Papers by Kimford J Meador
Neurology, Oct 1, 1991
We investigated neuropsychological effects of carbamazepine and phenytoin in 21 healthy adults us... more We investigated neuropsychological effects of carbamazepine and phenytoin in 21 healthy adults using a randomized, double-blind, double-crossover design and treating each subject with each drug for 1 month, separated by a 1-month washout. There were neuropsychological evaluations at baseline, the end of each treatment month, and 1 month after the last treatment phase.
Neurology, Dec 9, 2010
Background: Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuro... more Background: Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers. Objective: To establish whether TPM-induced neuropsychological impairment emerges in a dosedependent fashion and whether early cognitive response (6-week) predicts later performance (24-week). Methods: Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, doseranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis. Results: Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p Ͻ 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks. Conclusions: Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk. Classification of evidence: This study provides Class II evidence that TPM-induced cognitive impairment is dose-dependent with statistically significant effects at 192 mg/day (p Ͻ 0.01) and 384 mg/day (p Ͻ 0.0001). Neurology ® 2011;76:131-137 GLOSSARY AE ϭ adverse event; AED ϭ antiepileptic drug; BMI ϭ body mass index; CNTB ϭ Computerized Neuropsychological Test Battery; IVRS ϭ Interactive Voice Response System; NNH ϭ number needed to harm; RCI ϭ reliable change index; TPM ϭ topiramate.
Neurology, Apr 6, 2015
OBJECTIVE: To record bedside SSEP from intracranial electrodes BACKGROUND: SSEP is an established... more OBJECTIVE: To record bedside SSEP from intracranial electrodes BACKGROUND: SSEP is an established neurophysiologic technique for identifying the primary somatosensory pathway recorded from surface electrodes or directly from a cortical grid during intraoperative neuromonitoring under general anesthesia. Direct recording of SSEP from intracranial electrodes in awake patients has rarely been described in the literature. DESIGN/METHODS: This was an observational study to record bedside direct cortical SSEP in awake patients without sedation. Four medically refractory localization-related epilepsy patients had suspected seizure onset zones in the frontoparietal or parietal lobe and underwent electroencephalogram (EEG) monitoring with implanted with intracranial electrodes. The median nerve and posterior tibial nerve were stimulated at 6.0-18.0 milliamps and 200 trials were averaged. The low cut filter was 30 Hertz (Hz) and the high cut filter was 3000Hz. Intracranial electrodes were referenced to a scalp electrode (Fz). RESULTS: Upper extremity SSEP were recorded directly from intracranial electrodes from all four cases with reproducible N20 latencies [18.1 - 21.4 milliseconds (ms)] and amplitudes [2.21 -21.04 microvolts (uV)]. Lower extremity SSEP were recorded in 2/4 patients with P37 latencies [37.5-40.0ms] and amplitudes [2.5-41.33uV]. A phase reversal was recorded from one patient; the other three patients did not have electrodes overlying primary motor cortex. All patients could perceive non-painful peripheral stimulation and they tolerated the procedure well. One patient had reflex sensory epilepsy and had two of his typical simple partial seizures between SSEP stimulations. After monitoring, two patients underwent focal resection and one patient had a responsive neurostimulator implanted. One patient is planning to have responsive neurostimulation implanted. CONCLUSIONS: Direct cortical bedside SSEP may be helpful in pre-surgical brain mapping for refractory epilepsy patients with seizure onset zones near the somatosensory cortex. Concurrent intracranial EEG will be analyzed for somatosensory induced band activity and its relationship to voluntary movements. Disclosure: Dr. Le has nothing to disclose. Dr. Parvizi has nothing to disclose. Dr. Meador has received personal compensation for activities on behalf the Epilepsy Study Consortium with Eisai Inc., NeuroPace, Inc., Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals as a consultant. Dr. Meador has rec
Annals of Neurology, Jan 20, 1990
Neurology, Apr 10, 2018
Objective: To use quantitative electrocorticographic (ECoG) data obtained from a responsive neuro... more Objective: To use quantitative electrocorticographic (ECoG) data obtained from a responsive neurostimulator (RNS® System, NeuroPace, Inc.) to assess the impact of interictal discharges on cognitive performance in adults with intractable focal onset epilepsy treated with responsive stimulation. Background: In a randomized controlled trial of the RNS® System, patients with mesial temporal lobe epilepsy (MTLE) had improvements in verbal memory, with maximal benefit in those with poorer baseline memory scores. However, improvements were not correlated with changes in clinical seizures. Here ECoG data were used to retrospectively assess the relationship between memory performance and interictal spikes. Design/Methods: Neuropsychological assessments were performed during a pre-implant baseline, after a blinded period, and at 1 and 2 years post-implant (Y1, Y2). Baseline memory scores were characterized as high/low using a median split for the Rey Auditory Learning Test (RAVLT). The average interictal spike rate (avg-ISR) was calculated from ECoGs stored based on time-of-day in the 3 months prior to each assessment. Pearson correlations were calculated between avg-ISR and RAVLT scores for Y1 and Y2, as well as between the change in RAVLT score and the change in avg-ISR for Y1 and Y2 compared to the blinded period. Results: MTLE patients with low baseline RAVLT scores had significant negative correlations between avg-ISR and RAVLT scores at Y1 (r=−0.59; p=0.0007; n=29) and Y2 (r=−0.42; 0.047; n=23), as well as between the change in the avg-ISR and change in RAVLT at Y1 (r=−0.47; p=0.01). Correlations were not significant between avg-ISRs and RAVLT scores for MTLE patients with high baseline scores (n=26). Significant correlations for patients with neocortical onsets were not observed (n=60). Conclusions: There is a statistically significant negative correlation between ISR and verbal memory scores in patients with MTLE and poor baseline performance. These results suggest that reduction in ISRs could improve memory performance in MTLE patients with baseline memory deficits. Study Supported by: NeuroPace, Inc. Disclosure: Dr. Meador has received research support from Sunovion Pharmaceuticals. Dr. Loring has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with NeuroPace. Dr. Loring has received personal compensation in an editorial capacity for Epilepsia and Neuropsychology Review. Dr. Loring has received research support from Medtronic. Dr. Crowder Skarpaas has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with NeuroPace. Dr. Crowder Skarpaas holds stock and/or stock options in NeuroPace, which sponsored research in which Dr. Crowder Skarpaas was involved as an investigator. Dr. Morrell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with NeuroPace. Dr. Morrell holds stock and/or stock options in NeuroPace, which sponsored research in which Dr. Morrell was involved as an investigator.
PubMed, Apr 1, 1993
Although asymmetries exist in both cerebral and somatic systems, their relationship is not well u... more Although asymmetries exist in both cerebral and somatic systems, their relationship is not well understood. One hypothesis suggests that some processes determining cerebral hemispheric dominance also affect immune systems. We employed histamine, a final common mediator for the immediate hypersensitivity immune response, to examine the relationship of skin response to cerebral lateralization (ie, left versus right brain dominance). Histamine skin wheal responses on the left and right forearms were measured using computerized planimetry in 176 consecutive patients undergoing allergy skin testing. Cerebral lateralization was determined by personal and family handedness via questionnaires. Subjects were classified as right handed (RH) with only RH relatives, RH with non-RH relatives, or non-RH (ie, left-handed or ambidextrous). Left/right arm asymmetries in wheal area were demonstrated and were related to cerebral dominance, but could not be explained by simple arm use. Right-handed subjects with only RH relatives had greater wheal size on the right arm, RH subjects with non-RH relatives had no significant left/right difference in wheal size, and non-RH subjects had greater wheal size on the left arm. Further, gender differences in these asymmetries appeared to be present for subjects with mixed cerebral dominance. The results suggest an association between process affecting cerebral and somatic asymmetries, and offer new insight into brain/body interactions.
Neurology, Feb 22, 2000
from functional MRI (fMRI) scans obtained in 12 healthy volunteers during unimanual left-and righ... more from functional MRI (fMRI) scans obtained in 12 healthy volunteers during unimanual left-and right-hand finger movements and during a verb generation language task. The language and right-hand motor asymmetry ratios were correlated (rho ϭ 0.71, p ϭ 0.005) as were the left-and right-hand ratios (rho ϭ Ϫ0.68, p ϭ 0.008). Subjects with greater relative left hemisphere lateralization of language exhibit greater relative unilateral hemisphere activation during right-hand movements.
Epilepsy & Behavior, May 1, 2021
Epilepsy is one of the most prevalent neurologic conditions, affecting almost 70 million people w... more Epilepsy is one of the most prevalent neurologic conditions, affecting almost 70 million people worldwide. In the United States, 1.3 million women with epilepsy (WWE) are in their active reproductive years. Women with epilepsy (WWE) face gender-specific challenges such as pregnancy, seizure exacerbation with hormonal pattern fluctuations, contraception, fertility, and menopause. Precision medicine, which applies state-of-the art molecular profiling to diagnostic, prognostic, and therapeutic problems, has the potential to advance the care of WWE by precisely tailoring individualized management to each patient's needs. For example, antiseizure medications (ASMs) are among the most common teratogens prescribed to women of childbearing potential. Teratogens act in a dose-dependent manner on a susceptible genotype. However, the genotypes at risk for ASM-induced teratogenic deficits are unknown. Here we summarize current challenging issues for WWE, review the state-of-art tools for clinical precision medicine approaches, perform a systematic review of pharmacogenomic approaches in management for WWE, and discuss potential future directions in this field. We envision a future in which precision medicine enables a new practice style that puts focus on early detection, prediction, and targeted therapies for WWE.
Epilepsy & Behavior, May 1, 2019
People with epilepsy are at increased risk for neuropsychological dysfunction due to multiple fac... more People with epilepsy are at increased risk for neuropsychological dysfunction due to multiple factors, of which the most amendable are antiseizure medications (ASMs). Antiseizure medication effectiveness is frequently determined by tolerability. In this study, we compared the neuropsychological effects of eslicarbazepine acetate (ESL) and carbamazepine immediate-release (CBZ) using a randomized, double-blind, crossover design in healthy volunteers with a 2-week titration and 4-week maintenance phase in each treatment arm (CBZ = 400 mg BID and ESL = 800 mg qAM). Neuropsychological testing was performed at the initial visit, repeated at 1st baseline nondrug condition, end treatment #1, 2nd nondrug condition one month after treatment #1, end treatment #2, and 3rd nondrug condition one month after treatment #2. Neuropsychological testing was conducted 2 h after morning dose and included computer (i.e., dual task test, selective attention test, symbol digit, verbal memory, visuospatial memory, and 1-& 2-back continuous performance) and noncomputer tasks (i.e., Medical College of Georgia (MCG) paragraph memory, Stroop, Symbol Digit Modalities Test, Profile of Mood States). z-Scores calculated from nondrug conditions were used to compare ESL and CBZ for the 23 completers. Follow-up analyses included individual test scores and distribution of individual raw means. Mean blood levels on test day were CBZ = 8.9 μg/ml and ESL = 15.3 μg/ml. Omnibus z-score was significantly better for ESL (p = .0001). For individual measures, executive function and selective attention tests were statistically significantly better for ESL. Individual test raw means favored ESL over CBZ on 22 of 30 measures (p = .016, 2tailed sign test). Eslicarbazepine acetate demonstrated less adverse neuropsychological effects than CBZ.
JAMA network open, Apr 13, 2021
IMPORTANCE The rapid increase of opioid-related overdoses and deaths has become a public health c... more IMPORTANCE The rapid increase of opioid-related overdoses and deaths has become a public health concern in the US. Use of prescription opioids in pregnant women has increased; results from teratogenicity studies remain controversial. OBJECTIVE To evaluate the association between maternal prescription opioid use (excluding opioid use disorders) during pregnancy and the incidence of congenital malformations.
Epilepsy & Behavior, Dec 1, 2018
Background: Laser interstitial thermal therapy (LITT) is a minimally invasive alternative with le... more Background: Laser interstitial thermal therapy (LITT) is a minimally invasive alternative with less cognitive risks compared with traditional surgery for focal drug-resistant epilepsy. Objective: We describe seizure outcomes and complications after LITT in our cohort with intractable mesial temporal lobe epilepsy (MTLE). Material and methods: We prospectively tracked Stanford's MTLE cases treated with LITT from October 2014 to October 2017. Primary endpoints were seizure outcomes by (1) Engel classification and (2) reduction in baseline seizure frequency. Secondary outcomes were postablation complications. Results: A total of 30 patients underwent selective amygdalohippocampotomy via LITT. Mesial temporal sclerosis (MTS) was present in 23/30 (77%) patients. Median follow-up was 18 ± 12 months (range: 6-44 months). Almost all 28/29 (97%) patients had N 50% reduction, and 22/29 (76%) patients had N 90% reduction in seizure frequency. Engel Class I outcome was achieved in 18/29 (62%) patients; with complete seizure freedom in 9/29 (31%) patients (Engel Class IA). Three (10%) patients have had only focal aware seizures (Engel Class 1B). Seizures only occurred with medication withdrawal in 6/29 (21%) patients (Engel Class ID). Class II was achieved by 6/29 (21%) and Class III by 5/29 (17%) patients. Complications included perioperative seizures in 10/29 (34%) and nonseizure complaints in 6/29 (21%) patients. Three (10%) patients had neurological deficits including one permanent superior quadrantanopsia, one transient trochlear, and one transient oculomotor nerve palsy. Conclusions: Overall, Engel Class I outcome was achieved in 62% of patients with MTLE, and 97% of patients achieved N 50% seizure frequency reduction. Complications were largely temporary, though there was one persistent visual field deficit. Laser ablation is well-tolerated and offers marked seizure reduction for the majority of patients.
Drug Safety, Jun 7, 2021
KEY POINTS Question. To evaluate the relationship between maternal prescription opioid use and in... more KEY POINTS Question. To evaluate the relationship between maternal prescription opioid use and incidence of neurodevelopmental disorders in children. Findings. In this retrospective cohort study, 7.6% of eligible children were exposed to prescription opioids during pregnancy. We observed no overall association between maternal prescription opioid use and the risk of neurodevelopmental disorders in children. However, significantly increased risks were observed in children with longer-term opioid exposure or high cumulative doses. Meaning. These findings suggest the need for a careful consideration of the benefits of opioid therapy during pregnancy versus potential risks of long-term neurodevelopmental disorders in children.
Clinical Neurology and Neurosurgery, Aug 1, 2022
Drug Safety, Oct 5, 2021
Prescription opioids are frequently used for pain management in pregnancy. Studies examining peri... more Prescription opioids are frequently used for pain management in pregnancy. Studies examining perinatal complications in mothers who received prescription opioids during pregnancy are still limited. The aim of this study was to assess the association of prescription opioid use and maternal pregnancy and obstetric complications. This retrospective cohort study with the Rhode Island (RI) Medicaid claims data linked to vital statistics throughout 2008–2015 included pregnant women aged 12–55 years with one or multiple live births. Women were excluded if they had cancer, opioid use disorder, or opioid dispensing prior to but not during pregnancy. Main outcomes included adverse pregnancy and obstetric complications. Marginal Structural Cox Models with time-varying exposure and covariates were applied to control for baseline and time-varying covariates. Analyses were conducted for outcomes that occurred 1 week after opioid exposure (primary) or within the same week as exposure (secondary). Sensitivity studies were conducted to assess the effects of different doses and individual opioids. Of 9823 eligible mothers, 545 (5.5%) filled one or more prescription opioid during pregnancy. Compared with those unexposed, no significant risk was observed in primary analyses, while in secondary analyses opioid-exposed mothers were associated with an increased risk of cesarean antepartum depression (HR 3.19; 95% CI 1.22–8.33), and cardiac events (HR 9.44; 95% CI 1.19–74.83). In sensitivity analyses, results are more prominent in high dose exposure and are consistent for individual opioids. Prescription opioid use during pregnancy is associated with an increased risk of maternal complications.
Applied Neuropsychology: Adult, Jul 31, 2020
Disagreements in science and medicine are not uncommon, and formal exchanges of disagreements ser... more Disagreements in science and medicine are not uncommon, and formal exchanges of disagreements serve a variety of valuable roles. As identified by a Nature Methods editorial entitled "The Power of Disagreement" (2016), disagreements bring attention to best practices so that differences in interpretation do not result from inferior data sets or confirmation bias, "prompting researchers to take a second look at evidence that is not in agreement with their hypothesis, rather than dismiss it as artifacts." Graver and Green published reasons why they disagree with a recent clinical case report and a decades old randomized control trial characterizing the effect of an acute 2 mg dosing of lorazepam on the Word Memory Test. In this article, we formally responded to their commentary to further clarify the reasons for our data interpretations. These two opposing views provide an excellent learning opportunity, particularly for students, demonstrating the importance of careful articulation of the rationale behind certain conclusions from different perspectives. We encourage careful review of the original articles being discussed so the neuropsychologists can read both positions and decide which interpretation of the findings they consider most sound.
Current Neurology and Neuroscience Reports, Jul 1, 2002
Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical ... more Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioral domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. To date, valproate is the most widely recognized AED to significantly negatively affect neurodevelopment, and demonstrates greater adverse effects than any other AEDs that have been assessed. Although some AEDs appear to have low risk (i.e., lamotrigine, levetiracetam), other AEDs have been implicated in a variety of studies detailed below, and many AEDs have not been adequately assessed. The purpose of this review article is to summarize our current understanding of the neurodevelopmental effects of AEDs.
Canadian Journal of Neurological Sciences, Aug 1, 1994
All of the established antiepileptic drugs (AEDs) can produce cognitive side effects, which are i... more All of the established antiepileptic drugs (AEDs) can produce cognitive side effects, which are increased with polypharmacy and with increasing dosage and anticonvulsant blood levels. However, cognitive side effects are usually modest for AED monotherapy with anticonvulsant blood levels within the standard therapeutic ranges. Further, these effects are offset in part by reduced seizure activity. Controversy exists regarding possible differential cognitive effects of AEDs. A large portion of the literature examining the comparative cognitive effects of AEDs is limited by inadequate study designs. When these design flaws are considered, there is no convincing evidence of clinically significant differences in cognitive side effects of AEDs except possibly for bromide, phenobarbital and benzodiazepines. The role of cognitive side effects should be kept in proper perspective when choosing AED therapy. The cognitive side effects of anticonvulsant drugs may be overt but many times are rather subtle. It is important though to be able to recognize these effects and to put them into perspective as to how they affect our patients. Resume: Effets secondaires cognitifs des anticonvulsivants. Tous les medicaments anti£pileptiques (MAEs) peuvent produire des effets secondaires cognitifs qui sont amplifies par la polypharmacie et l'augmentation de la posologie et des niveaux sanguins. Cependant, les effets secondaires cognitifs des MAEs utilises en monothirapie sont habituellement legers lorsque les taux sanguins demeurent dans la zone therapeutique standard. De plus, ces effets sont contrebalanc£s partiellement par une diminution des crises. La possibility qu'il existe des differences entre les effets secondaires cognitifs des MAEs est controversee. La validite d'une grande partie de la literature qui compare les effets cognitifs des MAEs est limited par le fait que les schemas d'dtudes sont inad6quats. Quand on tient compte de cette restriction, il n'existe pas d'eVidence convainquante qu'il y a des differences cliniques significatives dans les effets secondaires cognitifs des MAEs, exception faite peut-etre des bromures, du phenobarbital et des benzodiazepines. Le role des effets secondaires cognitifs devrait etre garde en perspective quand on choisit un MAE.
Stereotactic and Functional Neurosurgery, 1997
Fifty-three seizure focus resections limited to the frontal lobe were performed. Forty-nine had a... more Fifty-three seizure focus resections limited to the frontal lobe were performed. Forty-nine had adequate follow-up. Five of 17 (29%) nonlesional (NL) cases and 21 of 32 (66%) lesional (L) cases were seizure free (SF) at 1 year postoperatively. Eight of 9 (89%) L cases < or = 18 years old vs. 13 of 23 (57%) > 18 years old were SF. Eight of 10 (80%) tumor vs. 13 of 22 (59%) nontumor L cases were SF. Sixteen NL cases were localized by invasive recording. Five (31%) were SF. Ictal localization was obtained in 4 of 32 L cases. Three of 4 (75%) were SF. Eighteen of 24 (64%) L cases without ictal localization were SF. Nine of 12 (75%) lateral resections, 7 of 12 (58%) lobectomies, and 2 of 13 (15%) mesial resections were SF. Three of 20 cases with at least 90% reduction in seizures became SD > or = 2 years postresection. No case with < 90% seizure reduction at one year showed improvement with longer follow-up.
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Papers by Kimford J Meador