[Anticonvulsant therapy for brain tumour-related epilepsy]. / Antiepileptikabehandlung bei Hirntumor-bedingten epileptischen Anfällen.

The lifetime risk of patients with brain tumours to have focal epileptic seizures is 20-80%. Based on current evidence the management of tumour-related seizures does not differ substantially from that applied to epilepsies from other aetiologies. Therefore, the choice of an anticonvulsant is based, above all, on tolerability and pharmacokinetic interactions with chemotherapeutic drugs. Levetiracetam is recommended by many authors as first-line therapy in brain tumour-related epilepsy; this corresponds with the recommendation of the German guidelines on the treatment of focal seizures of any aetiology. Based on current evidence, the prophylactic prescription of long-term antiepileptic drugs in brain tumour patients who have not presented with seizures is not justified. Because of the high risk of recurrence, however, antiepileptic treatment should be strongly considered after a single brain tumour-related seizure.

[Combination therapy for epilepsy]. / Kombinationstherapie bei Epilepsie.

Use of Monotherapy is acknowledged as the standard anticonvulsant therapy although no more than about 65% of patients become seizure-free with a single antiepileptic drug. Therefore, up to 50% of patients with epilepsy are treated at least intermittently with more than one antiepileptic drug. The percentage of patients achieving complete seizure control with combination therapy after ineffective monotherapy is small. Monotherapy and combination therapy are not always contrary to each other; many anticonvulsants have different modes of action and are effectively a combination therapy in one drug. Combinations of anticonvulsants with differing mechanisms of action are called "rational polypharmacy". A superior efficacy of these combinations over combinations of anticonvulsants with identical or similar mechanisms of action have not been proved by randomised trials. Add-on trials with lacosamide and the combination of lamotrigine and valproic acid, however, suggest a superior tolerability and/or efficacy of combinations with differing mechanisms of action. Treatment with drug combinations should take into account, above all, efficacy and safety, interactions, and costs of each antiepileptic drug as well as comorbidity.

[Epileptic seizures during treatment with antidepressants and neuroleptics]. / Epileptische Anfälle unter der Behandlung mit Antidepressiva und Neuroleptika.

Epileptic seizures are observed during treatment with antidepressants and neuroleptics more frequently than is the case for other neuroactive substances. Evidence from experimental and observational studies is mixed, suggesting an increased incidence of seizures for certain drugs, whilst other drugs such as SSRIs appear to have a protective effect. There is robust evidence for an elevated seizure incidence (up to 4.5 % of treated patients) associated with clozapine treatment, but with other neuroleptics the effect is moderate (2-fold). The evaluation of data from FDA approval reports reveals lower standardised incidence rates associated with antidepressants vs. placebo except for clomipramine and bupropione. Psychiatric disorders such as schizophrenia, depression, and obsessive-compulsive disorder are associated with a considerably increased incidence of seizures. Therefore, in clinical practice, taking into account ictogenic properties of substances is required only in patients with a history of seizures.

[Cognitive deficits and psychiatric disorders in patients with new-onset epilepsy]. / Kognitive Defizite und psychiatrische Störungen in Frühstadien epileptischer Erkrankungen.

From a theoretical point of view it may be hypothezised that cognitive deficits are not uncommon in patients with new-onset epilepsy since causative brain lesions, genetic influences and interictal epileptic activity are likely to exist even before the first unprovoked seizure. We reviewed the literature concerning cognitive deficits in genetically determined epilepsy-syndromes and studies on cognitive and psychiatric deficits in patients with new-onset epilepsy. In several animal models hints of memory deficits or learning disorders even before the manifestation of epileptic seizures were found. Some learning disorders showed characteristics of the human attention-deficit-hyperactivity-disorder. In familial frontal epilepsies specific associations between cognitive deficits as well as psychiatric syndromes and certain mutations were described. Cognitive deficits in adult patients with new-onset epilepsy were described several times with regard to delayed recall in verbal memory, selective attention and psychomotor performance. Depression and suicide attempts were increased before the first seizure. In childhood cognitive deficits were regarded as causative factors for behavioral problems, which sometimes were even found before the first recognized seizure. Verbal memory deficits at the onset of epilepsy seemed to be a risk factor for the development of a therapy refractory course. But on the basis of the published data it is impossible to state whether cognitive deficits after a first unprovoked seizure in adulthood indicate an increased risk of recurrent seizures apart from the results of MRI and EEG studies.

[On the value of neuropsychological short tests in epileptology]. / Zur Wertigkeit neuropsychologischer Kurztests in der Epileptologie.

Cognitive deficits are common in patients with epilepsy refractive to therapy and have considerable influence on the quality of life in this group of patients. Therefore, neuropsychological investigations should play an important role in the comprehensive evaluation of patients with chronic epilepsy. The aim of this study was to examine whether a reliable screening for cognitive deficits in these patients may be reduced to the assessment of two bedside tests. In a prospective study we analyzed the results of 40 patients with epilepsy refractive to therapy subjected to a 45-min neuropsychological screening battery and compared them with the results of a short battery consisting of two bedside tests. Using the screening battery as the gold standard, the short battery had a sensitivity of 50% and a specificity of 100%. Changing the criteria for pathological results in the short battery, sensitivity could be raised to 81.25% but specificity fell to 50%. Therefore, bedside tests instead of longer neuropsychological testing cannot be recommended as a screening method for cognitive deficits in patients with chronic epilepsy.

The influence of folate serum levels on depressive mood and mental processing in patients with epilepsy treated with enzyme-inducing anti-epileptic drugs.

BACKGROUND: Folate deficiency is common in patients with epilepsy and also occurs in patients with depression or cognitive deficits. OBJECTIVE: This study investigates whether low serum folate levels may contribute to depressive mood and difficulties in mental processing in patients with epilepsy treated with anti-epileptic drugs inducing the cytochrome P450. METHODS: We analysed the serum folate levels, the score in the Self Rating Depression Scale (SDS) and the results of a bedside test in mental processing in 54 patients with epilepsy. RESULTS: There was a significant negative correlation between the serum folate levels and the score in SDS and significant positive correlations between the score in SDS and the time needed to process an interference task or a letter-reading task. CONCLUSIONS: Low serum folate levels may contribute to depressive mood and therefore to difficulties in mental processing. Further studies utilizing total plasma homocysteine as a sensitive measure of functional folate deficiency and more elaborate tests of mental processing are required to elucidate the impact of folate metabolism on depressive mood and cognitive function in patients with epilepsy.

Modification of slow cortical potentials in patients with refractory epilepsy: a controlled outcome study.

PURPOSE: To compare self-regulation of low-frequency EEG components (slow cortical potentials, SCPs) with other methods of seizure control for patients with drug-refractory partial epilepsy and to separate the real anticonvulsive effect from placebo effects. METHODS: Results of a treatment program of SCP self-regulation (experimental group) are compared with two groups of patients, one of which learned self-control of respiratory parameters (end-tidal CO2 and respiration rate: RES group); the other received medication with new anticonvulsive drugs (AEDs) in combination with psychosocial counseling (MED group). Clinical, cognitive, behavioral, and personality measures were assessed before and after treatment. In addition, to control for placebo responses, patients repeatedly estimated their beliefs in the efficiency of the respective treatment, their satisfaction and expectations, and the quality of the relationship with their therapists. RESULTS: SCP and MED groups showed a significant decrease of seizure frequency, but the RES group did not. Clear positive changes in the sociopsychological adjustment were obtained in all three groups, with the maximal improvement being attained in the RES group. CONCLUSIONS: All kinds of therapy result in considerable improvement of patients' emotional state, which may in part be due to potential placebo effects: however, this improvement is not related to the quality of the therapeutic effect proper (i.e., seizure reduction). Traditional double-blind control group designs are inappropriate for behavioral interventions or treatments with psychoactive pharmacologic drugs. Rather, specific tests can be developed to control the placebo effect and to separate it from the genuine therapeutic effects.

Possible oxcarbazepine interaction with cyclosporine serum levels: a single case study.

We studied the influence of an add-on medication with oxcarbazepine on the cyclosporine trough level in a kidney transplant recipient with pharmacoresistant epilepsy. Two weeks after the beginning of the trial we observed a decrease of the cyclosporine trough and the Na serum levels. Both could be corrected by a small-dose reduction of oxcarbazepine, an augmentation of the cyclosporine dosis, and oral sodium chloride substitution. After this episode the cyclosporine trough and the Na serum levels remained stable. Seizure frequency was reduced by 95%. The influence of oxcarbazepine on the cyclosporine serum level has to be studied carefully in other patients after transplantation before the use of oxcarbazepine can be recommended in patients with an immunosuppressive medication with cyclosporine. Our data suggest that oxcarbazepine may be an effective drug with tolerable side effects in this group of patients.

Biofeedback treatment in patients with refractory epilepsy: changes in depression and control orientation.

Depression is a common and serious interictal problem in patients with epilepsy. The genesis of depressive disorders is multifactorial. One aetiological aspect focuses on psychosocial factors. It was hypothesized that uncontrollable, unpredictable chronic aversive events (i.e. epileptic seizures) result in cognitive deficits of external control orientation. If this is true, biofeedback training could represent a possible treatment strategy to lower depression, because biofeedback is known to mediate success experiences and control. Measures of depression and locus of control were administered to 20 patients with refractory partial epilepsy before and after biofeedback treatment. The biofeedback consisted of slow cortical potentials or breathing parameters in 10 patients each. A clear relationship occurred between depression and locus of control in the subjects. After biofeedback training control orientation moved towards a more internal locus of control. Also, depression scores were significantly reduced six months after training. Results show that in patients with refractory epilepsy depression is highly correlated with locus of control, in a way that external control orientation relates to high depression scores. Biofeedback is able to improve internal control orientation through personal success mediation.

Treatment of pathological crying with citalopram.

Pathological laughing and/or crying may occur as a concomitant symptom of various diseases of the central nervous system. No known anatomical basis for any of these disorders exists at present. However, references to a disturbance in central serotoninergic neurotransmission have become frequent in the literature, implicating this as an important etiological factor. In the present communication three cases of successful treatment of pathological crying using the SSRI citalopram are reported. Besides the response of pathological crying in cerebral ischemia to SSRIs, which has already been described in earlier publications, this is the first report on the successful administration of citalopram for treating pathological crying in Parkinson's disease. Onset of response was very rapid in all cases.

[Drug therapy before and after surgery for epilepsy. Critical review and recommendations]. / Pharmakotherapie vor und nach epilepsiechirurgischen Eingriffen. Ein kritischer Uberblick und Empfehlungen.

As a result of a critical review of the literature and a survey at German epilepsy centers of usual pre- and postoperative drug treatment, the following strategy is recommended: 1. Patients under consideration for surgery should be referred to specialists. Experience has shown that surgery is reasonable for only about a third of all patients with refractory epilepsies. The patient should first have been treated for at least 3 years with at least two first-line drugs in monotherapy and subsequent combined therapy. This applies only to medial temporal lobe epilepsies with very good postoperative prognoses. All other surgically removable epilepsy syndromes with less positive prognosis should be treated with additional antiepileptic drugs before any surgery. 2. There is no exception to the continuation of drug treatment after epilepsy surgery. If the patient remains free of seizures for at least 2 years, discontinuing the drug treatment can be discussed, just as with patients who are free of seizures due to drug treatment alone. In general, the less successful the operative therapy, the longer and more intensive the drug treatment.

Negative potential shifts and the prediction of the outcome of neurofeedback therapy in epilepsy.

About two-thirds of epilepsy patients who learn to control their slow cortical potential shifts (SCP) reduce their seizure rate, but the remaining third does not demonstrate clinical improvement. In the present study, this finding was replicated in a group of 27 patients with focal epilepsy. We found that patients who consistently produced larger negative SCP in all conditions during the first phase of treatment, showed no decrease in seizure frequency during the six-month follow-up, as compared with the three-month baseline phase. The large negative SCP explained about one-third of the variance of the clinical outcome. Age, medication, seizure history, or the localization of focus were found to be unrelated to clinical improvement.

[Serum concentration of anticonvulsants. Practical guidelines for measuring and useful interpretation. Therapy Committee of the German Section of the International Epilepsy League]. / Serumkonzentration von Antiepileptika. Praktische Richtlinien zur Messung und sinnvollen Interpretation. Therapiekommission der Deutschen Sektion der Internationalen Liga gegen Epilepsie.

The clinical relevance of being informed on the serum concentration of antiepileptic drugs has been judged very differently during the last decades. Therefore the Commission on the treatment of epilepsy (German section of the International League against Epilepsy) had the task to outline the importance of therapeutic monitoring of anticonvulsant serum concentrations. The possibility of determining the serum concentration of anticonvulsants induced the elaboration of "therapeutic drug level ranges". The usefulness of determining serum concentrations of antiepileptic drugs in clinical management of patients with epilepsy depends decisively on the following questions: Can the efficacy of antiepileptic drug treatment be increased by serum concentration monitoring? Can the rate of adverse effects of antiepileptic drugs be reduced by serum concentration monitoring? Clinical experience suggests numerous indications of therapeutic drug monitoring, scientific studies however, supporting these empirical guidelines are not available. Therefore, therapeutic drug monitoring may be restricted for some special situations which have to be justified in every single case. Tailored determinations with specific purposes are e.g.: resistance to therapy, including suspected irregular intake; suspected intoxication, particularly during combined therapy; the possibility of significant changes in the dosage-serum concentration relationship (interactions with other drugs, unusual pharmacokinetics in childhood, in pregnancy etc.).

[Successful induction of tolerance in an epilepsy patient with phenobarbital allergy]. / Erfolgreiche Toleranzinduktion bei einer Epilepsiepatientin mit Phenobarbitalallergie.

We report on a 32-year-old female patient who had had a history of complex partial seizures since the age of 14. Phenobarbital was the most effective anticonvulsant drug in this patient. However, the drug treatment was complicated by a phenobarbital-induced exanthematous eruption. Reintroduction of the phenobarbital some years later resulted in a skin rash again; therefore, treatment with this substance had to be discontinued a second time. Because of the satisfactory antiepileptic efficacy, phenobarbital was introduced a third time using a desensitization procedure with increased oral doses, starting with a dose of 1 mg. After a daily dose of 90 mg phenobarbital, on day 6 an exanthematous eruption appeared. The exanthem disappeared parallel to a dose reduction of phenobarbital and with a gradually increasing dosage up to a maintenance dose of 200 mg. Tolerance to the allergic effect of phenobarbital was preserved and the seizure frequency was significantly reduced by phenobarbital monotherapy with a daily dose of 200-175 mg.

Stability of cortical self-regulation in epilepsy patients.

Biofeedback-supported self-regulation of slow cortical potentials (SCP) is increasingly being used for treatment of intractable epilepsy. However, it is unknown whether the acquired ability to regulate one's own cortical potentials remains stable over time. In this study, 18 patients with drug-resistant partial epilepsy performed 35 training sessions in which they learned to generate slow cortical potential shifts in either positive or negative direction. At the end of training, they differentiated significantly between required cortical positivity and required cortical negativity. Six months after this point, they still demonstrated an unchanged between-condition differentiation. The performance in the booster session was particularly good in trials without continuous SCP feedback. The ability to generate positive SCP shifts was related to decrease of seizure frequency during the 6 months follow-up period compared with the 3 month baseline period. This data indicate that the acquired ability of humans to regulate their cortical potentials did not decrease over a 6 month period but rather, tended to consolidate.

Self-regulation of slow cortical potentials in epilepsy: a retrial with analysis of influencing factors.

Twenty sessions of biofeedback training were carried out with 12 drug-resistant patients with focal epilepsy who learned to produce either negative or positive shifts of their slow cortical potentials (SCPs) at vertex. Feedback trials were interspersed with transfer trials in which only a discriminative stimulus (signalizing whether positivity or negativity was required) was presented, without feedback signal. Patients were able to differentiate significantly between the conditions of cortical positivity and cortical negativity, with larger differentiation scores being obtained in feedback trials than in transfer trials. The amplitude of positivity generated in the positivity condition increased linearly across sessions both in feedback and in transfer trials. The largest negativity was produced in the 5th session; after this, more transient negativities were generated, whose amplitude decreased towards the end of trial. The mean severity of seizures, estimated as the frequency of seizures weighted by their subjective 'strength', decreased significantly after training as compared to the pre-training phase. The data suggest that (1) patients could learn to achieve a state of cortical disfacilitation and (2) with progressed learning, they became less motivated for (or afraid of) producing considerable negative shifts, since extensive negativity may reflect cortical over-excitation and therefore be associated with early signs of seizures. The inability of producing cortical negativity is however not necessarily a bad predictor.

Red-cell and serum folate levels in depressed inpatients who commit violent suicide: a comparison with control groups.

There has been some discussion in the recent literature regarding the possible relationship between peripheral levels of folate and serotonin deficiency in the CNS. At the same time, such a serotonin deficiency has been implicated in the biology of suicidal behavior. Thus, decreased peripheral folate levels may be expected in patients who commit violent suicide. In this study, the red-cell and serum folate levels in nine persons who later committed suicide are compared with those in age- and sex-matched control groups. A one-way analysis of variance showed no significant difference between the groups.

Folate deficiency, anticonvulsant drugs, and psychiatric morbidity.

The folic acid (FOA) level was determined in serum and erythrocytes in 100 epileptic patients and 100 control patients using a luminescence assay. A lowered FOA concentration in serum, erythrocytes, or both was observed in 15% of the epileptic patients and in 2% of the control group. In the epileptic patients, the FOA in the serum and in the erythrocytes was significantly lower than that in the control group. Patients receiving carbamazepine monotherapy had a significantly lower FOA level in the erythrocytes than did patients receiving phenytoin monotherapy. The FOA level showed a negative correlation to the duration of epilepsy. None of the patients with lowered FOA had a normal mental status. The course of the supplementation treatment with 5 mg folinic acid (or FOA) of four patients with FOA deficiency could be monitored psychopathometrically. All four patients showed an improvement in their well-being and the majority of measured variables of the cognitive performance.

[Differential diagnosis of aggressive behavior in epilepsy]. / Differentialdiagnose aggressiven Verhaltens bei Epilepsie.

Aggressive behaviour in epileptics may have many causes which are connected more or less closely with epilepsy. Ictal aggression is very rare. In the case of a patient with complex partial seizures and a schizophrenia-like psychosis different forms of generation of aggressive behaviour are discussed.

[Psychiatric changes caused by epileptic seizures]. / Psychische Veränderungen durch epileptische Anfälle.

Frequent tonic-clonic seizures could probably lead to psychic disorders. In various studies a decrease in at least single functions of mental capability was found depending on the frequency of the seizures and/or the duration and/or the age of onset of the disease. The development of neuropsychological deficits depends on the type of seizures. Particularly BNS-seizures and the Lennox-Gastaut-syndrome have generally a poor prognosis concerning the intellectual development. Not only clinically manifest seizures but also subclinical discharges could disturb the psychic condition of epileptic patients. Epileptic seizures are probably a reason for neuronal damage in the hippocampus area. Psychogenic reactions and undesired effects of antiepileptic drugs have to be considered aside from functional disturbances due to epileptic seizures.