indicated that quantitative EEG was likely to be useful for the early diagnosis of SWS and for monitoring progression and treatment response in a clinical trial.
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    PURPOSE: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder with vascular malformations of the skin, brain, and eye. SWS results in ischemic brain injury, seizures, and neurologic deficits. We hypothesized that a decrease in quantitative EEG (qEEG) power, on the affected side, correlates with clinical severity in subjects with SWS. METHODS: Fourteen subjects had 16-channel scalp EEG recordings. Data were analyzed using fast Fourier transform and calculation of power asymmetry. Blinded investigators assigned scores for clinical neurological status and qualitative assessment of MRI and EEG asymmetry. RESULTS: The majority of subjects demonstrated lower total power on the affected side, usually involving all four frequency bands (delta, theta, alpha, and beta). qEEG asymmetry correlated strongly with neurologic clinical severity scores and MRI asymmetry scores. qEEG data generally agreed with the MRI evidence of regional brain involvement. In MRI-qEEG comparisons that did not agree, decreased power on qEEG in a brain region not affected on MRI was more likely to occur in subjects with more severe neurologic deficits. CONCLUSIONS: qEEG provides an objective measure of EEG asymmetry that correlates with clinical status and brain asymmetry seen on MRI. These findings support the conclusion that qEEG reflects the degree and extent of brain involvement and dysfunction in SWS. qEEG may potentially be a useful tool for early diagnosis and monitoring of disease progression in SWS. qEEG may prove useful, in severely affected individuals with SWS, for determining regions of brain dysfunction.

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• Dynamic MR perfusion and proton MR spectroscopic imaging in Sturge-Weber syndrome: correlation with neurological symptoms. Lin DD, Barker PB, Hatfield LA, Comi AM. J Magn Reson Imaging. 2006 Aug; 24(2):274-81.
  • Division of Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ddmlin@jhmi.edu
  • This work demonstrated that perfusion MR deficits correlate with the severity of neurologic impairment in SWS indicating that it will likely be useful for tracking response to treatment in a clinical trial and neurologic progression.
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    PURPOSE: To investigate physiological alterations in Sturge-Weber syndrome (SWS) using MR perfusion imaging (PWI) and proton spectroscopic imaging (MRSI), and their association with neurological status. MATERIALS AND METHODS: Six consecutive patients with a clinically established diagnosis of SWS underwent MRI using a 1.5 Tesla scanner. The protocol consisted of conventional anatomic scans, dynamic PWI, and multislice MRSI. A pediatric neurologist evaluated the neurological scores, and the imaging results were correlated with neurological scores using nonparametric correlation analysis. RESULTS: Two patients had classic neuroimaging findings of unilateral cerebral atrophy with corresponding leptomeningeal enhancement and hypoperfusion (prolonged mean transit time). Two patients had bilateral disease, and two had normal symmetric perfusion. Among clinical measures, the highest correlation was between hemiparesis index and hypoperfused tissue volume (Spearman's correlation coefficient, rho = 0.943, P < 0.05). There was also a trend of correlation, although not statistically significant (P = 0.06), between the hemiparesis score and the NAA/Cr ratio in the mid to posterior centrum semiovale, lateral gray matter (GM), and splenium. CONCLUSION: In SWS, PWI indicates cerebral hypoperfusion predominantly due to impaired venous drainage, with only the most severely affected regions in some patients also showing arterial perfusion deficiency. The extent and severity of the perfusion abnormality and neuronal loss/dysfunction reflect the severity of neurological symptoms and disability, and the highest correlation is found with the degree of hemiparesis. These parameters may be useful as quantitative measures of disease burden; however, further studies in larger number of patients (and with a more homogeneous age range) are required to confirm the preliminary findings reported here.

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• Quantitative atrophy analysis correlation with clinical severity in unilateral Sturge-Weber syndrome. Kelley TM, Hatfield LA, Lin DDM, Comi AM. J Child Neurol. 2005 Nov;20(11):867-70.
  • Department of Neurology, Johns Hopkins University, Baltimore, MD 21297-1000, USA.
  • This study validated the new SWS neuro score against measurements of brain atrophy indicating that the SWS neuro score should be useful for research and as an outcome measure for clinical trials.
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    Sturge-Weber syndrome is a neurocutaneous disorder with vascular malformations of the skin, brain, and eye. The objective of this study was to determine whether cortical atrophy in patients with Sturge-Weber syndrome correlates with clinical severity. Eighteen subjects (age 4 months-35 years) with unilateral Sturge-Weber syndrome received a neurologic examination and submitted previous magnetic resonance imaging (MRI) films. A blinded investigator assigned clinical severity scores based on seizures, hemiparesis, visual field cut, and cognitive impairments. Computer-aided analysis of MRIs produced laterality scores for cortical volume asymmetry. A significant relationship existed between clinical severity and laterality scores (Spearman's rho = -0.804; P < .001). Laterality scores also correlated well with hemiparesis subscores and weakly with cognitive impairment subscores (Kendall's tau b; P < .05). Using this simple, computer-aided analysis, cortical volume asymmetry correlated with clinical status. This method offers the advantages of relative simplicity, objectivity, and wide applicability to films from outside institutions, as would be encountered in clinical practice.

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• Early characteristics of Sturge-Weber syndrome shown by perfusion MR imaging and proton MR spectroscopic imaging. Lin DD, Barker PB, Kraut MA, Comi AM. AJNR Am J Neuroradiol. 2003 Oct;24(9):1912-5.
  • This research reported on the new MR perfusion imaging showing in SWS that the abnormal vasculature results in severely impaired venous drainage from the involved region resulting in arterial perfusion deficits in that region.
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    We report the case of a 9-month-old boy with Sturge-Weber syndrome and new onset of seizure. Perfusion MR imaging showed early changes compatible with impaired venous drainage in the affected hemisphere, whereas proton MR spectroscopic imaging revealed a focal parietal area of elevated choline without significant alteration of N-acetylaspartate levels. The perfusion and subtle metabolic abnormalities are comparable with the extent of the overlying leptomeningeal enhancement, illustrating the early pathophysiological manifestation of this disease.

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Studies To Better Understand The Pathogenesis (Cause) Of Sturge-Weber Syndrome

• Cell proliferation and oxidative stress pathways are modified in fibroblasts from Sturge-Weber syndrome patients. Kadam SD, Gucek M, Cole RN, Watkins PA, Comi AM. Arch Dermatol Res. 2012 Apr;304(3):229-35.
  • Employed isobaric tags for relative and absolute quantification (iTRAQ-8plex)-based liquid chromatography interfaced with tandem mass spectrometry (LC-MS/MS) approach to identify differentially expressed proteins between port-wine-derived and normal skin-derived fibroblasts of four individuals with SWS.

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• Sturge-Weber syndrome: altered blood vessel fibronectin expression and morphology. Comi AM, Weisz CJ, Highet BH, Skolasky RL, Pardo CA, Hess EJ. J Child Neuro. 2005 July; 20(7):572-7.
  • Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. acomi@jhmi.edu
  • This research studied how the extracellular matrix molecule fibronectin is expressed in the brain and skin tissue of individuals with SWS. It showed evidenced of abnormal expression in the brain. Fibronectin has important roles in the blood brain barrier, in blood vessel function and in the innervation of blood vessels. This papers discusses new hypotheses regarding the pathogenensis of SWS.
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    Sturge-Weber syndrome presents with vascular malformations of the brain, skin, and eye. Fibronectin has potent effects on angiogenesis, vessel remodeling, and vessel innervation density. To determine fibronectin expression in the blood vessels of Sturge-Weber syndrome brain and skin tissue and to quantify the density and circumference of Sturge-Weber syndrome blood vessels by type compared with controls, we performed in situ hybridization for fibronectin messenger ribonucleic acid (RNA) expression on six Sturge-Weber syndrome cortical brain samples, six epilepsy brain samples, skin from two port-wine stain skin lesions, and two normal skin samples from two subjects with Sturge-Weber syndrome. Fibronectin messenger RNA was expressed in blood vessels and endothelial cells in the parenchyma of both Sturge-Weber syndrome and control brain tissues and in skin samples. Fibronectin expression was significantly reduced by 23% in the Sturge-Weber syndrome meningeal vessels compared with the epilepsy controls (P < .01). Fibronectin expression was significantly increased by 19% in the Sturge-Weber syndrome parenchymal vessels compared with the epilepsy controls (P < .05). No difference was found in the expression of fibronectin in port-wine stain skin blood vessels. The density of leptomeningeal blood vessels in the Sturge-Weber syndrome brain tissue samples was 45% greater than in the epilepsy samples (P < .05). Blood vessel circumference was significantly decreased in the Sturge-Weber syndrome meningeal vessels compared with the controls (27%; P < .05). When blood vessels from different brain regions were compared, fibronectin expression was decreased in Sturge-Weber syndrome meningeal vessels and was increased in the parenchymal vessels. Altered blood vessel fibronectin expression in Sturge-Weber syndrome could contribute to abnormal vascular structure and function in this disorder.

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• Sturge-Weber syndrome associated with other abnormalities: a medical record and literature review. Comi AM, Mehta P, Hatfield LA, Dowling MM. Arch Neurol. 2005 Dec;62(12):1924-7.
  • Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. comi@kennedykrieger.org
  • This paper reported a series of patients with SWS and other malformations, tumors or abnormal conditions. This information was used to search databases and suggest a gene locus that may have some role in the eitiology of SWS.
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    OBJECTIVE: To develop hypotheses regarding the relationship between Sturge-Weber syndrome (SWS) and other abnormalities in a subset of patients. DESIGN: We retrospectively reviewed medical records in a group of 28 patients with SWS, noting the main features of SWS and accompanying unexpected abnormalities. We also conducted a literature review of abnormalities associated with SWS. RESULTS: Twenty-eight medical records of patients with SWS were reviewed. Of this number, we found 8 (29%, 2 female) patients who manifested other abnormalities. Our review of the literature uncovered 15 additional cases with associated abnormalities. CONCLUSIONS: We hypothesize that the abnormalities associated with SWS suggest testable insights regarding pathogenesis and that chromosome 17p1-p13 may be a candidate region for genes involved with SWS. We also propose that some patients with SWS may have disorders of cholesterol biosynthesis or carbohydrate glycosylation.

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• Pathophysiology of Sturge-Weber syndrome. Comi AM. J Child Neurol. 2003 Aug;18(8):509-16.
  • This review summarized the literature with regards to hypotheses and possible eitiologies of SWS and synthesized the data one the pathagenesis of the neurodegeneration in SWS.
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    Sturge-Weber syndrome is a neurocutaneous disorder classically presenting with a facial port-wine birthmark, 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.

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• Encephalofacial angiomatosis sparing the occipital lobe and without facial nevus: on the spectrum of Sturge-Weber syndrome variants? Comi AM, Fischer R, Kossoff EH. J Child Neurol. 2003 Jan;18(1):35-8.
  • This case series highlighted patients with brain involvement but without skin involvement of SWS and discusses why the somatic mutation hypothesis explains these clinical variations.
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    We report two cases of leptomeningeal angiomatosis in atypical frontoparietotemporal locations without an associated facial port-wine birthmark. Evidence of a leptomeningeal angioma was found in each when they were evaluated for headaches and seizures. The diagnosis of a leptomeningeal angioma was suggested by calcifications noted on computed tomographic scan of the head and confirmed with contrast-enhanced magnetic resonance images of the brain. We hypothesize that given the lack of occipital involvement with the angioma, and therefore the noncontiguous nature of this lesion with the developing upper facial ectoderm, the failure to develop a facial angioma would be expected. We found that the use of an anticonvulsant along with a migraine prophylactic medication appeared to have the greatest efficacy in these two cases, whereas anticonvulsants alone were less helpful. This diagnosis should be considered in any child presenting with seizures or complicated migraines and intracranial calcifications.

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• Increased fibronectin expression in Sturge-Weber syndrome fibroblasts and brain tissue. Comi AM, Hunt P, Vawter MP, Pardo CA, Becker KG, Pevsner J. Pediatr Res. 2003 May;53(5):762-9.
  • This study utilized state-of-the-art technique to identify fibronectin as an abnormally regulated protein in SWS. Fibronectin has important roles in blood vessel development and function.
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    Sturge-Weber syndrome (SWS) is a neurocutaneous disorder that presents with a facial port-wine birthmark and a leptomeningeal angioma. Fibronectin expression regulates angiogenesis and vasculogenesis and participates in brain tissue responses to ischemia and seizures. We therefore hypothesized that abnormal gene expression of fibronectin and other extracellular matrix genes would be found in SWS brain tissue and SWS port-wine skin fibroblasts. Fibronectin gene and protein expression from port-wine-derived fibroblasts were compared with that from normal skin-derived fibroblasts of four individuals with SWS using microarrays, reverse transcriptase-PCR, Western analysis, and immunocytochemistry. Fibronectin gene and/or protein expression from eight SWS surgical brain samples was compared with that in two surgical epilepsy brain samples and six postmortem brain samples using microarrays, reverse transcriptase-PCR, and Western analysis. The gene expression of fibronectin was significantly increased (p < 0.05) in the SWS port-wine-derived fibroblasts compared with that of fibroblasts from SWS normal skin. A trend for increased protein levels of fibronectin in port-wine fibroblasts was found by Western analysis. No difference in the pattern of fibronectin staining was detected. The gene expression of fibronectin was significantly increased (p < 0.05), and a trend for increased fibronectin protein expression was found in the SWS surgical brain samples compared with the postmortem controls. These results suggest a potential role for fibronectin in the pathogenesis of SWS and in the brain's response to chronic ischemic injury in SWS. The reproducible differences in fibronectin gene expression between the SWS port-wine-derived fibroblasts and the SWS normal skin-derived fibroblasts are consistent with the presence of a hypothesized somatic mutation underlying SWS.

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