metricas
covid
Buscar en
Revista Colombiana de Psiquiatría (English Edition)
Toda la web
Inicio Revista Colombiana de Psiquiatría (English Edition) Neuroleptic malignant syndrome in children and adolescents: Systematic review of...
Información de la revista
Vol. 50. Núm. 4.
Páginas 290-300 (octubre - diciembre 2021)
Visitas
1376
Vol. 50. Núm. 4.
Páginas 290-300 (octubre - diciembre 2021)
Review Article
Acceso a texto completo
Neuroleptic malignant syndrome in children and adolescents: Systematic review of case reports
Síndrome neuroléptico maligno en niños y adolescentes: revisión sistemática de reportes de caso
Visitas
1376
Deborah León-Ameneroa, Jeff Huarcaya-Victoriab,c,
Autor para correspondencia
a Médico psiquiatría de niños y adolescentes, Servicio de Psiquiatría Infanto-juvenil, Departamento de Psiquiatría, Hospital Nacional Guillermo Almenara Irigoyen, EsSalud, Lima, Peru
b Universidad de San Martín de Porres, Facultad de Medicina, Centro de Investigación en Salud Pública, Lima, Peru
c Médico psiquiatra, Servicio de Psiquiatría General, Departamento de Psiquiatría, Hospital Nacional Guillermo Almenara Irigoyen, EsSalud, Lima, Peru
Este artículo ha recibido
Información del artículo
Resumen
Texto completo
Bibliografía
Descargar PDF
Estadísticas
Figuras (1)
Tablas (6)
Table 1. Age, gender and diagnosis of 57 patients under 18 years of age with neuroleptic malignant syndrome reported between 2005 and 2018.
Table 2. Cases of NMS caused by antipsychotics and other psychotropic drugs in 57 patients under 18 years of age.
Table 3. Frequency of symptoms of 57 cases of patients under 18 years of age with antipsychotic-induced NMS.
Table 4. Laboratory tests of 57 cases of patients under 18 years of age with antipsychotic-induced NMS.
Table 5. Management of 57 cases of patients under 18 years of age with antipsychotic-induced NMS.
Table 6. Exploratory factor analysis of the symptoms of 57 cases of patients under 18 years of age with NMS.
Mostrar másMostrar menos
Abstract
Introduction

Neuroleptic malignant syndrome (NMS) is a rare and potentially fatal drug adverse reaction. There are still few studies of this entity in the child–adolescent population.

Objectives

Describe the clinical, laboratory and therapeutic characteristics of children and adolescent patients with NMS. Analyse the grouping of symptoms present in NMS in the same population.

Material and methods

A MEDLINE/PubMed search of all reported cases of NMS from January 2000 to November 2018 was performed and demographic, clinical, laboratory and therapeutic variables were identified. A factorial analysis of the symptoms was performed.

Results

57 patients (42 males and 15 females) were included, (mean age 13.65 ± 3.89 years). The onset of NMS occurred at 11.25 ± 20.27 days with typical antipsychotics and at 13.69 ± 22.43 days with atypical antipsychotics. The most common symptoms were muscle stiffness (84.2%), autonomic instability (84.2%) and fever (78.9). The most common laboratory findings were CPK elevation and leucocytosis (42.1%). The most used treatment was benzodiazepines (28.1%). In the exploratory factorial analysis of the symptoms we found 3 factors: 1) “Catatonic” with mutism (0.912), negativism (0.825) and waxy flexibility (0.522); 2) “Extrapyramidal” with altered gait (0.860), involuntary abnormal movements (0.605), muscle stiffness (0.534) and sialorrhoea (0.430); and 3) “Autonomic instability” with fever (0.798), impaired consciousness (0.795) and autonomic instability (0.387).

Conclusions

NMS in children and adolescents could be of 3 types: catatonic, extrapyramidal and autonomic unstable.

Keywords:
Malignant neuroleptic syndrome
Children
Adolescents
Resumen
Introducción

El síndrome neuroléptico maligno (SNM) es una rara y potencialmente fatal reacción adversa medicamentosa. Aún son pocos los estudios de esta entidad en la población infanto-juvenil.

Objetivos

Describir las características clínicas, de laboratorio y terapéuticas de los pacientes niños y adolescentes con SNM. Analizar la agrupación de síntomas presentes en el SNM en la misma población.

Material y métodos

Se realizó una búsqueda en MEDLINE/PubMed de todos los casos reportados de SNM desde enero del 2000 hasta noviembre del 2018 y se identificaron las variables demográficas, clínicas, laboratoriales y terapéuticas. Se realizó un análisis factorial de los síntomas.

Resultados

Se incluyó a 57 pacientes (42 varones y 15 mujeres), con edad promedio de 13,65 ± 3,89 años. La aparición del SNM ocurrió a los 11,25 ± 20,27 días (con antipsicóticos típicos) y a los 13,69 ± 22,43 días (con antipsicóticos atípicos). Los síntomas más frecuentes fueron la rigidez muscular (84,2%), inestabilidad autonómica (84,2%) y fiebre (78,9). Los hallazgos de laboratorio más frecuentes fueron la elevación del CK y leucocitosis (42.1%). El tratamiento más usado fue la indicación de benzodiacepinas (28,1%). En el análisis factorial exploratorio de los síntomas encontramos 3 factores: 1) «catatónico», con mutismo (0,912), negativismo (0,825) y flexibilidad cérea (0,522); 2) «extrapiramidal», con alteración de la marcha (0,860), movimientos anormales involuntarios (0,605), rigidez muscular (0,534) y sialorrea (0,430), y 3) «inestabilidad autonómica», con fiebre (0,798), alteración de la consciencia (0,795) e inestabilidad autonómica (0,387).

Conclusiones

El SNM en niños y adolescentes podría ser de 3 tipos: catatónico, extrapiramidal e inestable autonómico.

Palabras clave:
Síndrome neuroléptico maligno
Niños
Adolescentes
Texto completo
Introduction

The symptoms associated with neuroleptic malignant syndrome (NMS) were first described in 1956 by Ayd, and defined as such by Delay and Deniker in 1968, when they reported an unusual response to haloperidol.1 Initially, the term neuroleptic was used to describe those psychotropic drugs that controlled psychotic symptoms and produced extrapyramidal symptoms as a side effect — in other words, first-generation antipsychotics.2 Thus, NMS was described as a set of signs and symptoms that present as a potentially severe adverse reaction, secondary to the use of first-generation antipsychotics. However, over time it has been seen that it can also occur secondary to the use of atypical antipsychotics, mood stabilisers and even medication other than psychotropic drugs.

Initially, a prevalence of around 0.2%–3% was described in 1993,3 but in recent years a decrease in this has been observed, to 0.01%–0.02%,4 possibly due to greater care in the prescription and titration of medication. Four main symptoms are usually considered for its diagnosis: hyperthermia, muscular rigidity, altered consciousness and autonomic dysfunction. Added to these are diaphoresis, tremors, incontinence, leukocytosis and elevated creatine kinase (CK). Despite this, to date there is no consensus on universal diagnostic criteria.5

Although this adverse reaction can occur at any stage of life, in any gender and in people with both psychiatric and non-psychiatric illness, some risk factors associated with its appearance have been identified, such as advanced age, male gender, polypharmacy, dehydration, malnutrition, rapid administration of antipsychotics, structural brain damage and affective disorders.1,5 Among the main associated complications are the development of rhabdomyolysis, respiratory failure, kidney failure and sepsis, with a mortality of 5.6%. Among the predictive factors of mortality are advanced age, respiratory, renal and cardiovascular failure.6 It is, then, a widely described and studied syndrome, with various fatal complications. Despite this, there are still few studies in the child–adolescent population. Apparently, it is postulated that the course and treatment in children and adolescents is usually the same as in adults. However, more studies are needed in this regard.1,2 For this reason, the present work aims to describe the clinical and laboratory characteristics and the treatment of child and adolescent patients with NMS, and we will also analyse the grouping of the symptoms.

Methods

The guidelines of the PRISMA Statement7 guide were followed. A search was carried out in the MEDLINE/PubMed search engine of all the reported cases of NMS from 1 January 2000 to 3 November 2018, entering the terms: (children OR child OR paediatric OR pediatric OR school child OR adolescents OR adolescence OR teenage) AND (case OR report OR case report OR case reports) AND (neuroleptic malignant syndrome). We selected the articles that met the following characteristics: articles written in English or Spanish and case reports or case series of NMS in people <18 years of age.

The identification and initial screening of the articles were carried out by the co-author (JHV). The titles and abstracts of all articles found were reviewed first; then two investigators (DLA, JHV) reviewed the full text of potentially relevant articles.

After a bibliographic review, it was decided to search in each case for the following variables: 1) demographic: age; gender; 2) clinical: fever; muscular rigidity; waxy flexibility; echophenomena (echopraxia, echolalia); mutism; negativism; abnormal involuntary movements; gait disturbance; dysarthria; dysphagia; hypersalivation; alteration of consciousness; autonomic instability; 3) laboratory tests: myoglobinuria; leukocytosis; thrombocytosis; hydroelectrolytic disturbances; altered liver enzymes; CK peak; increased LDH; 4) history of NMS: drug responsible for NMS; onset of symptoms (days); diagnosis and treatment of NMS. The data were extracted by the two investigators (DLA, JHV) independently, and any discrepancies later resolved by consensus.

Statistical analysis was performed by one investigator (JHV). The percentages of each variable were found, as well as the average ages through the use of descriptive statistical techniques. Differences in the clinical picture, laboratory tests and treatment of NMS were searched for among the different antipsychotics responsible using the difference in two proportions test and analysis of variance (ANOVA).

An exploratory factor analysis was carried out with symptoms as variables, using the principal component analysis method, and then adjusted by Varimax rotation with Kaiser normalisation. The feasibility of performing a factor analysis of symptoms was evaluated using the Kaiser–Meyer–Olkin (KMO) measure of sampling adequacy and the Bartlett sphericity test. The number of factors was determined using the criterion of eigenvalue >1. The significance level of this study was 0.05. The data were analysed with the statistical program SPSS version 23 of IBM.

Results

The initial search yielded a total of 118 articles. Of these, 59 articles that were not case reports or series were discarded, leaving 59 articles with reports of cases of NMS in children and adolescents published between 1 January 2000 and 3 November 2018.1,3,8–64

From the review of these case reports, a total of 12 articles were excluded because the report was not accessible,56,60–63 was not written in English or Spanish,57,64 and did not have enough clinical data or was not a case of NMS.53–55,58,59 With the agreement of the investigators, 47 articles were included in the present study1,3,8–52 (Fig. 1).

Fig. 1.

Flow chart of the process for identifying and selecting articles.

(0.2MB).

The sample included 57 patients (42 men and 15 women), with an average age of 13.65 ± 3.89 years. The most frequent diagnosis was acute psychotic disorder (21.1%) (Table 1). The onset of NMS occurred at 11.25 ± 20.27 days when only typical antipsychotics were used (n = 8) and at 13.69 ± 22.43 days when atypical antipsychotics were used (n = 26) (Table 2).

Table 1.

Age, gender and diagnosis of 57 patients under 18 years of age with neuroleptic malignant syndrome reported between 2005 and 2018.

Characteristic  N. (%) 
Age, years, mean ±SD (range)  13.65 ± 3.89 (0.3–17) 
Gender
Male  42 (73.7) 
Female  15 (26.3) 
Diagnosis
Schizophrenia  4 (7) 
Bipolar affective disorder  9 (15.8) 
Autism spectrum disorder (ASD)  4 (7) 
Pervasive developmental disorder  3 (5.3) 
Organic mental illness  10 (17.5) 
Mental retardation  2 (3.5) 
Acute psychotic disorder  12 (21.1) 
Schizoaffective disorder  5 (8.8) 
Other  8 (14) 

SD: standard deviation.

Table 2.

Cases of NMS caused by antipsychotics and other psychotropic drugs in 57 patients under 18 years of age.

  Combination of antipsychotics (n = 11)  Haloperidol (n = 5)  Zuclopenthixol (n = 2)  Risperidone (n = 9)  Quetiapine (n = 3)  Olanzapine (n = 6)  Ziprasidone (n = 1)  Clozapine (n = 3)  Aripiprazole (n = 4)  Other typical (n = 2)  Other psychotropic drugs (n = 11)  Total (n = 57)  Statistics 
Age (years), mean ± SD  15.27 ± 2  16.2 ± 0.83  11 ± 4.24  14 ± 2.95  11.33 ± 6.65  15.5 ± 1.64  15  16.33 ± 0.57  13.75 ± 2.36  12 ± 1.41  10.11 ± 5.6  13.65 ± 3.89  F = 2.25, DF = 10, p = 0.03 
Gender (male)  5 (45.5%)  4 (80%)  1 (50%)  8 (88.9%)  3 (100%)  5 (83.3%)  1 (100%)  1 (33.3%)  3 (75%)  2 (100%)  9 (81.8%)  42 (73.7%)  χ2 = 11.60, DF = 10, p = 0.31 
Onset of symptoms (days), mean ± SD  11.42 ± 11.60  19.75 ± 27.53  4.5 ± 3.5  6.22 ± 9.82  4.66 ± 3.21  26.50 ± 32.49  56  20.66 ± 34.06  2.25 ± 0.5  1 ± 0  11.36 ± 20.63  12.51 ± 20.09  F = 1.264, DF = 10, p = 0.282 

SD: standard deviation; DF: degrees of freedom.

Clinical presentation

Table 3 shows the frequency of clinical symptoms by antipsychotic. The most frequent symptoms were muscle rigidity (84.2%), autonomic instability (84.2%) and fever (78.9%). The clinical presentation of NMS differed depending on the antipsychotic used, with Abnormal involuntary movements (p = 0.023) and gait disturbance (p = 0.023) being those related to the antipsychotic administered. Fever was observed in all cases in which olanzapine, ziprasidone and clozapine were administered. However, these differences were not statistically significant (p = 0.29). We found no fatal cases.

Table 3.

Frequency of symptoms of 57 cases of patients under 18 years of age with antipsychotic-induced NMS.

  Combination of antipsychotics (n = 11)  Haloperidol (n = 5)  Zuclopenthixol (n = 2)  Risperidone (n = 9)  Quetiapine (n = 3)  Olanzapine (n = 6)  Ziprasidone (n = 1)  Clozapine (n = 3)  Aripiprazole (n = 4)  Other typical (n = 2)  Other psychotropic drugs (n = 11)  Total (n = 57)  Statistics 
Fever  6 (54.5%)  4 (80%)  1 (50%)  8 (88.9%)  2 (66.7%)  6 (100%)  1 (100%)  3 (100%)  2 (50%)  2 (100%)  10 (90.9%)  45 (78.9%)  χ2 = 11.92, DF = 10, p = 0.29 
Muscular rigidity  7 (63.6%)  5 (100%)  2 (100%)  8 (88.9%)  1 (33.3%)  6 (100%)  1 (100%)  3 (100%)  4 (100%)  2 (100%)  9 (81.8%)  48 (84.2%)  χ2 = 13.85, DF = 10, p = 0.18 
Waxy flexibility  2 (18.2%)  1 (20%)  1 (16.7%)  4 (7%)  χ2 = 6.89, DF = 10, p = 0.736 
Ecophenomena  2 (18.2%)  1 (11.1%)  1 (25%)  4 (7%)  χ2 = 6.80, DF = 10, p = 0.744 
Mutism  5 (45.5%)  1 (20%)  1 (50%)  3 (33.3%)  1 (33.3%)  2 (33.3%)  1 (33.3%)  1 (25%)  1 (50%)  1 (9.1%)  17 (29.8%)  χ2 = 5.14, DF = 10, p = 0.881 
Negativism  3 (27.3%)  1 (20%)  3 (33.3%)  1 (33.3%)  1 (16.7%)  1 (100%)  1 (33.3%)  2 (18.2%)  13 (22.8%)  χ2 = 7.10, DF = 10, p = 0.716 
Abnormal involuntary movements  2 (18.2%)  2 (40%)  2 (100%)  2 (22.2%)  3 (75%)  2 (100%)  3 (27.3%)  16 (28.1%)  χ2 = 20.72, DF = 10, p = 0.023 
Gait disturbance  1 (9.1%)  1 (20%)  1 (50%)  4 (44.4%)  1 (33.3%)  4 (66.7%)  1 (100%)  2 (66.7%)  4 (100%)  2 (100%)  3 (27.3%)  24 (42.1%)  χ2 = 18.93, DF = 10, p = 0.041 
Dysarthria  1 (9.1%)  1 (11.1%)  1 (33.3%)  1 (25%)  1 (9.1%)  5 (8.8%)  χ2 = 5.46, DF = 10, p = 0.858 
Dysphagia  1 (9.1%)  2 (22.2%)  2 (18.2%)  5 (8.8%)  χ2 = 5.75, DF = 10, p = 0.836 
Hypersalivation  1 (9.1%)  1 (50%)  1 (11.1%)  1 (25%)  1 (50%)  5 (8.8%)  χ2 = 12.66, DF = 10, p = 0.243 
Altered consciousness  6 (54.5%)  2 (40%)  1 (50%)  7 (77.8%)  2 (66.7%)  6 (100%)  1 (100%)  3 (100%)  4 (100%)  2 (100%)  8 (72.7%)  42 (73.7%)  χ2 = 11.45, DF = 10, p = 0.323 
Autonomic instability  11 (100%)  4 (80%)  2 (100%)  6 (66.7%)  2 (66.7%)  6 (100%)  1 (100%)  3 (100%)  3 (75%)  2 (100%)  8 (72.7%)  48 (84.2%)  χ2 = 8.878, DF = 10, p = 0.544 

DF: degrees of freedom.

Laboratory tests

Table 4 presents the main laboratory findings by antipsychotic drug. The mean CK (100 IU/l) was 84.30 ± 214.53. In men, we found a mean CK of 96.64 ± 248.72, while in women it was 52.20 ± 69.22. However, these differences were not significant (p = 0.314). The most frequent laboratory finding, after elevated CK, was leukocytosis (42.1%).

Table 4.

Laboratory tests of 57 cases of patients under 18 years of age with antipsychotic-induced NMS.

  Combination of antipsychotics (n = 11)  Haloperidol (n = 5)  Zuclopenthixol (n = 2)  Risperidone (n = 9)  Quetiapine (n = 3)  Olanzapine (n = 6)  Ziprasidone (n = 1)  Clozapine (n = 3)  Aripiprazole (n = 4)  Other typical (n = 2)  Other psychotropic drugs (n = 11)  Total (n = 57)  Statistics 
Myoglobinuria  1 (50%)  1 (11.1%)  2 (18.2%)  4 (7%)  χ2 = 10.63, DF = 10, p = 0.387 
Leukocytosis  5 (45.5%)  1 (20%)  2 (100%)  4 (44.4%)  1 (33.3%)  2 (33.3%)  1 (100%)  2 (66.7%)  1 (25%)  1 (50%)  4 (36.4%)  24 (42.1%)  χ2 = 6.90, DF = 10, p = 0.734 
Thrombocytosis  1 (50%)  1 (1.8%)  χ2 = 27.99, DF = 10, p = 0.02 
Hydroelectrolytic disturbances  1 (9.1%)  1 (20%)  1 (33.3%)  3 (27.3%)  6 (10.5%)  χ2 = 8.60, DF = 10, p = 0.570 
Altered liver enzymes  3 (27.3%)  2 (40%)  2 (22.2%)  1 (33.3%)  1 (16.7%)  2 (66.7%)  1 (25%)  1 (50%)  3 (27.2%)  16 (28.1%)  χ2 = 4.819, DF = 10, p = 0.903 
CK peak (100 U/l), mean ± SD  58.29 ± 59.97  45.77 ± 45.97  711.5 ± 973.68  35.71 ± 33.75  11.48 ± 6  35.58 ± 24.84  773.3  77.49 ± 122.72  64.32 ± 112.77  41.35 ± 28.49  43.32 ± 51.07  84.30 ± 214.53  F = 5.3, DF = 10, p = 0.000 
Increased LDH  1 (9.1%)  2 (66.7%)  1 (25%)  3 (27.3%)  7 (12.3%)  χ2 = 15.15, DF = 10, p = 0.126 

CK: creatine kinase; DF: degrees of freedom; LDH: lactate dehydrogenase; SD: standard deviation.

Treatment

Table 5 shows the different NMS treatments used in the study sample, the most frequent one being benzodiazepines (28.1%) followed by supportive measures (24.6%).

Table 5.

Management of 57 cases of patients under 18 years of age with antipsychotic-induced NMS.

  Combination of antipsychotics (n = 11)  Haloperidol (n = 5)  Zuclopenthixol (n = 2)  Risperidone (n = 9)  Quetiapine (n = 3)  Olanzapine (n = 6)  Ziprasidone (n = 1)  Clozapine (n = 3)  Aripiprazole (n = 4)  Other typical (n = 2)  Other psychotropic drugs (n = 11)  Total (n = 57)  Statistics 
Support measures only  2 (18.2%)  1 (50%)  2 (22.2%)  2 (66.7%)  1 (16.7%)  1 (33.3%)  1 (50%)  4 (36.4%)  14 (24.6%)  χ2 = 53.89, DF = 50, p = 0.328
Benzodiazepines  7 (63.6%)  2 (40%)  3 (33.3%)  3 (75%)  1 (50%)  16 (28.1%) 
Amantadine  1 (16.7%)  1 (1.8%) 
Bromocriptine  1 (9.1%)  1 (20%)  1 (50%)  1 (11.1%)  2 (33.3%)  2 (66.7%)  2 (18.2%)  10 (17.5%) 
Dantrolene  2 (40%)  2 (22.2%)  1 (16.7%)  1 (100%)  1 (25%)  3 (27.3%)  10 (17.5%) 
Other  1 (9.1%)  1 (11.1%)  1 (33.3%)  1 (16.7%)  2 (18.2%)  6 (10.5%) 

DF: degrees of freedom.

Factor analysis of symptoms

The feasibility tests to perform the factor analysis were satisfactory (Bartlett’s sphericity test: χ2 = 114.92, p = 0.004; KMO value = 0.555). Symptoms are reduced when grouped into three factors: 1) “catatonic” (eigenvalue 1.884, with a variance of 18.837%); 2) “extrapyramidal syndrome” (eigenvalue 1.755, with a variance of 17.54%), and 3) “autonomic instability” (eigenvalue 1.493, with a variance of 14.92%). Table 6 shows the grouping of symptoms in the three factors.

Table 6.

Exploratory factor analysis of the symptoms of 57 cases of patients under 18 years of age with NMS.

  Factors
 
Mutism  0.912  0.007  −0.056 
Negativism  0.825  −0.055  0.202 
Waxy flexibility  0.522  0.121  0.000 
Gait disturbance  0.126  0.860  0.035 
Abnormal involuntary movements  0.188  0.605  −0.128 
Muscular rigidity  −0.046  0.534  0.094 
Hypersalivation  −0.049  0.430  −0.061 
Fever  −0.119  −0.128  0.798 
Altered consciousness  0.049  0.363  0.795 
Autonomic instability  0.163  −0.117  0.387 

Extraction method: principal component analysis. Varimax rotated solution with Kaiser normalisation.

Factor 1: catatonic; factor 2: extrapyramidal; factor 3: autonomically unstable.

Discussion

The current state of knowledge of NMS is based on case reports and series, few of which were carried out in children and adolescents. This study found that more cases were reported in males, similarly to Silva et al.,2 who found a higher frequency of NMS in males (63.63%) in case reports of children and adolescents. This is probably due to this population being more frequently exposed to antipsychotics, since many of the diseases in child and adolescent psychiatry predominantly affect males.65

The onset of symptoms occurred at 11.25 ± 20.27 days when only typical antipsychotics were used, and at 13.69 ± 22.43 days when atypical antipsychotics were used. However, this difference is not significant. In the literature, it has been reported that the time to the onset of symptoms was 8.7 ± 16.2 days in a sample of child–adolescent patients who developed NMS after the administration of atypical antipsychotics.66 These differences could be explained by the different sample sizes. These results are similar to those described in the adult population; as reported by Caroff and Mann,67 16% of patients develop NMS symptoms within the first 24 h, 66% within the first week, and 96% within a month. The clinical implications of this result suggest that we should maintain a watchful eye for the appearance of NMS symptoms for around two weeks.

The most frequently reported symptoms were: muscle rigidity, autonomic instability, fever and altered consciousness. These results are similar to those reported in other studies in a child–adolescent population exposed to typical and atypical antipsychotics,2 as well as to only atypical ones,66 Catatonic symptoms were also found, such as mutism and negativism, among others, which have been described in the literature since the 1980s. However, since then, more importance has been given to systemic than to catatonic manifestations.68 Some authors view malignant catatonia and NMS as two different conditions with overlapping clinical characteristics, while for others they are the same disorder.68 The appearance of catatonic symptoms in the adult population has been associated with greater severity and worse prognosis. This association is not entirely clear in the child–adolescent population.69,70

Abnormal involuntary movements were found more frequently in patients who received typical antipsychotics, with these differences being statistically significant. This was an expected finding, since dopamine blockade in the nigrostriatal pathway, caused by typical antipsychotics, tends to cause such clinical manifestations. Although dopamine blockade at the hypothalamus level would explain the autonomic alteration as well as thermoregulation, we found that these findings were not related to any particular antipsychotic.5

The main treatment used for NMS cases in our sample was benzodiazepines, followed by the exclusive use of life support measures. These results are different from that reported in another review, which found that the use of dantrolene was greater than that of benzodiazepines (39% vs. 30%).66 A possible explanation for this difference could be that the cases in our study were less severe, not requiring the use of dantrolene, which is reserved for severe cases of NMS This could be explained by the fact that in the last two decades greater care has been taken when titrating antipsychotics in children and adolescents.4

ECT is little used in the child–adolescent population,71 which would explain why it is the least used therapeutic measure in our sample. ECT can be considered as a second-line treatment, administered if the supportive measures and pharmacological treatment fail during the first seven days. Furthermore, it is used in those cases in which the underlying psychiatric diagnosis is psychotic depression or catatonia, which differs from the diagnoses of the cases that were reviewed in this study.72

In the factor analysis of symptoms, we found three factors: factor 1 (catatonia), factor 2 (extrapyramidal) and factor 3 (autonomic instability). In catatonic NMS, we found patients with a predominance of catatonic symptoms, which would partly explain the overlap between NMS and lethal catatonia. In extrapyramidal NMS, the predominance occurs in the usual extrapyramidal adverse reactions, while in autonomically unstable NMS there is a greater grouping of systemic symptoms. These findings could have therapeutic implications, with ECT and benzodiazepines being the treatment in NMS with catatonic predominance, bromocriptine or dantrolene used in extrapyramidal syndrome, and support measures used in autonomic instability.

This study’s potential limitations must be taken into consideration. The main one is related to the low representation and the small number of reported cases, which is because we analysed uncontrolled secondary sources. A systematic review of case reports cannot provide strong associations. However, it could report some hypotheses for later studies. Furthermore, we must emphasise that any attempt to apply the scientific method rigorously to the study of NMS must face the intrinsic challenges of this condition: it is unpredictable and appears infrequently, it has no established clinical markers and, often, it presents as an emerging disorder that threatens the life of the patient, making it difficult to obtain informed consent to participate in research protocols.

Conclusions

NMS in this sample was more frequent in males. The most frequently reported symptoms were: muscle rigidity, autonomic instability and fever. According to the factor analysis of symptoms, NMS could be of three types: catatonic, extrapyramidal and autonomically unstable.

Funding

Self-financed.

Conflicts of interest

The authors have no conflicts of interest to declare.

References
[1]
V. Yildirim, M.C. Direk, S. Gunes, C. Okuyaz, F. Toros.
Neuroleptic malignant syndrome associated with valproate in an adolescent.
Clin Psychopharmacol Neurosci, 15 (2017), pp. 76-78
[2]
R.R. Silva, D.M. Munoz, M. Alpert, I.R. Perlmutter, J. Diaz.
Neuroleptic malignant syndrome in children and adolescents.
J Am Acad Child Adolesc Psychiatry, 38 (1999), pp. 187-194
[3]
S. Vurucu, A. Congologlu, D. Altun, B. Unay, R. Akin.
Neuroleptic malignant syndrome due to risperidone treatment in a child with Joubert syndrome.
J Natl Med Assoc, 101 (2009), pp. 273-275
[4]
B.D. Berman.
Neuroleptic malignant syndrome: a review for neurohospitalists.
Neurohospitalist, 1 (2011), pp. 41-47
[5]
R. Velamoor.
Neuroleptic malignant syndrome: a neuro-psychiatric emergency: recognition, prevention, and management.
Asian J Psychiatr, 29 (2017), pp. 106-109
[6]
S. Modi, D. Dharaiya, L. Schultz, P. Varelas.
Neuroleptic malignant syndrome: complications, outcomes, and mortality.
Neurocrit Care, 24 (2016), pp. 97-103
[7]
A. Liberati, D.G. Altman, J. Tetzlaff, C. Mulrow, P.C. Gotzsche, J.P. Ioannidis, et al.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
BMJ (Clinical research ed), 339 (2009), pp. b2700
[8]
C. Sun, H. Sweet, A.B. Minns, D. Shapiro, W. Jenkins.
A mixed presentation of serotonin syndrome vs. neuroleptic malignant syndrome in a 12-year-old boy.
[9]
R. Sutar, A. Ray, S.P. Sheshadri.
Leukodystrophy presenting as hyperactivity and bipolarity with uncommon adverse drug reaction.
Indian J Psychol Med, 39 (2017), pp. 202-204
[10]
N. Ghaziuddin, M. Hendriks, P. Patel, L.E. Wachtel, D.M. Dhossche.
Neuroleptic malignant syndrome/malignant catatonia in child psychiatry: literature review and a case series.
J Child Adolesc Psychopharmacol, 27 (2017), pp. 359-365
[11]
O. Wittmann, E. Sadot, O. Bisker-Kassif, D. Scolnik, O. Tavor, M.M. Glatstein.
Neuroleptic malignant syndrome associated with metoclopramide use in a boy: case report and review of the literature.
Am J Ther, 23 (2016), pp. e1246-e1249
[12]
C. Tanidir, S. Aksoy, O. Canbek, G.F. Aras, A.G. Kilicoglu, A. Erdogan.
Treatment of neuroleptic malignant syndrome with electroconvulsive therapy in an adolescent with psychosis.
J Child Adolesc Psychopharmacol, 26 (2016), pp. 179-180
[13]
N. Sharon, C. Cullen, K. Martinez.
A complex presentation of pediatric neuroleptic malignant syndrome related to polypharmacy in a 12-year-old male.
J Child Adolesc Psychopharmacol, 26 (2016), pp. 571-573
[14]
H. Ayyildiz, S. Turan, D. Gulcu, C.A. Poyraz, E. Pehlivanoglu, F. Cullu, et al.
Olanzapine-induced atypical neuroleptic malignant syndrome in an adolescent man with anorexia nervosa.
Eat Weight Disord, 21 (2016), pp. 309-311
[15]
C. Westfall, C.J. Mullett, L.S. Nield.
Index of suspicion. Case 2: fever and Irritability in a 15-year-old boy with autism.
Pediatr Rev, 36 (2015), pp. 313-315
[16]
A. Berg, R. Byrne, B.J. Coffey.
Neuroleptic malignant syndrome in a boy with NMDA receptor encephalitis.
J Child Adolesc Psychopharmacol, 25 (2015), pp. 368-371
[17]
L. Kailas, S. Sugunan, G.S. Bindu, C.C. Thomas.
A case of neuroleptic malignant syndrome in an infant.
Indian J Pediatr, 81 (2014), pp. 1115-1116
[18]
A. Butwicka, S. Krystyna, W. Retka, T. Wolanczyk.
Neuroleptic malignant syndrome in an adolescent with CYP2D6 deficiency.
Eur J Pediatr, 173 (2014), pp. 1639-1642
[19]
B. Sharma, R.B. Sannegowda, P. Gandhi, P. Dubey, A. Panagariya.
Combination of Steven-Johnson syndrome and neuroleptic malignant syndrome following carbamazepine therapy: a rare occurrence.
[20]
D. Perry, P. Birthi, S. Salles, S. McDowell.
Neuroleptic malignant syndrome associated with the use of carbidopa/levodopa for dystonia in persons with cerebral palsy.
[21]
K.M. Matheson, G. Gray.
Clozapine-induced neuroleptic malignant syndrome in an adolescent.
J Child Adolesc Psychopharmacol, 22 (2012), pp. 322-324
[22]
T. Bhalla, D. Maxey, A. Sawardekar, J.D. Tobias.
Anesthetic management of a pediatric patient with neuroleptic malignant syndrome.
J Anesth, 26 (2012), pp. 250-253
[23]
R.B. Nayak, G.S. Bhogale, N.M. Patil, S.S. Chate, A.A. Pandurangi, V.N. Shetageri.
Paliperidone-induced neuroleptic malignant syndrome.
J Neuropsychiatry Clin Neurosci, 23 (2011), pp. E14-E15
[24]
T. Henderson.
Neuroleptic malignant syndrome in adolescents: Four probable cases in the Western Cape.
S Afr Med J, 101 (2011), pp. 405-407
[25]
A.E. Arslankoylu, M.O. Kutuk, C. Okuyaz, F. Toros.
Neuroleptic malignant syndrome due to risperidone misdiagnosed as status epilepticus.
Pediatr Rep, 3 (2011), pp. e19
[26]
T.C. Randolph.
Possible contribution of XYY syndrome to neuroleptic malignant syndrome in a child receiving quetiapine.
Am J Health Syst Pharm, 67 (2010), pp. 459-461
[27]
S.D. Wait, F.A. Ponce, B.D. Killory, D. Wallace, H.L. Rekate.
Neuroleptic malignant syndrome from central nervous system insult: 4 cases and a novel treatment strategy. Clinical article.
J Neurosurg Pediatr, 4 (2009), pp. 217-221
[28]
A.R. Rais, S. Kimmel, N. Shrestha, T.B. Rais, B.J. Coffey.
Atypical neuroleptic malignant syndrome in an adolescent.
J Child Adolesc Psychopharmacol, 18 (2008), pp. 215-220
[29]
N. Tsuchiya, E. Morimura, T. Hanafusa, T. Shinomura.
Postoperative neuroleptic malignant syndrome that occurred repeatedly in a patient with cerebral palsy.
Paediatr Anaesth, 17 (2007), pp. 281-284
[30]
H.B. Palakurthi, M.M. Parvin, S. Kaplan.
Neuroleptic malignant syndrome from aripiprazole in an agitated pediatric patient.
Clin Neuropharmacol, 30 (2007), pp. 47-51
[31]
S. Erermis, T. Bildik, M. Tamar, A. Gockay, H. Karasoy, E.S. Ercan.
Zuclopenthixol-induced neuroleptic malignant syndrome in an adolescent girl.
Clin Toxicol (Phila), 45 (2007), pp. 277-280
[32]
L.W. Choi-Kain, H.G. Pope.
«Atypical» neuroleptic malignant syndrome and the spectrum of malignant cerebrotoxic syndromes.
Harv Rev Psychiatry, 15 (2007), pp. 181-186
[33]
D.N. Mendhekar, H.S. Duggal.
Persistent amnesia as a sequel of olanzapine-induced neuroleptic malignant syndrome.
J Neuropsychiatry Clin Neurosci, 18 (2006), pp. 552-553
[34]
H.R. Martinez, L. Cantu-Martinez, H.C. Gonzalez, L. Flores L de, H.J. Villarreal, J. Onofre-Castillo.
Epilepsy, parkinsonism, and neuroleptic malignant syndrome in a child.
J Child Neurol, 21 (2006), pp. 1073-1075
[35]
S. Hammerman, C. Lam, S.N. Caroff.
Neuroleptic malignant syndrome and aripiprazole.
J Am Acad Child Adolesc Psychiatry, 45 (2006), pp. 639-641
[36]
M. Skarpathiotakis, N. Westreich.
NMS after clozapine initiation.
J Am Acad Child Adolesc Psychiatry, 44 (2005), pp. 1101-1102
[37]
A. Mane, I. Baeza, A. Morer, M.L. Lazaro, M. Bernardo.
Neuroleptic malignant syndrome associated with risperidone in a male with early-onset schizophrenia.
J Child Adolesc Psychopharmacol, 15 (2005), pp. 844-845
[38]
G. Eymin, M. Andresen, J. Godoy, G. Rada.
[Malignant neuroleptic syndrome and polyserositis associated to clozapine use: report of one case].
Rev Med Chil, 133 (2005), pp. 1225-1228
[39]
R.E. Dew, P.B. Rosenquist, W.V. McCall.
Aripiprazole for agitation in a 13-year-old girl with neuroleptic malignant syndrome.
Int J Adolesc Med Health, 17 (2005), pp. 187-188
[40]
D.S. Chungh, B.N. Kim, S.C. Cho.
Neuroleptic malignant syndrome due to three atypical antipsychotics in a child.
J Psychopharmacol, 19 (2005), pp. 422-425
[41]
G. Zalsman, R. Lewis, S. Konas, O. Loebstein, P. Goldberg, F. Burguillo, et al.
Atypical neuroleptic malignant syndrome associated with risperidone treatment in two adolescents.
Int J Adolesc Med Health, 16 (2004), pp. 179-182
[42]
S. Spalding, N.E. Alessi, K. Radwan.
Aripiprazole and atypical neuroleptic malignant syndrome.
J Am Acad Child Adolesc Psychiatry, 43 (2004), pp. 1457-1458
[43]
J. Leibold, V. Patel, R.A. Hasan.
Neuroleptic malignant syndrome associated with ziprasidone in an adolescent.
Clin Ther, 26 (2004), pp. 1105-1108
[44]
A. Hanft, C.F. Eggleston, J.A. Bourgeois.
Neuroleptic malignant syndrome in an adolescent after brief exposure to olanzapine.
J Child Adolesc Psychopharmacol, 14 (2004), pp. 481-487
[45]
I. Abu-Kishk, M. Toledano, A. Reis, D. Daniel, M. Berkovitch.
Neuroleptic malignant syndrome in a child treated with an atypical antipsychotic.
J Toxicol Clin Toxicol, 42 (2004), pp. 921-925
[46]
N. Berry, S. Pradhan, R. Sagar, S.K. Gupta.
Neuroleptic malignant syndrome in an adolescent receiving olanzapine-lithium combination therapy.
Pharmacotherapy, 23 (2003), pp. 255-259
[47]
B.T. Van Maldegem, L.M. Smit, D.J. Touw, R.J. Gemke.
Neuroleptic malignant syndrome in a 4-year-old girl associated with alimemazine.
Eur J Pediatr, 161 (2002), pp. 259-261
[48]
N. Ghaziuddin, I. Alkhouri, D. Champine, P. Quinlan, T. Fluent, M. Ghaziuddin.
ECT treatment of malignant catatonia/NMS in an adolescent: a useful lesson in delayed diagnosis and treatment.
[49]
E.B. Ty, A.D. Rothner.
Neuroleptic malignant syndrome in children and adolescents.
J Child Neurol, 16 (2001), pp. 157-163
[50]
M.E. Rubio-Gozalbo, D.A. van Waardenburg, P.P. Forget, L.J. Spaapen, A. Verrips, P.C. Vroomen.
Neuroleptic malignant syndrome during zuclopenthixol therapy in X-linked cerebral adrenoleukodystrophy.
J Inherit Metab Dis, 24 (2001), pp. 605-606
[51]
T. Ito, K. Shibata, A. Watanabe, J. Akabane.
Neuroleptic malignant syndrome following withdrawal of amantadine in a patient with influenza A encephalopathy.
Eur J Pediatr, 160 (2001), pp. 401
[52]
A.S. Robb, W. Chang, H.K. Lee, M.S. Cook.
Case study. Risperidone-induced neuroleptic malignant syndrome in an adolescent.
J Child Adolesc Psychopharmacol, 10 (2000), pp. 327-330
[53]
R. Sridaran, C.E. Nesbit.
Acute Dystonia versus neuroleptic malignant syndrome without fever in an eight-year-old child..
Pediatr Emerg Care, 33 (2017), pp. 38-40
[54]
L.T. Schumacher, A.P. Mann, J.G. MacKenzie.
Agitation management in pediatric males with anti-N-methyl-D-aspartate receptor encephalitis.
J Child Adolesc Psychopharmacol, 26 (2016), pp. 939-943
[55]
K.D. Jakobsen, C.H. Bruhn, A.K. Pagsberg, A. Fink-Jensen, J. Nielsen.
Neurological, metabolic, and psychiatric adverse events in children and adolescents treated with aripiprazole.
J Clin Psychopharmacol, 36 (2016), pp. 496-499
[56]
A. Yaman, T. Kendirli, C. Odek, C. Yildiz, F. Begde, H. Erkol, et al.
Neuroleptic malignant syndrome associated with metoclopramide in a child.
Turk J Pediatr, 56 (2014), pp. 535-537
[57]
F.O. Nabih, A. Benali, I. Adali, F. Manoudi, F. Asri.
Association of atypical neuroleptics with anticonvulsants and malignant syndrome. Report of 2 cases.
Pan Afr Med J, 18 (2014), pp. 220
[58]
M. Moscovich, F.T. Novak, A.F. Fernandes, T. Bruch, T. Tomelin, E.M. Novak, et al.
Neuroleptic malignant syndrome.
Arq Neuropsiquiatr, 69 (2011), pp. 751-755
[59]
K. Groff, B.J. Coffey.
Psychosis or atypical neuroleptic malignant syndrome in an adolescent?.
J Child Adolesc Psychopharmacol, 18 (2008), pp. 529-532
[60]
M.A. Boarati, I.L. Fu.
Use of olanzapine in adolescent with bipolar disorder after neuroleptic malignant syndrome.
Rev Bras Psiquiatr, 30 (2008), pp. 86
[61]
A. Panagariya, B. Sharma, R. Singh, V. Agarwal, A. Dev.
The neuroleptic malignant syndrome: a report of 14 cases from North India.
Neurol India, 55 (2007), pp. 166-168
[62]
D. Kasantikul, B. Kanchanatawan.
Neuroleptic malignant syndrome: a review and report of six cases.
J Med Assoc Thai, 89 (2006), pp. 2155-2160
[63]
R.E. Hillis, D.A. Lee.
Viral encephalitis complicated by neuroleptic malignant syndrome in a 7-year-old girl.
Pediatr Emerg Care, 19 (2003), pp. 99-100
[64]
B. Etain, M.F. Le Heuzey, M.C. Mouren-Simeoni.
[Electroconvulsive therapy in the adolescent: clinical considerations apropos of a series of cases].
Can J Psychiatry, 46 (2001), pp. 976-981
[65]
M.J. Mardomingo.
Tratado de psiquiatría del niño y del adolescente.
Díaz de Santos, (2015),
[66]
R.L.J. Neuhut, R. Silva.
Neuroleptic malignant syndrome in children and adolescents on atypical antipsychotic medication: a review.
J Child Adolesc Psychopharmacol, 19 (2009), pp. 415-422
[67]
S.N. Caroff, S.C. Mann.
Neuroleptic malignant syndrome.
Med Clin North Am, 77 (1993), pp. 185-202
[68]
M.T.M. Fink.
Catatonia. A clinician’s guide to diagnosis and treatment.
Cambridge University Press, (2003),
[69]
J.R. Strawn, P.E. Keck Jr, S.N. Caroff.
Neuroleptic malignant syndrome.
Am J Psychiatry, 164 (2007), pp. 870-876
[70]
M.M. Woodbury, M.A. Woodbury.
Neuroleptic-induced catatonia as a stage in the progression toward neuroleptic malignant syndrome.
J Am Acad Child Adolesc Psychiatry, 31 (1992), pp. 1161-1164
[71]
N. Ghaziuddin, S.P. Kutcher, P. Knapp, W. Bernet, V. Arnold, J. Beitchman, et al.
Practice parameter for use of electroconvulsive therapy with adolescents.
J Am Acad Child Adolesc Psychiatry, 43 (2004), pp. 1521-1539
[72]
J.N. Trollor, P.S. Sachdev.
Electroconvulsive treatment of neuroleptic malignant syndrome: a review and report of cases.
Aust N Z J Psychiatry, 33 (1999), pp. 650-659

Please cite this article as: León-Amenero D, Huarcaya-Victoria J. Síndrome neuroléptico maligno en niños y adolescentes: revisión sistemática de reportes de caso. Rev Colomb Psiquiat. 2021;50:290–300.

Copyright © 2019. Asociación Colombiana de Psiquiatría
Descargar PDF
Opciones de artículo