Cognitive performance in functional seizures compared with epilepsy and healthy controls: a systematic review and meta analysis.

BACKGROUND: Cognition is a core component of functional seizures, but the literature on cognition in this disorder has been heterogeneous, with no clear unifying profile emerging from individual studies. The aim of this study was to do a systematic review and meta-analysis of cognitive performance in adults with functional seizures compared with epilepsy (including left temporal lobe epilepsy) and compared with healthy non-seizure cohorts. METHODS: In this systematic review and meta-analysis, starting Feb 6, 2023, replicated and updated on Oct 31, 2023, a medical librarian searched MEDLINE, Embase, PsycINFO, and Web of Science. Inclusion criteria were full reports documenting raw or standardised cognitive test data in adults with functional seizures compared with adults with epilepsy, prospectively recruited healthy comparisons, or published norms. Grey literature was retained and there were no language or date restrictions. We excluded studies only reporting on mixed functional seizures and epilepsy, or mixed functional neurological samples, with no pure functional seizures group. Risk of bias was evaluated using a modified version of the Newcastle-Ottawa Scale. People with lived experiences were not involved in the design or execution of this study. This study is registered as CRD42023392385 in PROSPERO. FINDINGS: Of 3834 records initially identified, 84 articles were retained, including 8654 participants (functional seizures 4193, epilepsy 3638, and healthy comparisons 823). Mean age was 36 years (SD 12) for functional seizures, 36 years (12) for epilepsy, and 34 years (10) for healthy comparisons, and the proportion of women per group was 72% (range 18-100) for functional seizures, 59% (range 15-100) for epilepsy, and 69% (range 34-100) for healthy comparisons. Data on race or ethnicity were rarely reported in the individual studies. Risk of bias was moderate. Cognitive performance was better in people with functional seizures than those with epilepsy (Hedges' g=0·17 [95% CI 0·10-0·25)], p<0·0001), with moderate-to-high heterogeneity (Q[56]=128·91, p=0·0001, I2=57%). The functional seizures group performed better than the epilepsy group on global cognition and intelligence quotient (g=0·15 [0·02-0·28], p=0·022) and language (g=0·28 [0·14-0·43], p=0·0001), but not other cognitive domains. A larger effect was noted in language tests when comparing functional seizures with left temporal lobe epilepsy (k=5; g=0·51 [0·10 to 0·91], p=0·015). The functional seizures group underperformed relative to healthy comparisons (g=-0·61 [-0·78 to -0·44], p<0·0001), with significant differences in all cognitive domains. Meta regressions examining effects of multiple covariates on global cognition were not significant. INTERPRETATION: Patients with functional seizures have widespread cognitive impairments that are likely to be clinically meaningful on the basis of moderate effect sizes in multiple domains. These deficits might be slightly less severe than those seen in many patients with epilepsy but nevertheless argue for consideration of clinical assessment and treatment. FUNDING: Department of Veterans Affairs, Veterans Health Administration.

The role of neuropsychology in the care of patients with functional neurological symptom disorder.

OBJECTIVE: Functional neurological symptom disorder (FNSD) is a neuropsychiatric condition characterized by signs/symptoms associated with brain network dysfunction. FNSDs are common and are associated with high healthcare costs. FNSDs are relevant to neuropsychologists, as they frequently present with chronic neuropsychiatric symptoms, subjective cognitive concerns, and/or low neuropsychological test scores, with associated disability and reduced quality of life. However, neuropsychologists in some settings are not involved in care of patients with FNSDs. This review summarizes relevant FNSD literature with a focus on the role of neuropsychologists. METHODS: A brief review of the literature is provided with respect to epidemiology, public health impact, symptomatology, pathophysiology, and treatment. RESULTS: Two primary areas of focus for this review are the following: (1) increasing neuropsychologists' training in FNSDs, and (2) increasing neuropsychologists' role in assessment and treatment of FNSD patients. CONCLUSIONS: Patients with FNSD would benefit from increased involvement of neuropsychologists in their care.

Reduced Subjective Cognitive Concerns With Neurobehavioral Therapy in Functional Seizures and Traumatic Brain Injury.

OBJECTIVE: Functional seizures are common among people with traumatic brain injury (TBI). Subjective cognitive concerns refer to a person's own perception of problems with cognitive functioning in everyday life. The authors investigated the presence and correlates of subjective cognitive concerns and the response to neurobehavioral therapy among adults with TBI and functional seizures (TBI+FS group). METHODS: In this observational study, participants in the TBI+FS group (N=47) completed a 12-session neurobehavioral therapy protocol for seizures, while participants in the comparison group (TBI without seizures) (N=50) received usual treatment. Subjective cognitive concerns, objective cognition, mental health, and quality of life were assessed before and after treatment. Data collection occurred from 2018 to 2022. RESULTS: Baseline subjective cognitive concerns were reported for 37 (79%) participants in the TBI+FS group and 20 (40%) participants in the comparison group. In a multivariable regression model in the TBI+FS group, baseline global mental health (ß=-0.97) and obsessive-compulsive symptoms (ß=-1.01) were associated with subjective cognitive concerns at baseline. The TBI+FS group had fewer subjective cognitive concerns after treatment (η2=0.09), whereas the TBI comparison group showed a nonsignificant increase in subjective cognitive concerns. CONCLUSIONS: Subjective cognitive concerns are common among people with TBI and functional seizures and may be related to general mental health and obsessive-compulsive symptoms. Evidence-based neurobehavioral therapy for functional seizures is a reasonable treatment option to address such concerns in this population, although additional studies in culturally diverse samples are needed. In addition, people with functional seizures would likely benefit from rehabilitation specifically targeted toward cognitive functioning.

Improvements in Montreal Cognitive Assessment scores after neurobehavioral therapy in adults with functional (nonepileptic) seizures and traumatic brain injury.

Cognitive functioning impacts clinical symptoms, treatment response, and quality of life in adults with functional/nonepileptic seizures (FS/NES), but no study to date examines effects of behavioral FS/NES treatment on cognition in these patients. We hypothesized that there would be a reduction in cognitive symptoms in participants with FS/NES and traumatic brain injury (TBI) following neurobehavioral therapy (NBT). We also hypothesized that select seizure-related, medication, subjective cognitive, and mental health symptoms would be negatively correlated with improvements in cognitive performance after NBT. Participants were 37 adults with TBI + FS/NES and 35 adults with TBI only, recruited from medical centers in the northeastern or southeastern U.S. TBI + FS/NES participants completed a 12 session NBT intervention, and TBI without seizures participants were not treated. All participants completed pre-post assessments of cognition (Montreal Cognitive Assessment [MoCA]) and baseline sociodemographic factors and mental health symptoms. Pre-post MoCA scores increased significantly in TBI + FS/NES participants (28/37 [75.7%] improved) but not in TBI comparisons (10/35 [28.6%] improved). Language, memory, and visuospatial/executive functions, but not attention, improved over time in the TBI + FS/NES group. Gains in cognition were concentrated in those TBI + FS/NES participants with likely baseline cognitive impairments (MoCA total score <26), and 9/17 of these participants moved from the "impaired" range at baseline (<26) to the "intact" range at endpoint (≥26). Lastly, participants taking fewer medications and reporting lower subjective cognitive difficulties at baseline showed larger pre-post MoCA total score improvements. Overall, results from this study suggest the potential for positive change in cognition in FS/NES and co-occurring TBI using evidence-based psychotherapy.

Elevated Plasma Aß42 in Cognitively Impaired Individuals Taking ACE Inhibitor Antihypertensives.

BACKGROUND/RATIONALE: Accumulating evidence suggests that the use of angiotensin-converting enzyme inhibitor (ACE-I) medication protects against cognitive decline in the elderly patients. We investigated whether ACE-I use was associated with higher plasma levels of amyloid-ß (Aß), possibly indicating improved Aß clearance from brain to blood. METHODS: We measured and compared plasma concentrations of Aß42, Aß40, and creatinine in cognitively impaired individuals with amnestic mild cognitive impairment, probable Alzheimer's disease (AD) dementia, and mixed probable AD/vascular dementia. RESULTS: Plasma Aß42 levels and Aß42/Aß40 ratios of participants taking ACE-Is (n = 11) significantly exceeded ( t = 3.1, df = 19, P = .006; U = 24, P = .029, respectively) those not taking ACE-Is (n = 10). CONCLUSIONS: This study is the first to show an association between ACE-I use and increased plasma Aß42 level and Aß42/Aß40 ratio in cognitively impaired individuals. Future investigations should assess whether a possible ACE-I-induced increase in plasma Aß42 indicates improved Aß42 clearance from brain that contributes to protection from cognitive decline.

Dementia Evaluation, Management, and Outreach.

The Dementia Evaluation, Management, and Outreach (DEMO) program improves access and satisfaction for rural patients with cognitive deficits.

Cortisol reactivity and emotional memory after psychosocial stress in oral contraceptive users.

Oral contraceptive (OC) users typically show a blunted or no cortisol response to psychosocial stress. Although most OC regimens include both an inactive (dummy) and active pill phase, studies have not systematically investigated cortisol responses during these pill phases. Further, high levels of cortisol following a stressor diminish retrieval of emotional material, but the effects of stress on memory among OC users are poorly understood. We examined the effects of a psychosocial stressor, the Trier Social Stress Test, vs. a control condition on cortisol responsivity and emotional memory retrieval in women tested either during their active (n = 18) or inactive pill phase (n = 21). In secondary analyses, we quantitatively compared OC users with normally cycling women and showed a significant lack of cortisol response during both active and inactive pill phase. Emotional recall did not differ between active and inactive pill phases. Stress differentially diminished recall of negative words compared with positive or neutral words, but cortisol levels were unrelated to memory performance. These findings indicate that OC users have distinct cortisol and memory responses to stress that are similar between the active and inactive pill phases. © 2016 Wiley Periodicals, Inc.

Menstrual cycle effects on cortisol responsivity and emotional retrieval following a psychosocial stressor.

This article is part of a Special Issue "Estradiol and cognition". Laboratory-induced stress produces elevations in cortisol and deficits in memory, especially when stress is induced immediately before retrieval of emotionally valent stimuli. Sex and sex steroids appear to influence these stress-induced outcomes, though no study has directly compared the effects of laboratory-induced stress on cortisol and emotional retrieval across the menstrual cycle. We examined the effect of psychosocial stress on cortisol responsivity and emotional retrieval in women tested during either the follicular phase (low estradiol and progesterone) or the luteal phase (higher estradiol and progesterone). Forty women (50% White; age 18-40 years) participated in the study; 20 completed the task during the luteal phase and 20 during the follicular phase. Psychosocial stress was induced with the Trier Social Stress Test (TSST). On the day before the TSST, participants learned two lists of word pairs to 100% criterion. The next day, participants recalled one list after the control condition and the other after the TSST. Women in the follicular phase, but not the luteal phase, demonstrated a significant cortisol response to the TSST. There was a stress-induced decrease in emotional retrieval following the TSST, but this effect was not modified by menstrual phase. However, regression and correlational analyses showed that individual differences in stress-induced cortisol levels were associated with impaired emotional retrieval in the follicular phase only. The present findings indicate that cortisol responsivity and the impairing effects of cortisol on emotional memory are lower when levels of estradiol and progesterone are high compared to when levels are low.

Cognitive rehabilitation in traumatic brain injury.

OPINION STATEMENT: Traumatic brain injury (TBI) is a major public health problem with neurobehavioral sequelae contributing to the long-term disability that is often associated with the moderate to severe levels of injury. Rehabilitation of cognitive skills is central to encouraging the full participation of the individual in home, vocational, and social roles. The review of available evidence points to four major recommendations for the rehabilitation of cognition following brain injury: 1) Access to subacute rehabilitation that is holistic in nature and involves a multidisciplinary or transdisciplinary team to work in an integrated fashion to support physical, cognitive, and social skill retraining is vital to support positive outcome following TBI. The collaborative effort of these individuals allows for continual reinforcement and evaluation of treatment goals and will often involve the family and/or important others in the individual's life to prepare for community re-entry. 2) Trials of medication, especially methylphenidate, to assist individuals with significant attention and memory impairment appear well supported by the available evidence. Though some data suggest that the use of cholinesterase inhibitors may be of use for individuals with memory impairments, there is less support for this practice and there are indications that it may worsen the behavioral sequelae of the injury. 3) Randomized controlled trials demonstrate the utility of specific rehabilitation approaches to attention retraining and retraining of executive functioning skills. Future research is needed on rehabilitation techniques in other domains of cognition. 4) Training in the use of supportive devices (either a memory book or more technologically enhanced compensatory devices) to support the individual's daily activities remains central to the independent function of the individual in the community. Though emerging treatments (eg, virtual reality environments) show relative degrees of promise for inclusion in the rehabilitation of the individual with TBI, these need further evaluation in systematic trials.

Effects of menstrual cycle phase and oral contraceptive use on verbal memory.

Surgical or pharmacological suppression of ovarian hormones leads to declines in verbal memory, and estrogen treatment reverses these deficits. In the current study, we investigated the effects of menstrual cycle phase and oral contraceptives on verbal memory, as measured by the California Verbal Learning Test, in two groups of premenopausal women - 16 naturally cycling women and 20 current users of estrogen-based oral contraceptives (OCs). Naturally cycling women were assessed twice - once during the early follicular phase (Days 2-4) and once during the midluteal phase (Days 20-22) of the menstrual cycle. OC users were tested on the same cycle days, corresponding to inactive and active pill phases, respectively. We predicted that naturally cycling women would show improved verbal memory during the midluteal phase, when estradiol levels are high, compared with the follicular phase, when estradiol levels are low. We also predicted that OC users, who show no change in endogenous estradiol across the cycle, would show no change in verbal memory. Contrary to predictions, naturally cycling women showed no changes in verbal memory across the cycle, whereas OC users showed enhanced memory during the active pill phase (p<.05). None of the secondary cognitive outcome measures varied with cycle phase or OC use including measures of visuospatial memory, verbal fluency, visuospatial abilities, and attention. Overall, these results suggest that verbal memory performance in premenopausal women varies across the cycle with OC use, but does not vary systematically with changes in endogenous estradiol.

Intramuscular testosterone treatment in elderly men: evidence of memory decline and altered brain function.

CONTEXT: Recent clinical trials of im testosterone in eugonadal men suggest positive effects on verbal memory, but other studies find no effect. OBJECTIVE: Our objective was to determine whether supraphysiological testosterone influences verbal memory and brain function during a verbal memory task in healthy eugonadal older men. PATIENTS, DESIGN, AND SETTING: Fifteen cognitively normal men, aged 66-86 yr, participated in a randomized, double-blind, placebo-controlled crossover trial involving 9 months of participation per participant at a hospital-based research facility. INTERVENTION: We used testosterone enanthate (200 mg im every other week for 90 d) crossed over with placebo (sesame oil vehicle im) with a 90-d washout between treatments. MAIN OUTCOME MEASURES: Performance was assessed on a standardized verbal memory test, and brain activity (relative glucose metabolic rates) in medial temporal and frontal regions was measured with positron emission tomography during a verbal memory task. RESULTS: Treatment increased total testosterone by 241%. Behavioral results showed a significant decrease in short-delay verbal memory with treatment (P < 0.05, effect size = 0.59 sd) and a nonsignificant decrease on a composite verbal memory measure (P = 0.09, effect size = 0.48 sd). Positron emission tomography scans revealed decreased relative activity in ventromedial temporal cortex (i.e. right amygdala/entorhinal cortex) and increased relative activity in bilateral prefrontal cortex with treatment. CONCLUSIONS: Decreased verbal memory and altered relative activity in medial temporal and prefrontal regions suggest possible detrimental effects of supraphysiological testosterone supplementation in elderly men. The results do not rule out potential benefits with other regimens, cognitive tests, or populations.