Juri-Alexander Witt

The effects of levetiracetam on cognition: A non-interventional surveillance study

Objective and subjective cognitive measures were evaluated in 401 patients before and 3 and 6 months after introducing levetiracetam (LEV). Initially, cognitive impairment was indicated in 37-44% of the patients, and subjective impairments in 32-67%. With LEV, 87% of untreated patients changed to monotherapy, and 94% changed from mono- to polytherapy. The rate of retention of LEV was 97%; adverse events were reported by 7%. Under LEV, 36% achieved early seizure control, 25% achieved late seizure control, 33% continued to have seizures, and 7% had a relapse. Very good tolerance was reported by 68%, and cognitive improvement by 58%. Objective improvement was significant in 23-29% of the patients; 5-6% deteriorated. Better baseline scores, later-onset epilepsies, fewer initial antiepileptic drugs, and seizure control were predictive of a better cognitive outcome. Considering the uncontrolled study design and the increase in total drug load, LEV appeared safe and efficacious, and a general subjective and objective cognitive improvement could be noted. However, a controlled study design would be required to attribute these improvements to a specific drug action.

The longer-term cognitive effects of adjunctive antiepileptic treatment with lacosamide in comparison with lamotrigine and topiramate in a naturalistic outpatient setting

In this retrospective controlled study, the impact of adjunctive lacosamide (LCM) on cognition in patients with epilepsy was evaluated and compared with that of topiramate (TPM) and lamotrigine (LTG) in a naturalistic outpatient setting. Cognition was investigated by means of objective assessment of executive functions (EpiTrack®) and verbal memory and by subjective ratings of self-perceived side effects (cognition, mood, and vegetative). Quality of life was assessed using the QOLIE-10 questionnaire. Patients underwent assessment at baseline and after a median follow-up interval of 32 weeks. Forty-four patients were treated with LCM, 11 with LTG, and 15 with TPM. Treatment arms differed with regard to the age at onset of epilepsy (LTG>TPM) and to seizure control from baseline to follow-up, which was best in patients whose seizures were treated with LTG (55% vs. 16% in patients whose seizures were treated with LCM and 13% in patients whose seizures were treated with TPM). Groups did not differ in the type of epilepsy, daily drug load or drug load change, nor in baseline seizure frequency. Repeated measures statistics controlling for epilepsy onset and seizure outcome showed deteriorated executive functions with TPM (F=7.5, p=0.001). On an individual level (reliable change indices), 53% of the patients whose seizures were treated with TPM showed losses in this domain (LCM 14%, LTG 27%) and none of the patients showed improvement (LCM 23%, LTG 27%; χ(2)=11.8, p=0.019). No differences in memory, quality of life, or mood were noted among patients in the three treatment arms. Subjective cognitive complaints increased in 5 of the 9 patients whose seizures were treated with TPM (LCM 1/9, LTG 0/9; χ(2)=11.9, p=0.025). The findings of this study demonstrate for the first time that the cognitive side effect profile of LCM is comparable to that of LTG and superior to that of TPM. This is indicated by both subjective and objective measures. Given the naturalistic setting and the retrospective nature of the study, a follow-up prospective, randomized trial with larger sample sizes is required to confirm these findings.

Monitoring the cognitive effects of antiepileptic pharmacotherapy--approaching the individual patient.

Cognitive side effects of antiepileptic drugs are common and can negatively affect tolerability, compliance, and long-term retention of the treatment. Furthermore, adverse cognitive effects of pharmacotherapy significantly affect everyday functioning and quality of life. Consequently, preservation of cognitive functions is an important aspect of epilepsy therapy. Knowledge of the patients neuropsychological status before and after pharmacological interventions can help to decide on the appropriate treatment and, thus, can potentially improve individual medical care. Here, we suggest that cognitive monitoring of antiepileptic pharmacotherapy--like the assessment of seizure frequency, blood serum levels, electroencephalography or structural imaging--should be carried out as a matter of routine. In contrast to subjective measures, there are only very few neuropsychological instruments explicitly validated for the assessment of cognition along with antiepileptic pharmacotherapy. This review (1.) outlines indications and requirements for individual cognitive monitoring, (2.) discusses available diagnostic tools, and (3.) discloses relevant pitfalls. Neuropsychology, as demonstrated, provides evidence-based methods for monitoring cognitive effects of individual pharmacological treatments and, therefore, serves as a valuable tool for the quality and outcome control of antiepileptic therapies.

Cognitive outcome of antiepileptic treatment with levetiracetam versus carbamazepine monotherapy: A non-interventional surveillance trial

This open-label, non-interventional, controlled surveillance study evaluated the cognitive outcome of patients administered levetiracetam (LEV) or carbamazepine (CBZ) monotherapy as primary treatment or as substitution for previous treatment. Executive functions, verbal memory, and subjective ratings were assessed before and 6 months after initiation of LEV or CBZ monotherapy. Analyses included 498 patients: 370 received LEV (63% pretreated), and 128 CBZ (34% pretreated). Mostly because of the substitution condition, the seizure freedom rate was slightly higher with LEV as opposed to CBZ (78% vs 69%). Almost all cognitive measures improved with LEV but not with CBZ, and repeated-measures MANOVA did not indicate seizure control or pretreatment as decisive with respect to cognitive change. With LEV, executive functions improved in 15% and deteriorated in 5% of patients; the opposite pattern was seen under CBZ (improvement with LEV OR=2.3, deterioration with CBZ OR=3.4). The findings suggest a mild but definitely superior cognitive outcome with LEV as opposed to CBZ monotherapy.

Clinical neuropsychology in epilepsy: theoretical and practical issues

Abstract For an understanding of cognitive impairment in epilepsy, it is essential to appreciate that static and dynamic factors affect brain function in this disease. Whereas morphological lesions or structural changes are associated with more or less irreversible deficits, epileptic activity, seizures, and the treatment of epilepsy can cause dynamic and largely reversible impairments. The contribution of these factors varies depending on the type of epilepsy, the age at lesion/epilepsy onset, the localization and lateralization of the epilepsy, and individual demographic patient characteristics. Altered brain structure and function can result in epilepsy, but epilepsy can also alter the functional cerebral organization of the brain. Thus, epilepsy-related cognitive impairment must be seen within a developmental neuropsychological framework. From a neuropsychological point of view, it is essential as to whether epilepsy affects the maturing versus the mature or aging brain. Epilepsy can result in retardation, loss of acquired functions, or accelerated mental decline. Cognitive impairments in epilepsy often exist from the commencement of the epilepsy; early-onset lesions/epilepsy interfere with mental development; and a progressive etiology, severe seizures, and lesions secondary to epilepsy can accelerate mental decline. Uncontrolled epilepsy and epileptic activity, as well as the treatment of epilepsy, may reversibly and irreversibly affect cognition. Within this framework, neuropsychology has become an essential diagnostic tool for the early detection and monitoring of cognitive impairment and its determinants in newly established and chronic epilepsies. Neuropsychology serves as a valuable tool for quality and outcome control of the treatment of epilepsy and helps to improve the individual medical care of patients with epilepsy.

Adverse cognitive effects of antiepileptic pharmacotherapy: Each additional drug matters.

The study was set up to evaluate the impact of the total drug load of antiepileptic pharmacotherapy on cognition. Retrospective analyses were based on 834 patients with epilepsy who underwent a brief routine assessment of executive function and verbal memory (EpiTrack Plus) at our department. The total drug load was quantified in two ways: (1) number of concurrent antiepileptic drugs (AEDs) and (2) total drug load according to the defined daily dose (DDD) provided by the World Health Organization. The cognitive measures showed higher inverse correlations with the number of AEDs (executive function: r=-0.35, p<0.001; memory: r=-0.22, p<0.001) than with the total DDD (executive function: r=-0.27, p<0.001; memory: r=-0.17, p<0.001). Reanalysis with statistical control for disease severity hardly changed the aforementioned results. With each additional drug in polytherapy, we observed a significantly lower performance in executive function. In this regard an additional explorative approach revealed that regimens combining AEDs with favorable cognitive profiles were associated with higher cognitive performance. Correlations between indicators of disease severity and drug load indices were low: altogether explaining only up to 9% of the observed variance in drug load. The findings demonstrate a considerable adverse effect of a higher drug load on cognition, especially on executive functions. Simply counting the number of drugs may be sufficient as a rough estimate of the risk of side effects. However, the combination of AEDs with favorable cognitive profiles may attenuate the negative effect of the total drug load.

Automated volumetry of the mesiotemporal structures in antibody-associated limbic encephalitis

Objective Limbic encephalitis (LE) is an autoimmune mediated disease leading to temporal lobe epilepsy, mnestic and psychiatric symptoms. In recent years, several LE subforms defined by serum antibody findings have been described. MRI usually shows volume changes of the amygdala and hippocampus. However, studies quantifying longitudinal volume changes in the acute disease stage are lacking. Methods The aim of this retrospective observational study was to evaluate and quantify these volume changes by applying a fully automated volumetric approach to serial MRIs of 28 patients with antibody-associated LE. The results were compared with those of 28 age-matched and gender-matched healthy controls and analysed separately for the different antibody profiles and correlated with clinical parameters. Antibody profile analyses were exploratory due to the relatively small sample sizes. Results We found distinct volumetric and clinical courses depending on the associated antibody. While LE associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) showed highly significant larger volumes of both the amygdala and the hippocampus within the first 12 months after disease onset, LE associated with glutamic acid decarboxylase antibodies (GAD-LE) only displayed greater amygdala volumes at this disease stage. Both subgroups showed a reduction of the amygdala and hippocampus volumes during follow-up with higher volume changes in VGKC-LE. Conclusions These differences in the volumetric evolution corresponded to distinct clinical courses in terms of a more severe initial symptomatology regarding seizure, mnestic and psychiatric disturbances in VGKC-LE, which improved rapidly, corresponding to the evolution of the volumetric changes. In contrast to this, patients with GAD-LE were less severely affected at disease onset, showing a more unmodulated and chronic disease course during follow-up.

A second chance—reoperation in patients with failed surgery for intractable epilepsy: long-term outcome, neuropsychology and complications

Object Resective surgery is a safe and effective treatment of drug-resistant epilepsy. If surgery has failed reoperation after careful re-evaluation may be a reasonable option. This study was to summarise the risks and benefits of reoperation in patients with epilepsy. Methods This is a retrospective single centre study comprising clinical data, long-term seizure outcome, neuropsychological outcome and postoperative complications of patients, who had undergone a second resective epilepsy surgery from 1989 to 2009. Results A total of 66 patients with median follow-up of 10.3 years were included into the study. Fifty-one patients (77%) had surgery for temporal lobe epilepsy, the remaining 15 cases for extra-temporal lobe epilepsies. The most frequent histological findings were tumours (n=33, 50%), followed by dysplasia, gliosis (n=11, each) and hippocampus sclerosis (n=9). The main reasons for seizure recurrence were incomplete resection (59.1%) of the putative epileptogenic lesion. After reoperation 46 patients (69.7%) were completely seizure-free International League Against Epilepsy 1 (ILAE 1) at the last available follow-up. The neuropsychological evaluation demonstrated that repeated losses in the same cognitive domain, that is, successive changes from better to worse performance categories, were rare and that those losses after first surgery were followed by improvement rather than decline. However, reoperations lead to an increased rate of permanent neurological deficits (9%), overall surgical complications (9%) and visual field deficits (67%). Conclusions Reoperation after failed resective epilepsy surgery led to approximately 70% long-time seizure freedom and reasonable neuropsychological outcome. There is an increased risk of permanent postoperative neurological deficits, which should be taken into consideration when counselling for reoperation.

Cognition in the early stages of adult epilepsy

PURPOSE The impact of duration of epilepsy on cognition has been discussed for a long time. More recently, it has been recognized that cognitive deficits are often already present at the onset of epilepsy or even before. From an etiological point of view it is now understood that it is not really the question what comes first, epilepsy or cognitive comorbidity. Instead the evidence suggests that both problems rather originate from a common underlying pathology. METHODS We selected studies addressing cognition in adult new-onset or newly diagnosed epilepsies before treatment initiation. Potential factors are outlined that affect cognition prior to, around or after epilepsy onset. RESULTS Most studies investigated newly diagnosed patients, but many included individuals who already had a long history of seizures at the time of diagnosis. Fewer studies focused on new-onset epilepsies. Overall, cognitive problems in the early stages of adult onset epilepsy were found to be common. The occurrence of seizures may initially cause greater concern and lead to an underreporting of cognitive problems prior to or around the time of diagnosis. CONCLUSION The high prevalence of objective cognitive impairments present at epilepsy onset calls for early neuropsychological assessments soon after the diagnosis of epilepsy, and at best before medical treatment is initiated. Without such baseline assessments subsequent neuropsychological testing during follow-up is difficult to interpret in regard to the effects of treatment success or the course of underlying disease processes. Beyond that, the baseline assessment may also guide treatment choices and serve as an early indicator of the need for support or rehabilitation. In this way neuropsychological monitoring can improve individual medical care, and increase tolerability, adherence, and treatment retention from the point of diagnosis.

Which drug-induced side effects would be tolerated in the prospect of seizure control?

There is ample evidence that side effects of antiepileptic pharmacotherapy negatively affect quality of life, adherence, and long-term retention. The study was set up to evaluate the anticipated tolerance of common side effects provided that a 50% or 100% reduction of seizure frequency would be achieved. An anonymous inquiry in 79 consecutive patients with epilepsy comprised questions regarding the severity of epilepsy/seizures and the perceived impact of seizures and drug treatment on daily functioning and a 10-tiered rating which assesses 11 common behavioral/psychiatric, cognitive, physiological, or physical side effects according to the degree to which they would be tolerated. Least acceptance was evident for psychiatric side effects followed by cognitive, physiological, and physical side effects. Weight gain and tiredness were the most tolerated side effects. The overall low acceptance of negative side effects was slightly higher in the case of a 100% vs. 50% seizure frequency reduction (28% vs. 21% of the maximum toleration score regarding all side effects). Surely, there is a trade-off between the severity of epilepsy, seizure control, and the acceptance of adverse treatment effects. However, the data disclose that psychiatric and cognitive side effects are least accepted. Thus, consideration of individual tolerance and monitoring of side effects in addition to seizures may increase adherence and therapy success.