Brain damage and IQ in unilateral Sturge–Weber syndrome: Support for a “fresh start” hypothesis

doi:10.1016/j.yebeh.2011.07.010

Epilepsy & Behavior

Volume 22, Issue 2, October 2011, Pages 352-357

https://doi.org/10.1016/j.yebeh.2011.07.010 Get rights and content

Abstract

We tested the hypothesis that extent of severe hypometabolism measured by fluorodeoxyglucose PET has a U-shaped (nonlinear) relationship to IQ in children with unilateral Sturge–Weber syndrome. Thirty-five consecutive children (age range: 30–153 months) with Sturge–Weber syndrome and unilateral brain involvement were enrolled in the study. Participants underwent cognitive assessment and interictal fluorodeoxyglucose PET scans. Regression analyses tested whether a quadratic model best accounted for the relationship between extent of severe cortical hypometabolism and IQ, controlling for seizure variables. A significant quadratic relationship was found between IQ and extent of severe (but not total) hypometabolism. Seizure variables also contributed significant variance to cognitive functions. Results suggest that intermediate size of severe hemispheric hypometabolism is associated with the worst cognitive outcomes, and small or absent lesions, with the best cognitive outcomes. Children in whom a very large extent of the hemisphere is severely affected are likely to have relatively preserved cognitive function.

Highlights

► The relationship of extent of severe hypometabolism (on fluorodeoxyglucose positron emission tomography) to IQ outcome is U-shaped. ► Small extent of severe hypometabolism is associated with good cognitive function. ► Large extent may also be associated with preserved (although not normal) IQ outcome. ► When the extent of severe hypometabolism is < 15%, a good outcome is probable. ► As the area of severe hypometabolism increases > 60%, IQ increases.

Introduction

Sturge–Weber syndrome (SWS) is a neurocutaneous disorder characterized by congenital facial cutaneous angioma (port-wine stain), leptomeningeal angioma, intracranial calcifications, and glaucoma [1], [2], [3]. The intracranial pathology in SWS is most commonly unilateral (85%), and impaired cognitive development is apparent in about one-half of the patients [1], [4], [5]. However, neurocognitive outcome is difficult to predict on clinical grounds or conventional imaging. Early studies of brain glucose metabolism using 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography (FDG-PET) in SWS demonstrated reduced glucose metabolism of the cortex underlying the leptomeningeal lesion, often extending beyond the area of structural abnormality depicted by CT or MRI [6]. A subsequent small study of 13 children with unilateral SWS suggested an apparently paradoxical relationship between cortical glucose hypometabolism on PET and cognitive function: several patients with extensive severe hypometabolism showed relatively preserved IQ [7]. This could be attributed to functional reorganization, but it remained unclear how this relationship was affected by age or epilepsy [8], and also what extent of cortical damage is required to facilitate effective reorganization.

Sturge–Weber syndrome with unilateral hemispheric involvement represents an etiologically homogeneous disease group and is an excellent clinical model to study the relationship between unilateral, early-onset brain lesions and cognitive development, because: (1) the structural abnormality is strictly unilateral, (2) lesions start early in life, and (3) there is a highly variable rate of progression. As a result, there is great potential for interhemispheric reorganization of critical brain functions in unilateral SWS because the contralateral hemisphere is basically normal early in the course of the disease [9].

In the present study we tested the hypothesis that moderate-sized unilateral metabolic abnormalities will be associated with poor cognitive outcomes, whereas small or extensive areas of unilateral glucose hypometabolism will be associated with relatively preserved cognitive function in children with SWS. We also tested if this presumed relationship between hemispheric hypometabolism and cognitive functions is affected by age, seizure variables, lesion side, and location or severity of hypometabolism. Further, we aimed to determine if there is a threshold to the extent of hemispheric hypometabolism above which cognitive functions started to increase above severe impairment. Finally, we tested if seizure-related variables explained the IQ variations seen in patients with only mild (or no) metabolic abnormalities.

Section snippets

Methods

Thirty-five children (mean age: 73 ± 38 months, age range: 30–153 months; 17 males) with unilateral SWS (16 left-sided) underwent neurocognitive assessment, neurological examination, MRI, and interictal FDG-PET scans. Twenty-two children were right-handed, 12 left-handed, and one mixed-handed. Participants were recruited from the Neurology Clinics in Children's Hospital of Michigan and the Sturge–Weber Foundation and/or were self-referred. They were all enrolled in a prospective clinical and

Results

Age at seizure onset had three positive outliers, which were winsorized. Median age at seizure onset was 6 months (interquartile range: 5–18 months); mean age at time of PET scan was 72.8 months (SD = 38.2); mean duration of epilepsy was 59.6 months (SD = 40.1); and mean seizure frequency was 2.1 (SD = 1.1). Forty percent (n = 14) of the patients had hypometabolism that extended into the frontal lobe. Extent of hypometabolic cortex ranged from 0 to 98% (mean = 42%, SD = 33%). For severely hypometabolic cortex

Discussion

Sparing and/or reorganization of cortical function following brain damage may depend on a number of factors including age, size, and location of lesion, integrity of surrounding and contralateral brain regions, and disease characteristics (e.g., epilepsy) [9]. The present study demonstrates a close relationship between cognitive functions and extent of unilateral brain damage (reflected by glucose hypometabolism) in children with early-onset unihemispheric injury caused by SWS, even after

Conflict of interest statement

None are reported.

Contributors

The first author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Behen, Juhasz, Wolfe-Christensen, Chugani. Acquisition of data: Behen, Wolfe-Christensen, Guy, Halverson. Analysis and interpretation of data: Behen, Juhasz, Janisse, Chugani. Drafting of the article: Behen, Juhasz, Wolfe-Christensen. Critical revision of the article for important intellectual content: Rothermel,

Acknowledgments

This work was supported in part by Grant NS041922 (to Dr. Juhasz) from the National Institute of Neurological Disorders and Stroke (Dr. Juhasz). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke.

We thank Cathie Germain for assisting patient recruitment and scheduling, Majid Khalaf, Jane Corbet, and Anne Deboard for performing sedation, as well as Angela Wigeluk, Galina

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Deep Venous Remodeling in Unilateral Sturge-Weber Syndrome: Robust Hemispheric Differences and Clinical Correlates
2023, Pediatric Neurology
Enlarged deep medullary veins (EDMVs) in patients with Sturge-Weber syndrome (SWS) may provide compensatory venous drainage for brain regions affected by the leptomeningeal venous malformation (LVM). We evaluated the prevalence, extent, hemispheric differences, and clinical correlates of EDMVs in SWS.
Fifty children (median age: 4.5 years) with unilateral SWS underwent brain magnetic resonance imaging prospectively including susceptibility-weighted imaging (SWI); children aged 2.5 years or older also had a formal neurocognitive evaluation. The extent of EDMVs was assessed on SWI by using an EDMV hemispheric score, which was compared between patients with right and left SWS and correlated with clinical variables.
EDMVs were present in 89% (24 of 27) of right and 78% (18 of 23) of left SWS brains. Extensive EDMVs (score >6) were more frequent in right (33%) than in left SWS (9%; P = 0.046) and commonly occurred in young children with right SWS. Patients with EDMV scores >4 had rare (less than monthly) seizures, whereas 35% (11 of 31) of patients with EDMV scores ≤4 had monthly or more frequent seizures (P = 0.003). In patients with right SWS and at least two LVM-affected lobes, higher EDMV scores were associated with higher intelligence quotient (P < 0.05).
Enlarged deep medullary veins are common in unilateral SWS, but extensive EDMVs appear to develop more commonly and earlier in right hemispheric SWS. Deep venous remodeling may be a compensatory mechanism contributing to better clinical outcomes in some patients with SWS.
PET imaging in epilepsy
2022, Nuclear Medicine and Molecular Imaging: Volume 1-4
Epilepsy is a common, albeit heterogeneous, neurological disorder affecting 0.5–1% of the population; however, not much is known with certainty about the etiopathogenesis underlying the various types of epileptic disorders. It appears that the basic mechanisms of epileptogenesis are at the cellular or molecular level, even when a structural lesion is obvious. As these microscopic changes cannot be detected by conventional radiological imaging techniques due to limitation of their spatial resolution, nuclear medicine imaging techniques, such as positron emission tomography (PET), which can probe further into the functional changes occurring at the cellular and sub-cellular levels, can play an important role in the study of human epilepsy. Although PET imaging can improve our understanding of the molecular and biochemical alterations underlying epilepsy, as well as the effects of seizures on the brain, presently its main role is in the presurgical evaluation of patients with intractable seizures for lateralization and localization of the epileptic focus.
Another strong argument for the early, aggressive management of seizures to optimize neuro-cognitive outcome in Sturge-Weber syndrome
2021, European Journal of Paediatric Neurology
Neurological presentations and cognitive outcome in Sturge-Weber syndrome
2021, European Journal of Paediatric Neurology
Citation Excerpt :
This concurs with upper estimates for intellectual impairment in previous studies (32%–56%) [41–44] although applying different cut-offs (IQ ≤ 70–75). Three-tenths of patients had no impairment (IQ/DQ ≥ 80), consistent with the lower estimates of intact intellectual function (33%–43%) [41,43,44]. Overall, this study finds greater prevalence of intellectual disability and a smaller proportion of intact intellectual function.
This study of children with Sturge-Weber syndrome (SWS) profiled neurological presentations; compared patients with (+) and without (−) port-wine stain (PWS); and determined risk factors for intellectual and language impairments.
A retrospective case note review was conducted at a national centre.
This cohort (n = 140, male 72, median follow up 114 months) showed sex parity. Intellectual disability (“ID”: IQ ≤ 70) affected half (66), being severe (IQ ≤ 40) in two-fifths (27) with ID. Language disorder (core score≤70) affected half (57). Neurological presentations were: status epilepticus 57% (80), hemiplegia 58% (81), headaches 36% (50) and acutely acquired neurological deficits lasting over 24 h 40% (56). One-seventh (20) were PWS(−). This group had: fewer lobes with angioma (p < 0.0001); and less frequent ID (p = 0.002) or language disorder (p = 0.013). Seizure frequency and status epilepticus prevalence did not differ from PWS(+).
ID and language disorder were associated with: more lobes with angioma; earlier seizure onset; more frequent status epilepticus and seizure clusters. On multivariable analysis recurrent status epilepticus (p = 0.037) and multi-lobe involvement (p = 0.002) increased the risk of severe intellectual disability. Active epilepsy was associated with language disorder (p = 0.030).
This is the largest reported series documenting detailed developmental profiles of children with SWS, including ID and ASD. PWS(+) shows high rates of ID and language disorder. PWS(−) SWS has a more favourable outcome. Cognitive outcome is contingent on number of affected lobes and bilateral involvement. Epilepsy exerts an additional deleterious effect on language and cognition. A high percentage of children have a history of status epilepticus, with evidence that this impacts language and cognitive outcomes. Acutely acquired neurological deficits did not penalise either. Regular structured clinical and developmental assessment permit greater identification of neurological and neurodevelopmental impairments in SWS, and appropriate support.
Quality of Life in Children With Sturge-Weber Syndrome
2019, Pediatric Neurology
We assessed the utilization of the National Institutes of Health Quality of Life in Neurological Disorders (Neuro-QoL) in pediatric patients with Sturge-Weber syndrome, a rare neurovascular disorder which frequently results in seizures, brain atrophy, calcification, and a range of neurological impairments.
Subjects were seen clinically and consented for research. All 22 patients filled out the Pediatric Neuro-QoL. The Neuro-QoL subscores were converted to T-scores to compare with the referenced control population. Twenty-one participants also filled out the Brain Vascular Malformation Consortium Database Questionnaire containing data pertaining to Sturge-Weber syndrome–related medical history, medications, comorbidities, and family history. All data were analyzed with a significance threshold of P < 0.05.
Cognitive function quality of life was significantly lower (P < 0.001) in pediatric patients with Sturge-Weber syndrome compared with referenced control subjects. Male gender (P = 0.02) was associated with lower cognitive function Neuro-QoL. The extent of skin (R = −0.46, P = 0.04), total eyelid port-wine birthmark (R = −0.56, P = 0.007), eye (R = −0.58, P = 0.005), and total Sturge-Weber syndrome involvement (R = −0.63, P = 0.002) were negatively correlated with cognitive function Neuro-QoL. A younger age at seizure onset was associated with lower cognitive function Neuro-QoL (hazard ratio = 0.90, P = 0.004) even after controlling for extent of brain, skin, or eye involvement. Antidepressant use was associated with lower cognitive function Neuro-QoL (P = 0.005), and cognitive function Neuro-QoL was negatively correlated with depression Neuro-QoL; however, after adjusting for depression this relationship was no longer significant.
The results suggest targeting cognitive function Neuro-QoL in treatment trials and reiterate the prognostic value of early seizure onset. In addition, sex-related differences were noted, which should be further studied.
A Multidisciplinary Consensus for Clinical Care and Research Needs for Sturge-Weber Syndrome
2018, Pediatric Neurology
Sturge-Weber syndrome is a neurocutaneous disorder associated with port-wine birthmark, leptomeningeal capillary malformations, and glaucoma. It is associated with an unpredictable clinical course. Because of its rarity and complexity, many physicians are unaware of the disease and its complications. A major focus moving ahead will be to turn knowledge gaps and unmet needs into new research directions.
On October 1-3, 2017, the Sturge-Weber Foundation assembled clinicians from the Clinical Care Network with patients from the Patient Engagement Network of the Sturge-Weber Foundation to identify our current state of knowledge, knowledge gaps, and unmet needs.
One clear unmet need is a need for consensus guidelines on care and surveillance. It was strongly recommended that patients be followed by multidisciplinary clinical teams with life-long follow-up for children and adults to monitor disease progression in the skin, eye, and brain. Standardized neuroimaging modalities at specified time points are needed together with a stronger clinicopathologic understanding. Uniform tissue banking and clinical data acquisition strategies are needed with cross-center, longitudinal studies that will set the stage for new clinical trials. A better understanding of the pathogenic roles of cerebral calcifications and stroke-like symptoms is a clear unmet need with potentially devastating consequences.
Biomarkers capable of predicting disease progression will be needed to advance new therapeutic strategies. Importantly, how to deal with the emotional and psychological effects of Sturge-Weber syndrome and its impact on quality of life is a clear unmet need.

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Brain damage and IQ in unilateral Sturge–Weber syndrome: Support for a “fresh start” hypothesis

Abstract

Highlights

Introduction

Section snippets

Methods

Results

Discussion

Conflict of interest statement

Contributors

Acknowledgments

J Pediatr

Brain Dev

Eur J Paediatr Neurol

Brain Res Rev

Encephalotrigeminal angiomatosis (Sturge–Weber disease); clinical study of thirty-five cases

JAMA

Neurologic manifestations of Sturge–Weber syndrome

Sturge–Weber syndrome

Int Pediatr

Outcome of Sturge–Weber syndrome in 52 adults

Am J Med Genet

Sturge–Weber syndrome: correlation between clinical course and FDG PET findings

Neurology

Outcome of infants with unilateral Sturge–Weber syndrome and early onset seizures

Dev Med Child Neurol

Wechsler Preschool and Primary Scale of Intelligence III

Manual for the Wechsler Intelligence Scale for Children

Assessment of children: cognitive applications