The changing landscape of electrical stimulation language mapping with subdural electrodes and stereoelectroencephalography for pediatric epilepsy: A literature review and commentary.

Electrical stimulation mapping (ESM) is used to locate the brain areas supporting language directly within the human cortex to minimize the risk of functional decline following epilepsy surgery. ESM is completed by utilizing subdural grid or depth electrodes (stereo-electroencephalography [sEEG]) in combination with behavioral evaluation of language. Despite technological advances, there is no standardized method of assessing language during pediatric ESM. To identify current clinical practices for pediatric ESM of language, we surveyed neuropsychologists in the Pediatric Epilepsy Research Consortium. Results indicated that sEEG is used for functional mapping at >80% of participating epilepsy surgery centers (n = 13/16) in the United States. However, >65% of sites did not report a standardized protocol to map language. Survey results indicated a clear need for practice recommendations regarding ESM of language. We then utilized PubMed/Medline and PsychInfo to identify 42 articles that reported on ESM of language, of which 18 met inclusion criteria, which included use of ESM/signal recording to localize language regions in children (<21 years) and a detailed account of the procedure and language measures used, and region-specific language localization outcomes. Articles were grouped based on the language domain assessed, language measures used, and the brain regions involved. Our review revealed the need for evidence-based clinical guidelines for pediatric language paradigms during ESM and a standardized language mapping protocol as well as standardized reporting of brain regions in research. Relevant limitations and future directions are discussed with a focus on considerations for pediatric language mapping.

Leveraging expertise and optimizing clinical research: Initial success of a pediatric epilepsy surgery collaborative.

OBJECTIVE: Improve data-driven research to inform clinical decision-making with pediatric epilepsy surgery patients by expanding the Pediatric Epilepsy Research Consortium Epilepsy Surgery (PERC-Surgery) Workgroup to include neuropsychological data. This article reports on the process and initial success of this effort and characterizes the cognitive functioning of the largest multi-site pediatric epilepsy surgery cohort in the United States. METHODS: Pediatric neuropsychologists from 18 institutions completed surveys regarding neuropsychological practice and the impact of involvement in the collaborative. Neuropsychological data were entered through an online database. Descriptive analyses examined the survey responses and cognitive functioning of the cohort. Statistical analyses examined which patients were evaluated and if composite scores differed by domain, demographics, measures used, or epilepsy characteristics. RESULTS: Positive impact of participation was evident by attendance, survey responses, and the neuropsychological data entry of 534 presurgical epilepsy patients. This cohort, ages 6 months to 21 years, were majority White and non-Hispanic, and more likely to have private insurance. Mean intelligence quotient (IQ) scores were below to low average, with weaknesses in working memory and processing speed. Full-scale IQ (FSIQ) was lowest for patients with younger age at seizure onset, daily seizures, and magnetic resonance imaging (MRI) abnormalities. SIGNIFICANCE: We established a collaborative network and fundamental infrastructure to address questions outlined by the Epilepsy Research Benchmarks. There is a wide range in the age and IQ of patients considered for pediatric epilepsy surgery, yet it appears that social determinants of health impact access to care. Consistent with other national cohorts, this US cohort has a downward shift in IQ associated with seizure severity.

Assessing risk: Characterizing language performance in pediatric patients with intractable epilepsy pre- and post-surgical resection.

Neuropsychologists play an important role in assessing risk for post-surgical cognitive decline in pediatric patients with medically refractory epilepsy. Families, neurologists, and neurosurgeons are particularly concerned about the possibility for language decline for patients with a dominant, most often left, hemisphere epileptic focus and planned surgical resection. This study aims to describe language functioning in pediatric epilepsy patients following resection and evaluate the accuracy of a clinical approach of assessing risk. This study proposes a risk assessment method that considers a patient's pattern of lateralized dysfunction across cognitive domains, suspected neuroanatomical reorganization of language functions, and planned site of resection. Pediatric patients (N = 47) were dichotomized as being at minimal risk or at greater risk for post-surgical language decline based on the proposed risk assessment method. Retrospective chart review was utilized to obtain neuropsychological (Boston Naming Test and Weschler Vocabulary subtest) and clinical variables of interest. Patients in the minimal risk group demonstrated significantly improved BNT scores at post-surgery. Most patients remained stable in their Vocabulary knowledge. The proposed risk assessment method correctly classified patients 77% of the time based on BNT performance. Cluster analysis examining the individual components of the proposed method revealed three distinct patient subgroups. Clinical implications are discussed.

Determination of language dominance in pediatric patients with epilepsy for clinical decision-making: Correspondence of intracarotid amobarbitol procedure and fMRI modalities.

Identification of the language dominant hemisphere is an essential part of the evaluation of potential pediatric epilepsy surgery patients. Historically, language dominance has been determined using the intracarotid amobarbitol procedure (IAP), but use of functional Magnetic Resonance Imaging (fMRI) scanning is becoming more common. Few studies examine the correspondence between fMRI and IAP in pediatric samples. The current study examined the agreement of hemispheric lateralization as determined by fMRI and IAP in a consecutive sample of 10 pediatric patients with epilepsy evaluated for epilepsy surgery. Data showed a strong correlation between IAP and fMRI lateralilty indices (r=.91) and 70% agreement in determination of hemispheric dominance, despite increased demonstration of bilateral or atypical language representation in this pediatric sample. Clinical implications and interpretation challenges are discussed.

Awake craniotomy for supratentorial tumors or epileptogenic lesions in pediatric patients: a 16-year retrospective cohort study.

OBJECTIVE: Awake craniotomy with intraoperative mapping is the widely accepted procedure for adult patients undergoing supratentorial tumor or epileptogenic focus resection near eloquent cortex. In children, awake craniotomies are notably less common due to concerns for compliance and emotional or psychological repercussions. Despite this, successfully tolerated awake craniotomies have been reported in patients as young as 8 years of age, with success rates comparable to those of adults. The authors sought to describe their experience with pediatric awake craniotomies, including insight regarding feasibility and outcomes. METHODS: A retrospective review was completed for all pediatric (age < 18 years) patients at Children's Wisconsin for whom an awake craniotomy was attempted from January 2004 until March 2020. Institutional review board approval was granted. RESULTS: Candidate patients had intact verbal ability, cognitive profile, and no considerable anxiety concerns during neuropsychology assessment. Nine patients presented with seizure. Five patients were diagnosed with tumor and secondary epilepsy, 3 with tumor only, and 3 with epilepsy only. All patients who underwent preoperative functional MRI successfully completed and tolerated testing paradigms. A total of 12 awake craniotomies were attempted in 11 patients, with 1 procedure aborted due to intraoperative bleeding. One patient had a repeat procedure. The mean patient age was 15.5 years (range 11.5-17.9 years). All patients returned to or maintained baseline motor and speech functions by the latest follow-up (range 14-130 months). Temporary deficits included transient speech errors, mild decline in visuospatial reasoning, leg numbness, and expected hemiparesis. Of the 8 patients with a diagnosis of epilepsy prior to surgery, 7 patients achieved Engel class I designation at the 1-year follow-up, 6 of whom remained in class I at the latest follow-up. CONCLUSIONS: This study analyzes one of the largest cohorts of pediatric patients who underwent awake craniotomy for maximal safe resection of tumor or epileptogenic lesions. For candidate patients, awake craniotomy is safe, feasible, and effective in carefully selected children.

Beta-HPV 5 and 8 E6 promote p300 degradation by blocking AKT/p300 association.

The E6 oncoprotein from high-risk genus alpha human papillomaviruses (α-HPVs), such as HPV 16, has been well characterized with respect to the host-cell proteins it interacts with and corresponding signaling pathways that are disrupted due to these interactions. Less is known regarding the interacting partners of E6 from the genus beta papillomaviruses (ß-HPVs); however, it is generally thought that ß-HPV E6 proteins do not interact with many of the proteins known to bind to α-HPV E6. Here we identify p300 as a protein that interacts directly with E6 from both α- and ß-HPV types. Importantly, this association appears much stronger with ß-HPV types 5 and 8-E6 than with α-HPV type 16-E6 or ß-HPV type 38-E6. We demonstrate that the enhanced association between 5/8-E6 and p300 leads to p300 degradation in a proteasomal-dependent but E6AP-independent manner. Rather, 5/8-E6 inhibit the association of AKT with p300, an event necessary to ensure p300 stability within the cell. Finally, we demonstrate that the decreased p300 protein levels concomitantly affect downstream signaling events, such as the expression of differentiation markers K1, K10 and Involucrin. Together, these results demonstrate a unique way in which ß-HPV E6 proteins are able to affect host-cell signaling in a manner distinct from that of the α-HPVs.

Neural representations of self-perception of voice: An intracortical evoked potential analysis based on an adolescent with right temporal lobe epilepsy.

INTRODUCTION: The neural bases for language perception have been studied elsewhere using Transcranial Magnetic Stimulation, functional Magnetic Resonance Imaging and Direct Cortical Stimulation. However, to our knowledge, there is no previous report about a patient identifying the change in his voice tone, speed, and prosody because of right temporal cortical stimulation. Nor has there been a cortico-cortical evoked potential (CCEP) assessment of the network underlying this process. CASE REPORT: We present CCEP from a patient with right focal refractory temporal lobe epilepsy of tumoral etiology who reported changes in the perception of his own speech prosody during stimulation. This report will serve as a complement to the understanding of the neural networks of language and prosody. CONCLUSION: The present report shows that right superior temporal gyrus, transverse temporal gyrus, right amygdala, hippocampus, and fusiform gyrus (FG) are part of the neural network subjacent to own human voice perception.

Factor analysis of neuropsychological domains in a preschool clinic.

INTRODUCTION: The clinical practice of preschool neuropsychology assumes that our assessment tools are measuring underlying neuropsychological functions, and that these functions are negatively impacted by early life neurological injury, disease, and disorder. This study hypothesized that general intellectual capacity and specific cognitive skills, both "broad" neuropsychological domains and "specific" subdomains within those broader clusters, would be differentiable in a preschool-age clinical population. METHODS: Using neuropsychological data from 580 children (6 and 71 months) seen for a clinical neuropsychological evaluation in the Preschool and Infant Neuropsychological Testing (PINT) Clinic, exploratory factor analyses (EFA) were conducted. Results: A one-factor model provided a good fit when considering verbal, nonverbal, and adaptive functions. Consideration of one- versus two-factor solutions for broad neuropsychological domains indicated that a 2-factor solution provided a significantly better fit for the data. Factor 1 was defined by motor, language, and nonverbal reasoning abilities; Factor 2 was defined by inhibitory control and attention. Further consideration of specific neuropsychological functions also supported a 2-factor solution. Factor 1 ("thinking") was defined by nonverbal reasoning, receptive language, and expressive language; Factor 2 ("processing") was defined by impulse control, inhibitory control, inattention, visual-motor integration, and visuo-constructional abilities. Motor skills cross-loaded onto both factors. Secondary analyses suggest these models provide the best fit for preschool-aged children with > 70 overall intellectual functioning and no comorbid medical diagnosis. CONCLUSIONS: In a clinical sample of preschool-age children, neuropsychological assessment data appears to assess a general level of intellectual capacity or functioning. Further differentiation between assessing "thinking" (knowledge and reasoning skills) and "processing" (cognitive attention and processing of information) can be considered clinically. Next steps include more recent clinical sample replication, consideration of whether neuropsychological profiles are detectable in the preschool-age range and whether the results of early life assessment are predictive of future functioning.

Differential access to neuropsychological evaluation in children with perinatal complications or autism spectrum disorder: Impact of sociodemographic factors.

OBJECTIVE: Early childhood evaluation can identify deficits related to disruptions in early brain development and facilitate interventions. Access to care may differ by race/ethnicity or socioeconomic status. We explored neuropsychological evaluation access patterns and examined potential sociodemographic disparities in evaluation timing. Method: Participants were 213 children (age: M = 46.4 months, SD = 15.3 months) with a history of disrupted neural development due to perinatal complications (PC; n = 109) or autism spectrum disorder (ASD; n = 104). We used chi square tests of independence and one-way ANOVAs to compare groups on sociodemographics, referral sources, and cognition. Clinical sample means for cognitive and adaptive variables were compared to normative means to determine the presence of developmental delays. Differences in age at evaluation by race/ethnicity, caregiver education, and referral source, accounting for cognition, were explored with ANCOVAs. Results: The ASD group included significantly more White children and the PC group relatively more Black/African Americans. Children with ASD were referred by primary care physicians and caregivers/school staff; those with PC were referred by other medical providers. All participants performed more poorly than expected across all intellectual and adaptive domains, with greater delays in the ASD group. Children of caregivers with lower education were evaluated earlier in the PC group. For ASD, participants referred by primary care physicians were evaluated earlier. Conclusions: Children with PC and ASD exhibit cognitive delays and require neuropsychological evaluation. Disparities in access to care exist, particularly for minority children with ASD. Ways to promote equal access are discussed.

Sociodemographic disparities in fetal surgery for myelomeningocele: a single-center retrospective review.

OBJECTIVE: Fetal surgery for myelomeningocele has become an established treatment that offers less risk of requiring a ventricular shunt and improved functional outcomes for patients. An increasing body of literature has suggested that social determinants of health have a profound influence on health outcomes. The authors sought to determine the socioeconomic and racial and ethnic backgrounds of patients who were treated with fetal surgery versus those who underwent postnatal repair. METHODS: Demographic data, the method of myelomeningocele repair, insurance status, and zip code data for patients entered into the National Spina Bifida Patient Registry (NSBPR) from Children's Wisconsin were collected. The zip code was used to determine the Distressed Communities Index (DCI) score, a composite socioeconomic ranking with scores ranging from 0 (no distress) to 100 (severe distress). The zip code was also used to determine the median household income for each patient based on the US Census Bureau 2013-2017 American Community Survey 5-year estimates. RESULTS: A total of 205 patients were identified with zip code and insurance data. There were 23 patients in the fetal surgery group and 182 patients in the postnatal surgery group. All patients were born between 2000 and 2019. Patients in the fetal surgery group were more likely to have commercial insurance (100% vs 52.2%, p < 0.001). Fetal surgery patients were also more likely to be non-Hispanic White (95.7% vs 68.7%, p = 0.058), just missing the level of statistical significance. Patients who underwent fetal surgery tended to reside in zip codes with a higher median household income (mean $66,507 vs $59,133, p = 0.122) and less-distressed communities (mean DCI score 31.3 vs 38.5, p = 0.289); however, these differences did not reach statistical significance. CONCLUSIONS: Patients treated with fetal surgery were more likely to have commercial insurance and have a non-Hispanic White racial and ethnic background. The preliminary data suggest that socioeconomic and racial and ethnic disparities may exist regarding access to fetal surgery, and investigation of a larger population of spina bifida patients is warranted.

E6 proteins from multiple human betapapillomavirus types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation.

Human papillomavirus (HPV) types from the beta genus (beta-HPVs) have been implicated in the development of skin cancer. A potentially important aspect of their carcinogenic role is the ability of the E6 protein to degrade the proapoptotic family member Bak, which gives cells the ability to survive UV damage. However, it is unknown if the ability to degrade Bak is limited to certain beta-HPV types or whether E6 expression in keratinocytes affects other proteins important for apoptosis signaling. We tested the abilities of E6 proteins from several representative members of the beta-HPVs to degrade Bak and protect UV-treated keratinocytes from apoptosis. The E6 proteins of the beta-HPV type 5 (HPV5), -8, -20, -22, -38, -76, -92, and -96, as well as the alpha genus HPV HPV16, all degraded Bak or prevented its accumulation following UV treatment but did not degrade Bak constitutively. In addition, when tested using HPV16 E6 (16E6) and 8E6 as representative E6 proteins from the alpha and beta genera, respectively, Bak degradation was dependent on the E3 ubiquitin ligase, E6AP. Other important regulators of apoptotic signaling were examined and found to be unperturbed by the expression of the beta-HPV E6 proteins. Importantly, the expression of beta-HPV E6 proteins protected keratinocytes from apoptosis to the same extent as 16E6-expressing cells. In conclusion, several of the beta-HPV types possess the ability to protect UV-treated keratinocytes from apoptosis by reducing levels of Bak in those cells, thus blocking the intrinsic apoptotic pathway.

The relationship of neuropsychological functioning to adaptation outcome in adolescents with spina bifida.

Adolescents with spina bifida (SB) vary in their ability to adapt to the disease, and it is likely that numerous risk and protective factors affect adaptation outcomes. The primary aim was to test neuropsychological impairment, exemplified herein by executive dysfunction, as a risk factor in the Ecological Model of Adaptation for Adolescents with SB. Specific hypotheses were that: (1) executive functioning predicts the adaptation outcome of functional independence in adolescents with SB; (2) executive functioning mediates the impact of neurological severity on functional independence; and (3) family and adolescent protective factors are related to functional independence and moderate the relationship between executive functioning and functional independence. Forty-three adolescents aged 12-21 years completed neuropsychological measures and an interview that assessed risk, adolescent and family protective factors, and functional independence. Age, level of lesion, executive functioning, and the protective factor adolescent activities were significantly correlated with the functional independence outcome. In hierarchical regression analysis, the model accounted for 61% of the variance in functional independence outcomes. Executive functioning mediated the impact of neurological severity on functional independence.

Telomere erosion and chromosomal instability in cells expressing the HPV oncogene 16E6.

Progression to advanced-stage cervical carcinomas is characterized by a recurrent pattern of chromosomal rearrangements. Structural chromosome rearrangements are generated through the fusion of broken chromosome ends. These chromosome breaks may be induced by mutagenic agents such as ionizing radiation, or chromosome ends may be exposed through extensive telomere shortening. The human papilloma virus oncogene 16E6 induces telomerase activity in human keratinocytes, a model system for cervical tumor formation. The present study explores the relationship between 16E6 expression, telomerase activity, and chromosomal instability. We show that the frequency of anaphase bridges is dependent on the level of telomerase activity in 16E6/E7-expressing clones, and is the result of telomere shortening. High frequencies of anaphase bridges, associated with low telomerase activity, correlate with increased chromosome instability. Anaphase bridge formation is also associated with the presence of micronuclei, which are shown to contain unstable chromosomes frequently involved in rearrangements. As anaphase bridges are observed in both high and low telomerase 16E6/E7 clones, but not in hTERT-expressing control clones, expression of 16E6 in these immortalized clones is not sufficient to stabilize shortened telomeres completely. We suggest a model in which HPV-induced tumorigenesis may be dependent on persistent bridge-breakage-fusion cycles that allow for continued genomic rearrangements.

Neuropsychological correlates of electroencephalograms in children with epilepsy.

INTRODUCTION: This study examined the degree to which neurophysiological activity on routine clinical EEG is associated with neuropsychological deficiencies in children with epilepsy. METHODS: Ninety-five children with epilepsy (58 chronic, 37 recent-onset; mean age = 10.41 years, S.D. = 2.87 years; mean age at onset = 5.86 years, S.D. = 3.46 years) completed a neuropsychological battery. Neurophysiological data were collected from the most recent EEG. RESULTS: In the recent-onset sample, no neuropsychological scores were related to any EEG variable. In the chronic sample, however, presence of slow-wave activity was related to memory impairment (p < 0.01). Post-hoc analyses on other neuropsychological measures showed localization of epileptiform activity (EA) might be related to verbal learning. DISCUSSION: Children with slow-wave activity on EEG might be at increased risk for developing neuropsychological deficits. When these abnormalities are observed on a child's EEG, closer monitoring of cognitive and academic functioning seems warranted. Differences between these findings and past research suggest that conclusions drawn from adult surgical studies cannot be generalized to pediatric patients, especially recent-onset samples, without qualification. Differences between the recent-onset and chronic samples in this cross-sectional study raise the possibility that neurophysiological abnormalities have a cumulative effect on cognitive development.

Is it ACT yet? Real-world examples of evaluating the degree of implementation for assertive community treatment.

Despite growing interest in assessment of program implementation, little is known about the best way to evaluate whether a particular program has implemented the intended service to a level that is minimally acceptable to a funding source, such as a state mental health authority. Such is the case for assertive community treatment (ACT), an evidence-based practice being widely disseminated. Using an exploratory, actuarial approach to defining program standards, this study applies different statistical criteria for determining whether or not a program meets ACT standards using the 28-item Dartmouth Assertive Community Treatment Scale. The sample consists of 51 ACT programs, 25 intensive case management programs, and 11 brokered case management programs which were compared to identify levels of fidelity that discriminated between programs, but were still attainable by the majority of ACT programs. A grading system based on mean total score for a reduced set of 21 items appeared to be most attainable, but still discriminated ACT programs from other forms of case management. Implications for setting and evaluating ACT program standards are discussed.

Development of the DPA Fidelity Scale: using fidelity to define an existing vocational model.

Psychiatric rehabilitation practices are often poorly defined, hindering implementation, research, and dissemination efforts. Documentation of adherence to a specific psychiatric rehabilitation approach is particularly important in conducting randomized controlled trials. This paper outlines steps taken to define and measure the Diversified Placement Approach (DPA), a well-regarded vocational program for people with severe mental illnesses. Details of scale development are described, and the scale's utility for model clarification and detection of experimental drift are discussed.

Fifty consecutive hemispherectomies: outcomes, evolution of technique, complications, and lessons learned.

BACKGROUND: Techniques for achieving hemispheric disconnection in patients with epilepsy continue to evolve. OBJECTIVE: To review the outcomes of the first 50 hemispherectomy surgeries performed by a single surgeon with an emphasis on outcomes, complications, and how these results led to changes in practice. METHODS: The first 50 hemispherectomy cases performed by the lead author were identified from a prospectively maintained database. Patient demographics, surgical details, clinical outcomes, and complications were critically reviewed. RESULTS: From 2004 to 2012, 50 patients underwent hemispherectomy surgery (mean follow-up time, 3.5 years). Modified lateral hemispherotomy became the preferred technique and was performed on 44 patients. Forty patients (80%) achieved complete seizure freedom (Engel I). Presurgical and postsurgical neuropsychological evaluations demonstrated cognitive stability. Two cases were performed for palliation only. Previous hemispherectomy surgery was associated with worsened seizure outcome (2 of 6 seizure free; P .005). The use of Avitene was associated with a higher incidence of postoperative hydrocephalus (56% vs 18%; P = .03). In modified lateral hemispherotomy patients without the use of Avitene, the incidence of hydrocephalus was 13%. Complications included infection (n = 3), incomplete disconnection requiring reoperation (n = 1), reversible ischemic neurological deficit (n = 1), and craniosynostosis (n = 1). There were no (unanticipated) permanent neurological deficits or deaths. Minor technique modifications were made in response to specific complications. CONCLUSION: The modified lateral hemispherotomy is effective and safe for both initial and revision hemispherectomy surgery. Avitene use appears to result in a greater incidence of postoperative hydrocephalus.

Corpus callosotomy in multistage epilepsy surgery in the pediatric population.

OBJECT: The object of this study was to evaluate surgical outcome in a select group of patients with medically refractory epilepsy who had undergone corpus callosotomy combined with bilateral subdural electroencephalography (EEG) electrode placement as the initial step in multistage epilepsy surgery. METHODS: A retrospective chart review of 18 children (ages 3.5-18 years) with medically refractory symptomatic generalized or localization-related epilepsy was undertaken. A corpus callosotomy with subdural bihemispheric EEG electrode placement was performed as the initial step in multistage epilepsy surgery. All of the patients had tonic and atonic seizures; 6 patients also experienced complex partial seizures. All of the patients had frequent generalized epileptiform discharges as well as multifocal independent epileptiform discharges on surface EEG monitoring. Most of the patients (94%) had either normal (44%) MR imaging studies of the brain or bihemispheric abnormalities (50%). One patient had a suspected unilateral lesion (prominent sylvian fissure). RESULTS: Of the 18 patients who underwent corpus callosotomy and placement of subdural strips and grids, 12 progressed to further resection based on localizing data obtained during invasive EEG monitoring. The mean patient age was 10.9 years. The duration of invasive monitoring ranged from 3 to 14 days, and the follow-up ranged from 6 to 70 months (mean 35 months). Six (50%) of the 12 patients who had undergone resection had an excellent outcome (Engel Class I or II). There were no permanent neurological deficits or deaths. CONCLUSIONS: The addition of invasive monitoring for patients undergoing corpus callosotomy for medically refractory epilepsy may lead to the localization of surgically amenable seizure foci, targeted resections, and improved seizure outcomes in a select group of patients typically believed to be candidates for palliative surgery alone.