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Antiepileptic Treatment in Paediatric Oncology – Antiepileptische Therapie in der pädiatrischen Onkologie – Epileptic seizures are a common and clinically relevant problem Epileptische Anfälle stellen in der pädiatrischen Onkologie ein in paediatric oncology. Attributable to the heterogeneity of this häufiges und klinisch relevantes Problem dar. Bedingt durch die group of patients and a number of possible comorbidities anti- Heterogenität der betroffenen Patientengruppe und einer Viel- epileptic treatment in paediatric oncology poses a number of di- zahl von möglichen Komorbiditäten sind sowohl das diagnos- agnostic and therapeutic challenges. This requires a close inter- tische Vorgehen als auch die antikonvulsive Therapie eine be- disciplinary approach to the seizing child or adolescent. A sondere Herausforderung, die ein interdisziplinäres Vorgehen prompt and detailed diagnostic work-up is needed in every case erfordert. Diagnostisch sind neben einer Vielzahl von potenziell in order to establish the diagnosis and, equally important, to de- epileptogenen Medikamenten vor allem akute Begleiterkran- tect secondary aetiological factors, e. g. epileptogenic drugs or kungen im Verlauf der Krebstherapie zu berücksichtigen, die ur- any acute underlying pathology, such as metabolic or toxic ence- sächlich für das Auftreten von Anfällen sein können. Beispiele phalopathies, CNS-infections or cerebrovascular events. This sind metabolische oder toxische Encephalopathien, ZNS-Infek- might offer the opportunity for a specific causative treatment tionen oder auch zerebrovaskuläre Ereignisse. Da diese zum Teil and thus prevent unnecessary long-term antiepileptic drug lebensbedrohlichen Erkrankungen zum Teil kausal behandelbar (AED) treatment. If AED treatment is initiated several aspects sind, erfordert jedes anfallsverdächtige Ereignisses eine rasche have to be taken into account. Most importantly, AEDs and che- und umfassende Abklärung. So können spezifische Ursachen er- motherapeutic drugs (CTDs) may interact. Depending on the co- kannt und behandelt sowie unnötige antikonvulsive Langzeit- medication this may result in reduced tumour or seizure control therapien vermieden werden. Besteht eine Therapieindikation or unexpected toxicity of AEDs or CTDs. Understanding these in- zur antikonvulsiven Dauertherapie so liegt die Schwierigkeit pri- teractions will allow to anticipate clinically relevant adverse ef- mär in einer Vielzahl von Komedikationen und damit der Gefahr fects. AED may be further complicated by side-effects, some of von Wechselwirkungen insbesondere zwischen Antikonvulsiva them of particular concern for children or adolescents, such as und Chemotherapeutika. Das Wissen um diese Wechselwirkun- cognitive effects, myelotoxicity, serious rashes, endocrinological gen ist wichtig, da sowohl die Prognose der Krebserkrankung, als disturbances, and many more. Beside critically questioning the auch die der Epilepsie hierdurch nennenswert beeinflusst wer- need for AED treatment it is therefore important to prefer AED den kann. Zusätzlich erschweren eine Reihe onkologisch rele- with a good safety-profile in this population. Enzyme-inducing vanter Nebenwirkungen die Entscheidungsfindung bei der Aus- and inhibiting AED should be avoided if possible. Preliminary wahl der Antiepileptika. Dies betrifft z. B. kognitive Nebenwir- studies indicate that gabapentin and levetiracetam may provide kungen, myelotoxische Wirkungen, Dermatosen, endokrinolo- Affiliation1 Department of General Paediatrics, University Children’s Hospital, Düsseldorf, Germany2 Clinic for Paediatric Oncology, Haematology and Immunology, University Children’s Hospital, Düsseldorf, CorrespondenceDr. Daniel Tibussek · Department of General Paediatrics · University Children’s Hospital · Moorenstrasse 5 ·40225 Düsseldorf · Germany · Tel.: +49/211/8 1176 87 · Fax: +49/211/8 1187 57 ·E-mail: daniel.tibussek@med.uni-duesseldorf.de BibliographyKlin Pädiatr 2006; 218: 340–349 Georg Thieme Verlag KG Stuttgart · New YorkDOI 10.1055/s-2006-942257ISSN 0300-8630 good options in terms of efficacy and safety. However, more gische Effekte und andere mehr. Neben der kritischen Indika- properly designed clinical studies are warranted to raise the lev- tionsstellung einer antikonvulsiven Therapie gilt es daher bevor- el of evidence for robust clinical recommendations. Until that zugt Antikonvulsiva einzusetzen, die ein günstiges Nebenwir- time, clinicians will need to continue to question current policies kungsprofil in dieser Patientengruppe haben und zusätzlich and adapt their daily practice to evolving scientific data.
durch fehlende Enzyminduktion bzw. Inhibition gekennzeichnet sind. Nach aktuellem Kenntnisstand scheinen hier vor allem Ga- bapentin und Levetiracetam günstige Optionen darzustellen. An- gesichts einer sehr schlechten Studienlage sind jedoch weitere klinische Studien zu diesen wichtigen Fragestellungen dringendzu fordern, aktuelle Therapieregime kritisch zu hinterfragen und gegebenenfalls der aktuellen Datenlage anzupassen.
Cancer · seizures · antiepileptic drugs · drug interaction Krebs · Krampfanfälle · Antiepileptika · Wechselwirkungen The current review aims to summarize some key aspects of antic- onvulsive treatment in paediatric oncology. We also intend to criti- cally question some current clinical policies and point out areas suitable for future interdisciplinary research in this field.
Aetiology of seizures in paediatric oncology The exact pathophysiology of seizures during the course of ma- lignant diseases is often multifactorial and not well understood.
Seizures in patients with brain tumours are usually directly re- lated to focal cerebral damages and effects on the surrounding non-tumoural, cerebral tissue. This may be due to the tumour it- self or to anti-cancer treatment (neurosurgery, irradiation, che- motherapy). Etiological mechanisms include theories of altered peritumoural amino acids, changes in regional metabolism in- volving pH, neuronal or glial enzyme and protein expression, and localized immunological changes. Distribution and function of the NMDA subclass of glutamate receptors may also play a role [3]. Certain tumours (e. g., oligodendroglioma, DNET, gang- lioglioma) and tumour localisations appear to be associated with a higher seizure risk (see Table 1 and 2). However, there is some variation in seizure incidence even within a single histolo- gical tumour subtype. Therefore, reliable risk factors are cur-rently difficult to define particularly in the paediatric age group, Seizures are a common complication in paediatric oncology and where only limited data are available [36].
often significantly impact the quality of life of patients and rela- tives. This applies not only to children with brain tumours, where an incidence of up to 70 % depending on the type of tumour has been reported [30], but also to systemic malignancies. A sizable Possible risk factors for seizure occurrence in patients with proportion of patients with systemic cancer present with at least one seizure during the course of the disease. As an example, in possible risk factors for seizures in brain tumours children and adolescents with acute lymphoblastic leukaemia a seizure prevalence between 8 and 13 % has been reported [45, lower-grade, slower growing tumours (epilepsy) 52, 76]. Aetiology includes a number of possibly preventable or higher-grade rapidly progressive tumours (seizures at presentation) treatable conditions, which may be directly related to secondary effects of anti-cancer treatment. Moreover, anticonvulsive drug treatment in this particular group of patients comprises a num- ber of difficulties, making seizures an interdisciplinary challenge.
Apart from the potential for serious side effects of antiepileptic drugs (AEDs), some of them of particular concern for children, re- cent years have seen new appreciation of drug interactions with AEDs that are important in neoplastic disorders.
Tibussek D et al. Antiepileptic Treatment in … Klin Pädiatr 2006; 218: 340 – 349 Example of seizure incidence in paediatric brain tumours In general, acute neurological symptoms under certain CTDs are not uncommon [35, 55, 75]. The toxicity of CTDs to the central ner- vous system is directly related to their ability to cross the BBB.
Clinical signs suggestive of neurotoxicity are usually non-specific: altered level of consciousness, behavioural disorders and/or motor deficits. Seizures are often part of the acute presentation [53].
The diagnosis of chemotherapy-induced seizures is made clini- cally, and is based on the temporal relationship between drug administration and neurological complication and, equally im- portant, knowledge of side effects of specific agents. Therefore, some clinically important CTDs associated with seizures are dis- MTX has the potential to cause both acute and delayed neuro- toxicity, particularly after intrathecal (i. t.) or high dose intrave- nous (i. v.) administration [52, 58] The mechanism of MTX-re- lated neurotoxicity is still unclear. An excess of homocystein and consecutively of excitatory neurotransmitters has been found in some children [57]. Neurotoxicity usually manifests as seizures, occurring a median of 10–11 days after i. t. MTX. The frequency of seizures or other acute CNS effects during ALL ther-apy in childhood has been reported at 3 to 13 % [17, 45]. Neuro- toxicity is usually self-limited and the risk of recurrence appears ASP has been repeatedly related to cerebrovascular complica- tions, which may be related to deficiencies of antithrombin III, plasminogen, and fibrinogen [55]. In a recent case series Kieslich Possible aetiological factors of seizures in oncological patients.
et al. [38] reported five children with neurological complications presenting with headache and seizures during the first three In systemic cancer the aetiology may be even more complex (see weeks of ASP treatment. Three patients had venous thrombosis, Fig. 1). Indirect effects of the cancer or its treatment such as brain one presented a parenchymal haemorrhage.
metastasis or leptomeningeal disease, hypertension, fever, CNS infections, cerebral infarction or bleeding, electrolyte distur- A study of DiMario and Packer [17] found that almost half of the bances (hyponatraemia, hypocalaemia, hypomagnesaemia), me- seizures occurring in children with systemic cancers were attri- tabolic or toxic encephalopathies are possible reasons for epilep- butable to complications of ASP treatment. The epileptogenic ef- tic seizures. Chemotherapy and certain other drugs used for sup- fect of L-asparaginase may result from cleaving asparagine and portive care in oncology are epileptogenic, especially in patients glutamine into aspartic acid, ammonia, and glutamate, an excita- with an altered blood-brain barrier (BBB) (see Table 3). These secondary effects are often associated with the type and time- course of the underlying malignancy, type of CTD, comedica- tions, and acute illnesses related to tumour treatment. From the Encephalopathy is a known adverse effect of IFO. The pathophy- clinical perspective it has to be stressed that a number of these siology seems to be related to intoxication with chloracetalde- aetiological factors are treatable and/or preventable [17].
hyde, a metabolic product of IFO [55]. The presentation and se-verity varies greatly and involves a clinical spectrum ranging from subclinical electroencephalographic changes, complicated seizures to coma. Nonconvulsive status epilepticus has been de- Cancer treatment associated with seizure occurrence scribed in children and adults under IFO with reduced level of consciousness [39, 56]. Onset of symptoms may be within hours of administration without evidence of a dose-response curve. It asparaginase, etoposide (IA), interleukin-2, busulphan (HD), erythropoietin,levamisole, BCNU, 5-Fluorouracil, mechloramine, carboplatin (IA), is generally self-limiting and reversible between 48 and 72 h after fludarabine, methotrexate, chorambucil (HD), GM-CSF, mitotane, cytosine discontinuation of IFO. However, severe and even fatal cases have arabinoside (HD or IT), hexamethylmelamine, pentostatin, dacarbazine, been reported [20]. Therefore, as effective therapy is available ifosfamide, thalidomide, interferon (IT), vinca alkaloids especially for patients with severe symptoms of toxicity early di- HD: high-dose; IT: intra-thecal; IA: intra-arterial.
agnosis is essential (see Table 4; references [50, 54]. Whether re- Tibussek D et al. Antiepileptic Treatment in … Klin Pädiatr 2006; 218: 340 – 349 tial diagnosis of paroxysmal events in infancy and childhood andmisdiagnosis as epilepsy is common [35, 72] Conversely, more Methylene blue in IFO-encephalopathy [54] subtle ictal events such as confusion, sensory or autonomic symptoms might be misinterpreted as non-epileptic. Therefore, the most important help to diagnosis is the clinical history sup- ported by detailed seizure description from a witness to the epi- sode [9]. Further information can sometimes be obtained from an EEG. However, a normal interictal EEG does not exclude epi- lepsy and vice versa. The gold standard for diagnosis would be administration should be performed under prophylactic treat- video-EEG-monitoring in order to document an ictal event. How- ment with methylen blue remains controversial. However, in ever, in clinical practice this is often not feasible. In patients with paediatric oncology, instead of re-administration replacement of reduced consciousness a non-convulsive status epilepticus has IFO by cyclophosphamide will usually be preferred.
to be strongly considered and early EEG should become a general routine in such cases, particularly under certain CTDs, such as CIS has principally been related to peripheral neurotoxicity.
However, CNS disorders such as the posterior reversible ence- If a clear seizure has been documented it has to be differentiated phalopathy syndrome (cortical blindness, hemiparesis, aphasia, between a single seizure, which may be situation-related, and and coma) and isolated seizures have also been reported. CIS-re- epilepsy. Strong efforts have to be made to classify the patients lated seizures may start within a few hours of the last CIS expo- seizure, or less likely in oncology, place seizures in the context sure, and are not related to the cumulative CIS dose. Usually of an epilepsy syndrome. Seizures may be febrile or non-febrile.
these effects are completely reversible. Metabolic changes (e. g.
They might include a single symptom or have complex sympto- hypocalcaemia, hypomagnesaemia, and hyponatraemia) may matology. Description of seizures should be focused on precipi- contribute to seizure susceptibility [75].
tating factors, the very initial ictal manifestations (aura? focal onset?), and include the whole sequence of ictal symptoms as well as postictal abnormalities. The initial symptomatology BUS is a common component of conditioning regimens for haema- may have localising value pointing to a specific seizure onset topoietic stem cell transplantation. It rapidly crosses the BBB.
zone [60]. Seizures may be generalised (e. g. absences, tonic-clo- Neurotoxicity is a widely known complication of high-dose BU, nic, myoclonic) or partial (focal onset) with or without second- with seizures occurring in up to 7.5 % of children without AED pro- ary generalisation. Classification will often be essential for indi- phylaxis [29]. Seizures may occur during BUS administration or cation and selection of appropriate AEDs [27]. Brain tumour-re- within 24 hours after the last dose, but seem to rarely happen be- lated epileptic seizures are mostly focal, although generalization fore the seventh dose [16, 29]. It is now common practice to give is common and may occur so quickly that the focal phase re- anticonvulsant prophylaxis along with high-dose BUS (see below).
mains unnoticed. Generalized seizures are more common in children with systemic malignancies. It can be assumed that most seizures in oncology will be symptomatic. However, there Although not a classical CTD, CSA is often part of the therapeutic may be cases where a genetic seizure susceptibility is unmasked regime in oncology. Neurotoxicity is one of the most significant by an acute illness and/or epileptogenic drugs.
clinical side effects of the CSA, occurring in up to 60 % of trans- plant patients [66]. It is considered a drug with high epilepto- Secondly, strong efforts have to be made to identify specific sec- genic potential [62]. However, the mechanism is poorly under- ondary effects that may have lead to increased seizure suscept- stood. There might be some interference of CSA with mitochon- ibility. In oncology some of these may even pose potentially life- drial energy metabolism [66]. Neurotoxicity may occur during threatening conditions, such as CNS infections or cerebral bleed- long-term treatment even when blood concentrations of CSA are ings, intoxications or metabolic encephalopathies. Importantly, within the therapeutic range. Single seizures, status epilepticus causal treatment of the underlying condition may be possible in and development of the posterior reversible encephalopathy syn- a relevant proportion of patients. Therefore, an aggressive diag- drome have frequently been published. Dose reduction or with- nostic work-up should be initiated promptly if a seizure occurs drawal of CSA usually results in resolution of clinical symptoms.
during the course of a malignancy (see Fig. 2). Although cur- rently not routinely performed, we propose to include detectionof drug levels of CTDs and/or their toxic metabolites (blood, CSF) Diagnostic approach after first seizure in paediatric oncology if possible. Toxic drug levels may be identified resulting in mod- ification of therapy regimes. In addition, pooling these data with- Due to the complexity and variability of the paediatric oncologi- in clinical trials may enable clinicians to better understand the cal population it is not possible to provide universal recommen- pathophysiology of neurotoxicity of certain CTDs.
dations how to approach seizures in these children. However, some general aspects of the diagnostic work-up of a child after a first seizure have to be considered.
Treatment of seizures and epilepsy in paediatric oncology Firstly, the importance of the correct diagnosis before initiation In general, the clinical decision to initiate an AED is based on the of AED treatment cannot be overstated. There is a wide differen- judgement that the risk of seizure occurrence outweighs the risk Tibussek D et al. Antiepileptic Treatment in … Klin Pädiatr 2006; 218: 340 – 349 of AEDs and their possible toxic effects [21]. Predicting the risk of age and sex of the patient, comorbidities, and comedications.
seizure recurrence forms another essential part of the decision for An individualized approach is therefore required in any such or against AED treatment. However, this may be particularly diffi- case. We strongly suggest that a paediatrician with expertise in cult in paediatric oncology. In general, seizure recurrence in chil- epilepsies in children should always be involved in this complex dren who suffered the first seizure during the intensive CTD treat- decision process, the regular review of antiepileptic manage- ment phase tends to be infrequent, usually occurring within three to six months of the first seizure. Often, AED may be discontinued shortly after the causative abnormality has been corrected, thus preventing unnecessary initiation of long-term AED treatment [30, 37]. Options may be treatment of CNS infections, correctionof electrolyte disturbances including the critical review of the cur- A main challenge of AED treatment in paediatric oncology is the rent hydration regime and/or diuretic treatment, correction of high number of comedications to be expected in the majority of blood sugar, discontinuation of potentially causal CTD, and, if patients [43, 74]. This will inevitably imply the potential for available, antagonistic treatment (e. g. IFO). If a CTD is likely causal pharmacokinetic and pharmacodynamic drug interactions and for seizure occurrence its indication, dosage, and infusion rate it may be almost impossible to predict every pharmacological should be critically questioned. In addition, the patient should be modification caused by the variety of drugs given at the same immediately reported to the clinical trial office. Alternative treat- time. Pharmacokinetic drug interactions may result in changes ment should be considered before re-exposure for those patients of absorption, elimination, protein binding, or distribution of a who developed seizures attributable to a certain CTD.
drug. Drug metabolism accounts for most clinically relevant pharmacokinetic drug interactions between AEDs and CTDs, par- However, the recurrence risk may be significantly higher in chil- ticularly those involving cytochrome P450 (CYP) isoenzymes in dren with fixed neurological abnormalities and certain cerebral hepatic metabolism. Many of the drugs in use in paediatric on- defects [45]. In adults with brain tumours it appeared that the cology are metabolised by the CYP isoenzyme system and thus earlier seizures occurred in the course of illness, the more likely interactions mainly derive from inhibition or induction of these they are to recur [69]. Brain imaging might sometimes offer im- isoenzymes. The main isoenzymes in AED metabolism are portant information contributing to the treatment decision.
CYP3A4, CYP2C9, and CYP2C19. For CTD metabolism, CYP3A4 isthe most important. In addition, UDP-glucoronosyltransferase If initiation of AED treatment is indicated, the choice of AED in (UGT) enzymes can also play a role. The potential of enzyme in- paediatric oncology is based on the classification of seizures, duction and inhibition varies widely among AED (see Table 5).
Tibussek D et al. Antiepileptic Treatment in … Klin Pädiatr 2006; 218: 340 – 349 cutive children treated for acute lymphoblastic leukaemia re-ceived treatment for 30 days or longer with enzyme-inducing Enzyme-inducing or inhibiting characteristics of different anticonvulsants (PHT, PBT, CBZ, or a combination) at the same time as antileukaemic therapy. In this study anticonvulsant ther- apy was significantly related to worse event-free survival with occurrence of more haematological, and CNS relapses among the 566 patients with B-lineage leukaemia. A faster clearance of teniposide and methotrexate was found among patients receiv- A very recent retrospective study by Oberndorfer et al. [51] eval- uated the effects of coadministration of AED on survival rates of patients with glioblastoma multiforme, who underwent surgery, radiotherapy and chemotherapy. A significant decline of survival rates in the group of patients who received enzyme-inducing Another clinically important example refers to data provided from Hassan et al. [29] who were first to systematically study the influence of PHT as preventative AED on BUS pharmacoki- netics and pharamcodynamics in patients during conditioning prior to bone marrow transplantation using BUS. They reported a significantly faster clearance, a lower area under the concen- According to the systematic approach by Vecht et al. [74] the most tration-time curve and a shorter half-life if the BUS regime was relevant clinical consequences of drug interactions or altered pharmacodynamics, respectively, can be summarized as follows: a) reduced efficacy of antiepileptic drugs, b) reduced efficacy of CTD, c) increased toxicity of AED, d) increased toxicity of CTD.
Very little data are available on this possible effect of interaction.
Fluorouracil, an inhibitor of the CPY2C9 isoezyme, has been re- Although only very few clinical studies have focussed on these ported to induce toxic plasma concentrations of PHT leading to special issues, case reports provide alarming evidence that this severe neurological deficits mainly attributed to cerebellar dis- is by no means only a theoretical matter, but has strong impact turbances (Brickel et al. 2003). It can be speculated that in- on clinical routine and decision making. This is illustrated by creased toxicity of AEDs under certain enzyme-inhibiting CTDs some exemplary data provided by current literature.
is underrepresented in current literature.
A number of case-reports of adult patients demonstrated a VPA is a potent inhibitor of the CYP isoenzymes, mainly of CYP2C9.
marked drop of phenytoin (PHT) concentrations of up to 50 % As VPA has very recently been studied as an adjunctive therapy for after CTD administration. This was mainly attributed to cisplatin acute myeloid leukaemia and myelodysplastic syndrome [10], in- [22]. In a retrospective study by Grossmann et al. [26] all pa- teractions with certain CTDs might become more relevant in fu- tients who received three or more cycles of cisplatin and car- ture. In a follow-up study of 70 adults with high-grade gliomas mustine chemotherapy for primary brain tumours required an an association of VPA with a fotemustine-cisplatin regimen re- average increase in their maintenance PHT dose of 41 % to sulted in a three-fold higher incidence of reversible thrombopenia, neutropenia or both. Haematological side-effects decreased after AED modification during the continued chemotherapy [7].
Valproic acid (VPA) has also been reported to be influenced by cisplatin. In a patient receiving daily VPA, severe seizures were Increased toxicity of IFO has been reported in a paediatric patient observed 7 weeks after the first cisplatin-based chemotherapy who received PBT as comedication. He developed IFO-encephalo- cycle, when the serum VPA concentration was found to be re- pathy, which was attributed to the enzyme inducing activity of duced by approximately 50 % of the initial level [32]. Another PBT leading to a higher amount of toxic IFO-metabolites [23].
case report described the recurrence of tonic-clonic seizure in a child with acute lymphoblastic leukaemia under VPA therapy a few hours after high-dose MTX. An acute decline of the serum Interactions between corticosteroids and PHT and/or PBT may be VPA concentration to about 25 % of the pre-MTX value could be almost unpredictable. A variety of effects have been observed.
PHT and PBT have the potential to shorten the half-life and in- crease total body clearance of dexamethasone and prednisone [11]. On the other hand, both increased and lowered levels of The potential of drug interactions to significantly worsen the PHT were seen under comedication with dexamethasone. Lack- outcome of malignant diseases under CTD was impressively illu- ner [40] reported a patient receiving dexamethasone who re- strated by a study of Relling et al. [59]. Forty of 716 (5.6 %) conse- quired a daily PHT dose of greater than 10 mg/kg to maintain Tibussek D et al. Antiepileptic Treatment in … Klin Pädiatr 2006; 218: 340 – 349 therapeutic serum concentration. The concentration increased AED related haematological side effects are particularly un- by nearly 300 % after dexamethasone was discontinued. Con- wanted in paediatric oncology. Although the overall incidence trary, Lawson et al. [42] reported increased levels of PHT in pa- in non-oncological patients seems to be low [6], it has been re- tients receiving PHT and dexamethasone. This may be attributed ported that, when AEDs are used in combination with antineo- to competition on protein binding leading to intoxications, plastic agents, these effects can be pronounced [7]. Aplastic which also might mimic tumour progression. It has been hy- anaemia (CBZ, PBT, PHT, ETX) and thrombopenia (VPA) are most pothesized that decreased levels may be caused by induction of hepatic metabolism causing a loss of seizure control [61]. How- ever, the real pathophysiology of these contradictory effects is Serious rashes, including Stevens-Johnson syndrome and anti- convulsant hypersensitivity syndrome are rare, but potentially fatal adverse effects that can occur and are more common when Summarizing these results it can be stated that drug interactions certain AEDs (PHT, PBT, CBZ) are used in combination with irra- between AEDs and CTDs can have substantial effects on clinical outcome. We therefore propose that therapeutic drug monitor- ing may contribute to improving cancer chemotherapy and One of the most severe long-term sequelae of childhood cancer should therefore be further investigated particularly in view of treatment may be neurocognitive disorders [4]. In this context a variety of possible drug interactions between AEDs and CTDs.
CNS side-effects of AEDs are particularly worrying. No AED ap- pears to be completely exempt from unfavourable cognitive and/or behavioural effects [2]. Previous clinical studies indicate Adverse effects of AED relevant in paediatric oncology that older AEDs have the most negative cognitive profile, mainly PB and PHT [18, 49]. However, even the “new” AEDs, e. g., topira- Newer and more aggressive treatments of malignancies in child- mate or levetiracetam, have been associated with adverse cogni- hood have lead to significantly longer survival rates of affected tive or neurobehavioral effects. Lamotrigine seems to have a fa- children. Therefore, adverse effects of long-term anticonvulsive vourable cognitive profile [1, 46, 67].
treatment have to be considered. It is beyond the scope of thisreview to cover all these aspects of AED treatment in detail. A Appetite regulation can be a relevant clinical problem in oncol- summary of the most relevant side effects of frequently used ogy in both terms, uncontrolled eating, mainly in cerebral malig- AED in paediatrics is given in Table 6. Some aspects are of special nancies or anorexia, either due to CTDs or the malignancy itself.
These effects may be worsen by certain AED (see Table 6).
Commonly prescribed AED in childhood, dosage, side-effects [2, 5, 13, 27] rash, aplastic anaemia (rare), ataxia,diplopia cardiac arrythmia, purple glove syn-drome nephrolithiasis, glaucoma, hypohydro-sis, metabolic acidosis thrombopenia, hepatic failure, hyper-ammonemia, pancreatic failure, tre-mor * add-on enzyme-inducers: 5–15 mg/kg; add-on VPA: 1–3 mg/kg Tibussek D et al. Antiepileptic Treatment in … Klin Pädiatr 2006; 218: 340 – 349 Effects of long-term AED treatment on hormonal function, con- CTDs and AEDs is essential. If possible, therapy should rapidly traception, sexuality, and pregnancy is an important issue for be changed to non-enzyme inducing or inhibiting AED once the adolescents [33]. Early counselling on effective contraception is patient’s status has stabilized. It needs to be stressed that this essential in female teenagers with cancer in order to prevent un- may again lead to significant alterations of CTD levels.
wanted pregnancies particularly in view of potentially terato- genic and mutagenic drugs during cancer treatment [41]. The in- Patients with progressive tumours or severe mucositis might lose fluence of AED selection on current or future choices of contra- the ability to swallow even suspensions. Beside i. v.- and i. m.- ceptive methods needs to be considered when choosing an AED preparations (e. g. PB; [34]), buccal application might be consid- for those patients who are likely to continue treatment into their ered on this occasion. This is an option for lorazepam and mida- childbearing years. Nonenzyme-inducing AEDs do not show any zolam. Sedative side-effects of these AED may even be desirable.
interactions with the oral contraceptive pill and should therefore In addition, lorazepam has antiemetic and anxiolytic properties.
be preferred in these patients [14, 78]. Reduced fertility in wom- en with epilepsy and foetal damages due to AEDs used during As mentioned above, epilepsy treatment in female teenagers pregnancy are additional concerns [71].
pose a number of additional difficulties. Treatment decisions should follow currently existing guidelines for the management Different regimens have been suggested as preventative AED The primary concern of AED treatment is maintaining adequate treatment in patients undergoing high-dose busulfan therapy seizure control. Although exact epidemiological data are missing (see Table 7). PHT should no longer be used for its potential for it can be presumed that the majority of seizures in paediatric on- drug interaction and a unfavourable profile of adverse effects [29].
cology will be partial or secondary generalized. A variety of older and newer AED have been shown good effectiveness in children Last but not least it is noteworthy to mention that especially in with focal epilepsy [27]. However, the use of enzyme-inducing brain tumour patients seizures may be refractory to medical man- AED as drugs of first choice is still wide routine in paediatric on- agement and epilepsy surgery can sometimes be performed [69].
cology departments, mainly PHT, PBT, and CBZ. VPA has also been recommended [30]. However, having in mind the above de- scribed potentially fatal effects of drug interactions between Seizure prophylaxis in children with brain tumours AED and CTD it seems reasonable to propose that AEDs not in- ducing or inhibiting the cytochrome P450 system should be pre- Because a substantial number of patients with brain tumours may ferred. As rapid titration is often required, gabapentin or levetir- develop seizures, it remains common practice among neurooncol- acetam have been suggested as possible candidates with good ogists and neurosurgeons to initiate preventive AED treatment efficacy and a favourable safety profile [34, 36, 74]. Gabapentin even in the absence of seizures. Many patients who have experi- has been proven effective in partial seizures [19]. There is some enced a single seizure attributable to brain tumours will be put experience that gabapentin is well tolerated and provide effec- on regular AED and often keep on taking their anticonvulsive tive seizure control in children under CTD [36]. Levetiracetam is medication for years. The rational for this policy has been ad- considered as a wide-spectrum AED effective in both partial and dressed in several studies, but continues to be controversial [68].
generalized seizures [19, 63]. In adults with end stage brain tu- However, growing evidence clearly points against the usefulness mours levetiracetam has been reported as a good option due to of preventive AED treatment. A practice parameter established by its efficacy and tolerability [34]. In children with treatment-re- the American Academy of Neurology [24] recommended that pro- sistant partial seizures it was effective and well tolerated as ad- phylactic anticonvulsants should not be used routinely in patients with newly diagnosed brain tumours. Perioperative prophylaxis should be tapered off after the first postoperative week. In support However, it has to be stressed that recommendations of long- of this view, two recent meta-analyses found no evidence to sup- term AED treatment in the oncology patient are not supported port AED prophylaxis with PBT, PHT, or valproic acid in patients by robust empirical evidence. In addition, due to the complexity with brain tumours and no history of seizures, regardless of neo- of patients under cancer treatment an individualized approach plastic type [68, 70]. However, currently available data need to be to any such child with epilepsy is required. According to the spe- interpreted with some caution. None of the studies included in cific patients needs different AED treatment regimes may be in-dicated, including enzyme-inducing AED or combination ther- apy. Therefore, the right choice of treatment requires consider- Busulfan and options of preventive AED treatment able expertise in the care of paediatric epilepsy patients.
If only short-term use is expected, clonazepan may be a candidate with an excellent broad-spectrum efficacy. Its use is sometimes limited by sedating effects, hypersalivation, ataxia, and most im- portantly, the development of tolerance, usually after 3–6 months.
Short-term use of PHT, PB or VPA may be justified if i.v.-applica- tion is necessary. However, closed monitoring of drug levels of Tibussek D et al. Antiepileptic Treatment in … Klin Pädiatr 2006; 218: 340 – 349 meta-analyses were performed using newer AED. Moreover, there 5 Biton V. Effect of antiepileptic drugs on bodyweight: overview and is a lack of reliable risk-factors predictive for seizure occurrence clinical implications for the treatment of epilepsy. CNS Drugs 2003;17: 781 – 791 6 Blackburn SC, Oliart AD, Garcia Rodriguez LA, Perez Gutthann S. Anti- epileptics and blood dyscrasias: a cohort study. Pharmacotherapy In addition, it needs to be stressed, that once a patient experi- ences a seizure clearly attributable to a brain tumor, long-term Bourg V, Lebrun C, Chichmanian RM, Thomas P, Frenay M. Nitroso-urea-cisplatin-based chemotherapy associated with valproate: in- treatment with AED is generally accepted as proper medical crease of haematologic toxicity. Ann Oncol 2001; 12: 217 – 219 care due to the high risk of recurrence [69].
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