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.

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.

A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy.

PURPOSE: To identify the psychiatric and epilepsy variables predictive of postsurgical seizure outcome after anterotemporal lobectomy (ATL). METHODS: Retrospective study of 100 consecutive patients with temporal lobe epilepsy (TLE) who underwent ATL. The mean (+/- SD) follow-up period was 8.3 (+/- 3.1) years. Three types of surgical outcomes were examined at 2 years after surgery and at last contact: class IA (no disabling seizures no auras), class IA + IB (no disabling seizures), and class IA + IB + IC (no or rare disabling seizures in the first postsurgical year). Logistic regression analyses were performed separately for the three types of surgical outcomes. The epilepsy-related independent variables included age at onset, cause of TLE (mesial temporal sclerosis, lesional and cryptogenic TLE), extent of resection of mesial structures, neuropathologic abnormalities, having only complex partial seizures, and duration of the seizure disorder. The psychiatric independent variables included a postsurgical and presurgical lifetime history of mood, anxiety, attention deficit hyperactivity, and psychotic disorders. RESULTS: The absence of a psychiatric history was an independent predictor of all three types of surgical outcomes. In addition, a larger resection of mesial structures was a predictor for class IA outcome, and having only complex partial seizures (vs generalized tonic-clonic seizures) was a predictor for class IA + IB and IA + IB + IC. Having mesial temporal sclerosis (vs other causes of TLE) was a predictor for class IA + IB + IC as well. CONCLUSIONS: These data indicate that a lifetime psychiatric history may be predictive of a worse postsurgical seizure outcome after an anterotemporal lobectomy.

Rapid infusion with valproate sodium is well tolerated in patients with epilepsy.

Many IV antiepileptic drugs administered in emergency situations to patients with prolonged seizures have serious adverse effects. For this reason, the authors conducted a multicenter, open-label, prospective, dose-escalation study of IV valproate sodium administered to patients with epilepsy at rates of infusion of up to 6 mg/kg/minute and doses of up to 30 mg/kg. Valproate sodium had no clinically significant negative effects on blood pressure and pulse rate and caused only mild-to-moderate, reversible adverse events.

Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. RESULTS: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

The "forgotten" cross-tolerance between phenobarbital and primidone: it can prevent acute primidone-related toxicity.

PURPOSE: We report on the effect that pretreating patients with phenobarbital has on averting adverse events when primidone is introduced. METHODS: Thirty patients with intractable partial epilepsy were pretreated with phenobarbital before starting primidone. Therapy with primidone was started at a dosage of 500 mg/day, and the phenobarbital was stopped. The primidone dose was then increased by 125 to 250 mg every 3 weeks until adverse events or a seizure-free state was reached. All previous antiepileptic medications were tapered down to yield a primidone monotherapy regimen. RESULTS: Twenty-six patients (87%) tolerated the introduction of primidone with minimal or no adverse events. Only one patient had to discontinue primidone during the initial 4 weeks because of severe dizziness. This was the only patient in whom primidone monotherapy could not be reached because of adverse events. Three other patients experienced dizziness severe enough to interfere with their activities. This symptom disappeared in two patients after the dose was lowered; in the other patient, primidone was stopped and phenobarbital was restarted for another 4 days. No symptoms recurred when primidone was reintroduced on the fifth day. CONCLUSIONS: Pretreatment with phenobarbital can minimize the occurrence of intolerable adverse events associated with the introduction of primidone.

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.

Depression in epilepsy: a common but often unrecognized comorbid malady.

Depressive disorders (DDs) represent the most frequent psychiatric comorbidity in epilepsy (1-5). Despite their relatively high prevalence, DDs remain unrecognized and untreated in many patients with epilepsy. The purpose of this review is to examine the reasons behind the failure to recognize and treat DDs in epilepsy. We highlight the essential epidemiologic, etiopathogenic, and clinical aspects that need to be considered in the evaluation of every epileptic patient and dedicate the last section of this paper to the review of the most relevant treatment issues. If we are successful in our goals, the reader will be impressed by the significant impact of DDs on the quality of life of these patients, and by the need to investigate treatment modalities with the same scientific rigor used in the assessment of efficacy of antiepileptic drugs in the control of seizures.

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.

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.