|Year : 2017 | Volume
| Issue : 4 | Page : 1178-1185
Patterns of antiepileptic drugs–poisoned cases arrived at Menoufia University Poison and Dependence Control Center
Safaa A Amin, Azza W Zanaty, Fatma S Kandeel, Maha S El-Nady
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||12-Feb-2017|
|Date of Acceptance||23-Apr-2017|
|Date of Web Publication||04-Apr-2018|
Maha S El-Nady
Source of Support: None, Conflict of Interest: None
The present work aims to study antiepileptic drugs (AEDs)–poisoned cases arrived at Menoufia University Poison and Dependence Control Center regarding sociodemographic pattern, clinical presentation, investigations, poison severity score, and outcome.
AEDs are groups of pharmacological agents used to treat several neurological and psychiatric disorders such as epilepsy, prophylaxis of migraine, neuropathic pain, and bipolar disorders. In poisoning with AEDs, central nervous system is the most affected region; therefore, loss of consciousness, hyper-reflexia, hyporeflexia, ataxia, tremor, hallucinations, pupillary changes, dizziness, headache, insomnia, convulsions, and even death are the most expected symptoms. AEDs could be classified into first, second, and third generations. Among AED intoxication cases, most are caused by first-generation antiepileptic drugs, whereas intoxications with new-generation antiepileptics are rarely seen.
Patient and methods
The study was conducted on all cases with AEDs poisoning that arrived at Menoufia University Poison and Dependence Control Center throughout the 1-year period from the first of February 2014 to the last of January 2015. For every case, clinical toxicological sheet was fulfilled after taking his/her consent. Cases were classified according to clinical manifestation and investigations by using poison severity score. Outcome of cases was determined.
Of 98 poisoned cases, the most affected age group was more than 20–40 years (38.8%). Females outnumbered males (74.5 and 25.5%, respectively). Carbamazepine represented the highest percent of cases at 49% followed by benzodiazepines (38.8%). Suicidal cases represented 74.5%.
Intentional drug exposures are at a high prevalence in AEDs ingestions. It is mostly seen in the adult group and females. The most frequently ingested drugs are carbamazepine and benzodiazepines.
Keywords: antiepileptic drugs, carbamazepine, poisoning
|How to cite this article:|
Amin SA, Zanaty AW, Kandeel FS, El-Nady MS. Patterns of antiepileptic drugs–poisoned cases arrived at Menoufia University Poison and Dependence Control Center. Menoufia Med J 2017;30:1178-85
|How to cite this URL:|
Amin SA, Zanaty AW, Kandeel FS, El-Nady MS. Patterns of antiepileptic drugs–poisoned cases arrived at Menoufia University Poison and Dependence Control Center. Menoufia Med J [serial online] 2017 [cited 2020 Feb 16];30:1178-85. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1178/229224
| Introduction|| |
Antiepileptic drugs (AEDs) are used in many neurological and psychiatric disorders. For most AEDs, the primary mechanisms of action involve decreasing the excitation of neurons by either blocking sodium and/or calcium channels or antagonizing receptors of glutamate. Another mechanism includes inhibition of neurons by increasing or enhancing γ-aminobutyric acid,. According to the 2011 annual report of American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS), AED poisonings represented 3% of drug poisoning seen in adults (older than 20 years). A study of risk factors of acute poisoning among children at a poisoning unit of Al-Azhar University Hospital, Egypt, in 2012 showed drug overdose as a cause, with 23.3% of the poisoned cases, and the most common drugs were antiepileptics. Drug overdose is a major and longstanding source of morbidity worldwide, and there are numerous drugs that can cause an overdose. The present work aims to study AEDs–poisoned cases arrived at Menoufia University Poison and Dependence Control Center (MPCC) throughout a 1-year period.
| Patients and Methods|| |
The study was conducted on all cases that arrived at MPCC with AEDs poisoning throughout the 1-year period from the first of February 2014 to the last of January 2015. The data of the patients admitted in the first 6 months were collected from hospital records retrospectively, and the data of those admitted in the followed 6 months were collected prospectively. Valid consent was taken from each case or his/her guardian to be involved in the study, after explaining to them the aim and methods of the work. The study was approved by the Ethical Committee of Faculty of Medicine, Menoufia University. Clinical toxicological sheet was fulfilled for every case regarding personal, present, and past history and clinical examination. Routine investigations, ECG, arterial blood gases, and specific toxicological investigations such as Toxi-Lab and rapid immunoassay kits were done as needed. Cases were classified according to clinical manifestation and investigation by using poison severity score (PSS).
The data collected were tabulated and statistically analyzed using a personal computer with Statistical Package of Social Science (SPSS) version 20 and the following statistics were applied: descriptive statistics as percentage and analytic statistics as χ2 test and Pearson's (r) correlation. P value greater than 0.05 was considered statistically nonsignificant. P value less than 0.05 was considered statistically significant. P value less than 0.001 was considered statistically highly significant.
| Results|| |
The total number of the studied cases was 98, of which 38.8% were in the age group more than 20–40 years, followed by the age group more than 10–20 (33.7%) years. Regarding sex, it was found that females outnumbered males (74.5 and 25.5%, respectively). Regarding residence, most cases were from rural areas, which represented 79.6% [Table 1].
|Table 1: Sociodemographic characteristics of the studied cases and distribution of the cases according to poison history (n=98)|
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The current study illustrated a statistically highly significant relation between age and sex (P< 0.001). Males were mostly represented in the age group less than or equal to 5 (44%) years. Females were commonly represented in the age group more than 10–20 (43.8%) years [Figure 1].
Suicidal cases represented 74.5%, and accidental cases represented 25.5% [Table 1]. There was a statistically highly significant relation regarding mode of exposure and age, where accidental mode was higher at age group less than or equal to 5 (76%) years and suicidal mode was higher at age group more than 20–40 (52.1%) years. The results showed a statistically significant relation regarding mode of exposure and sex. Suicidal and accidental modes were higher in females at 82.2 and 52%, respectively (P = 0.003) [Table 2].
|Table 2: Relation between mode of exposure and age, sex, and poison severity score of the studied cases (n=98)|
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Regarding type of drug overdose, carbamazepine represented the highest percent, with 49% of cases, followed by benzodiazepine (38.8%). Drug coingestion was found in 21.4%. Most common coingested drugs were antipsychotic and tricyclic antidepressants [Table 1].
Cases that came immediately within 3 h represented 44.9%, followed by cases that came from 3 to 6 h after ingestion, which represented 29.6%, and then lastly, the cases that came after 6 h, which were 25.5% [Table 1].
According to PSS, 50% of cases were of minor grade, followed by cases of none grade (34.7%). Moderate grade cases represented 13.3%, and the least were cases of severe grade, which represented 2% [Figure 2].
|Figure 2: Distribution of the severity grades of the studied cases according to Poison Severity Score.|
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The study showed a statistically significant relation between mode of exposure and the severity grades (P = 0.01). According to suicidal mode, 47.9% of the cases were minor grade, 42.5% were none grade, 8.2% were moderate, and 1.4% represented severe grade. Regarding accidental mode, minor grade cases represented 56%, whereas moderate grade represented 28%, followed by none grade at 12% and severe cases at 4% [Table 2] and [Figure 3].
|Figure 3: Relation between Mode of exposure and the severity grades of the studied cases according to Poison Severity Score.|
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Regarding correlation coefficient between age and PSS, it is revealed that the more the age was, the less the PSS would be [Figure 4].
|Figure 4: Correlation coefficient between age and Poison severity score.|
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According to the clinical signs found upon examination of the cases. Hypotension was found in 16.3% of the cases, whereas 33.7% of the studied cases had tachycardia. Concerning respiratory rate, apnea was found only in 1% of cases. According to pupil examination, 21.4% of cases developed dilated pupil, 3.1% of cases developed constricted pupil, and most cases (75.5%) had normal pupil. Ataxia was found in 15.3% of the cases [Table 3].
|Table 3: Frequency distribution of the studied cases according to general examination (n=98)|
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Regarding electrolytes abnormalities, 17.3% of cases developed hyponatremia, and 3.1% of cases developed hypokalemia. Only one case developed hypocalcemia. The most common ECG change was inverted T wave, representing 29.6%, whereas sinus tachycardia alone and with inverted T wave were 14.3% of cases for each one. Moreover, inverted T wave with extrasystole or with prolonged PR interval was 1% of cases for each one [Table 4].
|Table 4: Frequency distribution of the studied cases according to serum electrolytes levels, arterial blood gases changes, electrocardiogram changes, and specific toxicological investigations (n=98)|
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Regarding arterial blood gases, metabolic acidosis was found in 21.4% of cases, compensated metabolic acidosis in 6.1% of cases, and respiratory acidosis in 4.1% of cases [Table 4].
Regarding the distribution of the studied cases according to specific toxicological investigations, rapid detection kits were done for 39.8% of cases, 38.8% of cases were positive to benzodiazepine, and 1.0% of cases were positive to barbiturates and tramadol. Toxi-lab test was done for 22.4% of the cases, where the results of 20.4% of cases were positive for carbamazepine and 2% of cases were positive for benzodiazepine [Table 4].
According to the duration of hospital stay, 67.4% of the cases stayed 24 h or less, 25.5% of the cases stayed from 24 to 48 h, where 7.1% of the cases stayed for more than 48 h. According to the outcome, 93.9% of cases improved, whereas cases that demanded discharge before completing their treatment represented 6.1%. The study showed no fatal outcome [Table 5]. There was a statistically highly significant relation regarding duration of hospital stay and severity grades of the studied cases (P< 0.001) [Figure 5].
|Table 5: Frequency distribution of the studied cases according to duration of hospital stay and outcome (n=98)|
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|Figure 5: Relation between duration of hospital stay and the severity grades of the studied cases according to Poison Severity Score.|
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| Discussion|| |
AEDs affect the central nerve system (CNS) through different mechanisms. In recent years, AEDs are increasingly prescribed for different indications, so their misuse is frequently encountered with adverse effects and overdose ingestion.
Regarding age, most of the patients were in the age groups more than 20–40 years and more than 10–20 years.
Celenk et al. stated that drug overdose is more frequent in young adults in Turkey as well as all over the world. This is in agreement with Ozkose and Ayoglu, Goksu et al., Tufekci et al., Lee et al., and Hassanian et al..
A prospective study by Sane and Goudarzi was conducted in the Shiraz Shoushtari Hospital in Iran during a 2-year period from 2010 to 2012, and it showed that the mean age of patients was 26.2 years.
The same results were observed by Nixon et al. who found that the median age was 34 years (23–44 years) in a retrospective observational study examining the patterns of AED overdose in patients admitted to the Edinburgh Poisons Unit in UK.
On studying the mode of exposure in the current study, 74.5% represented suicidal cases, and 25.5% of cases had taken the drug accidentally. There were no reported homicidal cases in this study. Causes of suicide included economic problems, love failure, quarrels, unemployment, examination failure, and chronic illness.
The predominance of females over males and the higher percentage of suicidal attempts in females can be explained by a lower rate of employment and suppression of personal freedom by parents. The same results were observed by many studies ,,,,,.
The cause of increasing suicidal rates with AEDs overdose may be because of these drugs being used formany disorders such as epilepsy, mood disorders, andneuropathic pain syndromes, with increased risk ofsuicidality and depression in these patients.
A retrospective study by Günaydın et al. included 95 cases with AED overdose in a toxicology unit between January 2010 and February 2013 in Turkey, and it found that in 95.8% patients the reason for drug overdose is suicide.
On the contrary, according to the 2015 Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS), accidental exposuresaccounted for 79.4% and suicidal exposures accountedfor 16.7% of human exposures. However, in the ages 13-19years, suicidal exposures outnumbered accidental exposures.
In the present study, the relation between mode of AED exposure and different age groups was highly significant, where all cases below the age of 10 years old had taken the AED overdose accidentally, whereas the age groups more than 10–20 years and more than 20–40 years had taken the AED with suicidal intensions.
Alazab stated that accidental poisonings may occur as part of cognitive development in young children, less than 5 years, who put almost anything into their mouths while discovering the environment.
Hassan and Siam reported that the cause of poisoning in children up to the age of 10 years usually is accidental.
The present study showed a male predominance in the age group younger than 5 years, and this result was in agreement with the 2015 AAPCC, NPDS, and Hassan and Siam. This could be explained as males are more active than females, less obeying to orders, and having more exploratory character than females in childhood. Female predominance in age group more than 10–20 years old may be because of emotional troubles as love failure or educational problems such as examination failure.
Regarding residence, cases from rural areas represented 79.6%, whereas urban areas represented 20.4%. This is may be because of the rural nature of Menoufia Governorate.
In the current study, the commonest AED was carbamazepine (49%), followed by benzodiazepine (38.8%). This could be because carbamazepine is more frequently prescribed. This is in agreement with several studies ,,.
In a study from Iran, the most common AEDs overdose was due to carbamazepine, followed by phenobarbital, and lastly sodium valproate.
In contrary to this result, Sane and Goudarzi found that the most common overdosed AED was sodium valproate, followed by carbamazepine and phenytoin.
Regarding coingestion, 78.6% of cases had taken only AED drug, whereas 21.4% of cases had taken AED and another group of drugs. This is in agreement with the 2015 annual report of the AAPCC NPDS, which stated that single substance cases reflect the majority (75.9%) of all exposures.
Celenk et al. found that the percentage of patients with only AED exposure (54.7%) was greater than those who ingested AED together with other agent groups (45.3%).
In the current study, 44.9% of cases arrived at MPCC within 3 h and 29.6 and 25.5% of cases arrived within 3–6 h and more than 6 h, respectively. This is may be because the MPCC is known to be the only center treating poisoning cases in Menoufia Governorate, so cases came rapidly to it. Another reason is that most of people are aware that poisoned patients need an immediate medical care in a special poisoning center.
Sane and Goudarzi stated that median of the time interval between overdose and presentation to emergency department was 5.2 h.
In a study in Turkey by Celenk et al., it was found 39.1% of the patients were admitted to the emergency department within 2 h after drug ingestion.
According to PSS, 34.7% of cases were classified as none grade cases, 50% of cases were classified as minor grade cases, 13.3% of cases were classified as moderate grade, and 2% of cases were classified as severe grade.
Celenk et al. stated that the clinical presentation of the patients was examined according to poisoning severity score, and it was found that the cases that had no clinical findings or symptoms accounted for 59.4%, and those with minor finding represented 28%, whereas 7.8% had moderate finding. Cases with severe clinical findings and symptoms accounted for 4.7%.
Regarding the correlation coefficient between age and PSS, it revealed that the higher the age was, the less the PSS would be. This is may be because children tend to be at risk for the major toxicities at lower serum concentrations compared with adults. The increased incidence of toxicity in children at lower serum concentrations may be explained by the relative increase in production of the toxic metabolite carbamazepine-10, 11-epoxide in children compared with adults [24–27].
On studying the relation between mode of exposure and the severity grades of the studied cases according to PSS, it was significant. Suicidal cases were mainly minor and none grade (47.9 and 42.5%, respectively). Accidental cases were minor (56%), whereas moderate grade represented 28%, followed by none grade 12% and severe cases 4%. This may be because most of the suicide attempts do not aim for death but they merely aim to push others to feel guilt or to reach an already refused target; therefore, the taken dose is usually small.
Regarding blood pressure, hypotension was found in 16.3% of AEDs overdose cases. Hypotension is likely to be owing to CNS effects and dehydration rather than direct cardiac effects. On studying the pulse rate, 33.7% of AEDs poisoned cases developed tachycardia. Tachycardia is a part of anticholinergic effect of AEDs.
Regarding respiratory rate, only 1% of AEDs poisoned cases developed apnea. It is because of the CNS depressant effect of AEDs. Regarding pupil size, 21.4% of cases developed dilated pupil, whereas 3.1% of cases developed constricted pupil. Dilated pupil is a part of anticholinergic effect of AEDs, whereas constricted pupil was found in patients with benzodiazepine overdoses.
In the current study, the most common electrolyte abnormality was hyponatremia (17.3%), followed by hypokalemia (3.1%) (may be secondary to fluid loss owing to vomiting) and hypocalcemia (1%).
Hyponatremia has been associated with several AEDs, such as carbamazepine and oxcarbazepine (OXC), and occasionally with valproate and lamotrigine. The frequency of hyponatremia in OXC (a 10-keto analogue of carbamazepine)-treated patients is even higher than in those receiving carbamazepine.
Ranta and Wooten reported that the mechanisms whereby carbamazepine and OXC cause hyponatremia are not entirely clear; however, a peripheral process – the induction of excessive water reabsorption in the collecting tubule – is thought to be the cause.
AEDs increased hepatic metabolism of calcidiol and lead to vitamin D deficiency and hypocalcemia.
Sane and Goudarzi stated that the most frequent electrolyte disorder was hypocalcemia which was seen in 49% of patients. Overall, 13.5% of patients developed hypokalemia. Hyponatremia was detected in 12.5% of patients.
In the current study, the commonest ECG abnormality was inverted T wave (29.6%), and then sinus tachycardia with or without inverted T wave. AEDs interfere with action potentials in purkinje fibers and the Hiss bundles, which may lead to atrioventricular block and arrhythmias.
In the current study, metabolic acidosis represented 21.4% of the cases. Respiratory acidosis was seen in 4.1% of the studied cases. Respiratory acidosis can be caused by respiratory center depression that is associated with CNS depression caused by AEDs.
In a study of seizures in patients with AED overdose in Iran by Sane and Goudarzi, it was found that 31.5% of patients had metabolic acidosis.
According to the duration of hospital stay, 67.4% of studied cases stayed up to 24 h, and only 7.1% of cases stayed more than 48 h.
There was a highly significant relation between duration of hospital stay and the severity grades of the studied cases, where 100 and 38.5% of severe grade and moderate grade cases, respectively, stayed more than 48 h, whereas 97.1, 63.3, and 15.4% of none, minor, and moderate grade cases, respectively, stayed only up to 24 h.
This is in agreement with Celenk et al. who found that the median hospital stay of all the admissions was 24 h.
In this study, 93.9% of cases improved, and 6.1% of cases discharged on their will, so their outcome could not be determined. The study showed no fatality.
This coincides with Celenk et al. who stated that 90.6% of cases had a complete recovery, whereas in 9.4% of cases, the outcome not determined because they left the hospital voluntarily against the doctor advice before their follow-up finished, with no reported fatality.
This result differs from Sane and Goudarzi who stated that two (1%) patients died in their study (one carbamazepine overdose case and one sodium valproate overdose case), and they explained that the death was owing to status epilepticus and aspiration pneumonia. Moreover, Günaydın et al. found that 1.1% of patients died, and their study showed no fatal outcome with carbamazepine overdose.
| Conclusion|| |
AEDs are increasingly used in patients with psychiatric disorders who are at increased risk of self-harm. This might increase the likelihood that these agents are used as means of overdose. From the current study, the following results can be concluded, females outnumbered males. The most affected age group was more than 20–40 years. Cases from rural areas were more frequent than those from urban areas. Suicidal mode comprised a higher frequency than accidental mode. Carbamazepine represented the highest percentage of AEDs poisoned cases followed by benzodiazepines. Most of the studied cases improved, and the study showed no fatality.
In view of the aforementioned results, it is recommended that various household medicines should be kept under the supervision of an elderly, physically and mentally healthy person and away from the reach of children. Public awareness should be increased about the seriousness of problem of drug overdosing through health education.
Routine and toxicological investigations should be done for evaluation and health prognosis of AEDs poisoned cases.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]