The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

Concordance between Wada, Transcranial Magnetic Stimulation, and Magnetoencephalography for Determining Hemispheric Dominance for Language: A Retrospective Study.

Determination of language hemispheric dominance (HD) in patients undergoing evaluation for epilepsy surgery has traditionally relied on the sodium amobarbital (Wada) test. The emergence of non-invasive methods for determining language laterality has increasingly shown to be a viable alternative. In this study, we assessed the efficacy of transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG), compared to the Wada test, in determining language HD in a sample of 12 patients. TMS-induced speech errors were classified as speech arrest, semantic, or performance errors, and the HD was based on the total number of errors in each hemisphere with equal weighting of all errors (classic) and with a higher weighting of speech arrests and semantic errors (weighted). Using MEG, HD for language was based on the spatial extent of long-latency activity sources localized to receptive language regions. Based on the classic and weighted language laterality index (LI) in 12 patients, TMS was concordant with the Wada in 58.33% and 66.67% of patients, respectively. In eight patients, MEG language mapping was deemed conclusive, with a concordance rate of 75% with the Wada test. Our results indicate that TMS and MEG have moderate and strong agreement, respectively, with the Wada test, suggesting they could be used as non-invasive substitutes.

Publications in Pediatric Epilepsy: Using Bibliometrics to Determine Readings in the Field.

Bibliometrics and citation analysis are popular forms of analyzing medical literature based on article impact as determined by the number of citations an article has received from other publications. Many bibliometric studies published within the past 10 years have assembled lists of highly cited papers, top 100 papers, or citation classics of specialties, subspecialties, and specific morbidities. For pediatric epilepsy, there is only 1 study that bibliometrically examines articles in this subspecialty. Although bibliometrics generally examines trends in the literature, we used bibliometrics as a methodology for determining a core set of pediatric epilepsy articles with the highest impact (ie, citation count) that could be used as an introductory reading list for residents, fellows, and early career epileptologists. Therefore, we searched Web of Science to identify the 100 top-cited pediatric epilepsy articles and develop 10 topic areas into which we sorted each article. These recommended articles could be used as essential readings for pediatric epilepsy.

Presurgical language mapping in bilingual children using transcranial magnetic stimulation: illustrative case.

BACKGROUND: Presurgical mapping of eloquent cortex in young patients undergoing neurosurgery is critical but presents challenges unique to the pediatric population, including motion artifact, noncompliance, and sedation requirements. Furthermore, as bilingualism in children increases, functional mapping of more than one language is becoming increasingly critical. Transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique, is well suited to evaluate language areas in children since it does not require the patient to remain still during mapping. OBSERVATIONS: A 13-year-old bilingual male with glioblastoma multiforme involving the left parietal lobe and deep occipital white matter underwent preoperative language mapping using magnetic resonance imaging-guided TMS. Language-specific cortices were successfully identified in both hemispheres. TMS findings aided in discussing with the family the risks of postsurgical deficits of tumor resection; postoperatively, the patient had intact bilingual speech and was referred for chemotherapy and radiation. LESSONS: The authors' findings add to the evolving case for preoperative dual language mapping in bilingual neurosurgical candidates. The authors illustrate the feasibility and utility of TMS as a noninvasive functional mapping tool in this child. TMS is safe, effective, and can be used for preoperative mapping of language cortex in bilingual children to aid in surgical planning and discussion with families.

Clinical Utility of Transcranial Magnetic Stimulation (TMS) in the Presurgical Evaluation of Motor, Speech, and Language Functions in Young Children With Refractory Epilepsy or Brain Tumor: Preliminary Evidence.

Accurate presurgical mapping of motor, speech, and language cortices, while crucial for neurosurgical planning and minimizing post-operative functional deficits, is challenging in young children with neurological disease. In such children, both invasive (cortical stimulation mapping) and non-invasive functional mapping imaging methods (MEG, fMRI) have limited success, often leading to delayed surgery or adverse post-surgical outcomes. We therefore examined the clinical utility of transcranial magnetic stimulation (TMS) in young children who require functional mapping. In a retrospective chart review of TMS studies performed on children with refractory epilepsy or a brain tumor, at our institution, we identified 47 mapping sessions in 36 children 3 years of age or younger, in whom upper and lower extremity motor mapping was attempted; and 13 children 5-6 years old in whom language mapping, using a naming paradigm, was attempted. The primary hand motor cortex was identified in at least one hemisphere in 33 of 36 patients, and in both hemispheres in 27 children. In 17 children, primary leg motor cortex was also successfully identified. The language cortices in temporal regions were successfully mapped in 11 of 13 patients, and in six of them language cortices in frontal regions were also mapped, with most children (n = 5) showing right hemisphere dominance for expressive language. Ten children had a seizure that was consistent with their clinical semiology during or immediately following TMS, none of which required intervention or impeded completion of mapping. Using TMS, both normal motor, speech, and language developmental patterns and apparent disease induced reorganization were demonstrated in this young cohort. The successful localization of motor, speech, and language cortices in young children improved the understanding of the risk-benefit ratio prior to surgery and facilitated surgical planning aimed at preserving motor, speech, and language functions. Post-operatively, motor function was preserved or improved in nine out of 11 children who underwent surgery, as was language function in all seven children who had surgery for lesions near eloquent cortices. We provide feasibility data that TMS is a safe, reliable, and effective tool to map eloquent cortices in young children.

Dravet Syndrome: A Review of Current Management.

Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new genetic testing options will allow diagnosis closer to disease onset. Three new medicines-stiripentol, cannabidiol, and fenfluramine-have documented efficacy and safety as adjunctive therapies for treating pharmacoresistant Dravet syndrome. Early diagnosis resulting in earlier treatment with these and other medications may improve prognosis of long-term outcomes, including less severity of cognitive, motor, and behavioral impairments. New rescue medication formulations can now manage acute seizures and help prevent status epilepticus via intranasal, buccal, and intramuscular routes as opposed to rectal administration. Preventing status epilepticus and generalized tonic-clonic seizures could potentially lower the risk of sudden unexpected death in epilepsy. With this changing landscape in diagnostic and treatment options comes questions and controversies for the practicing clinician, especially as diagnostic techniques outpace clinical treatment strategies. Critical decision points include when to start treatment, what pharmacotherapy combinations to try first, which rescue medication to recommend, and how to advise parents on controversial topics (e.g., immunizations). Given that most patients require polypharmacy, clinicians must be cognizant of drug-drug interactions between new medicines, existing anti-epileptic drugs, and other medications to manage comorbidities and must have an understanding of available therapeutic drug monitoring strategies and pharmacokinetic parameters. This review places new diagnostic, treatment and acute care options into the modern era and provides an overview of the challenges and opportunities facing the pediatric epileptologist in this rapidly changing landscape.

Localization of Expressive Language Cortex in a 2-Year-Old Child Using High-Gamma Electrocorticography.

Cortical stimulation mapping is the gold standard for presurgical language mapping; however, it cannot be reliably performed in very young patients. Language mapping using noninvasive modalities is also challenging in very young patients. Although utility of language mapping using power of high-gamma in electrocorticographic recordings was demonstrated in adults and older children, there is a gap of knowledge in the ability of this procedure for localizing language-specific cortex in very young patients. We describe a case of a 2-year-old patient who, to our knowledge, is the youngest person to undergo successful high-gamma electrocorticographic presurgical language mapping for localization of the expressive language cortex (Broca area). The surgical plan was to resect a cortical tuber within the left inferior frontal gyrus and there was a strong concern about postoperative language deficit after resection. Presurgical language mapping using noninvasive modalities were attempted without success. Cortical stimulation mapping was not feasible in this patient. Therefore, high-gamma electrocorticography was the only viable option for language mapping, and it successfully localized the expressive language cortex. The patient underwent surgery for resection of the IFG tuber based on results of high-gamma electrocorticography and had no postoperative language deficit. High-gamma electrocorticography can be used for localizing language-specific cortex, especially Broca's area, in very young patients.

Predicting postoperative language outcome using presurgical fMRI, MEG, TMS, and high gamma ECoG.

OBJECTIVE: To predict the postoperative language outcome using the support vector regression (SVR) and results of multimodal presurgical language mapping. METHODS: Eleven patients with epilepsy received presurgical language mapping using functional MRI (fMRI), magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), and high-gamma electrocorticography (hgECoG), as well as pre- and postoperative neuropsychological evaluation of language. We constructed 15 (24-1) SVR models by considering the extent of resected language areas identified by all subsets of four modalities as input feature vector and the postoperative language outcome as output. We trained and cross-validated SVR models, and compared the cross-validation (CV) errors of all models for prediction of language outcome. RESULTS: Seven patients had some level of postoperative language decline and two of them had significant postoperative decline in naming. Some parts of language areas identified by four modalities were resected in these patients. We found that an SVR model consisting of fMRI, MEG, and hgECoG provided minimum CV error, although an SVR model consisting of fMRI and MEG was the optimal model that facilitated the best trade-off between model complexity and prediction accuracy. CONCLUSIONS: A multimodal SVR can be used to predict the language outcome. SIGNIFICANCE: The developed multimodal SVR models in this study can be utilized to calculate the language outcomes of different resection plans prior to surgery and select the optimal surgical plan.

Epilepsy in 22q11.2 Deletion Syndrome: A Case Series and Literature Review.

BACKGROUND: The 22q11.2 deletion syndrome affects multiple organ systems, and the neurological manifestations are an important aspect of this disorder. Many are aware of cardiac anomalies associated with this uncommon genetic disorder. However, the different types of seizures, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) findings seen in this condition are not appreciated. METHODS: Medical records of four patients with epilepsy due to 22q11.2 deletion syndrome were retrospectively reviewed for documentation of seizure types, EEG, and brain MRI findings. In addition, we also did a literature review of previously reported individuals with unprovoked seizures in this condition. RESULTS: A review of all published cases including our patients reveals that focal epilepsy (39 of 88, 44%) is the most common type followed by genetic generalized epilepsy (24 of 88, 27%). Diffuse cerebral atrophy and polymicrogyria were the most frequent MRI findings. CONCLUSIONS: Patients with structural brain abnormalities, especially polymicrogyria and associated epilepsy should have a chromosomal microarray (CMA) performed to screen for the 22q11.2 deletion syndrome. Focal epilepsy and genetic generalized epilepsy are the most frequent epilepsy types reported in this condition.

Vagus Nerve Stimulation in Intractable Epilepsy Associated With SCN1A Gene Abnormalities.

Mutations in the SCN1A gene cause a spectrum of epilepsy syndromes. There are 2 syndromes that are on the severe end of this spectrum. The classic severe form, Dravet syndrome, is an epileptic encephalopathy of childhood, causing cognitive decline as well as intractable seizures. Severe Myoclonic Epilepsy of Infancy-Borderline (SMEIB) is a term used to include cases with similar severities as those with Dravet syndrome, but lacking a single feature of classic severe myoclonic epilepsy of infancy. Vagus nerve stimulation is a nonpharmacologic treatment for intractable epilepsy. A retrospective review was conducted of patients with deleterious SCN1A mutations who had vagus nerve stimulation placement for treatment of their intractable epilepsy. These children had onset of their epilepsy between 3 and 29 months of age. Seizure control was assessed 6 months after implantation. Twenty patients are included in the study, with 12 implanted at our institution. Nine of the 12 patients implanted at our institution, who had confirmed pre- and post-implantation seizure assessments, showed improvement in seizure control, which was defined as >50% reduction in generalized tonic-clonic seizures, and 4 of those 12 reported improvement in cognitive or speech development. Seven of the 8 patients not implanted at our institution reported subjective benefit, with 4 relating "marked improvement" or seizure freedom. Vagus nerve stimulation appears to impart a benefit to children with deleterious SCN1A gene abnormalities associated with intractable epilepsy.

Language mapping using high gamma electrocorticography, fMRI, and TMS versus electrocortical stimulation.

OBJECTIVE: The aim of the present study was to compare localization of the language cortex using cortical stimulation mapping (CSM), high gamma electrocorticography (hgECoG), functional magnetic resonance imaging (fMRI), and transcranial magnetic stimulation (TMS). METHODS: Language mapping using CSM, hgECoG, fMRI, and TMS were compared in nine patients with epilepsy. Considering CSM as reference, we compared language mapping approaches based on hgECoG, fMRI, and TMS using their sensitivity, specificity, and the results of receiver operating characteristic (ROC) analyses. RESULTS: Our results show that areas involved in language processing can be identified by hgECoG, fMRI, and TMS. The average sensitivity/specificity of hgECoG, fMRI, and TMS across all patients was 100%/85%, 50%/80%, and 67%/66%, respectively. The average area under the ROC curve of hgECoG, fMRI, and TMS across CSM-positive patients was 0.98, 0.76, and 0.68, respectively. CONCLUSIONS: There is considerable concordance between CSM, hgECoG, fMRI, and TMS language mapping. Our results reveal that hgECoG, fMRI, and TMS are valuable tools for presurgical language mapping. SIGNIFICANCE: Language mapping on the basis of hgECoG, fMRI, and TMS can provide important additional information, therefore, these methods can be used in conjunction with CSM or as an alternative, when the latter is deemed impractical.

SmartWatch by SmartMonitor: Assessment of Seizure Detection Efficacy for Various Seizure Types in Children, a Large Prospective Single-Center Study.

INTRODUCTION: Patients with epilepsy and their caregivers are constantly burdened with the possibility of a seizure and its consequences, such as accidents, injuries, and sudden unexplained death in epilepsy. It is the unpredictable nature of seizures that often affects both patients with seizures and their caregivers, limits independence, and hinders quality of life. There are several types of motion detectors on the market, each with varying degrees of sensitivity. MATERIAL AND METHODS: We prospectively tested the SmartWatch, a wrist-worn monitor, on children, adolescents, and young adults with various types of seizures in an epilepsy monitoring unit. Confirmation of seizure type and if there was rhythmic upper extremity jerking associated with the seizure was determined by review of the video electroencephalograph. This was compared with the standard detection system of the watch. RESULTS: This study analyzed a total of 191 seizures in 41 patients aged 5-41 years. Fifty-one of the seizures were generalized tonic-clonic. Forty-seven of the seizures had a rhythmic arm movement component. The SmartWatch detected 30 seizures (16%) of the total, 16 (31%) of the generalized tonic-clonic seizures, and 16 (34%) seizures associated with rhythmic arm movements. DISCUSSION: Overall, only a minority of generalized tonic-clonic seizures or seizures with rhythmic movements were detected, highlighting the need for an effective seizure detection device.

Assessing motor function in young children with transcranial magnetic stimulation.

OBJECTIVE: Accurate noninvasive assessment of motor function using functional MRI (fMRI) and magnetoencephalography (MEG) is a challenge in patients who are very young or who are developmentally delayed. In such cases, passive mapping of the sensorimotor cortex is performed under sedation. We examined the feasibility of using transcranial magnetic stimulation (TMS) as a motor mapping tool in awake children younger than 3 years of age. METHODS: Six children underwent motor mapping with TMS while awake as well as passive sensorimotor mapping under conscious sedation with MEG during tactile stimulation (n = 5) and fMRI during passive hand movements (n = 4). RESULTS: Stimulation of the motor cortex via TMS successfully elicited evoked responses in contralateral hand muscles in 5 patients. The location of primary motor cortex in the precentral gyrus identified by TMS corresponded with the postcentral location of the primary sensory cortex identified by MEG in 2 patients and to the sensorimotor cortex identified by fMRI in 3 children. In this cohort, we demonstrate that TMS can illuminate abnormalities in motor physiology including motor reorganization. We also demonstrate the feasibility of using TMS-derived contralateral silent periods to approximate the location of motor cortex in the absence of an evoked response. When compared to chronological age, performance functioning level appears to be better in predicting successful mapping outcome with TMS. CONCLUSIONS: Our findings indicate that awake TMS is a safe alternative to MEG and fMRI performed under sedation to localize the motor cortex and provides additional insight into the underlying pathophysiology and motor plasticity in toddlers.

Variation in the topography of the speech production cortex verified by cortical stimulation and high gamma activity.

In this study, we have addressed the question of functional brain reorganization for language in the presence and absence of anatomical lesions in two patients with epilepsy using cortical stimulation mapping and high gamma (HG) activity in subdural grid recordings. In both, the expressive language cortex was defined as the cortical patch below the electrode(s) that when stimulated resulted in speech arrest, and during speech expression tasks generated HG activity. This patch fell within the borders of Broca's area, as defined anatomically, in the case of the patient with a lesion, but outside that area in the other, lesion-free patient. Such results highlight the necessity for presurgical language mapping in all cases of surgery involving the language-dominant hemisphere and suggest that HG activity during expressive language tasks can be informative and helpful in conjunction with cortical stimulation mapping for expressive language mapping.

Prospective Study of the Emfit Movement Monitor.

Sudden unexplained death in epilepsy (SUDEP) is associated with generalized tonic-clonic seizures and occurs most often when patients are in bed. There are several seizure detection monitors on the market, but little data are available on the sensitivity and specificity of these devices. We recently tested 2 models of seizure detection alarms with disappointing results. Here we tested the Emfit movement monitor on children with various seizure types who also had standard video electroencephalography (EEG), cardiopulmonary, and nursing monitoring. Video EEG records were reviewed to detect any seizures. In 45 patients, 78 seizures were recorded by video EEG. The Emfit movement monitor captured 23 seizure events (30%) in total, and 15 of the 28 (54%) that occurred during sleep. Most importantly, the alarm was activated with 11 of the 13 (85%) generalized tonic-clonic seizures that occurred in sleeping children. The Emfit movement monitor performed very well in comparison to previously tested devices.

Prospective Study of 2 Bed Alarms for Detection of Nocturnal Seizures.

For parents of children with epilepsy, seizures occurring in sleep are a major concern. Risk factors for sudden unexplained death in epilepsy patients include being in bed and generalized tonic-clonic seizures. A device for detecting nocturnal seizure activity would be valuable. Children with various seizure types undergoing evaluation had standard video electroencephalography (EEG), cardiopulmonary and nursing monitoring, and 1 of 2 models (ST-2 and MP5) of a Medpage bed alarm. The video EEG record was reviewed to detect any seizures missed by the bed alarms or caregivers. The ability of the bed alarms to detect motor seizures in general and specific seizure types was tested. In 15 patients, 69 seizures were recorded by video EEG. The ST-2 did not detect any nocturnal seizures. The MP5 alarm detected 1 of 15 in sleeping patients: a generalized tonic-clonic seizure. The Medpage seizure alarms do not appear to adequately detect nocturnal seizures.

Passive language mapping with magnetoencephalography in pediatric patients with epilepsy.

OBJECT: Functional mapping is important for determining surgical candidacy and also in epilepsy surgery planning. However, in young children and uncooperative patients, language mapping has been particularly challenging despite the advances in performing noninvasive functional studies. In this study the authors review a series of children with epilepsy who underwent language mapping with magnetoencephalography (MEG) while sedated or sleeping, to determine receptive language localization for presurgical evaluation. METHODS: The authors undertook a retrospective review of patients who underwent MEG between December 2007 and July 2009, and identified 15 individuals who underwent passive language testing as part of their presurgical evaluation because they were unable to participate in traditional language testing, such as Wada or functional MRI. Factors necessitating passive language testing included age and neurocognitive development. RESULTS: Three of the 15 patients were deemed candidates for epilepsy surgery based on the results from standard preoperative testing, including video electroencephalography, MRI, and passive receptive language testing using MEG technology. The MEG studies were used successfully to localize language in all 3 patients, creating opportunities for seizure freedom through surgery that would not otherwise have been available. All 3 patients then underwent resective epilepsy surgery without experiencing postoperative language deficits. CONCLUSIONS: This case series is the first to look at language mapping during sleep (passive language mapping) in which MEG was used and is the first to evaluate passive language testing in a patient population with intracranial pathological entities. This case series demonstrates that MEG can provide an alternative method for receptive language localization in patients with barriers to more traditional language testing, and in these 3 cases surgery was performed safely based on the results.

Angiocentric glioma-induced seizures in a 2-year-old child.

A 2-year-old child presented with medically refractory seizures and was found to have a right frontoparietal parasagittal angiocentric glioma. Depth electrodes were used to document ictal onset from within the tumor rather than from the surrounding tissues. Ictal activity then spread to a wide area on the cortical surface, including the region around the tumor and hand motor cortex. Lesionectomy permitted sparing of adjacent areas of eloquent cortex, and the child is now seizure-free on monotherapy.