The effect of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes in drug-resistant epilepsy.

OBJECTIVE: The impact of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes has not been extensively evaluated outside of the original clinical trials and post-approval studies. The goal of this study was to ascertain the potential real-world effects of RNS on cognitive, psychiatric, and quality of life (QOL) outcomes in relation to seizure outcomes by examining 50 patients undergoing RNS implantation for drug-resistant epilepsy (DRE). METHODS: We performed a retrospective review of all patients treated at our institution with RNS for DRE with at least 12 months of follow-up. In addition to baseline demographic and disease-related characteristics, we collected cognitive (Full-Scale Intelligence Quotient, Verbal Comprehension, and Perceptual Reasoning Index), psychiatric (Beck Depression and Anxiety Inventory Scores), and QOL (QOLIE-31) outcomes at 6 and 12 months after RNS implantation and correlated them with seizure outcomes. RESULTS: Fifty patients (median age 39.5 years, 64% female) were treated with RNS for DRE in our institution from 2005 to 2020. Of the 37 of them who had well-documented pre and post-implantation seizure diaries, the 6-month median seizure frequency reduction was 88%, the response rate (50% or greater seizure frequency reduction) was 78%, and 32% of patients were free of disabling seizures in this timeframe. There was no statistically significant difference at a group level in any of the evaluated cognitive, psychiatric, and QOL outcomes at 6 and 12 months post-implantation compared to the pre-implantation baseline, irrespective of seizure outcomes, although a subset of patients experienced a decline in mood or cognitive variables. SIGNIFICANCE: Responsive neurostimulation does not appear to have a statistically significant negative or positive impact on neuropsychiatric and psychosocial status at the group level. We observed significant variability in outcome, with a minority of patients experiencing worse behavioral outcomes, which seemed related to RNS implantation. Careful outcome monitoring is required to identify the subset of patients experiencing a poor response and to make appropriate adjustments in care.

Concurrent EEG monitoring helps interpret neuropsychological testing results in patients with epilepsy.

OBJECTIVE: We sought to determine if global cognitive function in patients with epilepsy (PWE) differs when electroencephalographic (EEG) abnormalities are present during concurrent neuropsychological (NP) evaluation. METHODS: We explored the association between subclinical epileptiform discharges (sEDs) and interictal epileptiform discharges (IEDs) and global aspects of cognition in 79 consecutive PWE who underwent continuous EEG monitoring during NP evaluation for diagnostic (15%) or presurgical (85%) purposes while on their standard antiseizure medication (ASM) regimens. As some researchers have suggested that the apparent link between IEDs and cognition represent epiphenomena of an underlying damaged neural substrate, we used functional status as a stratifying covariate to allow us to address this position. RESULTS: Despite being on their standard ASM regimen, EEG was abnormal in 68% of patients. Epileptiform abnormalities (IEDs, sEDs, or both) were seen in isolation or coupled with diffuse or focal slowing in 38% of patients. Individuals with IEDs occurring during their NP evaluation demonstrated poorer scores in attention/working memory (forward and backward digit span), processing speed (symbol searching and coding), and speeded components of language (semantic fluency) tests compared with those with normal EEG tracings matched by their real-world, functional status. In two high functioning patients, performance was significantly better when these individuals were tested in the absence of IEDs, with performances appearing invalid when tested during periods of IED activity. No significant association was found between NP performance and nonepileptiform EEG abnormalities. SIGNIFICANCE: A substantial proportion of PWE undergoing NP evaluation manifest concurrent EEG abnormalities, with epileptiform abnormalities associated with poorer global cognitive performance. As this pattern was observed regardless of functional status, this association appears to represent more than unrelated features coincidentally shared by the lowest functioning cohort. Coupled with our individual case data, our findings suggest that NP testing may be adversely affected by IEDs and sEDs going unrecognized in the absence of simultaneous EEG recordings, and set the stage for future studies to definitively establish this possible relationship.

Selective Posterior Cerebral Artery Wada Better Predicts Good Memory and Naming Outcomes Following Selective Stereotactic Thermal Ablation for Medial Temporal Lobe Epilepsy Than Internal Carotid Artery Wada.

The conventional intracarotid amobarbital (Wada) test has been used to assess memory function in patients being considered for temporal lobe epilepsy (TLE) surgery. Minimally invasive approaches that target the medial temporal lobe (MTL) and spare neocortex are increasingly used, but a knowledge gap remains in how to assess memory and language risk from these procedures. We retrospectively compared results of two versions of the Wada test, the intracarotid artery (ICA-Wada) and posterior cerebral artery (PCA-Wada) approaches, with respect to predicting subsequent memory and language outcomes, particularly after stereotactic laser amygdalohippocampotomy (SLAH). We included all patients being considered for SLAH who underwent both ICA-Wada and PCA-Wada at a single institution. Memory and confrontation naming assessments were conducted using standardized neuropsychological tests to assess pre- to post-surgical changes in cognitive performance. Of 13 patients who initially failed the ICA-Wada, only one patient subsequently failed the PCA-Wada (p=0.003, two-sided binomial test with p 0 =0.5) demonstrating that these tests assess different brain regions or networks. PCA-Wada had a high negative predictive value for the safety of SLAH, compared to ICA-Wada, as none of the patients who underwent SLAH after passing the PCA-Wada experienced catastrophic memory decline (0 of 9 subjects, p <.004, two-sided binomial test with p 0 =0.5), and all experienced a good cognitive outcome. In contrast, the single patient who received a left anterior temporal lobectomy after failed ICA- and passed PCA-Wada experienced a persistent, near catastrophic memory decline. On confrontation naming, few patients exhibited disturbance during the PCA-Wada. Following surgery, SLAH patients showed no naming decline, while open resection patients, whose surgeries all included ipsilateral temporal lobe neocortex, experienced significant naming difficulties (Fisher's exact test, p <.05). These findings demonstrate that (1) failing the ICA-Wada falsely predicts memory decline following SLAH, (2) PCA-Wada better predicts good memory outcomes of SLAH for MTLE, and (3) the MTL brain structures affected by both PCA-Wada and SLAH are not directly involved in language processing.

Pragmatic deficits and social impairment in children with ADHD.

BACKGROUND: Impaired social functioning has been well documented in individuals with attention-deficit/hyperactivity disorder (ADHD). Existing treatments for ADHD are effective for managing core symptoms, but have limited effectiveness at improving social skills, suggesting that social deficits in ADHD may not be directly related to core symptoms of the disorder. Language problems are also common in ADHD, with accumulating evidence of pragmatic language difficulties. Pragmatic deficits are associated with social impairment in several neurodevelopmental disorders. This study systematically examined pragmatic language functioning in children with ADHD and whether social impairment in ADHD is mediated by pragmatic deficits. METHOD: Sixty-three children (28 ADHD; 35 typically developing), ages 7-11 years, underwent a comprehensive assessment of pragmatic language, including parent ratings, standardized tests, and a narrative task. Parents also rated children's social skills on the Social Skills Improvement System. RESULTS: Children with ADHD had poorer pragmatic language skills relative to peers across all measures, even after controlling for general language abilities. Furthermore, pragmatic abilities as measured by parent ratings, mediated the relation between ADHD and social skills. CONCLUSIONS: Pragmatic language skills are impaired in many children with ADHD and may partially account for high rates of social impairment. Implications for treatment and possible prevention of social problems in children with ADHD are discussed.

Patients with Cognitive Impairment in Parkinson's Disease Benefit from Deep Brain Stimulation: A Case-Control Study.

Background: Deep brain stimulation (DBS) for Parkinson's disease (PD) is generally contraindicated in persons with dementia but it is frequently performed in people with mild cognitive impairment or normal cognition, and current clinical guidelines are primarily based on these cohorts. Objectives: To determine if moderately cognitive impaired individuals including those with mild dementia could meaningfully benefit from DBS in terms of motor and non-motor outcomes. Methods: In this retrospective case-control study, we identified a cohort of 40 patients with PD who exhibited moderate (two or more standard deviations below normative scores) cognitive impairment (CI) during presurgical workup and compared their 1-year clinical outcomes to a cohort of 40 matched patients with normal cognition (NC). The surgery targeted subthalamus, pallidus or motor thalamus, in a unilateral, bilateral or staged approach. Results: At preoperative baseline, the CI cohort had higher Unified Parkinson's Disease Rating Scale (UPDRS) subscores, but similar levodopa responsiveness compared to the NC cohort. The NC and CI cohorts demonstrated comparable degrees of postoperative improvement in the OFF-medication motor scores, motor fluctuations, and medication reduction. There was no difference in adverse event rates between the two cohorts. Outcomes in the CI cohort did not depend on the target, surgical staging, or impaired cognitive domain. Conclusions: Moderately cognitively impaired patients with PD can experience meaningful motor benefit and medication reduction with DBS.

Electrical Wada for pre-surgical memory testing: a case report.

We report a case study of a surgical candidate, a 51-year-old woman with left temporal lobe epilepsy, who failed a left injection intracarotid amobarbital procedure (e.g., Wada test), scoring 0 of 8 items. This raised concerns for postoperative memory decline. However, the patient was uninterested in a neuromodulatory approach and wished to be reconsidered for surgery. A stereotactic laser amygdalohippocampotomy (SLAH) was considered, encouraging the need for an alternative test to evaluate risk of memory decline. We developed a novel approach to testing memory during stimulation of a depth electrode implanted in the hippocampus, i.e., an electric Wada. During multiple stimulation trials across a range of amplitudes, the patient scored up to 8 of 8 items, which suggested strong contralateral memory support. The surgical team proceeded with a radiofrequency ablation and a subsequent SLAH. The patient remains seizure-free at 12 months post SLAH with no evidence of verbal or visuospatial memory decline based on a post-surgical neuropsychological battery. We believe that this case study provides a proof of concept for the feasibility and possible utility of an electric version of the Wada procedure. Future studies are needed to develop an optimal paradigm and to validate this approach.

Patient-Reported Outcomes Measurement Information System (PROMIS) Assessment of Non-Motor Features in Deep Brain Stimulation Candidates: Relationship to the Beck Depression and Anxiety Inventories.

OBJECTIVE: To compare Patient-Reported Outcomes Measurement Information System (PROMIS) measures of depression and anxiety to the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and explore patterns of selected PROMIS measures in patients undergoing evaluation for Deep Brain Stimulation (DBS). METHOD: BDI-II, BAI, and seven PROMIS measures were administered to 163 DBS candidates with diagnoses of Parkinson Disease (PD, n = 102), Essential Tremor (ET, n = 45), or Dystonia (n = 16). RESULTS: Elevated PROMIS Depression using BDI-II Crosswalk equivalents predicted elevated BDI-II with 63% sensitivity and 94% specificity. On other PROMIS measures, 69 patients (42%) reported low Physical Function (T ≤ 40) with Pain Interference being the next most frequent abnormal score (n = 51, 31%). Group differences were present for PROMIS Physical Function, Sleep Disturbance, and Pain. CONCLUSIONS: These preliminary findings provide initial support for PROMIS Depression to assess mood disturbance in DBS candidates, and characterize other PROMIS measures in DBS candidates including group differences reflecting disease specific contribution to Quality of Life.

NIH Toolbox Picture Sequence Memory Test for Assessing Clinical Memory Function: Diagnostic Relationship to the Rey Auditory Verbal Learning Test.

BACKGROUND: The NIH Cognitive Toolbox Picture Sequence Memory Test (PSMT) was developed as a measure of learning ability. PSMT use in clinical populations is only beginning to be investigated. METHOD: PSMT performance was analyzed in a retrospective series of 221 patients referred to either the Deep Brain Stimulation Clinic (n = 128) for presurgical evaluation, or to the Cognitive Screening Clinic (n = 93). Patients were also administered the Rey Verbal Auditory Verbal Learning test (AVLT). In addition to correlation between measures, classification agreement was examined based upon performance ratings of normal (>16th percentile), borderline (5-16th percentile), or impaired (<5th percentile). RESULTS: Correlation between measures was significant (r = 0.48, p < .0001), with classification agreement of 62% (weighted Kappa = 0.43). For patients with valid PVT scores (n = 147), correlation between tests was 0.67 (p < .0001) with a classification agreement of 72% (weighted Kappa = 0.44). Multiple level likelihood ratios (LRs) relating PSMT to various dichotomous AVLT learning classifications were modest, with the largest group LR obtained for impaired PSMT increasing the likelihood of obtaining impaired AVLT by 7.62 (95% CI = 3.54-16.42). CONCLUSION: Despite significant correlations between measures, the NIH Toolbox PSMT and AVLT learning score often generate different interpretive results. Impaired PSMT appears better at predicting impaired AVLT performance rather than predicting combined borderline/impaired AVLT performance. Ultimately, individual clinicians will need to determine whether the PSMT can be used independently without other memory tests in the clinical environment in which they practice while further validation studies are performed.

Childhood stimulant treatment and teen depression: is there a relationship?

Recent preclinical data have raised the possibility that prepubertal treatment of attention-deficit/hyperactivity disorder (ADHD) with stimulant medication might increase risk for later depression. The current longitudinal study investigated whether children with ADHD who were treated with stimulant medication displayed heightened levels of adolescent depression. Adolescents diagnosed with ADHD during childhood who had received a minimum of 1 year of treatment with stimulant medication were compared to adolescents with a childhood history of ADHD who were never treated with stimulants and a demographically matched comparison group on self-reports of depressive symptoms and diagnoses of depressive disorders. Both subgroups with childhood ADHD reported significantly higher dimensional ratings of depression and categorical rates of depressive disorders relative to the comparison group (all p<0.05), yet those who were and were not medicated did not differ from one another. Results indicate that, while childhood ADHD increases risk for adolescent depression, stimulant treatment for ADHD neither heightens nor protects against such risk.