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.

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.

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.

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.

Stimulus timing effects on Wada memory testing.

OBJECTIVE: To determine the effects of presenting Wada memory stimuli at different times after intracarotid amobarbital injection on Wada memory asymmetries. DESIGN: Wada memory asymmetries from three timing series were related to the laterality of eventual temporal lobectomy. SETTING: Academic institution epilepsy surgery program. PATIENTS: Forty-three patients with complex partial seizures who later underwent anterior temporal lobectomy (left temporal lobectomy, 24 patients; right temporal lobectomy, 19 patients). No patient included had abnormalities on magnetic resonance imaging scans to suggest a lesion other than gliosis. RESULTS: Memory performance for objects whose presentation began approximately 45 seconds after amobarbital administration differentiated laterality of seizure onset. Memory for items presented later and after partial return of language (on average 3 minutes 40 seconds postinjection) also differed as a function of ipsilateral vs contralateral injection, but at a lower level of statistical significance. Memory for items presented last during the procedure (on average 6 minutes postinjection) discriminated seizure groups at a still lower level of statistical significance. When used to predict lateralized temporal lobe impairment in individual patients, early object memory performance was significantly better than memory performance employing either middle (56%) or late (43%) stimulus presentation timings. CONCLUSION: The results of early object memory testing are superior to those obtained from stimulus presentation later in the procedure in documenting temporal lobe dysfunction associated with a lateralized seizure onset.

The relationship of neuropsychological functioning to quality of life in epilepsy.

OBJECTIVE: To examine the relationship of objectively assessed cognitive functioning to self-reported quality of life. DESIGN: Correlational, multiple regression, and factor analytic comparisons of a new self-report quality of life inventory with neuropsychological tests of cognition and mood. SUBJECTS: Two hundred fifty-seven patients with epilepsy. SETTING: Twenty-five epilepsy centers and neurology clinics across the United States. MEASURES: A recently developed self-report (ie, Quality of Life in Epilepsy-89 inventory) and objective tests of memory, verbal abilities, spatial functions, psychomotor and cognitive processing speed, cognitive flexibility, and mood. RESULTS: Factors that assessed mood, psychomotor speed, verbal memory, and language correlated significantly with selected scales of the Quality of Life in Epilepsy-89 inventory (P < .0001) and were predictive of overall quality of life (P < .002 to P < .0001). The mood factor showed the highest correlations (r = -.20 to r = -.73) and was the strongest predictor of quality of life in regression analyses (46.7% explained variance, P < .0001). CONCLUSIONS: Mood may be adversely affected by diminished quality of life, or perceived quality of life may be affected by mood disturbance. Quantitative quality of life assessments can be used in conjunction with formal neuropsychological testing of mood and cognition when evaluating patients with epilepsy.

Tinnitus from intracranial hypertension.

Five patients had unilateral tinnitus from increased intracranial pressure of different etiologies. In each case, the tinnitus was produced by a venous bruit and could be decreased by Valsalva's maneuver, head turning to the ipsilateral side, or by light pressure over the ipsilateral jugular vein. Correction of the increased intracranial pressure obliterated the tinnitus. Turbulence, created as blood flows from the hypertensive intracranial portion into the low pressure of the jugular bulb, is proposed as the mechanism producing the tinnitus.

Hemispheric asymmetries of limb-kinetic apraxia: a loss of deftness.

OBJECTIVES: Unlike patients with ideomotor apraxia who make temporal and spatial errors and patients with ideational or conceptual apraxia who make content errors, patients with limb-kinetic apraxia have loss of deftness, including fine and precise movements, independent finger movements, and difficulty coordinating simultaneous movements. This study was conducted to learn the relationship between limb-kinetic apraxia and hemisphere dysfunction by using selective hemisphere anesthesia, the Wada test. METHODS: Subjects were 90 patients undergoing Wada testing for intractable epilepsy. They were divided into typical (right-handed with left hemisphere language dominance) and atypical (nonright-handed, or without left hemisphere language dominance). Before and during Wada testing, subjects were shown line drawings of tools, four for each hand tested. After being shown each picture, subjects pantomimed the use of this tool. A behavioral neurologist and neuropsychologist scored the pantomimes for the presence of limb-kinetic errors. RESULTS: For the typical group, during left hemisphere anesthesia, the limb-kinetic errors made by the right and left hands did not differ, but during right hemisphere anesthesia the left hand made more errors than the right. Unlike the typical subjects, when the left hemisphere was anesthetized, the atypical subjects made more errors with their right hands than left. However, similar to the typical subjects with right hemisphere anesthesia, the atypical subjects made more left- than right-hand limb-kinetic errors. CONCLUSIONS: For people with typical brain organization, the left hemisphere mediates motor deftness for both hands, but the right hemisphere primarily controls deftness for the left hand. For people with atypical brain organization, each hemisphere primarily controls deftness for the contralateral hand.

Remote memory and neglect syndrome.

Three patients with right cerebral infarctions and neglect syndrome failed to recall left hemispatial remote memories, even when the imagined orientation was reversed by 180 degrees. One patient was retested 4 months later and, although improved, continued to consistently recall more right-sided items. He was tested at east and west mental orientations with his head/eyes oriented physically to each side. Recall for items imagined in left hemispace improved 26% when his head/eye orientation was physically shifted from right to left hemispace. Findings suggest that the engrams for left-sided visuospatial memories in neglect syndrome are not destroyed, but rather fail to be activated.

Transient global amnesia and meningioma.

A patient with episodes of transient global amnesia and transient partial amnesia was found to have a meningioma impinging on the right medial temporal lobe. Multiple partial complex seizures and EEG abnormalities suggested an epileptogenic disorder.

Anosognosia and asomatognosia during intracarotid amobarbital inactivation.

BACKGROUND: Anosognosia (i.e., denial of hemiparesis) and asomatognosia (i.e., inability to recognize the affected limb as one's own) occur more frequently with right cerebral lesions. However, the incidence, relative recovery, and underlying mechanisms remain unclear. METHODS: Anosognosia and asomatognosia were examined in 62 patients undergoing the intracarotid amobarbital procedure as part of their preoperative evaluation for epilepsy surgery. Additional questions were asked in the last 32 patients studied. RESULTS: During inactivation of the non-language-dominant cerebral hemisphere, 88% of the 62 patients were unaware of their paralysis, and 82% could not recognize their own hand at some point. Only 3% did not exhibit anosognosia or asomatognosia. In general, asomatognosia resolved earlier than anosognosia. When patients could not recognize their hand, they uniformly thought that it was someone else's hand. Dissociations in awareness were seen in the second series of 32 patients. Although 23 patients (72%) thought that both arms were in the air, 31% pointed to the correct position of the paralyzed arm on the table. Despite the inability of 24 of 32 patients (75%) to recognize their own hand, 21% of these patients were aware that their arm was weak, and 38% had correctly located their paralyzed arm on the angiography table. CONCLUSIONS: Anosognosia and asomatognosia are both common during acute dysfunction of the non-language-dominant cerebral hemisphere. Dissociations of perception of location, weakness, and ownership of the affected limb are frequent, as are misperceptions of location and body part identity. The dissociations suggest that multiple mechanisms are involved.

Cholinergic modulation of human P3 event-related potentials.

A paradigm for studying relations between behavioral, neurochemical, and electrophysiologic processes is presented. Scopolamine, a centrally acting anticholinergic agent, abolished the human auditory P3 event-related potential, but had no measurable effect on the pattern reversal visual evoked potential or alpha rhythm. Recent memory was significantly impaired, but assessment of digit span, reaction time, and distant memory showed no impairment. Physostigmine, an anticholinesterase, restored the P3 and reversed the recent memory impairment. These results strongly suggest a cholinergic role in generation of P3 potential and support the concept that P3 generation is related to memory processes.

Cognitive evoked potentials and disorders of recent memory.

P3 potentials evoked by spoken words were recorded from seven patients with disorders of recent memory and seven age-matched controls. Inclusion criteria included a clearly identifiable P3 to pure tone stimuli. Absence or marked decrement of P3 to word stimuli was seen in the patients even though they could perform the word task. The results are consistent with an encoding disorder and failure in elaboration of information processing.