[Alternative Psychoses and Forced Normalization after Seizure Control by Anticonvulsants with Special Consideration of the New Anticonvulsants]. / Alternativpsychose und forcierte Normalisierung durch Antiepileptika unter besonderer Berücksichtigung der neuen Antiepileptika.

In the case of alternative psychosis and forced normalization, the patient alternates between periods of clinically manifest seizures and normal behavior, and other periods of seizure freedom (or significant seizure reduction) accompanied by psychosis or behavioral disturbances. Unlike the clinically defined alternative psychosis, forced normalization is based on EEG findings. In clinical practice and in the literature, both terms are mostly used synonymously, and they also describe the same clinical pictures. This allowed a joint evaluation of the publications about alternative psychosis and forced normalization. Most often, these two disorders occur after seizure control by anticonvulsants. In the period of older anticonvulsants, the succinimides for the treatment of absence seizures were most often associated with the development of an alternative psychosis or forced normalization. In the era of newer anticonvulsants that started with the introduction of vigabatrin, mostly patients with intractable focal seizures were affected. In 1987 - 31 years ago - paranoid hallucinatory psychosis, triggered by vigabatrin in a patient with epilepsy was reported for the first time. In the following years, reports of alternative psychosis and forced normalization appeared to be related to most of the new anticonvulsants. A comprehensive literature search provided 66 cases with detailed information on such events. More than twice as many women were likely to be affected as compared to men; the reason for this phenomenon is unclear. In four retrospective studies, another 176 alternative events were reported but no details were given. The risk of alternative psychosis and forced normalization seems to be particularly low with the new anticonvulsants oxcarbazepine, eslicarbazepine, gabapentin and pregabalin.

Epileptic Seizures Under Antidepressive Drug Treatment: Systematic Review.

OBJECTIVE: This paper is a systematic review on seizures under treatment with substances licensed for major depression. METHOD: Systematic review protocol is available in PROSPERO registration number CRD42016034010. Twenty-five substances were selected according to frequencies of prescriptions and publications. A PubMed search was conducted with "substance name" and "seizure." RESULTS: A total of 2291 articles were screened, out of which 164 fulfilled inclusion criteria. Data synthesis was possible only to a limited extent due to heterogeneity of included patients, observation periods, methods, and outcomes. Evidence for an at most moderate, but still low, risk (>0.1% under regular doses) was found highest for clomipramine, followed by quetiapine, amitriptyline, venlafaxine, citalopram, sertraline, trazodone, mirtazapine, paroxetine, bupropion, and escitalopram. For fluoxetine and duloxetine, the risk seems to be negligible. For the other, mostly newer, substances, sufficient evidence was not available. An increased risk for lithium, as reported in many reviews and textbooks, could not be confirmed. CONCLUSIONS: Antidepressive treatment is rather safe in terms of risk of seizures and also can be generally recommended in the treatment of patients with epilepsy.

The impact of antiepileptic polytherapy on mood and cognitive function.

This retrospective study was performed to reevaluate the effect of polytherapy on mood and cognitive function. 139 patients with refractory epilepsy were screened with a neuropsychological test battery and a depression score. Our regression model with age at admission, duration of the disorder and number of antiepileptic drugs as independent variables had a significant influence on 10 out of 11 neuropsychological parameters but not on depression. Looking at the significance of each predictor variable the number of antiepileptic drugs had a significant effect only on the estimation of the fluid intelligence. A significant effect on five neuropsychological parameters was found for the predictor variable duration of the disorder. Therefore our data do not support the commonly reported hypothesis that antiepileptic polytherapy itself is a substantial risk factor for cognitive deficits or depression in patients with refractory epilepsy. But there may be an influence of accumulative drug load during the course of the disorder as reflected by the effect of the duration of the disorder on five neuropsychological parameters.

Topiramate: a prospective study on the relationship between concentration, dosage and adverse events in epileptic patients on combination therapy.

RATIONALE: The relationship between topiramate (TPM) concentration, dosage and adverse events in patients with epilepsy is still controversial. We therefore performed a prospective study in patients with poorly controlled epilepsy treated with TPM, predominantly in combination with other antiepileptic drugs. The goal of the study was to investigate the relationship between the occurrence of adverse events due to TPM and its serum concentration or dosage, respectively. METHODS: The relationship between the occurrence of adverse events and TPM serum concentration or dosage, respectively, was examined in a group of 42 young adult and adult patients with poorly controlled epilepsy. Within 22 months, all patients treated with TPM had been included in the study. The 8 adverse events occurring most frequently (difference > or = 10%) in TPM-treated patients in 5, double-blind, placebo-controlled, parallel group studies, were checked regularly. This side effect profile has been presented by Reife et al. (1995a). Other possible or probable adverse events were also documented. RESULTS: The difference in TPM serum concentrations and TPM dosages (mg/kg) for patients without an adverse event, and patients with a given adverse event was statistically significant for "abnormal thinking, impaired concentration, weight loss, dizziness, speech problems, somnolence, ataxia, increased seizure frequency and paresthesia". To avoid adverse events, we recommend an initial "maintenance serum concentration" of below 4 microg/mL. As regards the TPM dosage, our results suggest initial maintenance dosages of 100 TPM or lower, 1.5 mg/kg or lower, respectively. These conclusions are limited by the relatively small number of patients.

Prospective study on concentration-efficacy and concentration-toxicity: correlations with lamotrigine serum levels.

RATIONALE: The relationship between lamotrigine (LTG) serum concentration and clinical response in patients with epilepsy is still controversial. We therefore performed a prospective study in which LTG was added to the existing therapeutic regimen in patients with poorly controlled epilepsy. The goal of the study was to determine the serum levels of patients with seizure reduction of at least 50% after addition of LTG, and to assess a possible relationship between the occurrence of adverse effects due to LTG and its serum concentration. METHODS: Fifteen adult patients were evaluated with respect to seizure reduction. Nine patients had focal seizures with or without generalization, six patients had generalized seizures (Group I). The correlation between the occurrence of adverse effects and LTG serum concentration was calculated in a second group of 63 young adult, and adult patients with epilepsy (Group II). RESULTS: The range of the LTG serum concentration in the 15 patients with a 50% or greater reduction of seizure frequency was 1.3-7.1 microg/ml (median = 3.6 microg/ml). In group II patients the serum concentration associated with an adverse effect was not significantly different from the serum concentration in patients without adverse effects. There was, however, a tendency for higher serum concentrations in patients with adverse effects. In the serum concentration range of 5 to 13 microg/ml, the frequency of LTG levels which were accompanied by an adverse effect increased only slowly, whereas above 13-14 microg/ml, there was a steep increase in adverse effects. The serum concentration of four patients with tremor (mean = 14 +/- 2.8 microg/ml) was significantly higher than the LTG level which were in 42 patients who did not have adverse effects at any time (mean = 4.8 +/- 4.1 microg/ml), P = 0.003. CONCLUSION: Our results suggest a target range for LTG serum concentrations of 1-13 microg/ml, especially, if LTG is used as an add on-drug.

Low risk of development of substance dependence for barbiturates and clobazam prescribed as antiepileptic drugs: results from a questionnaire study.

There is no systematical research about the topic of dependence on antiepileptic drugs (AED) for patients with epilepsy, despite the fact that barbiturates and benzodiazepines comprise a potential risk of dependence. We hypothesize that there is no psychological substance dependence for patients with epilepsy, possibly because of their outcome expectations. The aim of the study was to examine these patients in terms of substance dependence. One hundred inpatients at the Lake Constance Epilepsy Center were asked about their experiences with AED in terms of dependence in a structured interview. We registered general statements about dependence of AED, markers for substance dependence, and outcome expectations. About 50% of the patients reported withdrawal symptoms and the development of tolerance, but less than 10% noticed loss of control and craving. Withdrawal symptoms and development of tolerance were significantly lower in a group of patients without barbiturates or clobazam versus patients with barbiturates or/and clobazam. There was no significant difference between these two groups in psychological criteria of dependence, that is, loss of control and craving. Outcome expectations of AED were clearly related to the efficacy against seizures, and only to a small amount to psychotropic effects. The study demonstrates that physiological variables of dependence are present more in patients with epilepsy with a permanent intake of barbiturates or clobazam, but psychological variables of dependence are rarely present in epileptic patients, with or without an intake of barbiturates and clobazam. These results confirm our hypothesis that substance dependence is not a major problem in benzodiazepines and barbiturates in patients with epilepsy. Outcome expectations seem to be related mainly to the anticonvulsant and not the psychotropic effect. This might be the reason for the absence of dependence.

Low serum folate levels as a risk factor for depressive mood in patients with chronic epilepsy.

This study takes into consideration whether low serum folate levels may contribute to depressive mood in patients with chronic epilepsy. The serum folate levels and the score on the Self-Rating Depression Scale (SDS) were examined in 46 patients with chronic epilepsy. Patients with a score indicating at least minor depression on the SDS had a significantly lower serum folate level than patients with a normal score on SDS. There was a significant negative correlation between the serum folate levels and the SDS score. A serum folate level below 7.5 ng/ml was significantly associated with a pathological score on SDS. Because a serum folate level of 7.5 ng/ml is in the normal range for many laboratories, further studies using total plasma homocysteine as a sensitive measure of functional folate deficiency are required to elucidate the impact of folate metabolism on depressive mood in patients with chronic epilepsy.

The importance of drug interactions in epilepsy therapy.

Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)]. The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZ-epoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.