Cessation of gamma activity in the dorsomedial nucleus associated with loss of consciousness during focal seizures.

RATIONALE: Impaired consciousness during seizures may be mediated by ictal propagation to the thalamus. Functions of individual thalamic nuclei with respect to consciousness, however, are largely unknown. The dorsomedial (DM) nucleus of the thalamus likely plays a role in arousal and cognition. We propose that alterations of firing patterns within the DM nucleus contribute to impaired arousal during focal seizures. METHODS: Electroencephalograph data were collected from electrodes within the left DM thalamus and midcingulate cortex (MCC) in a patient undergoing seizure monitoring. Spectral power was computed across ictal states (preictal, ictal, and postictal) and level of consciousness (stupor/sleep vs. awake) in the DM nucleus and MCC. RESULTS: Eighty-seven seizures of multifocal left frontal and temporal onsets were analyzed, characterized by loss of consciousness. At baseline, the left DM nucleus demonstrated rhythmic bursts of gamma activity, most frequently and with greatest amplitude during wakefulness. This activity ceased as ictal discharges spread to the MCC, and consciousness was impaired, and it recurred at the end of each seizure as awareness was regained. The analysis of gamma (30-40Hz) power demonstrated that when seizures occurred during wakefulness, there was lower DM ictal power (p<0.0001) and higher DM postictal power (p<0.0001) relative to the preictal epoch. This spectral pattern was not evident within the MCC or when seizures occurred during sleep. CONCLUSIONS: Data revealed a characteristic pattern of DM gamma bursts during wakefulness, which disappeared during partial seizures associated with impaired consciousness. The findings are consistent with studies suggesting that the DM nucleus participates in cognition and arousal.

Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy.

The aims of the study were to characterize the magnitude of clearance changes during pregnancy for multiple antiepileptic drugs (AEDs) and to assess seizure frequency and factors increasing seizure risk in pregnant women with epilepsy. A retrospective analysis was performed for 115 pregnancies in 95 women with epilepsy followed at the Emory Epilepsy Center between 1999 and 2012. Antiepileptic drug blood levels (ABLs) obtained during routine clinical practice were used to calculate AED clearance at multiple points during pregnancy. Antiepileptic drug doses and seizure activity were also recorded. The data were analyzed for changes in clearance and dose across pregnancy and for an association between ABL and changes in seizure frequency. Significant changes in clearance during pregnancy were observed for lamotrigine (p<0.001) and levetiracetam (p<0.006). Average peak clearance increased by 191% for lamotrigine and 207% for levetiracetam from nonpregnant baseline. Marked variance was present across individual women and also across repeat pregnancies in individual women. Despite increased AED dose across most AEDs, seizures increased in 38.4% of patients during pregnancy. Seizure deterioration was significantly more likely in patients with seizures in the 12 months prior to conception (p<0.001) and those with localization-related epilepsy (p=0.005). When ABL fell >35% from preconception baseline, seizures worsened significantly during the second trimester when controlling for seizure occurrence in the year prior to conception. Substantial pharmacokinetic changes during pregnancy occur with multiple AEDs and may increase seizure risk. Monitoring of AED serum concentrations with dose adjustment is recommended in pregnant women with epilepsy. Further studies are needed for many AEDs.

Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Primary care physicians' and psychiatrists' approaches to treating mild depression.

OBJECTIVE: To measure how primary care physicians (PCPs) and psychiatrists treat mild depression. METHOD: We surveyed a national sample of US PCPs and psychiatrists using a vignette of a 52-year-old man with depressive symptoms not meeting Major Depressive Episode criteria. Physicians were asked how likely they were to recommend an antidepressant counseling, combined medication, and counseling or to make a psychiatric referral. RESULTS: Response rate was 896/1427 PCPs and 312/487 for psychiatrists. Compared with PCPs, psychiatrists were more likely to recommend an antidepressant (70% vs. 56%), counseling (86% vs. 54%), or the combination of medication and counseling (61% vs. 30%). More psychiatrists (44%) than PCPs (15%) were 'very likely' to promote psychiatric referral. PCPs who frequently attended religious services were less likely (than infrequent attenders) to refer the patient to a psychiatrist (12% vs. 18%); and more likely to recommend increased involvement in meaningful relationships/activities (50% vs. 41%) and religious community (33% vs. 17%). CONCLUSION: Psychiatrists treat mild depression more aggressively than PCPs. Both are inclined to use antidepressants for patients with mild depression.

Differential effects of antiepileptic drugs on neonatal outcomes.

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.

Religiosity is an important part of coping with grief in pregnancy after a traumatic second trimester loss.

Women (n = 15) who were pregnant after a traumatic late pregnancy loss (termination because of fetal death or serious anomalies) completed psychometric screening tests and scales, including the Perinatal Grief Scale (PGS), the Impact of Event Scale (IES), the Duke Depression Inventory (DDI), the Generalized Anxiety Disorder-7 (GAD), and the Hoge Scale for Intrinsic Religiosity (IR). Despite a mean elapsed time since the prior loss of 27 (range, 7-47) months, half (7/15, 47%) of the combined groups had high levels of grief on the PGS. Multiple positive scores on psychometric tests were frequent: Sixty percent (9/15) had high scores on the PGS Active Grief subscale or on the IES. Forty percent (6/15) had a high score on the DDI, and 17% (3/15) on the GAD. IR scores significantly and negatively correlated with scores on the Despair subscale of the PGS. The results from this pilot study suggest that high levels of grief and PTS symptoms are significant problems for pregnant women who have suffered late loss of a wanted pregnancy. Religiosity may play an important part in maternal coping during these stressful pregnancies.

Emotional indifference in Alzheimer's disease.

One of the most common and disabling symptoms of Alzheimer's disease is apathy. Patients with Alzheimer's disease might appear apathetic for several reasons, including deficits in emotional communication, presence of depression, perceptual-semantic-cognitive deficits, and a degeneration of areas of the brain important in experiencing emotions. The purpose of this study was to learn if patients with Alzheimer's disease have a reduction in the depth of their emotional experiences. Participants with Alzheimer's disease and healthy comparison subjects were asked to view pleasant and unpleasant pictures and to rate these pictures by making a mark on pieces of paper that had a happy face on one end (proximal or distal) and a sad face at the other end. The more pleasant they found this picture, the closer their mark should be to the happy face and vice versa. Patients with Alzheimer's disease judged these pictures' emotional valence as less intense than did the comparison subjects and also made more valence-inconsistent responses. These results might have been induced by impaired picture comprehension or a reduction of emotional experiences induced by degeneration of the limbic-cortical-reticular networks.

Is antiepileptic drug use related to depression and suicidal ideation among patients with epilepsy?

Depression and suicide are increased in patients with epilepsy. The U.S. Food and Drug Administration warns that antiepileptic drugs (AEDs) are associated with increased risk of suicidality. This study examines the relationship among depression, suicidal ideation, and AEDs in a prospective cohort of 163 patients with epilepsy from a registry at the University of Florida (January 2006 to August 2008). The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was used to measure mood and suicidal ideation across two time points (median = 154 days). Groups included: (1) No AED Change, (2) New AED Added, (3) AED Dose Increased, (4) AED Reduced/Stopped, (5) Multiple AED Changes, and (6) Combined Any AED Change (groups 2-5 combined). No group had worsening mood or suicidal ideation. Significant improvements in proportions of depression and suicidal ideation were seen only for the No AED Change group, which differed only with the AED Dose Increased group with respect to suicidal ideation.

Cognitive disorders in epilepsy II: Clinical targets, indications and selection of test instruments.

This is the second of two narrative reviews on cognitive disorders in epilepsy (companion manuscript: Cognitive disorders in epilepsy I: Clinical experience, real-world evidence and recommendations). Its focus is on the clinical targets, indications, and the selection of neuropsychological test instruments. Cognitive assessment has become an essential tool for the diagnosis and outcome control in the clinical management of epilepsy. The diagnostics of basic and higher brain functions can provide valuable information on lateralized and localized brain dysfunctions associated with epilepsy, its underlying pathologies and treatment. In addition to the detection or verification of deficits, neuropsychology reveals the patient's cognitive strengths and, thus, information about the patient reserve capacities for functional restitution and compensation. Neuropsychology is an integral part of diagnostic evaluations mainly in the context of epilepsy surgery to avoid new or additional damage to preexisting neurocognitive impairments. In addition and increasingly, neuropsychology is being used as a tool for monitoring of the disease and its underlying pathologies, and it is suited for the quality and outcome control of pharmacological or other non-invasive medical intervention. This narrative review summarizes the present state of neuropsychological assessments in epilepsy, reveals diagnostic gaps, and shows the great need for education, homogenization, translation and standardization of instruments.

Subjective perception of cognition is related to mood and not performance.

OBJECTIVE: Clinicians monitor cognitive effects of drugs primarily by asking patients to describe their side effects. We examined the relationship of subjective perception of cognition to mood and objective cognitive performance in healthy volunteers and neurological patients. METHODS: Three separate experiments used healthy adults treated with lamotrigine (LTG) and topiramate (TPM), adults with epilepsy on LTG or TPM, and patients with idiopathic Parkinson's disease. Correlations were calculated for change scores on and off drugs in the first two experiments and for the single assessment in Experiment 3. RESULTS: Across all three experiments, significant correlations were more frequent (chi(2)=259, P < or = 0.000) for mood versus subjective cognitive perception (59%) compared with subjective versus objective cognition (2%) and mood versus objective cognitive performance (2%). CONCLUSIONS: Subjective perception of cognitive effects is related more to mood than objective performance. Clinicians should be aware of this relationship when assessing patients' cognitive complaints.

Adverse effects of antiepileptic drugs.

Adverse effects of antiepileptic drugs (AEDs) are common, can have a considerable impact on quality of life and contribute to treatment failure in up to 40% of patients. The adverse effect profiles of AEDs differ greatly and are often a determining factor in drug selection because of the similar efficacy rates shown by most AEDs. The most common adverse effects are dose dependent and reversible. Cognitive impairment is of particular concern, especially for patients who work or study. Idiosyncratic effects, such as skin rashes, and chronic effects, such as weight gain, can lead to high rates of treatment discontinuation and complicate clinical management. Nearly all conventional AEDs increase the risk of congenital malformations when taken during pregnancy, with valproate posing a potentially greater risk, whereas the potential teratogenicity of new generation AEDs is largely unknown. Most conventional AEDs have a poor record when it comes to drug interactions, largely because of their tendency to interfere with hepatic drug metabolism. Some newer AEDs have no effect on hepatic drug metabolizing enzymes and are renally excreted, resulting in a lower potential for drug interactions. However, further research is needed to confirm the apparent improvement in tolerability offered by some of the newer AEDs.

Antipsychotics and the risk of sudden cardiac death.

BACKGROUND: Case reports link antipsychotic drugs with sudden cardiac deaths, which is consistent with dose-related electrophysiologic effects. Because this association has not been confirmed in controlled studies, we conducted a retrospective cohort study in Tennessee Medicaid enrollees, which included many antipsychotic users; there were also computer files describing medication use and comorbidity. The study was conducted before the introduction of risperidone and, thus, did not include the newer atypical agents. METHODS: The cohort included 481,744 persons with 1,282,996 person-years of follow-up. This included 26,749 person-years for current moderate-dose antipsychotic use (>100-mg thioridazine equivalents), 31,864 person-years for current low-dose antipsychotic use, 37,881 person-years for use in the past year only, and 1 186,501 person-years for no use. The cohort had 1487 confirmed sudden cardiac deaths; from these, we calculated multivariate rate ratios adjusted for potential confounding factors. RESULTS: When current moderate-dose antipsychotic use was compared with nonuse, the multivariate rate ratio was 2.39 (95% confidence interval, 1.77-3.22; P<.001). This was greater than that for current low-dose (rate ratio, 1.30; 95% confidence interval, 0.98-1.72; P=.003) and former (rate ratio, 1.20; 95% confidence interval, 0.91-1.58; P<.001) use. Among cohort members with severe cardiovascular disease, current moderate-dose users had a 3.53-fold (95% confidence interval, 1.66-7.51) increased rate relative to comparable nonusers ( P<.001), resulting in 367 additional deaths per 10,000 person-years of follow-up. CONCLUSIONS: Patients prescribed moderate doses of antipsychotics had large relative and absolute increases in the risk of sudden cardiac death. Although the study data cannot demonstrate causality, they suggest that the potential adverse cardiac effects of antipsychotics should be considered in clinical practice, particularly for patients with cardiovascular disease.

Depression in elderly hospitalized patients with medical illness.

Depressive symptoms and disorders were identified by structured psychiatric interview in 130 consecutively admitted male inpatients aged 70 years and over. Major depression was found in 11.5% and other depressive syndromes in 23%. While depressive symptoms and syndromes are common among the medically ill, this study demonstrated the need for careful diagnostic assessment of older patients with depressive symptoms before initiating treatment that may itself convey significant risk. Sociodemographic and health characteristics of older men at higher risk for depression were also identified. Patients more likely to be depressed were over age 75 years, had less formal education, experienced cognitive dysfunction, suffered from more severe medical illness (particularly recent myocardial infarction), and had a history of psychiatric illness. Depressive symptoms were also common among patients with renal or neurologic diseases, those having a family history of psychiatric illness, the unmarried, and the more severely disabled. Given the impact of depression on recovery from medical illness, compliance with medical therapy, and costs of extended hospital stays, detection and treatment of this disorder are imperative.

Reducing antipsychotic drug use in nursing homes. A controlled trial of provider education.

OBJECTIVE: In the United States, 20% or more of nursing home residents receive antipsychotic drugs, primarily for the behavioral manifestations of dementia. This high level of use of drugs with substantial toxicity has engendered a strong and persistent controversy and recently has led to explicit regulatory measures to curtail use (Omnibus Budget Reconciliation Act of 1987). We developed and tested a comprehensive program to reduce antipsychotic use through education of physicians, nurses, and other nursing home staff. The primary elements of the program were instruction in use of behavioral techniques to manage behavior problems and encouragement of a trial of gradual antipsychotic withdrawal. DESIGN: In a nonrandomized controlled trial, the program was implemented (beginning in August 1990) in two rural Tennessee community nursing homes with elevated antipsychotic use; two other comparable homes were selected as concurrent controls. PATIENTS: Throughout the study 194 residents were in the education homes and 184 were in the control homes. Residents in both groups of homes had comparable demographic characteristics and functional status, and each group had a baseline rate of 29 days of antipsychotic use per 100 days of nursing home residence. MAIN OUTCOME MEASURES: The primary end points were postintervention changes in administration of antipsychotics and other psychotropic drugs, use of physical restraints, and frequency of behavior problems. RESULTS: Days of antipsychotic use decreased by 72% in the education homes vs 13% in the control homes (P < .001). No significant changes were noted in the use of other psychotropic drugs in either group. Days of physical restraint use decreased 36% in the education homes vs 5% in the control homes (P < .001). Behavior problem frequency did not increase in either group, even among the 48% of baseline antipsychotic users in the education homes who had antipsychotic drug regimens discontinued for 3 or more months. CONCLUSIONS: The educational program led to a substantial reduction in antipsychotic use with no increase in the frequency of behavior problems. This suggests that for many antipsychotic drug users benefits may be marginal and that programs to reduce such drug use among the 250,000 US nursing home residents receiving these drugs should have high priority.

The DST and posttraumatic stress disorder.

The dexamethasone suppression test (DST) was administered to 28 male combat veterans with posttraumatic stress disorder. Six subjects (21%) were nonsuppressors. The nonsuppression rates for the subgroups with and without major depressive disorder according to the Research Diagnostic Criteria were 50% and 6%, respectively. The authors conclude that cortisol nonsuppression is rare in posttraumatic stress disorder unless there is concomitant major depression.

Use of antidepressants by nonpsychiatrists in the treatment of medically ill hospitalized depressed elderly patients.

OBJECTIVE: The purpose of this study was to examine antidepressant use by nonpsychiatrists in the treatment of depressed elderly medical inpatients. METHOD: Patients aged 60 or older who were admitted to medical services at Duke Hospital were evaluated by a geropsychiatrist who used a structured psychiatric interview to identify major or minor depressive disorder. Medical records of depressed patients were reviewed for use of antidepressants and benzodiazepines before admission, during hospitalization, and on discharge. After discharge, depressed patients were contacted four times by telephone at 12-week intervals to inquire about medication use (median follow-up time = 45 weeks). RESULTS: Of 153 depressed patients, 40.5% received antidepressants at some time during their hospital stay or follow-up period, 25.5% received only benzodiazepines, and 34.0% received neither. The most commonly prescribed antidepressant was amitriptyline (45.2% of treated patients), administered at an average maximum dose of 49 mg/day. Only 15 of 114 untreated depressed patients started antidepressant therapy during hospitalization (nine with amitriptyline). Of 91 depressed patients who did not receive antidepressants either before admission or during hospitalization, only 11% received any antidepressant therapy during the median 11-month follow-up; again, half were treated with amitriptyline at doses of 10-30 mg/day. Intensity of antidepressant therapy was predicted by severity of depressive symptoms, history of psychiatric problems, and higher income. CONCLUSIONS: A relatively low proportion of depressed older medical inpatients receive treatment with antidepressants. Patients treated with antidepressants often receive potentially dangerous tertiary tricyclics at inadequate doses. Unless depression is identified and treated during medical hospitalization, it is unlikely to be treated adequately after discharge.

Religious coping and depression among elderly, hospitalized medically ill men.

OBJECTIVE: The investigators examined the frequency of religious coping among older medical inpatients, the characteristics of those who use it, and the relation between this behavior and depression. METHOD: The subjects were 850 men aged 65 years and over, without psychiatric diagnoses, who were consecutively admitted to the medical or neurological services of a southern Veterans Administration medical center. Religious coping was assessed with a three-item index. Depressive symptoms were assessed by self-rating (the Geriatric Depression Scale) and observer rating (the Hamilton Rating Scale for Depression). RESULTS: One out of every five patients reported that religious thought and/or activity was the most important strategy used to cope with illness. Variables that were associated with religious coping included black race, older age, being retired, religious affiliation, high level of social support, infrequent alcohol use, a prior history of psychiatric problems, and higher cognitive functioning. Depressive symptoms were inversely related to religious coping, an association which persisted after other sociodemographic and health correlates were controlled. When 202 men were reevaluated during their subsequent hospital admissions an average of 6 months later, religious coping was the only baseline variable that predicted lower depression scores at follow-up. CONCLUSIONS: These findings suggest that religious coping is a common behavior that is inversely related to depression in hospitalized elderly men.

The intracarotid amobarbital sodium procedure. False-positive errors during recognition memory assessment.

Memory performance during the intracarotid amobarbital sodium (Amytal sodium) procedure was examined in 40 patients as part of their diagnostic work-up as candidates for epilepsy surgery. Free recall was significantly better following right hemisphere injection although no left/right difference was present during recognition assessment. However, the occurrence of false-positive (FP) recognition errors was significantly more frequent following left hemisphere injection. In all conditions, no relationship to seizure focus was observed. Patients with FP errors displayed poorer delayed verbal memory during baseline neuropsychological assessment compared with patients without FP errors. Data indicate an inverse relationship between FP errors and recent verbal memory function, and they suggest that impaired memory rather than failure to suppress incorrect responses secondary to poor self-monitoring capacity is responsible for the generation of FP and intrusion errors.

Allochiria vs allesthesia. Is there a misperception?

Allochiria is the mislocation of sensory stimuli to the corresponding opposite half of the body or space. Obersteiner (1882) introduced the term allochiria (Greek allos = other + chiria = hand), and more than 20 authors employed it in this context over the next 25 years. Stewart (1894) described a related phenomenon in which stimuli are displaced to a different point on the same extremity. He noted that the displacements were different than allochiria and coined the term allachaesthesia (ie, allesthesia) (Greek allaché = elsewhere + aisthésis = perception). Despite this historical background, Jones (1907) redefined both terms in an attempt to increase diagnostic specificity and attributed allochiria to hysteria. Jones' reinterpretation does not appear to be justified historically, etymologically, or scientifically and has resulted in contradictory definitions of allochiria and allesthesia in present-day medical dictionaries and neurologic textbooks. We advocate a return to usage consistent with the original descriptions and word derivations.

The P3 evoked potential and transient global amnesia.

The P3 evoked potential has been linked to memory mechanisms, but its neuronal generators are uncertain. Transient global amnesia (TGA) is a disorder of recent memory that has been postulated to result from ischemia or focal seizures in the medial temporal lobes and/or thalamus. To our knowledge, this is the first report of a recording of P3 evoked potential and sphenoidal electroencephalogram during TGA. The tonal P3 was not decremented in comparison to P3 recordings one month and two years after recovery. Sphenoidal electroencephalogram was normal. The results suggest that the neuronal networks which generate the tonal P3 are not involved in the part of the memory system affected by TGA.