Signs and symptoms of carbamazepine overdose

J Neurol (1995) 242:169-173 © Springer-Verlag 1995

Stephan Schmidt Mario Schmitz-Buhl

Signs and symptoms of carbamazepine overdose

Received: 27 January 1994 Received in revised form: 9 May 1994 Accepted: 17 May 1994

S. Schmidt Abteilung Neurologie, RLK Bonn, Kaiser-Karl-Ring 20, D-53111 Bonn, Germany

M. Schmitz-Buhl Forschungsstelle f/Jr Gesundheitserziehung, Erziehungswissenschaftliche Fakult~it, Gronewaldstrasse 2, D-50931 Cologne, Germany

S. Schmidt (~) Max Planck Institut ffir Psychiatrie, Abteilung Neuroimmunologie, Am Klopferspitz 18a, D-82125 Martinsried, Germany

Abst rac t Carbamazepine (CBZ) has been successfully employed in a va- riety of neurological and psychiatric disorders. The side-effects of CBZ treatment have been extensively studied. As little i.s known about the symptoms and prognosis of CBZ overdose, our objective was to iden- tify the factors relevant to its prognosis. In a retrospective study of 427 cases, we analysed the distribution of age, sex, total CBZ dose, CBZ plasma level, frequency of symptoms and their association with outcome. In those patients who recovered, coma, somnolence, cerebellar syndrome and epileptic seizures were the most common manifestations of

CBZ overdose. In fatal courses coma, epileptic seizures, respiratory depression and respiratory arrest ranked highest. Cardiac arrhythmias and other cardiovascular complications were rare. In 41 of 307 patients (13%) in whom outcome was reported, intoxication was fatal. The occurrence of seizures and CBZ doses exceeding 24g proved to be important indicators of a fatal outcome. The course of intoxication seems to be more benign in patients aged below 15 years.

Key words Carbamazepine Overdose • Symptoms • Prognosis

Introduction

Carbamazepine (CBZ) has been used extensively in patients with complex and generalized seizures, trigeminal neuralgia and bipolar affective disorders. Therapeutic use of CBZ has been associated with side effects that are neurological (diplopia, dizziness, tremor, headache, paraes- thesias), cardiovascular (arrhythmia, hypertension or hypotension), hepatic (increase of liver enzymes, hepatitis), haematological (anaemia, leukopenia, thrombocytopenia) and dermatological (exanthema, alopecia) [38]. Despite its extensive use, most published reports of CBZ overdose are anecdotal (for review, see [2l]) and the association between sex, age, total dose, CBZ plasma level, symptoms and outcome in cases of CBZ overdose have not been in- vestigated systematically.

Patients and methods

The records of 427 patients diagnosed as having a CBZ overdose between 1966 and 1992, filed at the Ciba Geigy Department of Drug Safety (Basle, Switzerland), were studied. The patients' records were not standardized. Therefore we rearranged the data with regard to the variables of age, sex, outcome (death, recovery, unknown), symptoms, cause of overdose (suicidal, accidental, unknown), indication for treatment (epilepsy, bipolar affective disor- der, pain syndromes, alcohol withdrawal), highest CBZ plasma level measured and total CBZ dose. These were encoded for statistical analysis. Cross-tabulations with chi-square test of indepen- dence were used for categoric data, analysis of variance, planned comparisons (contrast coefficient matrix) and post hoc tests (mul- tiple range test, Tukey-HSD, LSD and Scheffe procedures) for continuous variables to test for associations between age, sex, symptoms, cause of overdose, indication for treatment, symptoms, highest plasma level measured, total CBZ dose and outcome. All analyses were performed using the statistical package for the social sciences (SPSS).

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Results

The charts of 427 patients diagnosed as having a CBZ overdose were studied retrospectively. The patients were 207 (48.5%) males and 194 (45.4%) females. The sex was unknown in 26 (6%) cases. The mean (SD) age for all patients was 23 (16) years, for males 24 (15), for females 22 (17) years. The mean (SD) CBZ dose in the 271 (63%) reported cases was 10.8 (0.8)g (range 0.15-80). CBZ

Table 1 Frequency of symptoms in 427 cases of carbamazepine (CBZ) overdose

Symptoms Total number (percent of cases)

Coma 171 (40%) Somnolence 104 (24%) Cerebellar syndrome 58 (14%) Seizures 57 (13%) Respiratory depression 55 (13%) Vomiting 42 (10%) Dizziness 41 (10%) Nystagmus 36 (8%) Confusion 30 (7%) Dyskinesia 26 (6%) Hyperreflexia 23 (5%) Dysarthria 21 (5%) Hyporeflexia 21 (5%) Respiratory arrest 16 (4%) Light reaction sluggish or absent 16 (4%) Mydriasis 15 (3%) Myoclonia 10 (2%) Double vision 9 (2%) Blood pressure drop 8 (2%) Sinus tachycardia 7 (2%)

Table 2 Frequency of symptoms in 41 cases of CBZ overdose with fatal outcome

Symptoms Total number (percent of cases)

Coma 20 (49%) Seizures 14 (34%) Respiratory depression 9 (22%) Respiratory arrest 7 (17%) Light reaction sluggish or absent 3 (7%) Hyperreflexia 3 (7%) Myoclonia 3 (7%) Blood pressure drop 3 (7%) Nystagmus 2 (5%) Vomiting 2 (5%) Hyporeflexia 2 (5%) Dyskinesia 2 (5%) Bradycardia/AV-Block 2 (5%) Cardiac arrest 2 (5%) Renal failure 2 (5%)

plasma levels were reported in only 56 (13%) patients. The mean (SD) plasma level was 35.2 (2.1)gg/ml (range 8-82). Of 307 patients (72%) in whom the outcome was reported, 41 (13%) died and 266 (87%) recovered. The outcome was unknown in 120 (28%) cases. Suicidal overdose occurred in 214 patients (50%), accidental overdose in 81 patients (19%). Of a total of 156 patients, 97 (62%) were treated for seizures, 23 (15%) for bipolar affective disor- der, 22 (14%) for pain syndromes and 14 (9%) for alcohol withdrawal. Neurological dysfunction was the most common manifestation of an acute CBZ overdose (Table 1).

Concomitant medication at the time of the CBZ overdose was recorded in 108 (25%) patients, with phenobar- bital (n = 24), phenytoin (n = 16) and benzodiazepines (n = 15) being the most commonly reported drugs. In 319 patients (75%) no statement was made concerning concomitant medication. Of the patients who took a suicidal overdose co-medication was reported in 82 (38%), among whom alcohol intake (n = 16), phenytoin (n = 11), benzodiazepines (n --- 11) and phenobarbitone (n = 10) were mentioned most frequently. Five of 16 patients with concomitant alcohol ingestion died as compared with 2 of 11 with phenytoin, 1 of 11 with phenobarbitone and 1 of 11 with benzodiazepine co-medication. Analysis of variance to investigate the association between concomitant medication and outcome could not be performed owing to the lack of standardization in the patients' records. Of the 41 patients with a fatal outcome, 30 (73%) were males and 8 (19%) females. The mean age (SD) of this group was 28.1 (12.9) years [28.9 (12.9) for the males, 24.8 (10.7) years for the females]. The mean (SD) CBZ dose in 24 (58%) cases in the group with a fatal outcome was 23.6 (4.5)g (range 0.15-80); the mean (SD) CBZ plasma level in 8 (19%) patients was 36.9 (5.2)gg/ml (range 9-54). The most common clinical signs and symptoms of this group are summarized in Table 2. Chi square tests revealed a significant association with favourable outcome for indi- vidual symptoms such as cerebellar syndrome (P < 0.01), somnolence (P < 0.001) and confusion (P < 0.05), while seizures were significantly associated with fatality (P < 0.001). Cardiac arrest occurred in only 2 patients and both of them died. Acute renal failure was reported in 5 cases, with 2 fatalities. A total of 16 patients suffered from acute respiratory insufficiency and 7 (44%) of them died. The association between CBZ plasma level and CBZ dose was studied in only 28 cases (7%). There was a moderate but significant correlation (r = 0.52, P < 0.01). Outcome of CBZ overdose was significantly correlated with the amount of CBZ ingested. The mean CBZ dose in the group with a fatal outcome was 23.6 g as compared with 9.5 g in the group that recovered (P < 0.05). This finding was confirmed in a separate analysis of variance for patients with doses of less than 20 g CBZ (1 death observed, 5.2 expected; P < 0.05) and for the group with over 20g CBZ (10 deaths observed, 5.8 expected; P < 0.05). Con- versely, there was no significant association between out-

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come and CBZ plasma level, which was 37 gg/ml in the lethal and 35 gg/ml in the nonlethal group (P < 0.05). Chi square tests disclosed that male sex was significantly correlated (P < 0.01) with fatality (19.7 deaths expected, 30 observed) but multivariant analysis including the variables of age, sex and CBZ dose failed to confirm this correlation. Finally, separate analysis of different age groups revealed a significant correlation (P < 0.05) in that there were only 5 deaths (4%) for patients aged below 15 years (n = 124) as compared to 33 deaths (13%) in the group over 15 years of age (n = 262), which could also be confirmed in a multivariant analysis including the variables of age, sex and CBZ dose.

Discussion

General remarks

This study of CBZ overdose is the largest reported to date but interpretation of the data is impeded for several rea- sons. The 427 case reports filed at the Ciba Geigy Depart- ment for Drug Safety represent data collected over a pe- riod of 26 years from countries all over the world. The variables stated are not standardized. Concomitant or pre- vious illness such as heart, lung, liver or kidney disease are only occasionally mentioned. CBZ plasma levels are reported inconsistently and, if measured, the exact time of determination is not stated. There are only a few cases in which serial measurement of CBZ and its major pharmacologically active metabolite CBZ-10,11-epoxide (CBZ- E) was recorded. Patient weights were not included so that relative CBZ doses in mg/kg could not be calculated. No consistent information was provided about the therapeutic measures conducted. The patients' records we eval- uated were very heterogenous and incomplete at times with regard to the different variables. However, we be- lieve that limited statistical analysis of this large data set is justified and provides an indication of their prognostic value.

Frequency of symptoms and their prognostic value

Only about 100 reports on CBZ overdose have been published (for review see [21]). The outcome in the majority of patients has been reported to be favourable [ 16, 17, 19, 22, 26, 31, 39, 40, 44] and complicated courses have been treated successfully by charcoal haemoperfusion [1, 5, 7, 12, 15, 23, 30, 36], resin haemoperfusion [28] or combined haemoperfusion and haemodialysis [3]. The symptoms of CBZ overdose are very variable. In the majority of cases ataxia, tremor, diplopia, positive Babinski sign, seizures, respiratory depression, psychosis, somnolence and coma are mentioned most often, followed by cardiac arrhythmias, asystole, vomiting, diarrhoea, obstipation or

acute renal failure (for review see [21, 38]). The predom- inance of CNS symptoms was confirmed in our study (Ta- bles 1, 2). Moreover, cerebellar syndrome, somnolence and confusion were significantly associated with favourable outcome. Conversely, we demonstrated that seizures were highly significantly associated with fatality. There are few reports dealing with seizures as dominant features in fatal or complicated courses of CBZ overdose [11, 18, 27]. Otherwise the occurrence of seizures has been considered an uncommon "paradoxical" side-effect of CBZ overdose without prognostic relevance [21, 44]. The clinical course of acute CBZ overdose has been reported to be complicated in about 6-25% of patients by prolonged coma, respiratory and renal insufficiency, cardiac arrhythmias and hepatic failure [6, 8-10, 14, 16, 17, 21, 25, 34]. Coma appears to be a predominant feature of CBZ overdose in cases with a fatal outcome (Table 2), but no statistical significance could be demonstrated. In most cases of CBZ overdose respiratory depression develops subacutely with the transition from somnolence to coma, or acutely in association with cardiac arrest [21]. Very rarely, CBZ can cause acute pharmacogenic depression of the medullary breathing centre [21]. Respiratory insufficiency has not been considered a major risk factor in fatalities due to CBZ overdose [11, 17, 21]. Although not statistically significant we found respiratory depression and arrest ranking third and fourth in the list of symptoms in the group with a fatal outcome (Table 2). CBZ-associated renal complications such as proteinuria, haematuria, oliguria and acute renal failure represent about 2% of all side-effects recorded [37]. A case of reversible renal failure caused by tubular necrosis has been described [29], but in most cases renal symptoms are a consequence of diminshed renal perfusion due to arterial hypotension [21].

In our study renal failure developed in 5 patients and 2 of them died. CBZ can cause potentially lethal arrhythmias by its phenyt0in-like deceleration of the action po- tential in the His bundle [2, 4, 24, 35]. In our study cardiac arrhythmias were reported in only 12 cases with 2 fatalities due to cardiac arrest. A low incidence of cardiac complications in CBZ overdose has also been documented by other authors [17, 44].

No fatality due to liver failure was found. This also held true for the group of patients that were referred to as alcoholics or that simultaneously ingested alcohol.

Dose-dependent hyponatraemia is another well-known side-effect of CBZ [21]. We found only two reports of hyponatraemia with serum levels of 115 and 119mval/1, respectively. In one patient the outcome was unknown; the other recovered but had hypoxic brain damage. In all reported fatal cases due to cardiac, renal or respiratory complications the causal relationship to direct CBZ toxicity remains speculative because of the absence of information about the premorbid health condition and the exact course of intoxication.

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Total CBZ dose, CBZ plasma level and pharmacokinetics

From the present literature no clear correlation between total dose of CBZ ingested and prognosis can be deduced [1-3, 5-9, 11, 12, 14-17, 19, 21-24, 25-36, 38-40, 44]. In general, doses exceeding 20 g have been considered potentially lethal [21], but death due to CBZ overdose has been observed after a dose as low as 4g [21]. We were able to demonstrate that the mean total dose in the cases with a fatal outcome (23.6 g) was significantly higher than in the group that recovered, thus confirming the dose-dependency mentioned above. In our study 3 of 6 patients who ingested CBZ doses in excess of 60g died. In contrast to this finding there have been reports of massive CBZ overdose (80 g) with complete recovery [30]. In our study the small- est amount of CBZ ingested leading to death was 0.15 g in a newborn, followed by 3.2 and 6 g in 2 female adults.

Analysis of plasma levels in CBZ overdose has pro- duced contradictory and surprising results [6, 8, 10, 18, 20, 32, 37, 42]. Seventy to 80% of CBZ is bound to plasma proteins. Biotransformation is mainly characterized by the production of the pharmacologically active metabolite CBZ-E that appears in plasma at concentra- tions of 1 0 4 0 % of the parent compound [32, 42, 43]. Re- peated administration of CBZ results in an autoinduced acceleration of elimination half-life, which decreases from about 36h after single-dose administration to about 10h in chronic usage [10, 18, 20, 32, 37, 42]. Owing to its anticholinergic properties CBZ can decrease gastrointesti- nal motility and thereby interfere with its own absorption contributing to delayed absorption and late plasma peaks [6, 8]. Rising CBZ plasma levels during the course of intoxication can herald clinical deterioration [6-8, 30, 32] and sudden relapses during later stages of intoxication sometimes resembling biphasic or cyclic coma have been considered characteristic of CBZ overdose [6, 8, 11, 12, 15, 36]. A rise in the plasma levels of the metabolically active CBZ-E can as well contribute to delayed clinical deterioration in the course of intoxication [18, 32, 44]. The highest CBZ plasma level reported in the literature was 260gg/ml and was associated with a fatal course [35]. Plasma levels in the lethal (37 gg/ml) and the nonlethal groups (35 ~tg/ml) were not significantly different in our study. The highest CBZ plasma levels in our analysis were 72gg/ml and 82~tg/ml, respectively, and both patients recovered. A classification of CBZ overdose has been suggested based upon clinical data and serial analysis of CBZ and CBZ-E levels [44]. According to this in- vestigation CBZ overdose follows a distinct four-stage se- quence of clinical events with corresponding CBZ plasma levels. Stage I is characterized by coma and seizures with CBZ levels more than 25 gg/ml. During stage II patients are combative, hallucinate or display choreiform move- ments with a CBZ level of 15-25 ~tg/ml. Drowsiness and ataxia are the dominant features of stage III (CBZ levels 11-15 gg/ml), while stage IV is characterized as "poten-

tially catastrophic relapse" with CBZ levels of less than 11 p,g/ml. In our study we demonstrated a moderate association between CBZ dose and plasma levels but no significant association between plasma levels and outcome, Unfortunately, the patients' records did not include serial CBZ or CBZ-E plasma levels and the exact time when the levels were determined was not stated, Therefore a defin- itive conclusion about the prognostic association between CBZ dose and plasma levels cannot be drawn from our data. CBZ plasma levels are also influenced by co-administration of hepatically metabolized drugs or interactions with other highly protein bound drugs, or both [21, 41]. In our study concomitant medication was reported in only 108 patients, with phenobarbitone, phenytoin and benzodiazepines being the most common drugs. The association between co-medication and outcome could not be investi- gated systematically. In the suicidal group concomitant alcohol ingestion was more frequently associated with fatality as compared with other co-medications, but again the missing information about premorbid conditions makes the interpretation difficult.

Age and sex

In our study no evidence could be found that sex can be used as a prognostic indicator in cases of CBZ overdose. There was a striking preponderance of males in the lethal group (30 as compared with 8 females), although the overall distribution was almost balanced (207 males, 194 females). In keeping with data in the literature, multivariant analysis including the variables of age, sex, CBZ dose and outcome failed to reveal a statistically significant relationship between sex and outcome. In a review of 52 patients by Kr~imer [20] 27 were females and 23 males. Of the 12 fatalities, 5 were males and 4 females. In another study by Hruby et al. [17] including 33 patients, sex distribution was not analysed at all. Two patients died: one was male and the other female. Finally, age proved to be a prog- nostically relevant factor although only 2 cases in the group of patients aged below 15 years were recorded with CBZ doses in excess of 20 g. Our finding that lethality in CBZ overdose increases with age has been confirmed by other authors. In a series of 13 children with CBZ overdose Gau- dreault et al. [13] did not observe any fatalities despite complicated courses. This finding was confirmed by the study of Hruby et al. [17] in which no fatalities were observed in a group of 7 children aged between 3 months and 9 years.

Although the data obtained are insufficient to allow conclusive statements about prognostic features in CBZ overdose, we were able to quantify the frequency of signs and symptoms and demonstrate an association between outcome and certain symptoms, as well as age and total amount of CBZ ingested.

Acknowledgement We thank Ciba Geigy (Basel, Switzerland) for supplying the patients' records.

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Signs and symptoms of carbamazepine overdose

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