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© Borgis - Postępy Nauk Medycznych 11/2009, s. 869-873
*Cezary Siemianowski
Progress in studies on drug-resistant epilepsy
Postępy w badaniach nad lekoopornością padaczki
Department of Neurology and Epileptology, Postgraduate Medical Education Centre
Department Director: prof. dr hab. med. Urszula Fiszer
There exists no clear definition of drug resistant epilepsy. Although currently we can observe an important progress of research in genetic or molecular basic that is responsible for drug resistance in epileptic patients. Despite of rapid launching of the new antiepileptic drugs in the recent years and wider social access to the newest farmacological agents, about 30% of epileptic patients are resistant to modern theprapeutic strategies. There are still no well known pathomechanisms of drug resistant epilepsy and neurobiological background of this phenomenon. On the other side a quite fast development of molecular biology, genetics and immunochemistry allows for its better exploration. New trends and often fundamental results of many basic studies of drug resistant epilepsy are presented in this paper. We present influence of polymorphism of cytochrome P450 enzymes on drug metabolism and many side effects of antiepileptic drugs, conception of structural alternation in neuronal receptors and channels, hypothesis of multidrug resistance proteins activity in the brain, wall known genetic syndromes with intractable seizures and synaptic reorganisation after convulsions. We present also a proposal of use in every day neurological practice of some recent results of that studies.
Nadal nie istnieje jednolita definicja padaczki lekoopornej. Nie są też w pełni poznane mechanizmy neurobiologiczne leżące u podstaw lekooporności padaczki. Niemniej jednak odkrycia ostatnich lat przybliżają nas do istoty zjawisk odpowiedzialnych za niepowodzenie leczenia u wielu osób leczonych z powodu padaczki. Pomimo coraz szybszego wprowadzania do stosowania nowych leków przeciwpadaczkowych i ich zdecydowanie większej dostępności dla pacjentów nadal prawie jedna trzecia z nich wykazuje oporność współczesnych metod leczenia zachowawczego. Znaczący postęp badań molekularnych, genetycznych i immunochemicznych pozwala już na wyjaśnienie przyczyn lekooporności u niektórych z nich. Przegląd i kierunki w jakich dziedziny te zmierzają w eksplorowaniu zjawiska lekooporności, zawiera niniejszy artykuł. Omówione zostały zjawiska zmienności genetycznej enzymów biorących w metabolizmie leków przeciwpadaczkowych, hipoteza zmian strukturalnych receptorów i kanałów błonowych odpowiedzialnych za efekty działania leków w układzie nerwowym, teoria białek utrudniających dostęp leków do obszaru padaczkorodnego w mózgu, wpływ wywołanej drgawkami reorganizacji połączeń synaptycznych na efekty leczenia oraz niektóre dość dobrze już poznane zespoły uszkodzeń genetycznych warunkujących specyficzny obraz kliniczny padaczek lekoopornych. Przytoczono także przykłady propozycji zastosowania wyników wspomnianych obserwacji w codziennej praktyce klinicznej u pacjentów wykazujących oporność na dotychczasowe leczenie. Aczkolwiek daleko jeszcze do pełnego wyjaśnienia neurobiologicznych podstaw padaczki, a tym bardziej możliwości przewidzenia czy chory, u którego wprowadzamy dany lek okaże się pacjentem lekoopornym.

It has been known for a long time that almost 30% of patients treated for epilepsy belong to the group of patients resistant to standard pharmacological treatment. We are not able to predict, when starting the treatment, how the patient will respond to it; if it will have a satisfactory effect on the reduction of frequency of seizures; and finally in which group the patient will be – in the one responding well to treatment or in the drug-resistant one (1). The situation is complicated further by the fact that still there is not a uniform, commonly accepted definition of drug-resistant epilepsy, and taking into account what a heterogeneous disease epilepsy is, how multifactorial its neurobiological origin is, one should not expect such a definition in the near future.
Among numerous definitions proposed by various authors the most lucid and clear in terms of clinical practice seems to be the definition used in clinical studies of new drugs. In its light, epilepsy may be recognized as resistant to drugs if at least one tonic-clonic seizure or two partial (focal) seizures occur within a month and repeat in the following three months under the conditions of appropriate selection of the kind of drug for the type of seizure, their application in a dose adequate for the age and weight of the patient, and the lack of satisfactory control of seizures after applying the second-choice and third-choice drugs. A similar view is also expressed by Majkowski, by stating that we are dealing with drug-resistant epilepsy when the patient has six generalized seizures or twelve partial seizures within a year under the condition of their appropriate treatment (2). On the other hand, Genton believes the term drug-resistant epilepsy should be used when the seizures remain after two years of treatment with at least three basic antiepileptic drugs in monotherapy or their combination after assessment of the case by at least two neurologists (3). Undoubtedly we can observe several pathomechanisms conditioning resistance in a given patient with seizures resistant to treatment, which makes it even more difficult to provide a rational explanation. Although numerous studies on epilepsy resistance to pharmacological treatment have been carried out in many leading research centres worldwide, we are still far from knowing all of its mechanisms. Among those taken into account and partly understood one should list: differences in pharmacogenetic profile of individual patients and, connected with it, differences in metabolism of drugs and occurrence of some, particularly serious effects of undesirable drugs; the hypothesis of decreased sensitivity of brain receptors and ion channels to antiepileptic drugs; the phenomenon of increased expression of proteins participating in drug transport; neurodegeneration in targeted places of action of drugs; and reorganisation of synaptic contacts triggered by seizure activity in epileptic foci in the brain.
Moreover, in explaining the causes of resistance to treatment, many clinical aspects are considered, such as: early onset of disease, high frequency of seizures, in particular in the early period of treatment, organic brain damage, that is symptomatic aetiology of seizures, co-existing mental disability, family history of epilepsy, febrile convulsions in childhood, and interactions with other drugs or substances simultaneously used, e.g. caffeine or theophylline (4).
An example of studies on the role of changes in receptors in the brain generating epileptogenic activity is a study on the protective role of a lack of alpha-1b adrenergic receptors, reported this year by an Italian group of researchers. Perhaps finding a molecule blocking this type of receptor at the level of the brain would be significant in preventing the occurrence of seizures as well as their spread in the brain and modulating the seizure threshold. It was found that laboratory animals deprived of the mentioned receptor were resistant to convulsions triggered by giving them pilocarpine or kainates, and also that severity of the seizure itself and escalation of post-seizure symptoms were definitely less intense than in the group having this receptor. Furthermore, post-seizure neurodegeneration in the programmed cell death mechanism was not observed in them (5).
On the other hand, genetic polymorphism and its influence on the occurrence of resistance to antiepileptic drugs are illustrated well by the study of the relationship of polymorphism of the MCR2 gene to the response to the adrenocorticotropic hormones used in West syndrome (serious encephalopathy with infantile spasms, salaam spasms). It has been known for a long time that not all children with this syndrome respond well to the use of renal cortex hormones. A study carried out by Chinese authors and reported last year shows that polymorphism of the MC2R (melanocortin 2 receptor) gene promoter – homozygous or heterozygous carriers of the TCCT haplotype compared with non-carriers – is associated with a good response to ACTH or a lack of response (6).
Another interesting example of the influence of genetic polymorphism on the response to the applied treatment may be the already well studied polymorphism of microsomal enzymes of cytochrome P450: four main isoenzymes are distinguished, namely CYP 3A4, 2D6, 2C9 and 1A2. Metabolism of approximately 95% of all known drugs, including antiepileptic drugs, takes place with their participation. The CYP 2C9*6 variety is connected for instance with the occurrence of toxic responses to phenytoin, which was found in a group of Afro-American females from Florida (7). The CYP 2C9*2 and 3 varieties dominate among Caucasians and their presence is connected with decreased metabolism of phenytoin in comparison with other varieties of CYP 2C9; other varieties are dominant among Mongoloids (8, 9). Another known problem among patients treated with carbamazepine (the most frequently used antiepileptic drug worldwide) is its adverse interaction with erythromycin, leading sometimes to the toxic increase of carbamazepine concentration in the blood serum. This results from suppression of CYP 3A4 isoform by erythromycin, taking part in metabolism of carbamazepine (10).
Serious allergic responses to some antiepileptic drugs are also connected with polymorphism of protein coding genes involved in metabolism of drugs. A tendency to allergic responses after taking carbamazepine is shown by individuals having a group of three heat shock proteins (HSP) coded on the short arm of chromosome 6 in position 6p21.3. These proteins also take part in development of agranulocytosis after taking clozapine and abacavir allergy (11, 12). These observations confirm Garrod´s thesis, put forward at the beginning of the 20th century, stating that the adverse effects of drugs were genetically conditioned. Later observations led to the realisation that apart from genetic predispositions such factors as age, environmental impacts, type of diet, substances and other drugs may have an influence on metabolism of a given drug, and in the process its effectiveness, interactions and adverse effects.
In some countries it is already possible to determine the pharmacogenetic profile of the whole or selected isoenzymes of cytochrome P450 in vivo and in vitro. The cost of such an analysis in the USA is approximately 300 dollars and it uses various techniques, including PCR, protein chromatography and mass spectrometry. Therefore the identification of CYP 2C9 polymorphism allows one to determine in some cases the basis of drug resistance in epilepsy. Similar to epilepsy, identification of isoforms of cytochrome P450 will be most likely used soon in determining sensitivity to drugs applied in the treatment of depression, schizophrenia, Parkinson´s disease, asthma, breast cancer and many other diseases. These studies will also permit one to predict interaction of the prescribed drug with other simultaneously used drugs and potential adverse effects connected with its use.
An interesting example of genetically conditioned drug-resistant epilepsy with a bad prognosis is the ring chromosome 20 syndrome. Epileptic seizures and frequent non-convulsive status epilepticus are accompanied here with mental retardation, body dysmorphic disorder and various kinds of conduct disorders. Epilepsy in this syndrome, and in particular a tendency to non-convulsive status epileptici, results most likely from deficiency of dopaminergic transmission, which presents a certain new aspect in the discussion about the role of neurotransmitters in generating epileptic seizures – so far GABA and glutamates have been recognized as the main ones (13).

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otrzymano: 2009-08-13
zaakceptowano do druku: 2009-10-06

Adres do korespondencji:
*Cezary Siemianowski
Department of Neurology and Epileptology, Postgraduate Medical Education Centre
Czerniakowska 231 Str., 00-416 Warszawa
tel.: (0-22) 584-11-27
e-mail: cezars2001@interia.pl

Postępy Nauk Medycznych 11/2009
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