Common, Predictable, Rarely Serious
extrapyramidal side effects refers to untoward neurological manifestations of neuroleptic treatment (other nonneuroleptic medications may also elicit these symptoms). extrapyramidal side effects includes a constellation of symptoms such as tremor (Parkinsonian tremor), dystonias (acute dystonias, athetosis, muscular rigidity, gait disturbance, and others), oculogyric crisis, and akathisia. Sialorrhea frequently accompanies other extrapyramidal side effects symptoms. These symptoms maybe acute or chronic. Acute symptoms are commonly distressing, dramatic, and even painful, but rarely serious, except for the picture of laryngeal spasm that constitutes a true medical emergency, and the worrisome neuroleptic malignant syndrome (see below); in general, acute symptoms resolve promptly with appropriate treatment. Chronic symptoms (tardive dyskinesia, tardive akathisia, tardive Tourette’s, and others) maybe incapacitating and socially stigmatizing; these conditions are less responsive to treatment than acute symptoms.
Stimulant medications induce extrapyramidal side effects symptoms occasionally; in general, the extrapyramidal side effects-stimulant related symptoms are most commonly orobuccal dyskinesia (OBD). Symptoms are worst at the peak of the medication blood level; symptoms start waning as the blood levels decrease. When the symptoms are due to stimulant alone, children are symptomless in early morning before receiving the stimulant medication and after the medication wanes.
When patients receive stimulants and antipsychotics, concomitantly, diagnosis of the extrapyramidal side effects is more complex. Children with a history of neurological damage or those who had developed prior extrapyramidal side effects reactions to antipsychotics are vulnerable to the extrapyramidal side effects side effect from neuroleptics. Even for those patients with low extrapyramidal side effects potential, stimulants and related medications (like atomaxetine, see below), may induce involuntary movements. Sometimes, a medication that by itself does not produce extrapyramidal side effects may unleash this side effect when it interacts with other medications.
Atypical antipsychotics differ in the potential for eliciting neurological side effects. Risperidone is the closest to a typical antipsychotic in this regard, and as such, it is not uncommon for risperidone to induce acute dyskinesias and other extrapyramidal side effects symptoms. It is difficult to say if the other second generation antipsychotic are more benign than resperidone in this regard. Risperidone is somewhat unpredictable in this regard. For children and adolescents on risperidone, as the dose ascends over 3 to 4 mg/day there is a linear increase in the risks of dyskinesia. Children and adolescents are more susceptible to extrapyramidal side effects adverse event than adults (see above). All the atypical antipsychotics (including, although rarely, clozapine) produce extrapyramidal side effects adverse event in children and adolescents. In the CATIE I report there was no difference in extrapyramidal side effects rates among the studied antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, and perphenazine).
Dyskinesias do not always present with bilateral, symmetrical signs; occasionally, dyskinesias are more prominent on one side of the body or limited to only a sector of the body, such as a part of the face; this is also true for cogwheeling. Children may also display isolated, episodic, oculogyric crises, which create diagnostic confusion, mainly, considerations of a seizure disorder.
The complexities of diagnosing a neuroleptic related movement disorder is exemplified in the following vignette:
A 9-year-old white girl was referred for psychiatric evaluation by a child psychiatrist, for increased aggression and irritability. She had displayed extreme temper tantrums at home and school. The family was concerned with the child’s frequent “meltdowns,” lasting for up two hours. She was described as being mean to her siblings, irritable, and displayed “mood swings” and poor anger control.
The child had a prior acute psychiatric hospitalization at age 7, for six days, after she attempted to jump from a second floor window. The family reported that she had received the diagnosis of Asperger’s by a developmental pediatrician. Two years before, a psychological testing indicated the presence of a thought disorder; psychometric testing showed a VIQ: 84, PIQ: 83, and a FSIQ: 83.
The child had been under the care of her maternal grandmother since 7 months of age. Her biological mother was psychiatrically incapacitated, and the biological father was described as a violent man who suffered from drug abuse. Even though the natural mother was around, the patient was not attached to her; she was bonded preferentially to her grandmother, whom she considered the most important person in her life.
There was no history of developmental delays but there had been difficulties with learning in areas of math, reading, and comprehension. The family denied a history of seizures, head trauma, fractures, or surgeries. The child had been sexually molested at age 6 by a babysitter’s uncle who killed himself after he was accused of sexual perpetration. She had received treatment with sertraline, risperidone (up to 8 mg); she had also been tried on Adderall but this product activated her. At the time of the assessment the child had been receiving quetiapine 50 mg at bedtime.
Mental status examination: the child was small for her age and had difficulties warming up to the examiner; she was not spontaneous but she was cooperative and forthright in her answers. Her affect was constricted but appropriate. She endorsed paranoid ideation, feeling that people talked about her, watched her, and followed her. She denied any other perceptual disturbances as well as suicidal or homicidal ideation.
Neurological evaluation: she was fully oriented to day, date, month, and year. She had solid right and left orientation and performed contralateral limb commands without difficulties. There were no cerebellar signs or difficulties with finger sequencing. Fundoscopy was unremarkable. Right planter response: toes fanned up, except for the big toe; the left plantar response was flexor.
During the examination, she displayed intermittent rolling of the eyes up and to the right. There was mild cogwheeling at the neck and elbows. There was no tremor, no choreathetosis. The diagnosis of an unusual extrapyramidal side effects reaction was made.
Because the neurological features were unusual and an immediate neurological consultation was requested. The consultant neurologist reported presence of ocular dystonia. He also performed an EEG and found bilateral spiking, imaging was ordered. The MRf was unremarkable.
This patient had an uncommon form of extrapyramidal side effects, to a neuroleptic rarely causing this reaction. It is likely the patient had been sensitized to extrapyramidal side effects by her exposure to large doses of risperidone. The patient also had complex partial seizures.
Although, the most common cause of oculogyric crisis is neuroleptic medication or other antidopaminergic treatment, carbamazepine, lithium, and pentazocine have also been reported to evoke this side effect. A very bothersome and deceptive side effect is akathisia. Usually the patient or the patients parents complain that the child is restless, hyperactive, and uneasy, or that the child displays agitation, dysphoria, inability to sit still, insomnia, and the like. These symptoms may be misjudged to be psychotic agitation or uncontrolled mania, resulting in treatments that are inappropriate or that aggravate the condition (i.e., when the psychiatrist increases the anti-psychotic dose). Homicidal and suicidal behavior, severe impulsive behaviors, and sudden attempts to run away have been reported. Akathisia promotes medication noncompliance. For an overview of treatment of akathisi. Haan, Lavalaye, Booiij, et al. (2005) report that negative subjective experiences (akathisia) are related to D2 receptor occupancy by antipsychotics and that monitoring for feelings of comfort, self-confidence, and safety may guide clinicians and researchers in finding the optimal D2 occupancy. All 38 items of the Subjective Well-Being Under Neuroleptic scale were negatively correlated with D2 receptor occupancy as measured in SPECT imaging studies.
Drug induced Parkinsonism is another extrapyramidal side effects adverse event that occurs during the initiation of antipsychotics. In Parkinsonism, patients may look medicated. Negative symptoms related to a psychotic illness or depressive features related to a mood disorder are part of the differential diagnosis of antipsychotic-related Parkinsonism. Perioral tremor (rabbit syndrome) is an uncommon late form of extrapyramidal side effects. extrapyramidal side effects side effects are mainly due to the high affinity of atypicals for the D2 receptor. It is also likely that for the same reason, risperidone is associated with increased incidence of tardive dyskinesia and other tardive disorders (tardive akathisia, tardive dystonia, and even tardive Tourette’s). extrapyramidal side effects, in children and adolescents, has also been observed with ziprasidone and aripripazole, and to a less extent with olanzapine. Quetiapine rarely induces extrapyramidal side effects, but quetiapine-related Tourette’s disorder has been reported.
It is important to remember that stimulants and other psychotropic medications (i.e., SSRIs, and others) may either cause involuntary movement disorders by themselves or may aggravate preexistent or coexistent movement disorders. The author witnessed an acute orofacial dyskinesia after the smallest extended long-released methylphenidate 10 mg, on a 5-year-old girl. This case is similar to the 6-year-old girl who developed oraofacial dyskinesia after taking the first dose of methylphenidate (a 10 mg tablet). Facial contortions persisted the following day after the patient received only 5 mg. The movements were predominant in the lower face, mostly around the mouth including chewing and puckering movements, writhing, and slight protrusion of the tongue. The patient also made soft clucking sounds. The episodes occurred 30 minutes after the ingestion of 5 mg of methylphenidate and lasted for five hours. Orobuccal dyskinesias (OBD) need to be differentiated from oral apraxias; in the latter, there are no spontaneous involuntary movements, but the child labors with the production of speech, often making gestures as he or she makes efforts to articulate, resembling OBD.
Connor (1998) mentions that withdrawal dyskinesia may not improve until the stimulants are discontinued. “Continued stimulant treatment in the face of neuroleptic withdrawal may initiate, exacerbate, or prolong the duration of the neuroleptic withdrawal dyskinesia in certain children. Children with preexisting basal ganglia pathology maybe particularly vulnerable to this possible neuroleptic withdrawal-stimulant interaction”. Surprisingly, there are not too many reports on stimulants. A case of orofacial dyskinesia after a peak dose of methylphenidate (5 mg) was reported in another 6-year-old girl. It is not uncommon for children who receive higher doses of stimulants to display apparently involuntary movements including perioral and tongue movements simulating neuroleptic side effects (extrapyramidal side effects). On the other hand, extrapyramidal side effects-like movements are also described after stimulants are withdrawn.
Many cases of adverse side effects of SSRIs — extrapyramidal side effects — have been described. Pies (1997) wrote an editorial on the subject: “Must We Consider SSRIs Neuro-leptics?” Fluoxetine is the biggest offender in the literature on adults, and acute dystonia is the most common extrapyramidal side effects symptom reported. The authors reported on a 15-year-old female who developed torticollis, bradykinesia, and cogwheel rigidity on fluoxetine . Akathisia is a commonly reported extrapyramidal side effects reaction with SSRIs treatment. Other extrapyramidal side effects symptoms, such as oculogyric crisis, sustained upward eye gaze, and other extrapyramidal side effects symptoms have also been reported. It is well established that children with neurodevelopmental problems, including mental retardation, have increased vulnerability for the development of extrapyramidal side effects.