Drug-induced movement disorders in children at paediatric emergency department: ‘dystonia’
- 1Department of Pediatric Emergency, Gazi University Faculty of Medicine, Ankara, Turkey
- 2Department of Pediatrics, Gazi University Faculty of Medicine, Ankara, Turkey
- Correspondence to Dr Oksan Derinoz, Department of Pediatric Emergency, Gazi University Faculty of Medicine, Besevler, Ankara 06500, Turkey;
Contributors OD and AAC conceived the idea and framed the hypothesis. OD planned the methods to generate results, was responsible for creation of all or a substantive part of the manuscript, data analysis and interpretation. AAC conducted the experiments, managed patients, organised the study and reported the data.
- Accepted 12 February 2012
- Published Online First 7 March 2012
Aim To examine cases with drug-induced dystonic reactions (DIDRs), to identify the complaints of the application, to classify the drugs causing those dystonic reactions (DRs) and to determine the treatment options and protective measures to prevent DIDRs.
Method The authors retrospectively analysed 55 cases with DIDRs at paediatric emergency department (PED) in a 5-year period.
Results The mean age of the patients was 145.07±56.30 months, and of the 55 cases, 28 cases (50.9%) were boys. Antiemetics and antipsychotics were the most common causes of DIDRs. 35 (70%) patients developed DIDRs at therapeutic doses. Treatment side effect was the most common cause of the DIDRs (78.2%). The most common DIDRs were abnormal postures of the head and neck (56.6%). Laryngospasm was observed only in four cases (7.3%) that used either antipsychotics or psychostimulants. 51 (92.7%) children were treated with parenteral diphenhydramine successfully.
Conclusion Dystonia is a common side effect of certain drugs, even when therapeutic doses are administered. Although the most common DIDRs were abnormal postures of the head and neck, rare life-threatening conditions, may develop particularly due to use of antipsychotics. In treatment, diphenhydramine could effectively be used through parenteral way to eliminate the cholinergic effects of those drugs. However, the easiest and the safest way to prevent the development of DRs is to avoid unnecessary drug usage. In conclusion, physicians should be aware that antiemetic and antipsychotic drugs are associated with DRs in normal doses and that those drugs should be prescribed with a correct indication.
Dystonia is a neurological movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements or abnormal postures of the neck, jaw, tongue or the entire body. Upward or lateral movement of the eyes, dysphagia, dysarthria and difficulty in breathing may also occur.1 ,2
The mechanism of acute dystonia is still unclear. It is proposed that dystonic movements observed in patients receiving dopamine antagonists—such as antipsychotics, antiemetics and gastrointestinal motility agents—occur due to the imbalance between cholinergic and dopaminergic stimulation and therefore, anticholinergic agents such as biperiden and diphenhydramine are used in the treatment of dystonia.3–5
Although there are some case reports citing various drugs as a cause of drug-induced dystonic reactions (DIDRs), data about the causes, clinical features and outcomes of DIDRs are limited in childhood. In this 5-year retrospective study, patients admitted to the paediatric emergency department (PED) with the complaint of DIDRs were evaluated. Our goal was to examine and describe patients with DIDRs and identify the complaints at PED admission, to determine the drugs that cause DIDRs, the treatment options and protective measures.
This study was approved by the institutional ethics committee of Gazi University, School of Medicine, Ankara, Turkey. Patients with DIDRs between 1 January 2005 and 31 December 2010 were evaluated retrospectively via the hospital record system.
Data for all the patients such as age, gender, complaints at admission, reason for DIDRs (accidental, suicide, side effect of treatment, abuse and unknown reason), duration of drug intake, dosage of the drug(therapeutic dose, overdose and unknown dose), class of the drug, by whom the drug was delivered and recommended treatment were recorded, and data analysis was performed using SPSS for Windows V.11.5). Children were categorised according to the age as 0–72 months (≤6 years), 73–144 months (7–12 years) and 145–216 months (12–18 years).
During the study period, a total of 55 patients with mean age 145.07±56.30 (5–204) months, were admitted to the PED with DIDRs. Of the 55 patients, 28 (50.9%) patients were boys and 32 (58.2%) patients were between 13 and 18 years of age. The most frequent causes of DIDRs in patients were antiemetics (43.6%) and antipsychotics (43.6%) (table 1). Haloperidol was the most commonly used drug within antipsychotics in our cohort.
Antiemetics had been prescribed due to complaints of nausea, vomiting and dyspepsia. The diagnosis of patients who had taken antipsychotic drugs were attention deficient hyperactivity disorder (6/24), aggressive behaviour (5/24), tic disorder (4/24), anxiety disorder (4/24), psychosis (2/24) and stuttering (1/24). However, in two cases, we could not determine the indication of antipsychotic drug usage. None of the drugs that led to DIDRs had been prescribed in our hospital.
Of the children with DIDRs, 30 (56.6%) patients presented with abnormal postures of the head and neck region (table 2). Laryngospasm was observed only in four patients who had received antipsychotic or psychostimulant drugs (table 3). Four patients had a history of an epileptic disease, before the initiation of those drugs (antipsychotics in three patients and antiemetics in one patient).
Thirteen (32.5%) patients had received those drugs for less than 24 h, 22 (55%) patients had received for 2–14 days and five (12.5%) patients had received for more than 14 days (table 4).
In 35 (70%) patients, DIDRs developed with therapeutic doses. Five (10%) patients developed DIDRs with overdoses and in 10 (20%) patients, exact doses were obscure. We could not obtain the data about the drug dose in five patients. The most common cause of DIDRs was treatment side effects (78.2%), and treatment side effect-related DIDRs were most commonly seen in children >12 years (table 5).
In 43 patients (77.6%), dystonic reactions (DRs) emerged due to drugs that were prescribed by a physician. However, 18.4% of the patients obtained the drugs as over–the-counter drugs; additionally, antipsychotic drugs were abused by parents of two children for sedation effect.
While 51 (92.7%) of the patients were treated with parenteral diphenhydramine, 4 (7.3%) were treated with biperiden.
Dystonia is a neurological movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements or abnormal postures of the neck, and this disorder is one of the important reasons for PED admission. Dopaminergic receptors in the nigrostriatal pathway have a significant role in initiation and control of the movement. Thus, blockade of these receptors by drugs causes the disappearance of the inhibiting effect of dopamine on acetylcholine, and as a result, cholinergic system becomes relatively more dominant and leads to development of extrapyramidal movement disorders, such as dystonia.
In the present study, the high frequency of the DIDRs in 13–18 years of age group compared with the groups <12 years of age may be attributed to the increase in dopaminergic receptors along with the increase in age. This finding is also supported by adult studies, which showed the increased frequency of DIDRs in early adulthood. Furthermore, certain studies in literature proposed that the decrease in the prevalence of DIDRs in older people might be associated with a decrease in dopaminergic receptors with ageing.6 As the pathophysiology of dystonia is not well known, the blockage of dopaminergic system would be insufficient to explain the development of dystonia. This is one of the limitations of the present study, and further studies might illuminate the pathophysiological mechanisms better.
The most common reason of DIDRs is the side effects of certain drugs, and these side effects are most commonly observed in therapeutic doses. Our study also demonstrated that antiemetics (ie, metoclopramide) and antipsychotics, which were used in therapeutic doses, were the most common causes of DIDRs in children. Thus, emergency physicians should be aware that antiemetic and antipsychotic drugs are associated with DRs even at therapeutic doses and that those drugs should be prescribed with correct indication.
Children are prone to extrapyramidal effects of antiemetics. Antiemetics, especially, metoclopramide, are frequently preferred as prokinetic agent in treatment of gastro-oesophageal reflux disease, antiemetic in management of chemotherapy-induced nausea and vomiting or in gastrointestinal infections presenting with nausea and vomiting.7 ,8 Ondansetron is another antiemetic drug, which is used in children with the same indications like metoclopramide.9 Although rare, extrapyramidal reactions, including oculogyric crisis appearing alone or with other types of DRs, have also been reported with ondansetron use.9 ,10 Especially, the use of antiemetics in paediatric gastroenteritis is controversial and is not recommended by American Academy of Pediatrics. However, there are some studies about the usefulness of ondansetron in paediatric patients with acute gastroenteritis. In these studies, Ondansetron was found to be effective for decreasing hospital stay and need for intravenous fluid.11 ,12
Metoclopramide is, especially, contraindicated in patients with a seizure disorder. Because of its seizure-inducing effect, its use should be avoided in epileptic patients. While investigating the history of the case, families sometimes may indicate that the form of the patient's seizure changed or its frequency increased. As a result, DRs may be confused with epileptic seizures in patients with epilepsy. When a child with epilepsy is referred to the PED while using metoclopramide, DIDRs should be thought before giving an extra dose of the antiepileptic or increasing the dose of the antiepileptic drug. Furthermore, antiepileptics, such as phenitoin and carbamazepine, are known to cause DRs.13 ,14 Thus, the exact history should be taken and DRs should be distinguished from epileptic seizures.
Antipsychotic drugs are used in adults for treatment of psychotic disorders, such as schizophrenia, bipolar disorder, obsessive-compulsive disorder, tic disorders and eating disorders. Recently, they have also been used in children with the same indications.15
The anatomical distribution of the muscle involvement related to DIDRs varies. Most commonly cranial, pharyngeal, cervical and axial muscles are affected, but sometimes, just hands and fingers may be affected. Eventually, various forms of dystonia, such as torticollis, trismus, ‘mouth opening’ dystonia, grimacing, dysarthria, oculogyric crisis, blepharospasm and swallowing difficulties might be seen.16 ,17 Dystonia may be confused with partial seizures, encephalitis, tetanus, tetany, strychnine poisoning and electrolyte imbalances.5 ,7 The severity of symptoms is also variable. Acute dystonia may occur as opisthotonos, which is a painful and distressing form. Some clinical conditions may be life threatening, like laryngospasm,16 ,18 and immediate treatment is important for patients who have impaired respiration. However, there is little data for children who were admitted to the PED with presentation of dystonia. In our study, the most commonly observed presentations are involvement of head and neck regions. Additionally, only four children had life-threatening dystonia (ie, laryngospasm).
Recognising signs and symptoms of DRs after the administration of a drug is the first step of the diagnosis and the treatment is the discontinuation of the drug immediately. Sometimes dystonia patients may develop severe airway obstruction due to laryngospasm. Therefore, assessment of all these patients should begin with ensuring the airway patency and ventilation. After stabilising the patient, diphenhydramine or biperiden can be given for the treatment of acute DRs. Diphenhydramine and biperiden are both highly effective for the treatment.19 However, unlike many treatment protocols, parenteral diphenhydramine is recommended as first choice for the treatment of dystonia.20 Diphenhydramine is an H1-antagonist antihistaminic drug. Because of its anticholinergic properties, diphenhydramine is effective in the relief of nausea, vomiting and vertigo associated with motion sickness. It is also used commonly to treat drug-induced extrapyramidal symptoms. Diphenhydramine can be administered orally/intravenously/intramuscularly (5 mg/kg/day divided every 6 h as needed).21 Onset of action following oral administration of diphenhydramine occurs in 15–30 min, with peak concentrations occurring in about 2–4 h. The onset of antiextrapyramidal effects following an intramuscular injection is 15–30 min; it may be repeated in 20–30 min, if needed.9 Biperiden is an anticholinergic drug and can be administered orally or through parenteral route. Intravenous biperiden (2.5–5 mg/dose) are highly effective within minutes. Intravenous administration is necessary only if acute DRs are life threatening, such as stridor and laryngospasm. Intramuscular administration is usually effective within 20 min. If not effective, then second or third injections should be administered at 30 min interval. For treatment of antipsychotic drug-induced dystonia, if the drug cannot be discontinued, treatment with anticholinergics should be continued in addition to the treatment with antipscychotic drugs at least 24–48 h to prevent a recurrence.16 Although our experience is too limited with use of biperiden, we have frequently and successfully used parenteral diphenhydramine in our department. After administration, the patient was monitored for resolution of symptoms. None of the patients had treatment side effects. Therefore, parenteral diphenhydramine should be a relatively safe anticholinergic drug for treatment of dystonia in children.
The easiest and cheapest way to prevent development of DRs is to avoid unnecessary drug use. In the present study, the drugs that caused DRs were prescribed by physicians in 77.6% of the patients. In Turkey, some of the drugs causing dystonia can be obtained as over-the-counter drug from the pharmacies. Particularly, antiemetics are drugs that are commonly used by the families to prevent nausea and vomiting occurring during motion sickness or secondary to infections. If unnecessary drug use is avoided, development of this clinical condition can be prevented.
There are several strengths and limitations of this study that should be noted. The strengths of our study, to our knowledge, are that this is the first study and the largest cohort to examine DIDRS in children at PED. In the literature, there are a number of case reports about DIDRs but there are no case series in childhood. Another strength of our study is the treatment option; we successfully treated 92.7% of cases with parenteral diphenhydramine, which is safe, easily available and cheap. The limitations are our study was retrospective, in a single centre and we studied a small cohort.
In conclusion, DRs during childhood have similar clinical features as those of adults. Dystonia in children also develops commonly as treatment side effect during use of drugs as therapeutic doses. Both antiemetics and antipsychotics are the most common drug groups that cause dystonia. Although clinical findings usually occur at head and neck, life-threatening conditions, such as laryngospasm, may develop particularly due to the use of antipsychotics. When such a clinical condition is observed at the PED, drugs should definitely be questioned for differential diagnosis. In treatment, anticholinergic acting diphenhydramine could readily be used through parenteral way. However, the easiest and the most secure way to prevent development of DRs is to avoid unnecessary drug use. The physicians, who work at PED, should consider the DIDRs side effects of both antiemetics and antipsychotics and, therefore, prescribe those drugs with an accurate indication.
Competing interests None.
Ethics approval Ethics approval was provided by the institutional ethics committee of Gazi University, Faculty of Medicine, Ankara, Turkey.
Provenance and peer review Not commissioned; externally peer reviewed.