The relevance of neuropsychiatric symptoms and cognitive problems in new-onset epilepsy - Current knowledge and understanding.

Neurobehavioral and cognition problems are highly prevalent in epilepsy, but most research studies to date have not adequately addressed the precise nature of the relationship between these comorbidities and seizures. To address this complex issue and to facilitate collaborative, innovative research in the rising field of neurobehavioral comorbidities and cognition disturbances in new-onset epilepsy, international epilepsy experts met at the 3rd Halifax International Epilepsy Conference & Retreat at White Point, South Shore, Nova Scotia, Canada from September 18 to 20, 2014. This Conference Proceedings provides a summary of the conference proceedings. Specifically, the following topics are discussed: (i) role of comorbidities in epilepsy diagnosis and management, (ii) role of antiepileptic medications in understanding the relationship between epilepsy and neurobehavioral and cognition problems, and (iii) animal data and diagnostic approaches. Evidence to date, though limited, strongly suggests a bidirectional relationship between epilepsy and cognitive and psychiatric comorbidities. In fact, it is likely that seizures and neurobehavioral problems represent different symptoms of a common etiology or network-wide disturbance. As a reflection of this shared network, psychiatric comorbidities and/or cognition problems may actually precede the seizure occurrence and likely get often missed if not screened.

Validation of the Hamilton Rating Scale for Depression in adults with epilepsy.

PURPOSE: Mood disorders represent a frequent psychiatric comorbidity among patients with epilepsy, having a major impact on their quality of life and contributing considerably to the global burden of the disease. The availability of standardized clinical instruments validated in populations with epilepsy has important implications in terms of diagnosis and treatment. This aimed to validate the Hamilton Rating Scale for Depression (HRSD) in adult patients with epilepsy. METHODS: A consecutive sample of 120 adult outpatients with epilepsy was assessed using the Mini International Neuropsychiatric Inventory (MINI) Plus version 5.0.0 and the HRSD. RESULTS: Cronbach's alpha coefficient was 0.824 for the 17-item version and 0.833 for the 21-item version. Receiver operating characteristic analysis showed an area under the curve of 0.896 and 0.899, respectively, for the two versions. However, the HRSD-17 demonstrated the best psychometric properties compared to the HRSD-21 and, with a cutoff score of 6, showed a sensitivity of 94%, a specificity of 80%, a positive predictive value of 46%, and a negative predictive value of 99%. CONCLUSIONS: The HRSD proved to be reliable and valid in the epilepsy setting and will stimulate further research in this area.

Insomnia symptoms in South Florida military veterans with epilepsy.

BACKGROUND: Despite the high prevalence of insomnia in veterans with epilepsy, it remains understudied. Our aim was to identify the associations of insomnia with epilepsy, comorbidities, and treatment-related variables in South Florida veterans. METHODS: We performed a cross-sectional analysis of veterans attending an epilepsy clinic over 18 months. Participants completed standardized assessments of seizure and sleep. Insomnia was defined as 1) difficulty with sleep onset, maintenance, or premature awakenings with daytime consequences or 2) sedative-hypnotic use on most nights of the previous month. RESULTS: One hundred sixty-five veterans (87% male, age 56 ± 15 years) were included: 66 reporting insomnia (40%). In logistic regression analysis, insomnia was significantly associated with post-traumatic seizure etiology, lamotrigine prescription, and mood and psychotic disorders. Female gender and levetiracetam treatment were associated with lower odds for insomnia. CONCLUSION: Insomnia was associated with post-traumatic epilepsy, mood/psychotic comorbidities, and antiepileptic regimen. Insomnia represents an under-recognized opportunity to improve comprehensive epilepsy care.

Validation of the Italian version of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E).

The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was developed for the rapid detection of a major depressive episode in people with epilepsy. It has been proven to be a user-friendly screening instrument. This study describes the development, validation, and psychometric properties of the Italian version of the NDDI-E. A consecutive sample of 120 outpatients with epilepsy has been assessed using the M.I.N.I. Plus version 5.0.0 and the NDDI-E. All patients had no major difficulties in understanding or answering the questions of the Italian version. Cronbach's alpha coefficient was 0.851. Receiver operating characteristic analysis showed an area under the curve of 0.943 (CI95%=0.902-0.985; SE 0.021; p<0.001), a cut off score of 13, a sensitivity of 86.2%, a specificity of 89%, a positive predictive value of 71.4%, and a negative predictive value of 95.3%.

Risk of adverse events on epilepsy monitoring units: a survey of epilepsy professionals.

In 2008 a workgroup of health care professionals from the American Epilepsy Society (AES) was convened to address the lack of consensus regarding patient care in epilepsy monitoring units (EMUs). The group developed a questionnaire designed to identify the extent to which selected adverse events occurred in EMUs, and it was sent via email to all members of the AES. We asked that only one representative from each center report. Seventy responses were received. The number of centers reporting the following adverse events included: falls by 69%, status epilepticus by 63%, and postictal psychosis by 54%. Infrequent events with serious consequences were also reported including pneumonia by 10%, cardiac arrest by 7%, fractures by 6%, and death by 3% (N=2). Of the 58 respondents who reported using intracranial electrodes, 37.9% (N=22) reported that patients pulled out or dislodged electrodes. This study highlights the need for EMUs to identify and address potential safety risks in their environment, patient population, and system of care.

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.

Postictal psychiatric events during prolonged video-electroencephalographic monitoring studies.

BACKGROUND: Postictal psychiatric events presenting as postictal psychotic events and postictal nonpsychotic events are known to occur following seizure clusters. Accordingly, patients undergoing prolonged video-electroencephalographic (EEG) monitoring studies may be at increased risk of experiencing postictal psychiatric event, as they often have flurries of seizures during these studies. OBJECTIVES: To determine the annual incidence and clinical characteristics of postictal psychotic events and postictal nonpsychotic events in video-EEG monitoring studies in patients with partial seizure disorders and to identify potential pathogenic factors. RESULTS: Thirteen patients met the criteria for a postictal psychiatric event during the 18-month study period, 10 presenting as postictal psychotic events and three as postictal nonpsychotic events. The annual incidence of postictal psychiatric events at our monitoring unit for 1988 was 7.8%, 6.4% presenting as postictal psychotic events and 1.4% as postictal nonpsychotic events. Seven patients had their first-ever postictal psychiatric event during the monitoring study. In 12 of the 13 patients, the postictal psychiatric events mimicked well-defined psychiatric entities of shorter duration (mean, 66.5 hours); they appeared 12 to 72 hours after the last seizure and remitted spontaneously or with the use of low-dose psychotropic medication. No significant differences in EEG, neuroradiologic, psychiatric, medical, or psychosocial data were found between the patients with postictal psychiatric events and a group of 13 age-matched control patients. Follow-up data of comparable duration were available in nine patients with postictal psychiatric events and nine controls. Psychiatric events were reported more frequently by patients with postictal psychiatric events than by control patients (P=.03). In three patients, postictal psychiatric events converted to interictal events. CONCLUSION: These findings suggest that monitoring studies increase the risk for postictal psychiatric events, which neurologists need to be familiar with, as they represent important morbidity associated with these studies.

Tailored anterior temporal lobectomy. Relation between extent of resection of mesial structures and postsurgical seizure outcome.

OBJECTIVE: The purpose of this study was to assess the relationship between the extent of resection of mesial temporal structures and postsurgical seizure outcome in a group of patients who had undergone a tailored anterior temporal lobectomy. METHODS: Twenty-four patients with unilateral interictal and ictal foci restricted to anterior/mesial temporal regions underwent resection of mesial and temporal lateral structures, the extent of which was tailored by intraoperative electrocorticographic findings and functional mapping of eloquent cortex. The extent of resection was determined with postoperative magnetic resonance imaging scans, using a semiquantitative method, based on a 20-compartment model of the temporal lobe. The magnetic resonance imaging scans were rated by three investigators blinded to seizure outcome. Follow-up period ranged between 18 months and 5 years. RESULTS: Amygdala and hippocampus were spared in six patients; nine patients had a partial to total resection of amygdala, eight patients had a resection of amygdala and the anterior third of the hippocampus, and one patient underwent resection of amygdala and anterior two thirds of hippocampus. Twenty-one of the 24 patients were seizure free (Engel's class I) and three had rare seizures (Engel's class II). Among these three patients, one had a resection of amygdala; one had resection of amygdala and anterior third of hippocampus; while in the third patient, mesial structures were spared. CONCLUSION: These data suggest that in patients with an anterotemporal seizure focus, the sparing or limited resection of amygdala and/or hippocampus is not necessarily associated with a poor seizure outcome, as had been previously suggested, provided that the decision not to resect is based on the absence of epileptiform activity during intraoperative electrocorticography or during recordings with depth electrodes.

Adding valproate to lamotrigine: a study of their pharmacokinetic interaction.

The addition of valproic acid (VPA) to a lamotrigine monotherapy regimen (LTG) results in a decrement of LTG clearance. Whether this effect is related to the dose or concentration at steady state (Css) of VPA is yet to be established. This study was conducted to determine whether the dose or Css of VPA were inversely related to LTG clearance in 28 patients with intractable epilepsy who were treated with a combination of LTG and VPA. Correlations between LTG clearance and the dose and Css of VPA and comparisons of LTG clearance during low and high doses of VPA demonstrated that the degree of inhibition of LTG clearance is independent of the dose and Css of VPA.

Depressive disorders in epilepsy.

Depression is a common occurrence among epileptic patients and constitutes, along with anxiety disorders, the most frequent psychiatric condition in these patients. The relationship between depression and epilepsy is two-directional, because patients with major depression also have a higher frequency of epilepsy. In epileptic patients, depressive disorders can present as unipolar, bipolar, or dysthymic disorders. More characteristically, however, they present as an atypical depression, which can often go unrecognized for long periods of time. In the diagnostic evaluation of these patients, clinicians must rule out the possibility that the depressive disorder resulted from the administration of antiepileptic drugs (AEDs; e.g., barbiturates) or from the discontinuation of an AED with mood-stabilizing properties that were masking an underlying affective disorder. Although antidepressant drugs have been used in epileptic patients for a long time, to date there has only been one controlled study. The antidepressants of the family of selective serotonin reuptake inhibitors (SSRIs) should be considered as initial therapy for depressive disorders in these patients.

Psychiatric and neurologic predictors of psychogenic pseudoseizure outcome.

OBJECTIVE: To investigate the patterns of occurrence of psychogenic pseudoseizures (PPS) of 45 consecutive patients during a 6-month period after diagnosis, and to determine whether psychiatric and neurologic variables identified previously in PPS patient series can predict their recurrence after diagnosis, and whether any of these variables are associated with a particular outcome pattern. METHOD: Postdiagnosis PPS recurrence was assessed twice: during the first month and during a period ranging from the second to the sixth month. Outcome was categorized as follows: class I, complete cessation of PPS; class II, PPS only during one of the two observation periods; and class III, persistent PPS during the two observation periods. The authors used a logistic regression model to identify predictors of PPS recurrence (versus no PPS) among four neurologic and nine psychiatric variables, and compared their frequency among the three outcome classes. RESULTS: Class I, n = 13 (29%); class II, n = 12 (27%); and class III, n = 20 (44%). The presence of an abnormal MR image predicted PPS recurrence during the second observation period with a 75% accuracy. The presence of all nine psychiatric variables predicted PPS recurrence during both the first and second observation periods with a 93% and an 89% accuracy respectively. Patients with a class III outcome had a markedly higher frequency of recurrent major depression, dissociative and personality disorders, and a history of chronic abuse. Patients with a class II outcome displayed a notably higher frequency of denial of stressors and psychosocial problems, refusal of treatment recommendations, and new somatic symptoms after disclosure of diagnosis. Conversely, one episode of major depression was the one common diagnosis in patients with a class I outcome. CONCLUSIONS: PPS outcome after disclosure of diagnosis can be predicted by the presence of certain psychiatric characteristics. More than one psychopathogenic mechanism appears to operate in PPS.

Wada difference a day makes: interpretive cautions regarding same-day injections.

OBJECTIVE: To determine whether memory scores after second intracarotid amobarbital procedure (IAP) injections are affected by the time between the first and second injections. METHODS: Sixty-two patients received their second IAP injection on the day after the first injection. Forty-three other patients received the second injection on the same day as the first injection. Both groups underwent similar IAP protocols and memory assessments, except for the timing of the second injection. RESULTS: The second IAP memory scores in the two-day group were significantly higher (p < 0.05) than those in the one-day group. Timing of second injection was a significant correlate of second memory scores, but amobarbital dosage, first IAP memory score, and pre-IAP measures of memory and intelligence were not significant correlates. CONCLUSION: One-day and two-day IAP protocols do not result in similar memory scores after the second injection. Nineteen percent of a subset of patients in the one-day protocol were misclassified, in terms of IAP memory ratings, because of the deleterious effect of having both injections on the same day. It is recommended that correction scores be considered, for some patients who receive two IAP injections on one day, to approximate what the second IAP memory score would have been had the second injection occurred on a second day.

Supplementary motor seizures mimicking pseudoseizures: some clinical differences.

Supplementary motor seizures (SMS) are among the group of frontal lobe seizures that may often be misdiagnosed as pseudoseizures (PS). We designed this study to determine the value of clinical phenomena in distinguishing between the two. In a series of patients with SMS, we identified those with symptoms mimicking PS and compared the clinical phenomena with those of clinically similar PS. We found that SMS are short in duration, stereotypic, tend to occur in sleep, and often present with a tonic contraction of the upper extremities in abduction. This sign was specific for SMS, particularly when occurring at the onset. Conversely, PS are long in duration, nonstereotypic, and occur in the awake state. We conclude that clinical phenomena may be useful in distinguishing PS from SMS, although the final diagnosis must be documented by neurophysiologic means.

The utility of placing sphenoidal electrodes under the foramen ovale with fluoroscopic guidance.

Although sphenoidal electrodes are widely used to detect epileptiform activity, there is no agreement on an optimal target to which electrodes should be aimed. The purpose of this study was to determine whether fluoroscopic guidance is a reliable method for placing electrodes directly below the foramen ovale and whether such positioning enhances their capacity to detect epileptiform activity when compared to similar electrodes placed blindly into the infratemporal fossa. We examined the surface/sphenoidal EEG recordings of 17 patients with intractable partial seizures of anterotemporal origin, after fluoroscopically placed sphenoidal electrodes (FPSE) had been inserted to lie just below the foramen ovale. A criterion for eligibility was a previous prolonged video/EEG monitoring with blindly placed sphenoidal electrodes (BPSE) that failed to detect seizures with a focal onset. No blindly placed electrode, for which there was radiographic documentation, reached the foramen ovale. Fluoroscopic guidance assured accurate targeting. FPSE detected a unilateral anterotemporal interictal focus in four patients in whom BPSE had failed to record any interictal spikes and detected bitemporal independent interictal foci in one patient in whom BPSE had identified only unilateral spikes. In nine other patients, the spike count obtained with FPSE recordings increased by > 100% when compared to that obtained with BPSE recordings. FPSE recorded seizures with an anterotemporal focal onset pattern in 10 patients in whom BPSE had recorded seizures with a regional, lateralized, or nonlocalized onset pattern. In nine of these 10 patients, this was adequate to recommend surgery and avoid invasive monitoring. Fluoroscopic guidance assures accurate targeting of the foramen ovale. When compared to BPSE, FPSE resulted in better detection of interictal and ictal epileptiform activity of mesial-basal-temporal origin.

Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures.

The efficacy and safety of felbamate monotherapy were evaluated in 52 patients with refractory partial seizures with or without secondary generalization in a double-blind, randomized, placebo-controlled trial. Each patient completed a routine evaluation for epilepsy surgery and was randomized to receive either felbamate, titrated to a maximum daily dose of 3600 mg over 2 days, or placebo during the 10-day, inpatient, treatment phase. An intent-to-treat analysis was performed on the data of all 52 patients who received study medication, while a separate efficacy analysis also was performed on the data of 43 evaluable patients, which excluded protocol violators. The endpoint of the trial was completing 10 days of treatment or the occurrence of a fourth seizure. The primary efficacy variable was the average daily seizure frequency during the treatment phase for each patient. For the intent-to-treat analysis based on all 52 patients who received study medications, the mean rank of the daily seizure frequency for patients treated with felbamate was 21.6 compared to 29.6 for patients treated with placebo (P = 0.065). In the analysis based on the 43 evaluable patients, the mean rank of the daily seizure frequency for felbamate-treated patients was 17.0 compared to 25.4 for placebo-treated patients. This difference was statistically significant (P = 0.032) in favor of felbamate. Seizure frequency was decreased by 89.5% compared to baseline in nine patients who completed 10 days of felbamate therapy. This study permitted the rapid determination of the anticonvulsant activity of felbamate and demonstrated that felbamate is effective as monotherapy for the treatment of partial seizures.

Seizure control after chronic pharmacotherapy in epileptic disorders beginning after 40 years of age.

Few studies have been published on the pharmacologic response to treatment of patients whose seizures begin after 40 years of age. The purpose of this study was to assess the impact of chronic pharmacotherapy on the seizure control of such patients. We retrospectively studied the seizure frequency recorded during a 12-month period in a group of 94 outpatients whose seizure disorders began after 40 years of age (median age of seizure onset 56.5 years) and who had been treated with anticonvulsant medication for a median period of 6 years (range 18 months to 12 years). We assessed the relationship between the patients' seizure frequency during the last 12 months of treatment using (a) the present and previously prescribed pharmacologic regimens, (b) anticonvulsant blood levels of present regimen, (c) etiology and duration of seizure disorder, (d) age at onset of seizures, and (e) presence of electrographic (EEG) and neuroradiologic abnormalities. We only identified side effects occurring at blood levels within or below the drug's therapeutic range. Seventy-eight patients (83%) were seizure free during the last 12 months of treatment, 11 (11%) had rare seizures, and five (6%) had more than four seizures per year. Seizure frequency was not affected by duration and etiology of seizure disorder, age at onset of seizures, seizure type, neuroradiologic or electroencephalographic abnormalities, and present or previously prescribed pharmacologic regimens. Persistent side effects were reported in seven of 76 (9%) monotherapy regimens and in two of 12 (17%) polytherapy regimens. Our data suggest that seizures beginning after the age of 40 have a favorable prognosis after chronic pharmacotherapy.

Are we overusing the diagnosis of psychogenic non-epileptic events?

In order to determine how often results of video/EEG (V-EEG) studies may change the clinical diagnosis of paroxysmal events, we prospectively studied 100 consecutive patients (75 females, 25 males) admitted for diagnosis of recurrent paroxysmal spells. The presumed diagnosis of the referring physician was obtained. Episodes were classified as epileptic seizures (ES), psychogenic non-epileptic events (PNEE), or physiologic non-epileptic events (PhysNEE). Eighty-seven patients had diagnostic events. A final diagnosis of ES was made in 21 patients, PNEE in 39, PNEE + ES in 20, and PhysNEE in seven. All PhysNEE were unsuspected. ES were misdiagnosed as PNEE more frequently than the reverse (57% vs. 12%, P < 0.001). Among the 64 patients with recorded events who had been suspected of having PNEE, 14 (21.9%) were misdiagnosed: two had PhysNEE and 12 (18.75%) had ES. Among the 23 patients with recorded events who were thought to have ES, 12 (39.1%) were misdiagnosed: seven had PNEE, five PhysNEE. V-EEG changed the clinical diagnosis in 29.8% of the patients with recorded events. Our data suggests that clinicians have become more aware of PNEE since the advent of V-EEG and have little problem recognizing them. However, they may be more prone to make a false-positive diagnosis of PNEE in ES with some atypical features. At this point, efforts should be channeled to better training in the proper recognition of ES that mimic PNEE.