Recognising side effects of antipsychotics in children with intellectual disabilities

Abstract

Risperidone and aripiprazole are increasingly used for behavioural indications in children and adolescents with intellectual disabilities, including autism. Although there are some reports in literature, the side effect profile in this population remains poorly defined and there is a need to raise awareness among clinicians across specialties. We present two patients with significant intellectual disabilities who developed extrapyramidal side effects (EPSE) including oculogyric crisis following risperidone and aripiprazole use. The onset of these side effects can be insidious and the non-specific nature of the presentation, for example, poor mobility and increased drooling on a background of severe intellectual disability, can lend itself to delay in recognition and reporting by families. There is also reduced awareness among paediatricians, which can further delay the treatment of this reversible condition. There needs to be ongoing vigilance for EPSE as they can develop years after treatment has been initiated.

Background

Extrapyramidal side effects (EPSEs) are drug-induced movement disorders that conventionally occur secondary to antidopaminergic drugs. They are known to be precipitated by first-generation antipsychotics and are also, but less frequently, seen with second generation ‘atypical’ antipsychotics.¹ Atypical antipsychotics are increasingly being used for behavioural indications in younger populations. For example, aripiprazole and risperidone are commonly used to help mediate complex behavioural patterns in children with learning and developmental disorders.^{2 3} Nonetheless, their side effect profile in these groups remains poorly defined. Moreover, EPSE can be hard to discern, and particularly where they may be masked by a child’s complex patterns of behaviour.

Examples of EPSE include restlessness (akathisia), involuntary repetitive movements such as lip smacking (tardive dyskinesia), parkinsonian features such as tremor, slowness of movement and rigidity, and continuous muscle contraction (dystonia).^{4 5} Oculogyric crisis (OGC) is one such acute dystonic reaction and is characterised by prolonged and involuntary upward deviation of the eyes.⁶

This case series offers examples of EPSE, including OGC, in two teenagers with learning and behavioural difficulties treated with the second-generation antipsychotics aripiprazole and risperidone.

Case presentation

Our first case is an adolescent male who has a background of attention deficit hyperactivity disorder, autism spectrum disorder, severe intellectual disability and epilepsy (tonic-clonic seizures, with the last episode requiring hospitalisation being six years prior to this presentation).

He was admitted to our institution with intermittent episodes of upward eye deviation. The episodes were self-resolving and had first been noted by his parents 12–18 months prior to admission. They were brief, and most commonly occurred when our patient was tired. Discussed in clinic, the medical team did not feel these were epileptic events and a ‘wait and watch’ approach was initially adopted. Behavioural stereotypy/tic-like movements were felt to be a possibility.

In the months prior to the hospital admission, the episodes of eye rolling had been occurring with increasing frequency and duration. At admission, they were happening several times a day and lasting approximately 45–60 min. In addition, our patient had new features including sluggish movements, drooling and excessive fatigue. He was taking risperidone 4 mg once daily and aripiprazole 8 mg once daily for behaviour management, sodium valproate (400 mg every morning/700 mg every night) for epilepsy, and melatonin 6 mg every night for sleep. His dose of risperidone had been increased to 4 mg from 2.5 mg six months prior to presentation by his community mental health team. He had previously not responded well to stimulant medication (methylphenidate—Concentra and Ritalin) and fluoxetine. These had made his aggression worse.

On examination, in addition to episodic eye movements, our patient had hypomimia, bradykinesia, shuffling gait with reduced arm swinging and dysarthria. He showed difficulty in initiating his movements and had drooling of saliva. He exhibited no further neurological signs. A diagnosis was made of intermittent episodes of OGC, coupled with Parkinsonian symptoms secondary to drug-induced dopamine depletion.

Our second case involves a teenage male, who presented in the newborn period with hypotonia, bilateral ptosis and poor feeding. During late infancy, he achieved independent walking, although with a broad-based gait. He has intellectual and behavioural difficulties, and high levels of anxiety. The underlying cause is a complex chromosomal rearrangement (functionally a deletion of 18p).

In his early teens, our second patient was commenced on risperidone as he was unable to attend school due to anxiety. After two years on risperidone, his parents noticed a bilateral hand tremor, with persistence of the anxiety disorder. Risperidone was then replaced with aripiprazole. Over the following 18 months, there was a gradual decline in mobility such that the patient became wheelchair dependant and had a worsening tremor. In addition, his ptosis became more prominent, although there was no evidence of OGC. Events culminated in an episode lasting 90 min where the patient was still with his head tilted upwards, and he was unable to talk. There was some head rocking, but there was no eye deviation or abnormal postures or shaking of the limbs.

The working diagnosis was of a chronic dopamine depletion syndrome with some Parkinsonian features secondary to risperidone and aripiprazole. As aripiprazole was weaned the patient rapidly improved, and over several months has regained independent ambulation.

Investigations

Baseline blood tests were normal in both our patients including normal full blood count, liver and renal function, electrolytes, bone profile and thyroid function. In our first patient, we found borderline low levels of vitamin D which was treated with oral supplements.

Differential diagnosis

In children with significant intellectual disabilities including severe autism, OGC could be mistaken for a behavioural stereotypy or an ocular tic, especially during early stages. Parkinsonian symptoms such as drooling and paucity of movements can be misinterpreted as ‘non-specific’ in the context of children who may already have a degree of drooling and restricted movements given their background of intellectual disabilities.

Treatment

Our first patient was managed by first weaning and ultimately discontinuing risperidone. For our second patient, aripiprazole was weaned.

Outcome and follow-up

Patient 1

After cessation of risperidone, the episodes of OGC stopped, and all parkinsonian symptoms regressed. He continued with aripiprazole 7.5 mg and sodium valproate 1100 mg. An attempt to wean aripiprazole was made, but the patient’s behaviour became more challenging. A slightly reduced dose of 7.5 mg was thus maintained for a further eight months. However, towards the end of this eight month period, the patient began to experience OGC once more. In conjunction with psychiatry and social care, a weaning plan for aripiprazole and an alternative plan for behavioural management was made. Eye rolling ceased during this weaning regime after the daily dose of aripiprazole was reduced to 5 mg.

Video 1. Video showing patient 1 during an oculogyric crisis.

bcr-2022-251974supp001.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2022-251974.video01

Video 2. Video showing patient 1 at baseline.

bcr-2022-251974supp002.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2022-251974.video02

Patient 2

Symptoms improved rapidly while weaning aripiprazole, and over several months, he regained independent ambulation.

Discussion

Atypical antipsychotics such as aripiprazole and risperidone are increasingly used to help mediate complex behavioural patterns in children with learning and developmental disorders.² Previous work has shown them to be well tolerated, effective for treating disruptive behaviours in those with intellectual disabilities, and generally safe.³

Nonetheless, previous cases have described EPSE with risperidone and with aripiprazole use in the paediatric population.^{4 5 7} These EPSEs are thought to more commonly occur following long-term use of antipsychotics and/or when higher doses or combinations of these drugs are used^{5 8 9} and thus more dopamine depletion occurs. However, EPSEs have also been seen after first ingestion.^10–12 Some EPSEs such as OGC, although well documented in the adult population⁶ are infrequently reported in paediatric literature.^{13 14}

Certain groups of children are believed to be at increased risk for EPSE, including those with Mucopolysaccharidosis III type A,⁵ those with dysfunction of the CYP2D6 enzyme (a phase I drug-metabolising enzyme in the liver),¹⁵ or those with single-nucleotide polymorphisms in genes such as DRD2, SLC18A2, HTR2A and GRIK3.¹⁶

Nonetheless, it remains difficult to predict who might experience EPSE secondary to antipsychotic therapy. Features may be masked, as in the cases we describe, by underlying behavioural disorders, leading to a delay in diagnosis and management. The onset of EPSE can be insidious and the non-specific nature of the presentation, for example, poor mobility and increased drooling on a background of severe intellectual disability, can lend itself to delay in recognition and reporting by families. Conditions with ‘Parkinsonian features’ are not commonly encountered in the paediatric age group. This coupled with the fact that drugs like aripiprazole and risperidone are also not a familiar territory for most Paediatricians makes it more likely for there to be a delay in recognition of ESPE, especially in the subgroup of children with intellectual disabilities in whom clinical assessments can be challenging. Therefore, a high index of clinical suspicion for EPSE is required when treating the paediatric population, as well as ongoing vigilance as symptoms may develop years after treatment has been initiated. There is a need to alert families to features of EPSE, and for paediatricians to be more aware about looking for, and asking families about, EPSE.

Patient and parents perspective.

‘We are very keen to raise awareness among clinicians and also other families of the side effects of medications like Risperidone and Aripiprazole’

Learning points.

• These cases raise awareness about the potential presentation of extrapyramidal side effects and parkinsonism following atypical antipsychotic use for behavioural indications in the paediatric population.

• They illustrate how extrapyramidal side effects may be masked by behavioural or physical features of a child’s disability, even to family members and those closest to the child.

• They highlight the need for clinician awareness and strong clinical suspicion of extrapyramidal side effects in teenagers on antipsychotics for behavioural disorders presenting with behavioural change.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).