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Multicenter Research Data of Epilepsy Management in Patients With Sturge-Weber Syndrome

Smegal, Lindsay F; Sebold, Alison J; Hammill, Adrienne M; Juhász, Csaba; Lo, Warren D; Miles, Daniel K; Wilfong, Angus A; Levin, Alex V; Fisher, Brian; Ball, Karen L; Pinto, Anna L; Comi, Anne M
BACKGROUND:Epilepsy in typical Sturge-Weber syndrome (SWS) is common, and many questions remain regarding the treatment outcomes. We analyzed a large multicenter database with focus on neurological drug treatment in different demographic and SWS characteristic groups. METHODS:A total of 268 patients with brain involvement and a history of seizures were selected from a research data registry generated from a multicenter cross-sectional questionnaire. We examined associations between medication use and binary variables such as sex, ethnicity, and brain, skin, and eye involvement laterality. We analyzed group differences in mean number of antiseizure medications and age at diagnosis, enrollment, and seizure onset and examined differences in median SWS neurological scores in groups of interest. RESULTS:The most frequently used medications were levetiracetam (48.1%), low-dose aspirin (44.8%), oxcarbazepine (39.9%), and phenobarbital (14.9%). Lamotrigine was more frequently used in adults than in children (P = 0.001). History of neurosurgery was associated with no current antiseizure medication use (P = 0.001), whereas bilateral brain involvement and family history of seizures were associated with using a higher number of antiseizure medications (P = 0.002, P = 0.027, respectively). Subjects with bilateral brain involvement and early seizure onset were associated with using a higher number of antiseizure medications (P = 0.002) and phenobarbital use (0.003). CONCLUSIONS:Levetiracetam, low-dose aspirin, and oxcarbazepine were the most frequently used medications. More severely affected patients were frequently on a greater number of antiseizure medications. Surgery for epilepsy was associated with the ability to discontinue antiseizure medication. Longitudinal studies are needed to further investigate medication use in patients with SWS.
PMID: 33813331
ISSN: 1873-5150
CID: 4871472

Introduction: Epilepsy monitoring in pediatric and adolescent health care [Editorial]

Nelson, Aaron L A; Miles, Daniel K
PMID: 33308588
ISSN: 1538-3199
CID: 4735012

Reflex micturition defecation epilepsy in Angelman syndrome [Case Report]

Pellinen, Jacob; Hasan, Hunaid; Ortiz, Nidia; Bluvstein, Judith; Miles, Daniel
PMID: 32042494
ISSN: 2163-0402
CID: 4311462

Physical and Family History Variables Associated With Neurological and Cognitive Development in Sturge-Weber Syndrome

Day, Alyssa M; McCulloch, Charles E; Hammill, Adrienne M; Juhász, Csaba; Lo, Warren D; Pinto, Anna L; Miles, Daniel K; Fisher, Brian J; Ball, Karen L; Wilfong, Angus A; Levin, Alex V; Thau, Avrey J; Comi, Anne M; Koenig, Jim I; Lawton, Michael T; Marchuk, Douglas A; Moses, Marsha A; Freedman, Sharon F; Pevsner, Jonathan
BACKGROUND:Sturge-Weber syndrome (SWS) is caused by a somatic mutation in GNAQ leading to capillary venous malformations in the brain presenting with various neurological, ophthalmic, and cognitive symptoms of variable severity. This clinical variability makes accurate prognosis difficult. We hypothesized that the greater extent of physical factors (extent of skin, eye, and brain involvement), presence of possible genetic factors (gender and family history), and age of seizure onset may be associated with greater symptom severity and need for surgery in patients with SWS. METHODS:The questionnaire was collected from 277 participants (age: two months to 66 years) with SWS brain involvement at seven US sites. RESULTS:Bilateral brain involvement was associated with both learning disorder and intellectual disability, whereas port-wine birthmark extent was associated with epilepsy and an increased likelihood of glaucoma surgery. Subjects with family history of vascular birthmarks were also more likely to report symptomatic strokes, and family history of seizures was associated with earlier seizure onset. Learning disorder, intellectual disability, strokelike episodes, symptomatic stroke, hemiparesis, visual field deficit, and brain surgery were all significantly associated with earlier onset of seizures. CONCLUSION/CONCLUSIONS:The extent of brain and skin involvement in SWS, as well as the age of seizure onset, affect prognosis. Other genetic factors, particularly variants involved in vascular development and epilepsy, may also contribute to neurological prognosis, and further study is needed.
PMID: 30853154
ISSN: 1873-5150
CID: 3732882

Episodic Epileptic Verbal Auditory Agnosia in Landau Kleffner Syndrome Treated With Combination Diazepam and Corticosteroids

Devinsky, Orrin; Goldberg, Rina; Miles, Daniel; Bojko, Aviva; Riviello, James Jr
We report 2 pediatric patients who presented initially with seizures followed by subacute language regression characterized by a verbal auditory agnosia. These previously normal children had no evidence of expressive aphasia during their symptomatic periods. Further, in both cases, auditory agnosia was associated with sleep-activated electroencephalographic (EEG) epileptiform activity, consistent with Landau-Kleffner syndrome. However, both cases are unique since the episodic auditory agnosia and sleep-activated EEG epileptiform activity rapidly responded to combination therapy with pulse benzodiazepine and corticosteroids. Further, in each case, recurrences were characterized by similar symptoms, EEG findings, and beneficial responses to the pulse benzodiazepine and corticosteroid therapy. These observations suggest that pulse combination high-dose corticosteroid and benzodiazepine therapy may be especially effective in Landau-Kleffner syndrome.
PMID: 24453158
ISSN: 0883-0738
CID: 817102

The ability of high field strength 7-T magnetic resonance imaging to reveal previously uncharacterized brain lesions in patients with tuberous sclerosis complex

Chalifoux, Jason R; Perry, Nissa; Katz, Joel S; Wiggins, Graham C; Roth, Jonathan; Miles, Daniel; Devinsky, Orrin; Weiner, Howard L; Milla, Sarah S
Object Tuberous sclerosis complex (TSC) brain pathology is characterized on MRI by cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. Seizures, the prominent feature of TSC, are frequently intractable to medical therapy and, in many patients, resection of tubers results in seizure control. However, in approximately 40% of patients, resection of tubers does not control seizures. This fact, as well as evidence from invasive electrophysiological recordings and experimental animal models, suggests that in patients with TSC, there may be extratuberal epileptogenic brain that does not display any apparent abnormality on conventional MRI. The authors hypothesized that high field strength MRI might uncover lesions not seen on conventional MRI in these patients. Methods Institutional review board approval was obtained to scan 4 patients with TSC (ages 18-26 years) in a 7-T MR unit. Optimized 7-T sequences, including T1- and T2-weighted, FLAIR, SPACE FLAIR, T2*, and MPRAGE studies, were performed. Imaging studies were compared with identical sequences performed using a conventional 1.5-T MR scanner. Results In all 4 patients, there was improved visualization of the findings demonstrated on conventional imaging. Importantly, new lesions were detected in all 4 patients, which were not well visualized with conventional MRI. Newly detected lesions included microtubers, radial glial signal abnormalities, subependymal nodules arising from the caudate nucleus, and caudate nucleus lesions. Conclusions High field strength MRI detects previously uncharacterized lesions in patients with TSC and allows better detection and delineation of subtle abnormalities. In addition, the data demonstrate a compelling relationship between intraventricular lesions and the caudate nucleus. These data support previous electrophysiological and animal-model findings that demonstrate neurological pathology beyond the conventionally detected lesions in TSC.
PMID: 23289918
ISSN: 1933-0707
CID: 214222

Bilateral invasive electroencephalography in patients with tuberous sclerosis complex: a path to surgery?

Carlson, Chad; Teutonico, Federica; Elliott, Robert E; Moshel, Yaron A; LaJoie, Josiane; Miles, Daniel; Devinsky, Orrin; Weiner, Howard L
OBJECT: Many children with epilepsy and tuberous sclerosis complex (TSC) have multiple tubers on MR imaging and poorly localized/lateralized video electroencephalography (EEG) findings. Given the long-term risks associated with frequent seizures and multiple antiepileptic drugs, along with improved success in identifying focal epileptogenic zones in patients with multifocal lesions, the authors used bilateral intracranial EEG to lateralize the epileptogenic zone in patients with nonlateralizable noninvasive preoperative evaluations. METHODS: A retrospective analysis from January 1, 1998, to June 30, 2008, identified 62 children with TSC who were presented at a surgical conference. Of the 52 patients undergoing diagnostic or therapeutic procedures during the study period, 20 underwent bilateral intracranial EEG. The presurgical testing results, intracranial EEG findings, surgical interventions, and outcomes were reviewed. RESULTS: Fourteen of 20 patients had intracranial EEG findings consistent with a resectable epileptogenic zone. One patient is awaiting further resection. Five patients had findings consistent with a nonresectable epileptogenic zone, and 1 of these patients underwent a callosotomy. Seven patients had Engel Class I outcomes, 1 was Class II, 3 were Class III, and 3 were Class IV (mean follow-up 25 months). CONCLUSIONS: Bilateral intracranial EEG can identify potential resectable seizure foci in nonlateralizable epilepsy in TSC. Although 6 of 20 patients did not undergo resection (1 patient is pending future resection), significant improvements in seizures (Engel Class I or II) were noted in 8 patients. In the authors' experience, this invasive monitoring provided a safe method for identifying the ictal onset zone
PMID: 21456917
ISSN: 1933-0715
CID: 132575

Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

Dabora, Sandra L; Franz, David Neal; Ashwal, Stephen; Sagalowsky, Arthur; Dimario, Francis J Jr; Miles, Daniel; Cutler, Drew; Krueger, Darcy; Uppot, Raul N; Rabenou, Rahmin; Camposano, Susana; Paolini, Jan; Fennessy, Fiona; Lee, Nancy; Woodrum, Chelsey; Manola, Judith; Garber, Judy; Thiele, Elizabeth A
BACKGROUND: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. METHODS: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. RESULTS: 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). CONCLUSIONS: Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. TRIAL REGISTRATION: NCT00126672
PMID: 21915260
ISSN: 1932-6203
CID: 138089

Extraventricular subependymal giant cell tumor in a child with tuberous sclerosis complex [Case Report]

Bollo, Robert J; Berliner, Jonathan L; Fischer, Ingeborg; Miles, Daniel K; Thiele, Elizabeth A; Zagzag, David; Weiner, Howard L
Subependymal giant cell tumors (SGCTs) are observed in 5-20% of patients with tuberous sclerosis complex (TSC) but account for approximately 25% of neurological morbidity. The authors report the case of a 7-year-old girl with TSC and multiple cortical tubers who presented with worsening seizures in the context of the rapid growth of a cystic, calcified, extraventricular SGCT in the right frontal lobe, initially thought to represent a cortical tuber. The tumor and surrounding tubers were excised, and clinical seizures resolved. This is the first report of an extraventricular SGCT in a child with TSC outside the neonatal period
PMID: 19569916
ISSN: 1933-0707
CID: 100667


Teutonico, F; Carlson, C; LaJoie, J; Miles, D; Devinsky, O; Weiner, HL
ISSN: 0013-9580
CID: 91395