Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

BACKGROUND AND OBJECTIVE: Conventional protocols for inferior petrosal sinus sampling (IPSS) during the workup of hypercortisolemia require adrenocorticotrophic hormone (ACTH) measurement at multiple time points with corticotropic-releasing hormone (CRH) used as a stimulator. Modernized evidence-based protocols must also reflect the increased utilization of desmopressin (DDAVP) for ACTH stimulation as the manufacturing shortage of traditionally used CRH continues. We model the diagnostic accuracy and potential economic savings of DDAVP utilization and reduced time point sampling. METHODS: A single-institution, retrospective review of patients undergoing IPSS between 2007 and 2021 was performed. A computational search for the minimal set of time points which preserves conventional diagnostic accuracy was performed by testing all 1 through 5-point combinations generated using a binomial expansion. Economic savings were modeled using a publicly available hospital chargemaster. RESULTS: A total of 50 patients qualified for inclusion, 47 of whom were diagnosed with Cushing disease and 3 with ectopic Cushing syndrome. Single-point diagnostic accuracy for DDAVP-stimulated tests was 71.4%-92.9%, and seven 2-point combinations (5-25 procedural minutes) were found, which preserved conventional diagnostic accuracy. Single-point accuracy for CRH-stimulated tests was 67.9%-89.3%, and two 2-point combinations ( t = -15, t = +2 and t = -15, t = +10) preserved accuracy. For every time point removed, the cost of ACTH laboratory tests was reduced by $507 from $3042 for 6-point IPSS). The shortest and most economical stimulator and time point combination that preserved conventional accuracy was DDAVP sampling at t = 0 and t = +5 or t = +2 and t = +5 minutes, which cost $2028 total compared with the most expensive 6-point IPSS option with CRH ($6392). CONCLUSION: DDAVP is a cost-efficient and effective alternative to CRH during IPSS. Our results encourage prospective evaluation of potentially fewer sampling time points in the interest of time and cost efficiency balanced with preserved accuracy.

Subdural electrodes versus stereoelectroencephalography for pediatric epileptogenic zone localization: a retrospective cohort study.

OBJECTIVE: The objective of this study was to compare the relative safety and effectiveness of invasive monitoring with subdural electrodes (SDEs) and stereoelectroencephalography (sEEG) in pediatric patients with drug-resistant epilepsy. METHODS: A retrospective cohort study was performed in 176 patients who underwent invasive monitoring evaluations at UPMC Children's Hospital of Pittsburgh between January 2000 and September 2021. To examine differences between SDE and sEEG groups, independent-samples t-tests for continuous variables and Pearson chi-square tests for categorical variables were performed. A p value < 0.1 was considered statistically significant. RESULTS: There were 134 patients (76%) in the SDE group and 42 (24%) in the sEEG group. There was a difference in the proportion with complications (17.9% in the SDE group vs 7.1% in the sEEG group, p = 0.09) and resection (75.4% SDE vs 21.4% sEEG, p < 0.01) between SDE and sEEG patients. However, there was no observable difference in the rates of postresection seizure freedom at 1-year clinical follow-up (60.2% SDE vs 75.0% sEEG, p = 0.55). CONCLUSIONS: These findings reveal a difference in rates of surgical complications and resection between SDEs and sEEG. Larger prospective, multi-institutional pediatric comparative effectiveness studies may further explore these associations.

Neural responses in human superior temporal cortex support coding of voice representations.

The ability to recognize abstract features of voice during auditory perception is an intricate feat of human audition. For the listener, this occurs in near-automatic fashion to seamlessly extract complex cues from a highly variable auditory signal. Voice perception depends on specialized regions of auditory cortex, including superior temporal gyrus (STG) and superior temporal sulcus (STS). However, the nature of voice encoding at the cortical level remains poorly understood. We leverage intracerebral recordings across human auditory cortex during presentation of voice and nonvoice acoustic stimuli to examine voice encoding at the cortical level in 8 patient-participants undergoing epilepsy surgery evaluation. We show that voice selectivity increases along the auditory hierarchy from supratemporal plane (STP) to the STG and STS. Results show accurate decoding of vocalizations from human auditory cortical activity even in the complete absence of linguistic content. These findings show an early, less-selective temporal window of neural activity in the STG and STS followed by a sustained, strongly voice-selective window. Encoding models demonstrate divergence in the encoding of acoustic features along the auditory hierarchy, wherein STG/STS responses are best explained by voice category and acoustics, as opposed to acoustic features of voice stimuli alone. This is in contrast to neural activity recorded from STP, in which responses were accounted for by acoustic features. These findings support a model of voice perception that engages categorical encoding mechanisms within STG and STS to facilitate feature extraction.

One-year cost-effectiveness of callosotomy vs vagus nerve stimulation for drug-resistant seizures in Lennox-Gastaut Syndrome: A decision analytic model.

OBJECTIVE: Palliative epilepsy surgery via corpus callosotomy (CC) or vagus nerve stimulation (VNS) is commonly employed for drug-resistant seizures in Lennox-Gastaut Syndrome (LGS). VNS is less effective at reducing seizures but has fewer adverse events, CC is more effective for seizure control, particularly atonic seizures, but can be associated with serious adverse events, and yet their relative cost-effectiveness remains unknown. METHODS: To determine which option is most cost-effective, a decision analytic model was developed to evaluate the risks and benefits of CC and VNS at 1 year based on costs in the United States. Our primary outcome measure was positive seizure outcomes, defined as >50% seizure reduction without procedural complications. RESULTS: CC had a 15% greater likelihood of a positive seizure outcome, but per patient costs were $68 147 more than VNS, or $451 952 per positive seizure outcome gained. One-way sensitivity analyses demonstrate that probabilities of seizure freedom or reduction by VNS or CC and CC cost were most influential on results. When considering atonic seizures, CC had a 27% greater positive outcome likelihood than VNS, the same incremental cost, and cost $250 556 per positive seizure outcome gained. SIGNIFICANCE: This exploratory model suggests that VNS is more cost-effective relative to CC at 1 year.

Frequency-Following Responses to Speech Sounds Are Highly Conserved across Species and Contain Cortical Contributions.

Time-varying pitch is a vital cue for human speech perception. Neural processing of time-varying pitch has been extensively assayed using scalp-recorded frequency-following responses (FFRs), an electrophysiological signal thought to reflect integrated phase-locked neural ensemble activity from subcortical auditory areas. Emerging evidence increasingly points to a putative contribution of auditory cortical ensembles to the scalp-recorded FFRs. However, the properties of cortical FFRs and precise characterization of laminar sources are still unclear. Here we used direct human intracortical recordings as well as extracranial and intracranial recordings from macaques and guinea pigs to characterize the properties of cortical sources of FFRs to time-varying pitch patterns. We found robust FFRs in the auditory cortex across all species. We leveraged representational similarity analysis as a translational bridge to characterize similarities between the human and animal models. Laminar recordings in animal models showed FFRs emerging primarily from the thalamorecipient layers of the auditory cortex. FFRs arising from these cortical sources significantly contributed to the scalp-recorded FFRs via volume conduction. Our research paves the way for a wide array of studies to investigate the role of cortical FFRs in auditory perception and plasticity.

Traumatic atlanto-occipital dislocation in children: is external immobilization an option?

OBJECT: Traumatic atlanto-occipital dislocation (AOD) is a relatively uncommon traumatic cervical spine injury characterized by disruption and instability of the atlanto-occipital joint. At many centers, management of pediatric AOD includes occipitocervical arthrodesis, but whether external immobilization without surgery is a viable treatment option for some pediatric patients is unknown. To answer this question, we analyzed our outcomes of pediatric AOD at the Hospital for Sick Children. METHODS: We performed a retrospective chart review of all children with clinical and radiographic evidence of traumatic AOD. A total of 10 patients met criteria for traumatic AOD: 8 were treated with external immobilization alone and 2 were treated with occipitocervical arthrodesis. RESULTS: Eight patients were treated exclusively with 3 months of halo immobilization. Two patients were treated with occipitocervical instrumentation and arthrodesis. No patient undergoing halo immobilization required subsequent operative fusion. CONCLUSION: Halo immobilization is a safe, viable, and definitive treatment option for the selected children with AOD.

Efficacy of vagus nerve stimulation for drug-resistant epilepsy in children age six and younger.

OBJECTIVES: The objective of the study were to examine the safety and efficacy of vagus nerve stimulation (VNS) for reducing seizure frequency and antiepileptic drugs (AEDs) in children younger than six years and to examine long-term VNS efficacy for children who receive the device at ages 1-3 and at ages 4-6. METHODS: We conducted a 10-year retrospective analysis of VNS implantations at UPMC Children's Hospital of Pittsburgh. Relevant data were collected within 12 months of VNS implantation and at six months, one, two, and four years after VNS implantation. RESULTS: This analysis included 99 patients ages 0-3 (n = 40) and 4-6 (n = 59) at first VNS implantation. Eighty-six patients followed up for ≥4 years. There were no significant differences between age at VNS implant (0-3 vs. 4-6) and seizure etiology or most seizure semiologies. Patients took an average of 3.01 ±â€¯1.29 AEDs prior to VNS and 3.84 ±â€¯1.68 AEDs at their latest follow-up. The overall response to VNS therapy (≥50% seizure reduction) at one year, two years, and four years after VNS implantation was 55%, 60%, and 52%, respectively. At two years, 59% of 0- to 3-year-old patients responded to VNS and 52% of 4- to 6-year-old patients responded to VNS. The overall major complication rate was 5.6%, consistent with VNS use for older age groups. SIGNIFICANCE: This study demonstrates the safety and efficacy of VNS for children with drug-resistant epilepsy (DRE) younger than six. One, two, and four years after VNS implantation, 55%, 60%, and 52% of these patients, respectively, achieved ≥50% reduction in seizure frequency. The safety of VNS is also comparable with older, better studied, age groups. Based on these data, VNS therapy should be considered for children younger than six.

Emerging indications for stereotactic laser interstitial thermal therapy in pediatric neurosurgery.

Surgical treatment of deep or difficult to access lesions represents a unique and significant challenge for pediatric neurosurgeons. The introduction of stereotactic magnetic resonance-guided laser interstitial thermal therapy (LITT) over the last decade has had a dramatic impact on the landscape of pediatric neurosurgery. LITT provides a safe and effective option for children with epilepsy from hypothalamic hamartoma that represents a ground-breaking new therapy for a condition which was historically very difficult to treat with previous neurosurgical techniques. LITT has also been used as an alternative surgical technique for mesial temporal sclerosis, focal cortical dysplasia, MR-negative epilepsy, cavernoma-related epilepsy, insular epilepsy, and corpus callosotomy among other epilepsy etiologies. In some cases, LITT has been associated with improved cognitive outcomes compared to standard techniques, as in mesial temporal lobe epilepsy. Initial experiences with LITT for neuro-oncologic processes are also promising. LITT is often attractive to patients and providers as a minimally invasive approach, but the differences in safety and clinical outcome between LITT and traditional approaches are still being studied. In this review, we examine the emerging indications and clinical evidence for LITT in pediatric neurosurgery.

History of the Network Approach in Epilepsy Surgery.

We provide a history and overview of the network approach to epilepsy surgery. Models of the epileptogenic zone (EZ) have evolved considerably over the years with more recent models accounting for the connectivity and network properties of epileptic foci. Next, we describe several examples of network phenotypes of focal epilepsy and how these have the potential to influence surgical decision-making and patient outcome. Future research will provide new insight into how network models of the EZ can determine optimal surgical interventions that improve seizure outcomes and optimize cognitive outcomes.

Patient phenotypes and clinical outcomes in invasive monitoring for epilepsy: An individual patient data meta-analysis.

OBJECTIVE: Invasive monitoring provides valuable clinical information in patients with drug-resistant epilepsy (DRE). However, there is no clear evidence indicating either stereoelectroencephalography (SEEG) or subdural electrodes (SDE) as the optimal method. Our goal was to examine differences in postresection seizure freedom rates between SEEG- and SDE-informed resective epilepsy surgeries. Additionally, we aimed to determine potential clinical indicators for SEEG or SDE monitoring in patients with drug-resistant epilepsy. METHODS: A systematic literature review was performed in which we searched for primary articles using keywords such as "electroencephalography", "intracranial grid", and "epilepsy." Only studies containing individual patient data (IPD) were included for analysis. A one-stage IPD meta-analysis was performed to determine differences in rates of seizure freedom (International League Against Epilepsy (ILAE) guidelines and Engel classification) and resection status between SEEG and SDE patients. A Cox proportional-hazards regression was performed to determine the effect of time on seizure freedom status. Additionally, a principal component analysis was performed to investigate primary drivers of variance between these two groups. RESULTS: This IPD meta-analysis compared differences between SEEG and SDE invasive monitoring techniques in 595 patients from 33 studies. Our results demonstrate that while there was no difference in seizure freedom rates regardless of resection (p = 0.0565), SEEG was associated with a lower rate of resection compared with SDE (82.00% SEEG, 92.74% SDE, p = 0.0002). Additionally, while SDE was associated with a higher rate of postresection seizure freedom (54.04% SEEG, 64.32% SDE, p = 0.0247), the difference between seizure freedom rates following SEEG- or SDE-informed resection decreased with long-term follow-up. A principal component analysis showed that cases resulting in SEEG were associated with lower risk of morbidity than SDE cases, which were strongly collinear with multiple subpial transections, anterior temporal lobectomy, amygdalectomy, and hippocampectomy. SIGNIFICANCE: In this IPD meta-analysis of SEEG and SDE invasive monitoring techniques, SEEG and SDE were associated with similar rates of seizure freedom at latest follow-up. The former was associated with lower rates of resection. Furthermore, the clinical phenotypes of patients undergoing SEEG monitoring was associated with lower rates of complications. Future long-term prospective registries of IPD are promising options for clarifying the differences in these intracranial monitoring techniques as well as the unique patient phenotypes that may be associated with their indication.

Contributions of Robotics to the Safety and Efficacy of Invasive Monitoring With Stereoelectroencephalography.

The purpose of this review is to provide a discussion of the history and utility of robotics in invasive monitoring for epilepsy surgery using stereoelectroencephalography (sEEG). The authors conducted a literature review of available sources to describe how the advent of surgical robotics has improved the efficacy and ease of performing sEEG surgery. The sEEG method integrates anatomic, electrographic, and clinical information to test hypotheses regarding the localization of the epileptogenic zone (EZ) and has been used in Europe since the 1950s. One of the primary benefits of robot-assisted sEEG implantation techniques is the ability to seamlessly transition between both orthogonal and oblique trajectory types using a single technique. Based on available information, it is our view that, when applied appropriately, robotic sEEG can have a low rate of complications and many advantages over both non-robotic sEEG implantation and traditional craniotomy-based invasive monitoring methods.

Cross-national disparities contribute to heterogeneity in patient outcomes following invasive monitoring: A hierarchical mixed-effects analysis.

There is substantial variability in outcomes following invasive monitoring and surgical treatment of drug-resistant epilepsy (DRE). Patients with DRE are uniquely vulnerable to cross-national health care disparities, as their epilepsy is difficult to treat and requires extensive resources. In a large cross-national database of patients undergoing invasive monitoring for epilepsy surgery, we sought to evaluate the association between social, economic, and educational indicators of the country of treatment and patient outcomes following invasive monitoring. We performed a mixed-effects analysis of an individual patient database of 595 subjects enrolled in 33 studies encompassing 25 neurosurgical centers in 10 countries of invasive monitoring for epilepsy from 1996 to 2019. Upon preliminary univariate analysis, significant nation-level predictors of seizure outcome following either stereoelectroencephalography or subdural electrodes were hospital beds per 100,000 population, physician density, gross domestic product (GDP) growth, male and female educational attainment, and unemployment rate. On multivariate mixed-effects logistic regression, physician density (ß = -0.5112, P<.00697) and GDP growth (ß = 0.53822, P<.00404) were the only nation-level covariates of significance associated with seizure outcome. A higher physician density was associated with lesser seizure freedom rates, whereas higher GDP growth was associated with greater seizure freedom rates. Although patient-specific variables were the primary determinant of seizure outcomes, cross-national disparities also contribute to heterogeneities. Our findings highlight the importance of a systems-level dialogue to improve surgical outcomes for DRE patients.

Method of invasive monitoring in epilepsy surgery and seizure freedom and morbidity: A systematic review.

OBJECTIVE: Invasive monitoring is sometimes necessary to guide resective surgery in epilepsy patients, but the ideal method is unknown. In this systematic review, we assess the association of postresection seizure freedom and adverse events in stereoelectroencephalography (SEEG) and subdural electrodes (SDE). METHODS: We searched three electronic databases (MEDLINE, Embase, and CENTRAL [Cochrane Central Register of Controlled Trials]) from their inception to January 2018 with the keywords "electroencephalography," "intracranial grid," and "epilepsy." Studies that presented primary quantitative patient data for postresection seizure freedom with at least 1 year of follow-up or complication rates of SEEG- or SDE-monitored patients were included. Two trained investigators independently collected data from eligible studies. Weighted mean differences (WMDs) with 95% confidence interval (CIs) were used as a measure of the association of SEEG or SDE with seizure freedom and with adverse event outcomes. RESULTS: Of 11 462 screened records, 48 studies met inclusion criteria. These studies reported on 1973 SEEG patients and 2036 SDE patients. Our systematic review revealed SEEG was associated with 61.0% and SDE was associated with 56.4% seizure freedom after resection (WMD = +5.8%, 95% CI = 4.7-6.9%, P = .001). Furthermore, SEEG was associated with 4.8% and SDE was associated with 15.5% morbidity (WMD = -10.6%, 95% CI = -11.6 to -9.6%, P = .001). SEEG was associated with 0.2% mortality and SDE was associated with 0.4% mortality (WMD = -0.2%, 95% CI = -0.3 to -0.1%, P = .001). SIGNIFICANCE: In this systematic review of SEEG and SDE invasive monitoring techniques, SEEG was associated with fewer surgical resections yet better seizure freedom outcomes in those undergoing resections. SEEG was also associated with lower mortality and morbidity than SDE. Clinical studies directly comparing these modalities are necessary to understand the relative rates of seizure freedom, morbidity, and mortality associated with these techniques.