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.

Early Biomarkers from Conventional and Delayed-Contrast MRI to Predict the Response to Bevacizumab in Recurrent High-Grade Gliomas.

BACKGROUND AND PURPOSE: The interpretation of the radiologic response of bevacizumab-treated patients with recurrent high-grade gliomas represents a unique challenge. Delayed-contrast MR imaging was recently introduced for calculating treatment-response-assessment maps in patients with brain tumors, providing clear separation between active tumor and treatment effects. We studied the application of standard and delayed-contrast MR imaging for assessing and predicting the response to bevacizumab. MATERIALS AND METHODS: Twenty-four patients with recurrent high-grade gliomas were scanned before and during bevacizumab treatment by standard and delayed-contrast MR imaging. The mean change in lesion volumes of responders (overall survival, ≥1 year) and nonresponders (overall survival, <1 year) was studied. The lesion volumes at baseline and the changes in lesion volumes 1 month after treatment initiation, calculated from standard and delayed-contrast MRIs, were studied as possible predictors of outcome. In scans acquired at progression, the average change in lesion volume from previous follow-up in standard and delayed-contrast MRIs was compared. RESULTS: Response and progression patterns were identified from the mean change in lesion volumes, depicted from conventional T1WI, delayed contrast-enhanced MR imaging, and DSC MR imaging. Thresholds for early prediction of response were calculated by using these sequences. For each predictor, sensitivity, specificity, positive predictive values, and negative predictive values were calculated, reaching 85.7%, 87.5%, 75%, and 93.3% for conventional T1WI; 100%, 87.5%, 77.8%, and 100% for delayed-contrast MR imaging; and 75%, 78.6%, 50%, and 91.7% for DSC MR imaging. The benefit of delayed-contrast MR imaging in separating responders and nonresponders was further confirmed by using log-rank tests (conventional T1WI, P = .0022; delayed-contrast MR imaging, P < .0001; DSC MR imaging, P = .0232) and receiver operating characteristic analyses. At progression, the increase in lesion volumes in delayed-contrast MR imaging was 37.5% higher than the increase in conventional T1WI (P < .01); these findings suggest that progression may be depicted more effectively in treatment-response-assessment maps. CONCLUSIONS: The benefit of contrast-enhanced MR imaging for assessing and predicting the response to bevacizumab was demonstrated. The increased sensitivity of the treatment-response-assessment maps reflects their potential contribution to the management of bevacizumab-treated patients with recurrent high-grade glioma.

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%.

Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years.

OBJECTIVE: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. METHODS: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999-2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). RESULTS: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102-109), lamotrigine 106 (102-109), phenytoin 105 (102-109), valproate 96 (91-100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. CONCLUSIONS: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.

Acute cortisol release during stereotactic fractionated radiotherapy to an ACTH-secreting pituitary macroadenoma.

A 33-year old male was diagnosed with Cushing's disease due to a large and invasive ACTH-secreting macroadenoma. After surgical failure ketoconazole therapy was initiated to control cortisol hypersecretion and his symptoms. He was referred to radiotherapy, and fractionated stereotactic radiotherapy in 30 fractions was delivered. After 12 daily fractions of radiotherapy the urinary cortisol release increased abruptly together with clinical deterioration. The daily ketoconazole dose was increased, and 10 days after concluding radiotherapy his urinary cortisol returned to normal values. Hormonal remission was observed less than 1 year following radiotherapy.

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.

Effects of breastfeeding in children of women taking antiepileptic drugs.

BACKGROUND: Breastfeeding is known to have beneficial effects, but there is concern that breastfeeding during antiepileptic drug (AED) therapy may be harmful to cognitive development. Animal and human studies have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children. METHODS: The Neurodevelopmental Effects of Antiepileptic Drugs Study is an ongoing prospective multicenter observational investigation of long-term effects of in utero AED exposure on cognition. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single AED (carbamazepine, lamotrigine, phenytoin, or valproate). We recently reported on differential AED effects on age 3 year cognitive outcomes. In this report, we focus on the effects of breastfeeding during AED therapy on age 3 cognitive outcomes in 199 children. RESULTS: A total of 42% of children were breastfed. IQs for breastfed children did not differ from nonbreastfed children for all AEDs combined and for each of the 4 individual AED groups. Mean adjusted IQ scores (95% confidence intervals) across all AEDs were breastfed = 99 (96-103) and nonbreastfed = 98 (95-101). Power was 95% to detect a half SD IQ effect in the combined AED analysis, but was inadequate within groups. CONCLUSIONS: This preliminary analysis fails to demonstrate deleterious effects of breastfeeding during AED therapy on cognitive outcomes in children previously exposed in utero. However, caution is advised due to study limitations. Additional research is needed to confirm this observation and extend investigations to other AEDs and polytherapy.

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.

Improved tolerability and efficacy in epilepsy patients with extended-release carbamazepine.

The authors conducted a 3-month, prospective, open-label study assessing the effects of switching from immediate-release carbamazepine formulations to an equal total daily dose of carbamazepine extended-release capsules (CBZ-ERC) in adolescents and adults with epilepsy. Using validated, epilepsy-specific measures the authors found that switching to CBZ-ERC significantly improved patients' adverse events and quality-of-life measures. Switching to CBZ-ERC also improved seizure control.

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.

Postmarketing experience with topiramate and cognition.

Ideal antiepileptic drugs (AEDs) are designed to stop seizures with limited central nervous system (CNS) side effects. However, CNS-related treatment-emergent adverse events (TEAEs) often occur in patients receiving AEDs. Topiramate (TPM) is an AED proven to be safe and effective as adjunctive treatment for epilepsy patients with partial seizures. Double-blind, placebo-controlled, multicenter trials demonstrated potential effects on cognition. The P.A.D.S. (post-marketing antiepileptic drug survey) group, a cooperative group of 14 epilepsy centers that collaborate on obtaining data about new AEDs and devices, prospectively collected standardized data forms before and during treatment with TPM for epilepsy, and analyzed the postmarketing experience of CNS TEAEs with TPM. Our results from 701 treated patients show that cognitive complaints were the most common reason to discontinue TPM. The presence of complaints did have predictive value if the patient would discontinue TPM, although was not specific as to when discontinuation would occur. The spectrum of complaints in our open-label prospective multicenter postmarketing study was similar to those observed in controlled clinical trials. We were unable to demonstrate a specific population, dose titration, or concomitant AED that was at risk to discontinue treatment. We conclude that most patients treated with TPM will continue therapy beyond 6 months. Cognitive complaints and not efficacy reflect the primary reason for discontinuing therapy. Psychomotor slowing was the most common complaint, yet most patients elect to continue treatment, with "better" or "much better" ratings of both seizure and global improvement during treatment.

Outlet fenestration for isolated fourth ventricle with and without an internal shunt.

Conventional shunting of isolated fourth ventricle is notorious for leading to frequent and severe complications. We present four patients with isolated fourth ventricle who have been treated with open posterior fossa surgery together with either outlet fenestration alone or outlet fenestration and a fourth ventricle-spinal subarachnoid space (SSS) shunt. A survey of the relevant literature did not yield any other case reports of fourth ventricle shunting to the SSS under such circumstances. This paper discusses the reasons for choosing this mode of treatment. The main advantage of this technique is that the catheter is inserted along the anatomical long axis of the fourth ventricle. This positioning lessens the possibility of irritating or penetrating the brain stem. Moreover, as a more physiological solution, the shunt does not require a valve system. Because of these advantages, internal fourth ventricle-SSS shunting is proposed as a valid alternative to the "classic" fourth ventriculo-peritoneal shunt.

Safety of perioperative minidose heparin in patients undergoing brain tumor surgery: a prospective, randomized, double-blind study.

OBJECT: Thromboembolic phenomena (TEPs) continue to be a significant source of morbidity and mortality in patients undergoing neurosurgery. Although the efficacy of low-dose heparin in preventing TEPs in neurosurgical patients is well established, neurosurgeons are reluctant to use it perioperatively because of concern for increased bleeding complications. To clarify this issue, the authors used a prospective, randomized, double-blind design to evaluate the safety of minidose heparin treatment in patients undergoing surgery for supratentorial brain tumors. METHODS: One hundred three patients, all 40 years of age or older, were treated with either 5000 U of heparin (55 patients) or placebo (48 patients) starting 2 hours before surgery and continuing until full mobilization or for 7 days. Both groups were well matched for sex, weight, duration of surgery, and tumor diagnosis. Subjective and objective parameters were used to estimate and calculate the perioperative bleeding tendency in all patients. Red blood cell mass loss was calculated by assessing the preoperative and postoperative hematocrit and the patient's weight. Intraoperative blood loss was determined by measuring the quantity of blood in the suction containers and subtracting the amount of irrigation fluids. Postoperative bleeding was measured by determining the amount of fluid in the subgaleal drain, and blood cell replacement was monitored during and after the procedure. Intracranial bleeding was graded according to findings on the postoperative computerized tomography scan obtained 48 to 72 hours after surgery. In addition, the senior surgeon in each case was asked to assess each patient's bleeding tendency during the operation. The results showed that perioperative administration of heparin did not significantly alter bleeding tendency by any measured parameter. The surgeon was blinded to which group individual patients had been allocated. CONCLUSIONS: Perioperative minidose heparin is safe for use in patients undergoing craniotomy for supratentorial tumors. This relatively simple and inexpensive measure is recommended as a routine regimen for the prevention of TEPs in patients undergoing neurosurgery.

No evidence of epilepsy following endoscopic third ventriculostomy: a short-term follow-up.

Patients with ventriculo-peritoneal shunts are predisposed to various complications, including the appearance of seizures over time. The high rate of complications prompted an interest in alternative procedures such as endoscopic third venticulostomy (ETV) in selected patients. From 1996 to 1998, 42 patients underwent ETV in our center. Of the 27 operated children who were followed for an average of 32 months, none experienced seizures during that time. We conclude that, in addition to other benefits, ETV minimizes the risk of epilepsy following shunt insertion, probably due to the lack of direct cortical insult.