Racial disparities in the utilization of invasive neuromodulation devices for the treatment of drug-resistant focal epilepsy.

Racial disparities affect multiple dimensions of epilepsy care including epilepsy surgery. This study aims to further explore these disparities by determining the utilization of invasive neuromodulation devices according to race and ethnicity in a multicenter study of patients living with focal drug-resistant epilepsy (DRE). We performed a post hoc analysis of the Human Epilepsy Project 2 (HEP2) data. HEP2 is a prospective study of patients living with focal DRE involving 10 sites distributed across the United States. There were no statistical differences in the racial distribution of the study population compared to the US population using census data except for patients reporting more than one race. Of 154 patients enrolled in HEP2, 55 (36%) underwent invasive neuromodulation for DRE management at some point in the course of their epilepsy. Of those, 36 (71%) were patients who identified as White. Patients were significantly less likely to have a device if they identified solely as Black/African American than if they did not (odds ratio = .21, 95% confidence interval = .05-.96, p = .03). Invasive neuromodulation for management of DRE is underutilized in the Black/African American population, indicating a new facet of racial disparities in epilepsy care.

Prediction tools and risk stratification in epilepsy surgery.

OBJECTIVE: This study was undertaken to conduct external validation of previously published epilepsy surgery prediction tools using a large independent multicenter dataset and to assess whether these tools can stratify patients for being operated on and for becoming free of disabling seizures (International League Against Epilepsy stage 1 and 2). METHODS: We analyzed a dataset of 1562 patients, not used for tool development. We applied two scales: Epilepsy Surgery Grading Scale (ESGS) and Seizure Freedom Score (SFS); and two versions of Epilepsy Surgery Nomogram (ESN): the original version and the modified version, which included electroencephalographic data. For the ESNs, we used calibration curves and concordance indexes. We stratified the patients into three tiers for assessing the chances of attaining freedom from disabling seizures after surgery: high (ESGS = 1, SFS = 3-4, ESNs > 70%), moderate (ESGS = 2, SFS = 2, ESNs = 40%-70%), and low (ESGS = 2, SFS = 0-1, ESNs < 40%). We compared the three tiers as stratified by these tools, concerning the proportion of patients who were operated on, and for the proportion of patients who became free of disabling seizures. RESULTS: The concordance indexes for the various versions of the nomograms were between .56 and .69. Both scales (ESGS, SFS) and nomograms accurately stratified the patients for becoming free of disabling seizures, with significant differences among the three tiers (p < .05). In addition, ESGS and the modified ESN accurately stratified the patients for having been offered surgery, with significant difference among the three tiers (p < .05). SIGNIFICANCE: ESGS and the modified ESN (at thresholds of 40% and 70%) stratify patients undergoing presurgical evaluation into three tiers, with high, moderate, and low chance for favorable outcome, with significant differences between the groups concerning having surgery and becoming free of disabling seizures. Stratifying patients for epilepsy surgery has the potential to help select the optimal candidates in underprivileged areas and better allocate resources in developed countries.

Temporo-Parietal Extraventricular Approach for Deep Brain Stimulation Targeting the Anterior Nucleus of the Thalamus: Institutional Experience.

BACKGROUND AND OBJECTIVES: The anterior nucleus of the thalamus (ANT) is a common target for deep brain stimulation (DBS) for drug-resistant epilepsy (DRE). However, the surgical approach to the ANT remains challenging because of its unique anatomy. This study aims to summarize our experience with the posterior temporo-parietal extraventricular (TPEV) approach targeting the ANT for DBS in DRE. METHODS: We performed a retrospective analysis of patients with DRE who underwent ANT-DBS using the TPEV approach between January 2011 and February 2021. Subjects with at least 6-month follow-up were eligible. The final lead position and number of active contacts targeting the anteroventral nucleus (AV) of the ANT were assessed using Lead-DBS. Mean seizure frequency reduction percentage and responder rate (≥50% decrease in seizure frequency) were determined. RESULTS: Thirty-one patients (mean age: 32.9 years; 52% female patients) were included. The mean follow-up period was 27.6 months ± 13.9 (29, 16-36). The mean seizure frequency reduction percentage was 65% ± 26 (75, 50-82). Twenty-six of 31 participants (83%) were responders, P < .001. Two subjects (6%) were seizure-free for at least 6 months at the last evaluation. Antiepileptic drugs dose and/or number decreased in 17/31 subjects (55%). The success rate for placing at least 1 contact at AV was 87% (27/31 patients) bilaterally. The number of active contacts at the AV was significantly greater in the responder group, 3.1 ± 1.3 (3, 2-4) vs 1.8 ± 1.1 (2, 1-2.5); P = .041 with a positive correlation between the number of active contacts and seizure reduction percentage; r = 0.445, R 2 = 0.198, P = .012. CONCLUSION: The TPEV trajectory is a safe and effective approach to target the ANT for DBS. Future studies are needed to compare the clinical outcomes and target accuracy with the standard approaches.

Responsive neurostimulation with low-frequency stimulation.

Deep brain stimulation and responsive neurostimulation (RNS) use high-frequency stimulation (HFS) per the pivotal trials and manufacturer-recommended therapy protocols. However, not all patients respond to HFS. In this retrospective case series, 10 patients implanted with the RNS System were programmed with low-frequency stimulation (LFS) to treat their seizures; nine of these patients were previously treated with HFS (100 Hz or greater). LFS was defined as frequency < 10 Hz. Burst duration was increased to at least 1000 ms. With HFS, patients had a median seizure reduction (MSR) of 13% (interquartile range [IQR] = -67 to 54) after a median of 19 months (IQR = 8-49). In contrast, LFS was associated with a 67% MSR (IQR = 13-95) when compared to HFS and 76% MSR (IQR = 43-91) when compared to baseline prior to implantation. Charge delivered per hour and pulses per day were not significantly different between HFS and LFS, although time stimulated per day was longer for LFS (228 min) than for HFS (7 min). There were no LFS-specific adverse effects reported by any of the patients. LFS could represent an alternative, effective method for delivering stimulation in focal drug-resistant epilepsy patients treated with the RNS System.

Invasive neuromodulation for epilepsy: Comparison of multiple approaches from a single center.

BACKGROUND: Drug-resistant epilepsy (DRE) patients not amenable to epilepsy surgery can benefit from neurostimulation. Few data compare different neuromodulation strategies. OBJECTIVE: Compare five invasive neuromodulation strategies for the treatment of DRE: anterior thalamic nuclei deep brain stimulation (ANT-DBS), centromedian thalamic nuclei DBS (CM-DBS), responsive neurostimulation (RNS), chronic subthreshold stimulation (CSS), and vagus nerve stimulation (VNS). METHODS: Single center retrospective review and phone survey for patients implanted with invasive neuromodulation for 2004-2021. RESULTS: N = 159 (ANT-DBS = 38, CM-DBS = 19, RNS = 30, CSS = 32, VNS = 40). Total median seizure reduction (MSR) was 61 % for the entire cohort (IQR 5-90) and in descending order: CSS (85 %), CM-DBS (63 %), ANT-DBS (52 %), RNS (50 %), and VNS (50 %); p = 0.07. The responder rate was 60 % after a median follow-up time of 26 months. Seizure severity, life satisfaction, and quality of sleep were improved. Cortical stimulation (RNS and CSS) was associated with improved seizure reduction compared to subcortical stimulation (ANT-DBS, CM-DBS, and VNS) (67 % vs. 52 %). Effectiveness was similar for focal epilepsy vs. generalized epilepsy, closed-loop vs. open-loop stimulation, pediatric vs. adult cases, and high frequency (>100 Hz) vs. low frequency (<100 Hz) stimulation settings. Delivered charge per hour varied widely across approaches but was not correlated with improved seizure reduction. CONCLUSIONS: Multiple invasive neuromodulation approaches are available to treat DRE, but little evidence compares the approaches. This study used a uniform approach for single-center results and represents an effort to compare neuromodulation approaches.

Anterior Nucleus of the Thalamus Deep Brain Stimulation with Concomitant Vagus Nerve Stimulation for Drug-Resistant Epilepsy.

BACKGROUND: The Food and Drug Administration approved the deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) as an adjunctive therapy for drug-resistant epilepsy (DRE) in the United States in 2018. The DBS Therapy for Epilepsy Post-Approval Study is further evaluating the safety and effectiveness of ANT-DBS among different patients' groups. For this study, devices for vagus nerve stimulation (VNS) must be removed prior to enrolment. OBJECTIVE: To investigate the outcomes of concomitant ANT-DBS and VNS treatment for DRE. METHODS: A retrospective analysis was performed for 33 patients who underwent ANT-DBS using previous VNS to define distinct subgroups: standard ANT-DBS (9 subjects), ANT-DBS with functional VNS (12 subjects), and ANT-DBS with the VNS implantable pulse generator explanted or turned off at the time of the DBS (12 subjects). Effectiveness and safety data were analyzed across the whole population and among subgroups. RESULTS: A mean decrease in seizure frequency of 55% was observed after a mean follow-up of 25.5 mo. Approximately 67% of patients experienced ≥50% reduction in seizure frequency. Seizure reduction percentage was not significantly different among groups. Approximately 50% of subjects with no appreciable improvement and 75% of those who showed benefit after VNS (including improvement in seizure frequency, seizure severity, and seizure duration or quality of life) achieved a seizure reduction ≥50% after ANT-DBS surgery. There were no complications related to concomitant VNS and ANT-DBS. CONCLUSION: ANT-DBS for DRE provides excellent results despite previous and ongoing VNS therapy. Removal of VNS does not appear to be necessary before ANT-DBS.

Centromedian thalamic nucleus with or without anterior thalamic nucleus deep brain stimulation for epilepsy in children and adults: A retrospective case series.

The centromedian (CM) and anterior nucleus of the thalamus (ANT) are deep brain stimulation (DBS) targets for management of generalized, and focal drug resistant epilepsy (DRE), respectively. We report on a single center retrospective case series of 16 children and adults with DRE who underwent CM with simultaneous ANT (69 %) or CM without simultaneous ANT DBS (31 %). Seizure frequency, epilepsy severity, life satisfaction, and quality of sleep before and after DBS were compared. Baseline median seizure frequency was 323 seizures per month (IQR, 71-563 sz/mo). Median follow up time was 80 months (IQR 37-97 mo). Median seizure frequency reduction was 58 % (IQR 13-87 %, p = 0.002). Ten patients (63 %) reported ≥50 % seizure frequency reduction. Median seizure frequency reduction and responder rate were not significantly different for CM + ANT versus CM only. Seizure severity and life satisfaction were significantly improved. Three patients (19 %) developed device-related side effects, 2 of them (12.5 %) required surgical intervention. In a heterogenous population of children and adults with generalized, multifocal, posterior onset, and poorly localized DRE, CM with or without ANT DBS is feasible, relatively safe and is associated with reduced seizure frequency and severity, as well as improved life satisfaction.

Cortical and thalamic electrode implant followed by temporary continuous subthreshold stimulation yields long-term seizure freedom: A case report.

Neuromodulation strategies that target the epileptogenic network are options for treating focal drug-resistant epilepsy. These brain stimulation approaches include responsive neurostimulation and more recently, chronic subthreshold stimulation. Long-term seizure freedom with neuromodulation is uncommon. Seizure control typically requires ongoing froms of electrical stimulation. Here, we present the case of a patient implanted with three cortical electrodes targeting the inferior frontal lobe, insula, and one subcortical electrode targeting the ipsilateral anterior thalamic nucleus. This patient received continuous subthreshold electrical stimulation to the frontal electrodes for 7 months, at which time stimulation was inadvertently stopped. He has now been free of seizures for 42 months. This case suggests the possibility that neuromodulation can alter epileptogenic networks and lead to seizure freedom without ongoing electrical stimulation.

Correlates of depressive symptoms among older adults living with HIV.

OBJECTIVE: To establish the correlates of depressive symptoms among Mexican community-dwelling older people living with HIV (PLWHIV). METHODS: Cross-sectional, 2-center study of 328 participants aged 50 or older being followed in the outpatient HIV clinics of 2 tertiary care hospitals in Mexico. Data were obtained through a comprehensive geriatric assessment. Multivariate logistic regression analyses were performed to identify the correlates of depressive symptoms. RESULTS: Mean age of participants was 58.4 years (SD = 7.2), and 82.9% were men. Depressive symptoms were present in 15.9% of participants. The multivariate logistic regression models showed that frailty and disability for activities of daily living were both independently associated with depressive symptoms. CONCLUSION: Frailty and disability were independent correlates of depressive symptoms in older PLWHIV. Future studies should attempt to explore the role of physical frailty and disability on psychosocial morbidity among older PLWHIV.

Osteocalcin levels in a healthy population of western Mexico and comparison with populations from around the world. / Niveles de referencia de osteocalcina en población sana de México.

Introduction: Osteocalcin has been shown to have an inverse relationship with blood glucose, insulin resistance and adiposity. Objective: To determine osteocalcin normal serum concentration in Mexican healthy adults and compare it with values reported in other populations. Method: Carboxylated and undercarboxylated osteocalcin serum concentrations were determined in 100 healthy adults by means of enzyme immunoassay; osteocalcin total concentration was calculated. A descriptive comparison was made with other populations' values reported in the literature. Results: Carboxylated and undercarboxylated osteocalcin median concentrations were 3.22 ng/mL and 1.61 ng/mL, respectively. Mean total osteocalcin was 7.40 ± 5.11 ng/mL. There was no significant difference between the osteocalcin values in our population and those of populations where similar quantification methods to ours were used. Conclusion: Osteocalcin total serum concentration mean in the analyzed population was 7.40 ng/mL. There are subtle variations between populations that are attributable to genetic and population factors; however, the quantification method was the only variable that was shown to significantly influence on osteocalcin levels in healthy populations.

Introducción: Se ha demostrado que la osteocalcina tiene una relación inversa con la glucemia, resistencia a la insulina y adiposidad. Objetivo: Determinar la concentración sérica normal de osteocalcina en adultos sanos mexicanos y compararlos con los reportados en otras poblaciones. Método: Se determinó la concentración sérica de osteocalcina carboxilada y pobremente carboxilada en 100 adultos sanos mediante inmunoensayo enzimático; se calculó la concentración de osteocalcina total. Se hizo una comparación descriptiva con valores de otras poblaciones reportadas en la literatura. Resultados: Las medianas de las concentraciones de osteocalcina carboxilada y pobremente carboxilada fueron 3.22 ng/mL y 1.61 ng/mL, respectivamente; la media de osteocalcina total fue 7.40 ± 5.11 ng/mL. No hubo diferencia significativa entre los valores de osteocalcina total en nuestra población y los de poblaciones en las que se utilizaron métodos de cuantificación similares al nuestro. Conclusión: La concentración sérica promedio de osteocalcina total en la población analizada fue de 7.40 ng/mL. Las variaciones sutiles entre poblaciones son atribuibles a factores genéticos y poblacionales, sin embargo, el método de cuantificación fue el único que se comprobó influye significativamente en los niveles de osteocalcina en poblaciones sanas.

Association Between Frailty and HIV-Associated Neurodegenerative Disorders Among Older Adults Living with HIV.

The population of aging adults living with human immunodeficiency virus (HIV) is growing worldwide and evidence suggests that frailty occurs prematurely among them. In turn, frailty has been associated with cognitive decline. It is unknown, however, if people with both frailty and HIV infection have a higher risk of cognitive impairment compared with nonfrail HIV-infected persons. Therefore, the main objective of this study was to determine the association between the phenotype of frailty and HIV-associated neurocognitive disorders (HAND) among adults aged 50 years or older living with HIV/AIDS. A cross-sectional study was conducted on 206 adults living with HIV receiving care in a university-affiliated tertiary care hospital in Mexico City. Frailty was defined as per the Fried criteria. The presence of HAND was established according to the Antinori criteria: HIV-associated asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorder (MND), or cognitively nonimpaired. Multinomial logistic regression models were used to test the independent association between frailty and HAND adjusting for potential confounders. Mean age of participants was 60.5 ± 6.3 years and 84.9% were male. Prevalence of HAND and frailty phenotype was 66.0% and 2.9%, respectively. The unadjusted analysis showed that both prefrail and frail statuses were associated with MND but not with ANI. However, after adjustment, the association with MND remained significant only among prefrail participants and no longer for frail persons (risk ratio [RR] = 5.7, 95% confidence intervals [CI] 1.09-29.82; p = .039 and RR = 18.3, 95% CI 0.93-362.6; p = .056, respectively). Prefrailty is associated with symptomatic neurocognitive disorders in older adults living with HIV. The spectrum of the frailty phenotype in this already vulnerable population should serve as an indicator of concomitant cognitive decline.

Association of A-604G ghrelin gene polymorphism and serum ghrelin levels with the risk of obesity in a mexican population.

Obesity is a metabolic disorder that has a multifactorial etiology and affects millions of people worldwide. Ghrelin, a hormone coded by the GHRL gene, plays a role in human body composition and appetite. Single nucleotide polymorphisms (SNPs) of the GHRL gene have been associated with obesity and metabolic disorders. To evaluate the association of A-604G SNP of GHRL promoter region with serum ghrelin levels and the risk of obesity in a Mexican population. Two hundred and fifty individuals were enrolled and classified as obese or control subjects (CS) according to BMI. DNA samples, anthropometric measurements and biochemical parameters were obtained from all subjects. The A-604G SNP was genotyped using PCR-RFLPs technique. Ghrelin levels were measured using a commercial enzyme immunoassay. The G/G genotype was more frequent among obese individuals (p < 0.0001) when compared to CS. The G/A genotype and A allele were associated with protection against obesity (OR 0.29, p < 0.0001; OR 0.39, p < 0.0001 respectively), the A allele remained significant after adjusting for age and gender (OR: 0.25, p < 0.0001). Serum ghrelin levels were higher in obese patients (p = 0.004) than in CS, however, significance was lost after adjustment for age (p = 0.088). The G/G genotype was associated with higher levels of serum ghrelin (p = 0.02) independently of the effect of age. The G/G genotype of the A-604G SNP in the GHRL gene is associated with altered serum ghrelin levels and obesity. The A allele was also associated with protection against obesity in this study.

Serum levels of undercarboxylated osteocalcin are related to cardiovascular risk factors in patients with type 2 diabetes mellitus and healthy subjects.

AIM: To determine a potential relationship between serum undercarboxylated (ucOC) concentration and cardiovascular risk factors in type 2 diabetes (T2D) patients and healthy subjects (HS). METHODS: A cross-sectional study was conducted on 140 subjects classified into two groups, 70 with T2D and 70 HS. Medical history and physical examination with anthropometric measurements were obtained from all subjects. Body fat percentage was determined by bioelectrical impendency analysis. Serum ucOC concentration was determined by enzyme immunoassay, while serum levels of insulin and hsCRP were obtained using high sensitivity enzyme-linked immunosorbent assay. Insulin resistance was determined using the homeostasis model assessment-IR. Lipid profile [triglycerides, total cholesterol (TC), high-density lipoproteins (HDL-c), low density lipoproteins (LDL-c), very low-density lipoproteins] was determined by spectrophotometry and standard formulas when applicable. RESULTS: The T2D patient group showed significantly higher values of waist circumference, waist-to-hip ratio, systolic blood pressure (SBP), diastolic blood pressure (DBP), current smoking, and alcohol use when compared to the HS group (P < 0.05). We observed a significantly lower serum ucOC concentration in T2D than in HS (1.5 ± 1.4 vs 2.3 ± 1.8, P < 0.05). In the whole study population, ucOC concentration was inversely correlated with body mass index (BMI) (r = -0.236, P < 0.05), fasting plasma glucose (r = -0.283, P < 0.01) and HDL-c (r = -0.255, P < 0.05); and positively correlated with LDL-c/HDL-c ratio (r = 0.306, P < 0.05) and TC/HDL-c ratio (r = 0.284, P < 0.05). In the T2D group, serum ucOC concentration was inversely correlated with BMI (r = -0.310, P < 0.05) and body-fat percentage (r = -0.311, P < 0.05), and positively correlated with DBP (r = 0.450, P < 0.01). In HS group a positive correlation between serum levels of ucOC and SBP (r = 0.277, P < 0.05) was observed. CONCLUSION: Serum ucOC is a potential marker for cardiovascular risk in Mexicans because it is related to adiposity parameters, blood pressure and lipid profile.

Preoperative Ultrasonographic Prediction of Hamstring Tendon Diameter for Anterior Cruciate Ligament Repair.

The incidence of anterior cruciate ligament (ACL) injuries is rising every year. The autologous hamstring tendon graft, using semitendinosus tendon (SMT) and gracilis tendon (GR), is a common repair technique in the management of ACL injuries due to its multiple advantages. Using a final graft with a minimum diameter of 8 mm is necessary to avoid graft failure. The aim of this study was to find a correlation between preoperative ultrasound (USG) measurement of the SMT and GR tendon diameters (SMTd and GRd) and their actual diameters measured during the grafting procedure. In the present study, 33 male patients aged between 16 and 43 years with ACL injury that required grafting were enrolled. Before the grafting procedure, we sonographically measured the SMTd, GRd, and calculated the hamstring tendon diameter (SMTd + GRd) as the sum of these two. During surgery, we obtained the SMTd, GRd, and SMTd + GRd; we also obtained the length of both tendons and the final graft diameter (FGd). We then compared the obtained values. Mean age was 25.6 ± 7.9 years in our study population. The mean SMTd, GRd, and SMTd + GRd obtained by USG versus transoperatively were 4.9 versus 4.7 mm, 4.3 versus 3.8 mm, and 9.3 versus 8.6 mm, respectively. The mean of FGd was 8.4 mm and the mean length of both tendons was 14.2 cm. The GRd obtained by USG positively correlated with SMTd, SMT tendon length, GRd, and SMTd + GRd (r = 0.460, 0.404, 0.411, and 0.508, respectively). USG-obtained GRd predicts a final tendon diameter < 8 mm (high risk of failure) with a sensitivity, specificity, positive predictive value, and negative predictive value of 100, 54, 28 and 100%, respectively, using 4.5 mm as cutoff. Of all obtained grafts, 85% were deemed adequate (≥ 8 mm) using transoperative measurement, while 91% were ≥ 8 mm using USG measurement. The USG measurement of hamstring tendons is a useful method to predict their transoperative diameter. GRd obtained by USG is the best predictor of transoperative GRd and SMTd + GRd.

Molecular profiling of a simple rat model of open tibial fractures with hematoma and periosteum disruption.

Bone fractures are a worldwide public health concern. Therefore, improving understanding of the bone healing process at a molecular level, which could lead to the discovery of potential therapeutic targets, is important. In the present study, a model of open tibial fractures with hematoma disruption, periosteal rupture and internal fixation in 6-month-old male Wistar rats was established, in order to identify expression patterns of key genes and their protein products throughout the bone healing process. A tibial shaft fracture was produced using the three-point bending technique, the hematoma was drained through a 4-mm incision on the medial aspect of the tibia and the fracture stabilized by inserting a needle into the medullary canal. Radiographs confirmed that the induced fractures were diaphyseal and this model was highly reproducible (kappa inter-rater reliability, 0.82). Rats were sacrificed 5, 14, 21, 28 and 35 days post-fracture to obtain samples for histological, immunohistochemical and molecular analysis. Expression of interleukin-1ß (Il-1ß), transforming growth factor-ß2 (Tgf-ß2), bone morphogenetic protein-6 (Bmp-6), bone morphogenetic protein-7 (Bmp-7) and bone γ-carboxyglutamic acid-containing protein (Bglap) genes was determined by reverse transcription quantitative polymerase chain reaction and protein expression was evaluated by immunohistochemistry, while histological examination allowed characterization of the bone repair process. Il-1ß showed a biphasic expression, peaking 5 and 28 days post-fracture. Expression of Tgf-ß2, Bmp-6 and Bmp-7 was restricted to the period 21 days post-fracture. Bglap expression increased gradually, peaking 21 days post-fracture, although it was expressed in all evaluated stages. Protein expression corresponded with the increased expression of their corresponding genes. In conclusion, a clear and well-defined expression pattern of the evaluated genes and proteins was observed, where their maximal expression correlated with their known participation in each stage of the bone healing process.