Is there any support for routine use of blood status (Hb, white blood cell-WBC- count, poly/mononuc

Fråga: Is there any support for routine use of blood status (Hb, white blood cell-WBC- count, poly/mononucleocytes, thrombocytes) and liver function tests (ASAT, ALAT, GT) in children treated with different antiepileptics.

Sammanfattning: Most authors agree that identifying the risk factors and giving the importance to clinical monitoring by educating patients and relatives about the symptoms and signs of potential drug-related problems may be more important than blood monitoring. Screening laboratory studies before the initiation of antiepileptic drugs are important to have an idea about the baseline status of the patient.

Svar: It is estimated that there are around 4400 new epilepsy cases yearly, that of 1000 are children and approximately one sixth of epileptic patients (9000-10000) are in the age of 0 to 19-years old in Sweden (1). In Stockholm, the use of antiepileptic drugs, in five-year age groups (within 0-19 age range) was 0.3-1.3 (DDD/1000 inhabitants/day) for female and 0.4-2.4 for male patients in 1999 (2). Antiepileptics were valproic acid (3.0) (DDD/1000 inhabitants/day), carbamazepine (2.6), lamotrigin (1.1), vigabatrin (0.7), phenobarbital (0.4), phenytoin (0.4), topiramate (0.2), gabapentin (0.2), oxycarbamazepine (0.2), clonazepam (0.2), ethosuximide (0.1), primidione (0.02), felbamate (0.005) (2).

In Sweden, haematological (360 cases) and hepatic adverse drug reactions (ADRs) (244 cases) of antiepileptic drugs in all ages have been reported to The Swedish Adverse Drug Reactions Advisory Committee (SADRAC) since 1965 (3). Carbamazepine, phenytoin and valproate have the highest numbers of hepatic and haematological side effects according to this database. Thrombocytopenia, leukopenia, agranulocytosis, megaloblastic anaemia, pancytopenia, eosinophilia, aplastic anaemia are the main haematological ADRs. The major hepatic side effect is elevated liver enzymes. The others are jaundice, cholestasis, fatty liver, toxic hepatopathy, fatal hepatorenal syndrome and liver necrosis.

All of the major antiepileptic drugs can cause hepatotoxicity and haematological ADRs (4). These side effects are usually part of a hypersensitivity reaction in the early weeks of the treatment. Hepatic and haematological ADRs may rarely develop after more than 2 years of treatment (5,6). In the present review, these side effects, time of onset, SADRAC reports and necessity of blood monitoring are discussed for the antiepileptic drugs used in Sweden.

Valproate: Hepatic ADRs: The frequency of fatal hepatotoxicity with valproate has been estimated to be one to five in 50000 treated patients (7). Children treated with multiple antiepileptics, under the age of 2 years, with presumed metabolic disorders or with severe epilepsy accompanied with mental retardation and organic brain disease seemed to be more sensitive to valproate side effects (6). One in 500 children under 2-years of age died during valproate treatment (7). Fifteen children (out of 16) with fatal liver failure developed their first symptoms within the first six months of treatment while one developed them in the eleventh month (7). An intensive blood monitoring was recommended especially during the first six months considering the number of fatalities related to valproate (7). On the other hand the predictive value of blood monitoring was not discussed in that study (7). In some patients first sign and symptoms occurred up to 3 years (6, 8). The initial symptoms of toxicity included nausea, vomiting, anorexia, lethargy, edema, jaundice. Elevation of hepatic enzymes was typical during the illness (8). Careful observation of clinical signs were considered more important than blood monitoring (6). Asymptomatic liver enzyme elevations have not progressed to hepatic failure (6), even though it was suggested that it might be a marker for early valproate induced hepatotoxicity (8). On the other hand pathologic investigation of liver tissues showed chronic hepatotoxicity supporting a progressive hepatic damage rather than an acute reaction (8). However there are no clear data about routine laboratory monitoring in series of fatalities during the treatment course (8). The manufacturer states that liver function tests should be performed before therapy and at frequent intervals especially during the first six months in the risk group (9). It has been postulated that the metabolite 4-en-valproate or its further metabolites may be responsible for the hepatic toxicity (10), but routine measurement of serum 4-en-valproate was unlikely to be a useful predictor of risk for developing fatal hepatotoxicity (10).

Haematological ADRs: Valproate may cause dose dependent thrombocytopenia or increased bleeding time due to inhibition of platelet aggregation. The manufacturer does not recommend routine laboratory monitoring of platelet count during valproate treatment (9).

SADRAC reports: Valproate was the most commonly used antiepileptic drug among children in the Stockholm county in 1999. In five-year age groups (within 0-19 age range) it was 0.07-0.4 (DDD/1000 inhabitants/day) for female and 0.1-0.8 for male patients. There are 45 hepatic (mostly transaminase elevations) and 41 haematological side effects (mostly thrombocytopenia and leukopenia) reported to SADRAC.

Carbamazepine: Hepatic ADRs: There are hundreds of hepatic ADRs reported regarding carbamazepine use (11-14). Reversible hepatotoxic reactions in eleven cases appeared within the first month of treatment (11,12). Fatal hepatic reactions were observed in three patients after 8, 180 and 1460 days of therapy, but the third case with longtime onset was unlikely related to carbamazepine treatment (11). Reversible reactions with carbamazepine are mostly dose-related (11, 13). Inhibition of carbamazepine metabolism by erythromycin in a child suggested a dose-depended effect (13). Fever (65 per cent), anorexia (42 per cent), malaise and fatigue (42 per cent) were the most common signs of carbamazepine hepatotoxicity in 14 patients (11). Few hepatotoxicity cases in children were reported in literature but five of them were fatal (13, 14). Most common hepatic abnormalities are transient elevations of liver enzymes. In a study including 220 children, elevated liver function tests were noted in 13 patients but none of the elevations were of clinical significance and not predictive for more serious side effects (15).

Haematological ADRs: Approximately 10 per cent of children treated with carbamazepine develop leukopenia that does not progress during the therapy (15). Most of the leukopenia cases reversed spontaneously while therapy continued without any change in dosage (15). Aplastic anaemia is very rare but a serious adverse effect of carbamazepine therapy. Persistent leukopenia which is present in 2-10 per cent of the patients did not appear to predict the onset of severe bone marrow aplasia (8). Parallel to this, transient leukopenias and routine haematological monitoring did not predict the occurrence of severe side effects, either (15). However, detailed blood monitoring was advised for the patients that have white blood cell count less than 2500/mm3 (8). Antiepileptic drug related chronic leukopenia, if it is stable and if the absolute poly-morphonuclear nucleocyte count is consistently higher than 1000/ml was considered as safe (16).

SADRAC report: Carbamazepine is the second most commonly used antiepileptic among children in Stockholm county in 1999. In five-year age groups (within 0-19 age) it was 0.05-0.4 (DDD/1000 inhabitants/day) for female and 0.07-0.08 for male patients. There are 161 hepatotoxicity and 187 haematological side effects related to carbamazepine use in SADRAC. Transaminase, ALP and GT elevations, leukopenia, agranulocytosis, lymphadenopathia, aplastic anaemia and eosinofilia have been reported most commonly.

Lamotrigine: Hepatic and haematological ADRs: Lamotrigine was introduced in Europe in 1991. According to WHO registry, 17 cases were found to have systemic abnormality and 5 cases were associated with liver abnormality alone (17). A multisystem hypersensitivity reaction to lamotrigine including leucopenia, thrombocytopenia and liver enzyme abnormalities occurred in a 27-year-old woman on phenobarbital 11 days after beginning the treatment with lamotrigine (18).

SADRAC reports: The use of lamotrigine, in five-year age groups (within 0-19 age) was 0.01-0.2 (DDD/1000 inhabitants/day) for female and 0.02-0.3 for male patients in Stockholm county, in 1999. There are 12 cases possibly or probably related with lamotrigine use in SADRAC reports. Ten of those were femaa