Drug-Induced Movement Disorders in Children

Epidemiology

Low- and high-potency DRBAs have been prescribed for children over multiple decades. These agents are used to reduce aggressive behavior, particularly in children with intellectual impairment and autism. High potency DRBAs haloperidol and pimozide are Food and Drug Administration (FDA) approved to treat tic disorders, as is the partial agonist aripiprazole. In addition, the dopamine receptor blockers metoclopramide and prochlorperazine have been used in children as antiemetics and for migraine-associated nausea for many years. ^{, ,} Of particular relevance, several newer DRBAs are widely used to treat dysregulated mood and aggression in children with autism, and risperidone and aripiprazole have US FDA approval for this indication.

Studies of prescribing practices since the marketing in the US of the atypical DRBA risperidone in 1993 show dramatic increases in the use of this class of medications for a wide variety of behavior problems in children of all ages. ^{, ,} Although lagging behind their US counterparts, European physicians have also increasingly prescribed DRBAs for children and adolescents in the past 10 years. The use of these medications in early childhood has contributed to increased risk of obesity and metabolic syndromes, in addition to DIMDs.

Older DRBAs continue to be prescribed because of their effectiveness, relatively lower cost, and concerns about metabolic consequences of the newer, atypical DRBAs, including weight gain and increased risk of type 2 diabetes. ^, However, most of the increase in prescribing in children for the past 20 years involves the newer DRBAs. The use of DRBAs for their original indications for psychotic disorders is vastly outpaced in children by prescriptions to treat anger, unstable mood, aggression, and autistic spectrum disorder (ASD) behaviors. ^, Systematic monitoring of prescribing practices and adverse events is lacking in many countries. Some studies suggested a leveling off of psychotropic drug prescribing in children and adolescents after 2010.

It is important for neurologists to be aware of situations and groups of patients at risk for DIMDs. Table 22.3 is meant to aid in this process. Because DRBAs have many short-term and long-terms uses outside of neurology and psychiatry, Table 22.3 shows the US FDA-labeled and non-FDA-labeled indications, but there are other indications besides those listed. Further, while pediatric indications (underlined) form only a subset of the total uses, it is common for pediatric use to follow adult approval, even in the absence of specific pediatric approval or dosing recommendations. Side effects listed are limited to neurologic ones reported, but clinicians should be vigilant for a full spectrum of DIMDs in response to these agents, even if not specifically listed in databases and drug package inserts. Outside of the nervous system, these medications pose risks for a variety of other common side effects, for example, weight gain, and serious side effects, for example, prolonged QT intervals, ^, which are important for prescribers to be aware of but which lie outside the scope of this chapter.

Systematic studies have generated widely disparate estimates of risks of DIMDs in children prescribed DRBAs. Differences relate in part to patient case mix as well as ascertainment methodology. A meta-analysis of 10 open-label and controlled studies of atypical DRBAs with duration of 12 months or more, involving 783 children and adolescents, provided one important estimate. Most were studies of risperidone which has relatively high D2 receptor affinity compared to newer DRBAs. Eighty percent of patients were white. Adequate data were available on fewer than half of patients. The authors reported a prevalence of DIMDs of 16%. This included tardive dyskinesia in 0.4%, with two cases associated with risperidone and one with olanzapine. Although this study is important in providing a pediatric estimate across clinical trials, as the authors acknowledged, a number of limitations might have led to population underestimates. These include the use of different raters, different scales or no scale reported, and lack of consistent diagnostic criteria. In addition, it is important to note that exclusion criteria employed, for reasons of scientific validity, in controlled clinical trials can result in nonrepresentative samples. A major factor is that randomized controlled trials often disallow or limit polypharmacy, which is much more common in clinical practice. Still, this is a helpful starting-point estimate for the safety of DRBAs with in children with limited polypharmacy and limited prior exposure to DRBAs.

Another helpful estimate comes from a naturalistic study, where researchers at the Maryland Psychiatric Research Center managed a cohort of 424 pediatric psychiatry patients, ages 5–18 years, over a three-year period. This was a more ethnically diverse and representative sample, and many children carried multiple psychiatric diagnoses and were prescribed polypharmacy. Fewer than 20% of patients were being treated for a psychotic disorder. Most had a mood disorder (80%) and/or attention deficit/hyperactivity disorder (ADHD) (64%). The study had a high follow-up rate and a higher use of older DRBAs than we typically see. Researchers were blinded to diagnosis and specific DRBA medication treatment. Standardized scales were utilized, and raters underwent standardized training and reliability testing. The authors reported that 9.3% of their cohort developed a tardive syndrome. Risk factors included African American race, use of older (typical) DRBAs, and longer exposure. A similar estimate of rates of tardive syndromes in children was produced by a systematic literature review at that time. This suggests a number of generalizable factors, in combination with ongoing prescribing of older DRBAs, yields a higher risk of tardive syndromes.

As it is expected for the last decade that most prescriptions in children would be for newer, atypical DRBAs, it is instructive to gather updated estimates of DIMDs from a variety of study methodologies. A meta-analysis of 41 studies of aripiprazole including 2114 children reported an incidence of DIMDs of 17.1%. The most commonly reported were parkinsonism and tremor. Meta-analysis of RCTs and non-RCTs for aripiprazole showed a major cause for discontinuation was akathisia, but this was less common in pediatric compared to adult studies.

Nonrandomized studies have also been instructive, although these do not allow for valid comparisons between DRBAs, as treatment assignment is based on clinician preference and treated groups are likely not equivalent in other important ways. In an observational study involving 265 children and youth most of whom were prescribed risperidone, olanzapine, or quetiapine, 5.8% met criteria for tardive dyskinesia during 1 year of treatment. In another prospective study of DRBA-related adverse events in a DRBA-naïve cohort of 190 children and adolescents which included 29% having psychotic symptoms, systematic evaluation for adverse events was performed over a one-year period. The most commonly prescribed agents were risperidone (50%) and aripiprazole (36%), and polypharmacy was relatively common. Among 108 children completing follow-up at 12 months, the overall proportion at 1 year with any type of neurological side effect (including headache) was 51%. Unfortunately, there was not a straightforward estimate of percentages of children experiencing all DIMDs. A 12-week naturalistic treatment comparison in 342 youth treated with five different DRBAs (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) reported drug-induced parkinsonism in 15%, dyskinesia in 8.3%, akathisia in 4.8%, and discontinuation due to DIMDs in 3.3%. No patients were diagnosed with neuroleptic malignant syndrome (NMS).

Finally, case reports can highlight risks for which clinicians should be vigilant, although risk estimation is tenuous. Examples include a case of an eight-year old treated for 7 months who developed classic involuntary facial movements which started during a 7.5-month course of metoclopramide and persisted for 15 months after discontinuation ; a case of an infant treated with 5 times the recommended metoclopramide dose due to a metric mL/teaspoon prescribing error, for 7 days, followed by a 10 day taper, who displayed irritability during treatment, and developed body and tongue movements 1–2 months later, with the tongue movements persisting for at least another 9 months.

Clinical Features

As these various studies show, similar to adults, both older and newer DRBAs are prone to induce parkinsonism, dystonia, tics, tremor, oculogyric movements, orolingual and other dyskinesias, and akathisia. Tardive dyskinesia risk in childhood with the newer DRBAs is reduced but not eliminated. Symptoms may emerge at any time after treatment initiation Acute DIMDs, especially dystonia, oculogyric crises, and akathisia, are common in the first days of treatment. Akathisia may also emerge in a more subtle manor and persist undiagnosed. Chronic DIMDs occur after three or more months of treatment and may take the form of more subtle dystonia, tremor, and rigidity.

Tardive DIMD phenomenologies include dyskinesias, stereotypies, tics, dystonia, and oculogyric crises. The classic phenomenology of tardive dyskinesia is continuous stereotyped, choreoathetoid movements, complex orobuccolingual movements such as grimacing, lip smacking and puckering, and tongue protrusion or pushing it against the inside of the cheek. A question often arises of how to distinguish tardive dyskinesia from other types of involuntary movements disorder that commonly cooccur in children with autism or other complex neuropsychiatric disorders. Typically, the movements of tardive dyskinesia are continuous and cannot be suppressed with effort.

Dyskinesias of varying forms can develop in children when DRBAs are withdrawn or when dosage is reduced rapidly. This is termed the withdrawal emergent syndrome.

Pathophysiology

Much remains to be learned about the pathophysiology of DIMDs associated with dopamine receptor blocker use and how to predict and prevent them. ^, Analysis of pharmacokinetic data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study comparing risperidone, olanzapine, and ziprasidone supported a relationship between higher trough, but not peak, dopamine 2 receptor occupancy levels and risk for DIMDs.

The susceptibility to DIMDs in childhood may relate to a diathesis, or proneness to develop movement disorders prior to treatment. Genetic or epigenetic contributors to the neuropsychiatric symptoms may concurrently be risk factors for DIMDs. For example, in adults, stereotypies and other hyperkinetic movement disorders have been reported in young adults with schizophrenia for decades, prior to the availability of DRBAs. ^, Similarly, some general risk factors for tardive dyskinesia in adults, including older age, female sex, and being overweight, may also have biological relationships with risk factors for other psychiatric disorders. Interestingly, despite the not uncommon practice of treating severe tics with DRBAs, there are few reports of tardive dyskinesia in young adults with Tourette syndrome. Clinically, autism is more similar to schizophrenia, and in both disorders, DIMDs are seen quite commonly with DRBAs. The biological basis for apparent differences in susceptibility is unknown.

The pathophysiology of the risk for DIMDs may have an identifiable genetic component, although at this time most research in adults identifying genetic predispositions has been difficult to confirm and is not clinically actionable. ^, Commonly investigated candidates are genes for dopamine and other neurotransmitter receptors as well as drug-metabolizing enzymes. A comprehensive discussion of the genetic and environmental risk factors for tardive dyskinesia lies outside the scope of this chapter and; moreover, the most rigorous epidemiological and mechanistic research focuses on adults with schizophrenia. A study of over 600 Europeans with schizophrenia found no evidence that dopamine D2 receptor polymorphisms influence risk for DIMDs, whereas in other European cohorts evidence has been more supportive. Studies of other dopamine receptors have yielded similarly mixed results. Similarly, the data regarding risks related to poor- or intermediate- cytochrome P450 CYP2D6 metabolizer status has also been mixed. ^,

Other studies suggest that genes involved in GABAergic pathways raise the risk for tardive dyskinesia. ^, Some studies support risk related to polymorphisms in serotonergic systems. Overactivation with selective serotonin reuptake inhibitors (SSRIs) may be more common in children with ASD. Polymorphisms in genes encoding receptors 2A or 2C ^, but not 3A may increase risk for DIMDs in DRBA-treated adults with schizophrenia.

Based on views that susceptibility to oxidative stress might be important, researchers have assessed glutathione-S-transferase, glutathione peroxidase, catalase, and tumor necrosis factor alpha polymorphisms, but found no association with hyperkinetic DIMDs. On a cellular basis, mechanisms may include long-term effects on dopamine receptor density and function, damage to GABAergic striatal neurons, and damage to cholinergic interneurons. Genome-wide association studies may identify unsuspected pathways as well. ^,

Another line of research has investigated relationships between tardive dyskinesia risk and noncoding RNA—single nucleotide polymorphisms variants in microRNAs (miRNAs). MiRNA downregulates gene expression in brain and other organs through binding to their 3′ untranslated regions. In a case–control study of 1000 patients from Northern India with schizophrenia evaluating 33 candidate SNPs identified associations with MiRNA binding five genes, the strongest of which was SCN1A .

Diagnosis

Diagnosis of an acute DIMD is usually straightforward, when the DRBA has been prescribed for a routine indication during the appropriate antecedent timeframe and the phenomenology is characteristic. In the case of accidental ingestion, the acute onset of a hyperkinetic or dystonic disorder in a toddler should raise the diagnostic possibility of ingestion of a DRBA.

Diagnosis of a chronic or tardive DIMD in children should be considered based on the phenomenology and time course of the movement disorder. This diagnosis can be more challenging than acute DIMDs. Often, at the time of the first neurologic consultation, the baseline, pretreatment neurological examination by the primary physician or prescribing psychiatrist is not well documented. The diagnosis of tardive syndrome should be suspected when hypokinetic or hyperkinetic movement disorder emerges after at least 3 months of exposure to DRBAs. Tardive syndrome is an umbrella term used to describe a variety of DIMDs differentiated by their unique and predominant phenomenology. ^, Thus tardive dyskinesia is typically manifested by orofacial-lingual stereotypies that resemble a chewing movement. This is phenomenologically distinct from complex motor stereotypies in children (See Chapter 8 ).

Retrocollis and opisthotonic posturing are the classic manifestations of tardive dystonia, but cranial (e.g., blepharospasm) and oromandibular dystonia may be also present. This is more common in males. Features that tend to distinguish this from primary dystonia include older age, association with other hyperkinetic movements, and lack of alleviating maneuvers such as sensory tricks.

In tardive tourettism, the patient exhibits motor and/or phonic tics and other features of Tourette syndrome. Tic disorders usually begin prior to the age of 10 years, so in the setting of chronic neuroleptic use, new tics after that age of 10 years may raise suspicion. However, in established tic disorders, this can be more challenging as new tics continue to emerge in adolescence. Moreover, functional tic-like movements may also appear in adolescence. ^, These factors can make judging whether tics are emerging as DIMDs challenging.

Other tardive syndromes may present with akathisia, tremor, or myoclonus. Tardive akathisia refers to motor and sensory restlessness with an urge to move and inability to remain still. ^, Tardive pain, particularly involving mouth, tongue, and the genital region may be also a manifestation of tardive syndrome. When a new movement disorder occurs at the time of medication tapering or discontinuation, withdrawal emergent syndrome should be considered as a possibility. However, if symptoms are mild, then the differential diagnosis includes hyperkinetic movements that may have been masked during treatment with the DRBA. Resuming the prior medication and dose and reducing the medication dose at a slower rate can help clarify the diagnosis.

Ethical and Legal Considerations

There are ethical and legal considerations involved in iatrogenic disorders that are important to consider, although they are not unique to iatrogenic movement disorders or to DRBAs. Thus, topics described here can be applied to other classes of prescribed medications. A brief overview is placed here based on a relatively higher prevalence of DIMDs among children where DRBAs are prescribed, and due to concerns about permanent tardive movement disorders.

DIMDs, like other iatrogenic conditions, are a sensitive topic given the bioethical principle of nonmaleficence as well as concerns about litigation and liability. In the case of medications used for psychiatric diagnoses, this can seem especially morally fraught, as the diagnoses and symptoms are based on subjective ratings of multiple observers. It is important for clinicians to be vigilant, but humble, and to revisit the rationale for the prescribing decision as well as the broader social and scientific context relating to these classes of medications.

Decisions to prescribe psychiatric medications to children and adolescents involve some special challenges but also some considerations shared with other types of prescribing decisions. First, much prescribing of medication for central nervous system diagnoses is, necessarily, “off-label” (done outside the realm of US FDA-approved indications). Second, and related to the first point, the availability of high-quality, statistically robust clinical trial data for making clinical decisions for children is limited. This results from complex factors including the challenges to both validity and generalizability of clinical trial results arising from ill-defined symptom-based DSM5 categorical diagnoses, inconvenience or impracticality resulting in low incentives for families to participate in intensive clinical trials, understandable parental fears about both active investigational drugs and the risks of randomization to placebo, societal concerns about ethical issues of clinical trials in special populations, and economic disincentives for pharmaceutical companies due to the high risk and costs of pediatric clinical trials. Third, there are inherent risks in medical treatments of all kinds, and psychiatric disorders are no different. Prescriptions of DRBAs are ideally provided after considering the very significant risk to the child and family of not treating. Fourth, in many cases, even with better knowledge of iatrogenic risks than we have now, the substantial impact of psychiatric illnesses means that the benefit/risk ratio often still would favor treatment. Fifth, while medication use in pediatric psychiatric disorders should be part of a comprehensive treatment plan that includes appropriate behavioral therapies, the reality is that access to comprehensive behavioral health care for many families is limited by costs, insurance coverage, and access to providers with appropriate pediatric training.

In addition to worrying about their child, caregivers in this setting may have other emotions such as guilt or anger. It is helpful for the clinician to review with caregivers the factors above, when applicable, as elements of reasonable medical decisions. This may reduce caregiver guilt and/or blaming of the initial prescriber. In the end, it is most often the case that the neurologist will want to collaborate with a psychiatrist in management of the patient until the DIMD resolves.