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© Borgis - Postępy Nauk Medycznych 9/2013, s. 609-614
*Marzena Samardakiewicz1, Jakub Litak2, Aneta Szudy2, Agata Makarewicz3
Zaburzenia psychiczne indukowane steroidami u adolescentów w przebiegu leczenia ostrej białaczki limfoblastycznej
Mental disorders induced by steroids in the course of treatment for acute lymphoblastic leukemia in adolescents
1Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin
Head of Department: prof. Jerzy R. Kowalczyk, MD, PhD
2Medical Students’ Research Association, Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin
Head of Department: prof. Jerzy R. Kowalczyk MD, PhD
3Chair and Department of Psychiatry, Independent Public Teaching Hospital No 1 in Lublin, Lublin
Head of Department: prof. Andrzej Czernikiewicz, MD, PhD
Streszczenie
Wstęp. Kortykosteroidy/GKS stanowią ważny element w leczeniu wielu chorób nowotworowych wieku dziecięcego. Mogą prowadzić jednak do wystąpienia wielu niepożądanych objawów somatycznych i behawioralnych, w tym zaburzeń psychicznych, także jakościowych. Szczególnie narażeni są pacjenci z ostrą białaczką limfoblastyczną/ALL otrzymujący w protokołach terapeutycznych wysokie dawki prednizonu/PRED i deksametazonu/DEXA i pacjenci z chorobą Hodkina/HD wielokrotnie otrzymujący cykle z DEXA.
Cel pracy. Analiza przypadków zaburzeń psychicznych indukowanych przyjmowaniem steroidów w przebiegu leczenia ostrej białaczki limfoblastycznej u dzieci powyżej 12 roku życia.
Materiał i metody. Przedmiotem analizy był przebieg epizodów przejściowych zaburzeń psychicznych u dwóch pacjentów z ALL oraz ocena stanu psychicznego w określonych momentach czasowych w trakcie intensywnej terapii oraz podczas długofalowej obserwacji po zakończeniu leczenia podtrzymującego remisję. Epizody zaburzeń funkcji psychicznych wystąpiły dwukrotnie, w obu protokołach leczenia, w momencie redukcji steroidów.
Wyniki. Pacjent A (chłopiec, 14,9 at) z ALL (BFM 97; Prot I: 37 dni x 100mg PRED/dzień: 28 dni maks. dawka, 9 dni redukcja; Prot. II: 30 dni x 16 mg DEXA: 21 dni dawka max, 9 dni redukcja). W trakcie redukcji PRED (od 29. do 37. dnia) zaobserwowano u pacjenta spowolnienie psychoruchowe, pogorszenie kontaktu słownego, utratę zainteresowania otoczeniem i osobami, przygnębienie, izolację, ęk i płaczliwość. W trakcie pierwszego dnia redukcji DEXA (22. dzień terapii) chłopiec podjął zamiar próby samobójczej, przy próbie interwencji stawiał opór, był pobudzony, wyrażał głośno myśli samobójcze. Pacjent B (chłopiec, 15,2 at) z ALL (ALL-IC 2002; Prot. I: 37 dni x 115mg PRED/dzień:28 dni maks. dawka, 9 dni redukcja; Prot. II: 31 dni x 20 mg DEXA: 22 dni maks. dawka, 9 dni redukcja). 10 dni po rozpoczęciu PRED, po osiągnięciu maks. dawki, chłopiec stał się mało aktywny, izolujący się, w obniżonym nastroju. Objawy utrzymywały się na tym samym poziomie od 10. do 37. dnia. W pierwszym dniu redukcji dawki DEXA zaobserwowano u pacjenta niepokój, ęk, a behawioralne przesłanki wskazywały na intensywne doznania omamowe.
Wnioski. 1. Dzieci i młodzież otrzymujący wysokie dawki steroidów (PRED i /lub DEXA) w przebiegu leczenia nowotworów są narażone na wystąpienie zaburzeń psychicznych. 2. Epizody zaburzeń psychicznych u nastoletnich chłopców z ALL każdorazowo wystąpiły w momencie redukcji steroidów, w obrazie psychopatologicznym miały podobne elementy, ale różniły się w zakresie zastosowanej farmakoterapii i przebiegu późniejszego funkcjonowania pacjentów. 3. Rozpoznawanie i leczenie epizodów psychiatrycznych u dzieci z chorobami nowotworowymi wymaga wypracowania standardu postępowania w warunkach polskich ośrodków onkologii i hematologii dziecięcej, także po zakończeniu leczenia.
Summary
Introduction. Glicokorticosteroids/GKS are an important element in children’s cancer treatment. However, they can lead to many adverse somatic and behavioral symptoms, including psychic disorders, also quality ones. Especially exposed are the patients with acute lymphoblastic leukemia/ALL treated with high doses of Prednisone/PRED and Dexamethasone/DEXA, as well as patients with Hodgkin Disease/HD treated with multiple DEXA cycles.
Aim. Analysis of cases of mental disorders induced by taking steroids during treatment of acute lymphoblastic leukemia in children over 12 years of age.
Material and methods. The subject of analysis was the course of transient episodes of mental disorders in two patients with ALL and evaluation of mental state at certain points in time during intensive care and during long-term follow-up after completion of maintenance therapy. Episodes of mental dysfunction occurred twice, in both treatment protocols, at the time of reduction of steroids.
Results. Patient A (14.9 year-old boy) with ALL (BFM 97; Prot I: 37 days x 100mg of PRED daily: 28 days of max dose, 9 days of dose reduction; Prot. II: 30 days x 16 mg of DEXA: 21 days of the max dose, 9 days of reduction). During PRED dose reduction (on 29th-37th days) the patient was observed with psychomotor retardation, impaired verbal contact, oss of interest in surroundings and people, depression, isolation, anxiety and crying. During the first day of DEXA reduction (the 22th day) the boy attempted suicide, resisted to an attempt to intervene, he was excited, he expressed suicidal thoughts aloud. Patient B (15.2 year-old boy) with ALL (ALL-IC 2002; Prot. I: 37 days x 115mg of PRED daily: 28 days of max dose, 9 days of dose reduction; Prot. II: 31 days x 20 mg of DEXA: 22 days of full dose, 9 days of reduction). 10 days after the start of PRED therapy, after reaching the maximum dose, the boy has become very ittle active, secluded and in ow mood. Symptoms remained at the same evel from 10th to 37th day. And during the first day of DEXA dose reduction anxiety and fear were observed in the patient, and behavioral indications pointed to intense hallucinatory experience.
Conclusions. 1. Children and adolescents receiving high-dose steroids (PRED and/or DEXA) in the course of cancer treatment are at risk of developing mental disorders. 2. Episodes of mental disorders in adolescent boys with ALL occurred at the time of the reduction of steroids and had similar elements in the psychopathological image, but differed in the field of applied medication and course of the subsequent functioning of patients. 3. Diagnosis and treatment of psychiatric episodes in children with cancer requires the development of standards of procedure in conditions of Polish centers of pediatric oncology and hematology, also after the completion of treatment.
Introduction
Corticoids as widely available and used drugs are becoming an important weapon in the fight against many diseases encountered in pediatric practice. They also play a key role in the treatment of acute lymphoblastic leukemia (ALL). The effectiveness of these drugs seems to be unquestionable, playing fundamental role in the long-term treatment of ALL. Long-term use of glicocorticoids (GCS) causes serious side effects such as abnormal fat distribution, obesity, hypertension, diabetes, myopathy, osteopenia, hepatomegaly, or immunosuppression manifested as a tendency to infections. In addition to somatic changes corticosteroids may cause a number of mental disorders in the form of mood disorder. Among them we can highlight problems such as anxiety, agitation, insomnia, mania and depression, and even psychotic states with delusions and hallucinations (1, 2). Data from the literature estimate the incidence of these disorders in the 5 to 75% of patients treated for various reasons with doses of corticosteroids (3). A series of studies conducted in adult patients suggests that acute psychiatric states correlate with the amount of the dose. Severe psychiatric symptoms occurred in 1.3% of patients receiving < 40 mg prednisolone daily (or equivalent of the dose), in 4.6% of patients treated with prednisolone dose from 41 to 80 mg, and in 18.4% of patients treated with doses exceeding 80 mg per day. There are also other relevant factors, including family predisposition (4). Further studies show an increased incidence of psychiatric disorders in patients treated with doses of 40 mg of prednisone a day (5). Pediatric studies have confirmed that the dose of 40 mg/m2 of prednisone a day increased risk of psychotic disorders (6). Thus, the data coming from the publications and numerous studies describes pediatric patients with the diagnosis of ALL as a group of the highest risk of psychiatric disorders in connection with the intake of high doses of corticosteroids (7, 8). These disorders may occur at different times from the beginning of treatment with steroids. Lewis and Smith estimate 11.5 days as the average time from the start of treatment to the first symptoms of psychotic disorders, 39% of disorders occur in the first week, 62% within two weeks, 83% within 6 weeks (9). Mental disorders can also occur during dose reduction and withdrawal of the drug, most often manifesting as depression, anxiety, and fatigue (10) as well as mania and disorders of consciousness (11, 12).
The mechanism of function of corticosteroids triggering psychiatric conditions in patients is not fully known. The likely effects are impaired synthesis of monoamines (such as serotonin, dopamine, catecholamines) which is caused by exogenous corticosteroids, or disturbance in the economy neuropeptide transmitters. Corticosteroids increase the level of dopaminergic activity, and also reduce the central and peripheral serotonin secretion which may lead to psychotic states (13, 14). Another probable mechanism of steroids’ function is hippocampal nerve damage, which in the process of additive synergism with used chemotherapeutic drugs and cytostatics can increase the psychiatric side effects of treatment of ALL (15). In patients with episodes of steroid-induced psychiatric disorders elevated levels of corticosteroid receptor mRNA were stated, which may also indicate a genetic determinants of these processes (16). Elevated levels of endogenous corticosteroids (neurotransmitter) of tetrahydrodeoxycorticosteone (THDOC) induces a reduction in the level of allopregnanolone and can be found in many models of acute depression (17).
Aim
Analysis of cases of mental disorders induced by taking steroids during treatment of acute lymphoblastic leukemia in children over 12 years of age.
Material and methods
The subject of analysis was the course of transient episodes of mental disorders in two patients with ALL and evaluation of mental state at certain points in time during intensive care and during long-term follow-up after completion of maintenance therapy. The average age of patients at diagnosis was 14.9 years. Episodes of mental dysfunction occurred twice, in both treatment protocols, at the time of reduction of steroids.
Medical records of two patients treated for acute lymphoblastic leukemia in oncology and hematology ward for children at Pediatric Hospital in Lublin were analyzed. Criteria for selection of patients for analysis: identification of ALL, the age at diagnosis over 12 years, the occurrence of an episode of mental dysfunction during intensive treatment, temporal association of the episode with the intake of steroids, the ability to conduct follow-up. The patients were treated according to therapeutic protocols in force at the time of diagnosis (BFM 97 and ALL-IC 2002). These protocols treatment of acute lymphoblastic leukemia in children are composed of several stages, and during intensive treatment (induction of remission/Protocol I and the consolidation of remission/Protocol II) request similar doses of steroids. Patients receive in Protocol I prednisone (1-28 days 60 mg/m2/day and 3 x 3 days at a dose reduced), and in Protocol II dexamethasone (1-21 days 10 mg/m2/day and 3 x 3 days at a dose reduced). Between these protocols patients receive protocol M not containing steroids.
During the treatment, patients are supported by a planned psychological care. In the first month of treatment were assessed: intellectual functioning (WISC-R), emotional functioning (“How are you” Choynowski, Skrzypek), personality functioning (16PF Cattell) and the functioning of the family system (interview). In addition, the mental state of patients were analyzed on the basis of interview and psychiatric examination at certain points in time during the intensive care (T0 – at the beginning of treatment, E1 – during the first episode, E2 – during the second episode), and during long-term follow-up after the completion of maintenance therapy (T1 – after intensive treatment, T2 – 3 months after the end of treatment, T3 – 6 months after treatment).
Results
The subject of analysis was the course of psychiatric episodes showing temporal association with the intake of corticosteroids and evaluation of the mental state at specific points in time in two patients with ALL. The detailed course of disorders and psychiatric symptoms were presented in the case and table 1 shows a comparison of the course of mental state changes.
Table 1. Comparison of episodes of mental disorders in patients with ALL, taking into account the course of steroid therapy.
CharacteristicsPatient APatient B
Gender/Age (years)M/14.9M/15.2
Treatment protocolBFM 97ALL-IC 2002
Protocol I/Doses of GKS/
Number of days
100 mg PRED/28 days
Dose reduction/9 days
115 mg PRED/28 days
Dose reduction/9 days
Psychiatric symptoms in the first episode of mental disorders/E1Isolation
Worse contact
Psychomotor slowdown
Depression
Anxiety and crying
Isolation
Worse contact
Low mood
Time of occurrence29th day of steroid treatment10th day of steroid treatment
Length of occurrence E17 days27 days
Psychiatric consultationDoxepin 2 x 10 mgNo recommendations
Protocol II/Doses of GKS/Number of days16 mg DEXA/21 days
Dose reduction/9 days
20 mg DEXA/22 days
Dose reduction/9 days
Psychiatric symptoms in the second episode of mental disorders/E2Auditory hallucinations
Psychomotor agitation
Suicidal thoughts & tendencies
Irritability, Anxiety, Restlessness
Auditory hallucinations
Agitation
Fear of death
Vegetative symptoms
Time of occurrence22nd day of steroid treatment23rd day of steroid treatment
Length of occurrence E27 days9 days
Psychiatric consultationPernazine 3 x 25 mgOlanzapine 2 x 5 mg
Presentation cases
Patient A

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otrzymano: 2013-07-22
zaakceptowano do druku: 2013-08-26

Adres do korespondencji:
*Marzena Samardakiewicz
Klinika Hematologii, Onkologii i Transplantologii Dziecięcej UM
ul. Chodźki 2, 20-093 Lublin
tel.: +48 (81) 718-51-26
e-mail: psychonk@dsk.lublin.pl

Postępy Nauk Medycznych 9/2013
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