Anna Pinto

Epileptogenesis in neurocutaneous disorders with focus in Sturge Weber syndrome

Epilepsy is a major morbidity in Sturge Weber syndrome, a segmental vascular neurocutaneous disorder classically associated with facial angiomas, glaucoma, and leptomeningeal capillary-venous type vascular malformations. The extent of the latter correlates with neurological outcome. Post-zygotic mosaicism for the activating mutation p.R183Q of the GNAQ gene has been identified as the major cause. GNAQ encodes for an alpha subunit of a heterotrimeric G protein critical to blood vessel development. The earlier the timing of the mutation in development, the more severe the involvement, e.g. from isolated port-wine stains to the full syndrome. The strongest predictors of adverse outcomes are MRI and the presence of angiomas involving any part of the forehead, delineated inferiorly from the outer canthus of the eye to the top of the ear, and including the upper eyelid. The neurological course may be progressive and the typical constellation of symptoms is focal onset seizures, hemiparesis, headache, stroke-like episodes, behavior problems, intellectual disability, and visual field deficits. Antiseizure medications are effective in about half of patients. The presence of localized seizures, focal neurological deficits, and drug resistant epilepsy indicate epilepsy surgical evaluation. Earlier seizure onset, i.e. before six months of age, is associated with a more severe course with significant residual deficits. Factors contributing to epileptogenesis include decreased brain tissue perfusion due to abnormal venous drainage, anoxic injury contributing to cerebral calcification, breakdown of the blood-brain barrier, and the presence of developmental cortical malformations. Pre-symptomatic prophylactic treatment may be a future option to modify the course of the disease including the associated epileptogenesis.

Surgery for Intractable Epilepsy Due to Unilateral Brain Disease: A Retrospective Study Comparing Hemispherectomy Techniques

BACKGROUND Hemispherectomy is a surgical procedure used to treat medically intractable epilepsy in children with severe unilateral cortical disease secondary to acquired brain or congenital lesions. The major surgical approaches for hemispherectomy are anatomic hemispherectomy, traditional functional hemispherectomy, and peri-insular hemispherotomy. We describe the epilepsy outcome, including the need for reoperation, after hemispherectomy in patients with brain malformations or acquired brain lesions who underwent hemispherectomy for refractory epilepsy. METHODS We conducted a retrospective observational study at Childrens Hospital Boston. Cases were ascertained from a research database of patients who underwent epilepsy surgery from 1997 to 2011. Data were obtained from electronic medical records and office charts. Outcome after surgery was defined as improvement in seizures (quantity and severity) represented by the Engel classification score measured at last follow-up, with a minimum of 12 months of follow-up. The need for reoperation for completion of hemispheric disconnection. We also examined whether placement of ventriculoperitoneal shunt was required after hemispherectomy was a secondary outcome. RESULTS We identified 36 patients who underwent hemispherectomy for severe, medically intractable epilepsy. Group 1 (n = 14) had static acquired lesions, and group 2 (n = 22) had malformations of cortical development. Mean age at surgery for group 1 was 9 years (S.D. 5.5) and 2.77 years for group 2 (S.D. 4.01; P < 0.001). The seizure outcome was good in both groups (Engel score I for 25, II for three, III for six, and IV for two patients) and did not differ between the two groups. In group 1, five patients underwent anatomic hemispherectomy (one had prior focal resection), four underwent functional hemispherectomy, and five underwent peri-insular hemispherotomy; none required a second procedure. In group 2, a total of 14 patients had anatomic hemispherectomy (of these, three had had limited prior focal resection), five had functional hemispherectomy, and three had peri-insular hemispherotomy. Among the patients in group 2 who had had functional hemispherectomy, one required reoperation to complete the disconnection and one required peri-insular hemispherotomy because of persistent seizures. In group 1, three patients underwent a ventriculoperitoneal shunt, and from these patients two underwent anatomic hemispherectomy and one had functional hemispherectomy. In group 2, 12 patients had ventriculoperitoneal shunt, and all of them had anatomic hemispherectomy as a first or second procedure. CONCLUSION Seizure outcome after hemispherectomy is good in patients with acquired lesions and with developmental malformations. Although the seizure outcome was similar in the three procedures, the complication rate was higher with anatomic hemispherectomy than with the more recent functional hemispherectomy and peri-insular hemispherotomy. The group with cortical malformations generally had surgery at a younger age; two patients with malformations of cortical development who underwent functional hemispherectomy required second surgeries. The need for reoperation in these cases may reflect the anatomic complexity of developmental hemispheric malformations, which may lead to incomplete disconnection.

Leveraging a Sturge-Weber Gene Discovery: An Agenda for Future Research

Sturge-Weber syndrome (SWS) is a vascular neurocutaneous disorder that results from a somatic mosaic mutation in GNAQ, which is also responsible for isolated port-wine birthmarks. Infants with SWS are born with a cutaneous capillary malformation (port-wine birthmark) of the forehead or upper eyelid which can signal an increased risk of brain and/or eye involvement prior to the onset of specific symptoms. This symptom-free interval represents a time when a targeted intervention could help to minimize the neurological and ophthalmologic manifestations of the disorder. This paper summarizes a 2015 SWS workshop in Bethesda, Maryland that was sponsored by the National Institutes of Health. Meeting attendees included a diverse group of clinical and translational researchers with a goal of establishing research priorities for the next few years. The initial portion of the meeting included a thorough review of the recent genetic discovery and what is known of the pathogenesis of SWS. Breakout sessions related to neurology, dermatology, and ophthalmology aimed to establish SWS research priorities in each field. Key priorities for future development include the need for clinical consensus guidelines, further work to develop a clinical trial network, improvement of tissue banking for research purposes, and the need for multiple animal and cell culture models of SWS.

The stability of spike counts in children with interictal epileptiform activity

PURPOSE Little is known about the stability of serial measures of spike counts in children or whether spike counts are an inherently stable or unstable measure. We investigated the variation in first- and second-night spike counts in children undergoing 48-h ambulatory EEG recording. METHODS We analyzed 40 consecutive 48-h ambulatory EEGs performed at Boston Childrens Hospital that manifested spikes but no seizures. Distinct spike foci in the same child were counted separately. We visually counted all spikes in the first 20min after the first sleep spindle during nighttime sleep, comparing the first and second nights. RESULTS Fifty-five unique spike foci were counted in 40 children (age range: 9 months to 19 years; median: 8.4 years). Considerable variation was seen when comparing Night 1 and Night 2 spike counts: for all foci, Night 1 mean and median spike counts were 304.5 and 126 and Night 2 counts were 309.5 and 148, respectively. For each focus, the mean change in spike frequency between Night 1 and Night 2 was 42.1% (median=28.3%, IQR 19.0-50.0%). The coefficient of variation of 0.94 suggested a large amount of variation. The percentage change weighted according to high or low spike frequency was 25.1%. CONCLUSION In 40 children with 55 unique spike foci, significant variability in spike frequency was seen between consecutive nights of sleep, suggesting significant natural variation in spike frequency. A quarter of spike foci varied by 50% or more. Spike counts separated by longer intervals may show even more dramatic natural variation.

Localization of sleep spindles, k-complexes, and vertex waves with subdural electrodes in children.

Purpose: To describe for the first time in children the localization of sleep spindles, K-complexes, and vertex waves using subdural electrodes. Methods: We enrolled children who underwent presurgical evaluation of refractory epilepsy with subdural grid electrodes. We analyzed electroencephalogram data from subdural electrodes and simultaneous recording with Cz scalp electrode. Sleep spindles, K-complexes, and vertex waves were identified and localized based on their morphology on the subdural electrodes. Results: Sixteen patients (9 boys; age range, 3–18 years) were enrolled in the study. The inter-rater reliability on identification and localization of maximal amplitude was high with an intraclass correlation coefficient of 0.85 for vertex waves, 0.94 for sleep spindles, and 0.91 for K-complexes. Sleep spindles presented maximum amplitude around the perirolandic area with a field extending to the frontal regions. K-complexes presented maximum amplitude around the perirolandic area with a field extending to the frontal regions. Vertex waves presented maximum amplitude around the perirolandic areas. Conclusions: In our series of pediatric patients, sleep spindles, K-complexes, and vertex waves were localized around the perirolandic area.

Teaching NeuroImages: Mesial temporal sclerosis after a prolonged unprovoked seizure in an infant

At age 15 months, this previously healthy girl presented with an unprovoked seizure with right-sided clonic movements and facial twitching for 8 minutes. Serial MRIs revealed evolution from diffusion-weighted changes suggestive of edema to left hippocampal hyperintensity on T2 images and subsequently atrophy suggestive of mesial temporal sclerosis (MTS)1 (figures 1 and 2). After seizure freedom for 6 months, she presented with seizures characterized by staring, lip smacking, swallow automatisms, and gagging. Left temporal lobectomy for pharmacologically intractable epilepsy confirmed MTS on pathologic examination with seizure freedom since then. This case …

Quantitative Apparent Diffusion Coefficient Mapping May Predict Seizure Onset in Children with Sturge-Weber Syndrome

BACKGROUND Sturge-Weber syndrome (SWS) is often accompanied by seizures, stroke-like episodes, hemiparesis, and visual field deficits. This study aimed to identify early pathophysiologic changes that exist before the development of clinical symptoms and to evaluate if the apparent diffusion coefficient (ADC) map is a candidate early biomarker of seizure risk in patients with SWS. METHODS This is a prospective cross-sectional study using quantitative ADC analysis to predict onset of epilepsy. Inclusion criteria were presence of the port wine birthmark, brain MRI with abnormal leptomeningeal capillary malformation (LCM) and enlarged deep medullary veins, and absence of seizures or other neurological symptoms. We used our recently developed normative, age-specific ADC atlases to quantitatively identify ADC abnormalities, and correlated presymptomatic ADC abnormalities with risks for seizures. RESULTS We identified eight patients (three girls) with SWS, age range of 40 days to nine months. One patient had predominantly LCM, deep venous anomaly, and normal ADC values. This patient did not develop seizures. The remaining seven patients had large regions of abnormal ADC values, and all developed seizures; one of seven patients had late onset seizures. CONCLUSIONS Larger regions of decreased ADC values in the affected hemisphere, quantitatively identified by comparison with age-matched normative ADC atlases, are common in young children with SWS and were associated with later onset of seizures in this small study. Our findings suggest that quantitative ADC maps may identify patients at high risk of seizures in SWS, but larger prospective studies are needed to determine sensitivity and specificity.

Diagnostic and Therapeutic Management of a First Unprovoked Seizure in Children and Adolescents With a Focus on the Revised Diagnostic Criteria for Epilepsy

By definition, unprovoked seizures are not precipitated by an identifiable factor, such as fever or trauma. A thorough history and physical examination are essential to caring for pediatric patients with a potential first unprovoked seizure. Differential diagnosis, EEG, neuroimaging, laboratory tests, and initiation of treatment will be reviewed. Treatment is typically initiated after 2 unprovoked seizures, or after 1 seizure in select patients with distinct epilepsy syndromes. Recent expansion of the definition of epilepsy by the ILAE allows for the diagnosis of epilepsy to be made after the first seizure if the clinical presentation and supporting diagnostic studies suggest a greater than 60% chance of a second seizure. This review summarizes the current literature on the diagnostic and therapeutic management of first unprovoked seizure in children and adolescents while taking into consideration the revised diagnostic criteria of epilepsy.