Delayed-Onset Acute Chorea Following Anesthesia

Sudden-onset chorea and other hyperkinesias in childhood can compromise respiratory and autonomic stability and therefore require close monitoring—often at an intensive care level; when severe, they are managed within the status choreicus/dystonicus spectrum.^1,2 In school-age children, Sydenham chorea remains an important acquired cause; as such, anti–streptolysin O (ASO) / anti-DNase B testing and echocardiography to screen for carditis represent rational first-line evaluations. ³ In contrast, the most frequent behavioral issue in the immediate postoperative period is emergence agitation, with sevoflurane increasing risk; however, this typically occurs early after anesthesia and does not explain a 24-36-hour delayed onset. ⁴ Delayed-onset, antipsychotic-refractory chorea are uncommon and are often attributed to interactions between anesthetic/analgesic agents and individual susceptibility; in such hyperkinetic emergencies, benzodiazepine infusions can be an effective, well-tolerated option when antipsychotics fail.^1,5,6

Case

An otherwise healthy 11-year-old girl underwent orthopedic surgery for an ankle fracture under general anesthesia. Perioperative agents included propofol (induction/maintenance), fentanyl (analgesia), rocuronium (neuromuscular block), midazolam (premedication/sedation), cefazolin (infection prophylaxis), paracetamol (analgesia), tramadol (analgesia), and sugammadex (reversal). Twenty-four to 36 hours after surgery, she developed severe continuous chorea, accompanied by insomnia, screaming, and hallucinations. On presentation, she was unable to feed, attempts at nasogastric feeding were unsuccessful because she repeatedly removed the tube during agitation, and 2-3 caregivers were required to assist with toileting (Video S1). In the orofacial region, intermittent, involuntary, purposeless, flowing choreic movements were observed involving the facial musculature, perioral area, and jaw; lingual/intraoral components occurred intermittently. The cervical region was nearly continuously active, with sustained choreic bursts whose direction and amplitude varied over time. The trunk and all 4 limbs exhibited asynchronous, arrhythmic choreiform movements of variable amplitude, without a fixed dystonic posture or a consistent tremor pattern. Ambulation attempts were unsuccessful even over short distances, owing to both the recent ankle surgery with splinting and more importantly the presence of choreiform movements in the lower limbs. As first-line symptomatic therapy for chorea, haloperidol was initiated at a low dose with a plan for gradual titration (starting at ∼0.03 mg/kg/d in divided doses every 8-12 hours, with escalation up to 0.1 mg/kg/d according to clinical response). However, within a short time it became evident that under this watch-and-wait approach the patient's condition was clinically deteriorating because of sustained sleeplessness and inadequate oral/enteral intake. To achieve rapid control of agitation and suppress chorea, a continuous intravenous midazolam infusion (0.1 mg/kg/h) was commenced, behavioral outbursts abated by approximately 12 hours after initiation of midazolam therapy, whereas the concomitant chorea improved more gradually and had completely resolved by ∼48 hours of the infusion. Thereafter, to enable safe discharge without intravascular access, the haloperidol dose was titrated to a clinically effective level, whereas the midazolam infusion was gradually tapered and discontinued. Given the prominent symptom burden at admission (continuous chorea, insomnia, and risk of injury), short-term oral haloperidol was continued at discharge to mitigate early rebound; in the absence of recurrence, it was discontinued within 2 weeks (Video S2).

Diagnostics showed normal routine biochemistry, complete blood count, and urinalysis. Creatine kinase (CK) was 658 IU/L (reference: <190 IU/L). Brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) were unremarkable. Autoimmune encephalitis antibodies were negative; antinuclear antibody and anti-dsDNA (for lupus chorea) were negative. With respect to Sydenham chorea, ASO was normal and echocardiography was unremarkable. Throat culture and viral serologies were negative. Written consent was obtained from the family for case reporting and video use.

Discussion

In this patient, the 24-36-hour delayed onset, haloperidol refractoriness, and rapid response to midazolam infusion place the phenotype within the status choreicus/dystonicus spectrum.^1,6 The term “status choreicus” is used to denote an emergency with persistent/severe chorea-ballismus, yet unlike status dystonicus there are no universally agreed numerical criteria. Nevertheless, the combination of inability to sleep or feed, unremitting movements, requirement for multiperson assistance with basic needs, and trauma risk due to falls/collisions, together with nonresponse to first-line symptomatic therapy and clinical deterioration approaching an intensive care unit threshold (autonomic instability, hyperthermia, CK elevation/rhabdomyolysis risk), supports prompt labeling and management as “status choreicus” in practice.^1,6

The peri-anesthetic presentation is plausibly explained by convergent effects of several agents. Midazolam can trigger paradoxical reactions in children (agitation, screaming, hallucinations), whereas in emergencies a continuous infusion may suppress hyperkinesia; vulnerability varies with age and dose.^7,8 In children, paradoxical agitation/hallucinations have most often been described within minutes of intravenous bolus midazolam administration. ⁷ By contrast, in movement disorder emergencies, titrated continuous infusion has enabled clinical control by providing stable sedation and suppression of hyperkinesia.^1,9 The agitation and hallucinations that we attributed to a midazolam bolus may, by analogy with dystonia, be explained by excessive stimulation of dopaminergic receptors in striatal neurons, as highlighted in the literature. ¹⁰ This framework may likewise offer a biologically plausible mechanism for the behavioral manifestations observed in our case.

In our case, the infusion achieved rapid control of agitation in the acute phase, whereas complete resolution of chorea required approximately 48 hours. Tramadol increases neuro-excitability via serotonergic/noradrenergic reuptake inhibition; importantly, CYP2D6 polymorphisms, especially the ultrarapid metabolizer phenotype, raise levels of the active metabolite O-desmethyltramadol, thereby increasing the pediatric risk of agitation, myoclonic/seizure-like events, and serious adverse outcomes; thus, tramadol-free multimodal analgesia is rational in susceptible phenotypes.^5,11 Although propofol is generally safe, seizurelike phenomena and hyperkinetic/dystonic presentations are repeatedly reported, fitting a model of GABAergic network perturbation at the basal-ganglia output level.^12–14

In a 2002 systematic review of propofol-related seizurelike phenomena, 11 of 70 patients exhibited hyperkinetic/involuntary movement phenotypes; events clustered during induction (34%) and emergence (40%), with delayed presentations also reported, supporting the possibility of late-onset hyperkinesia after propofol. ¹³ Moreover, a recent case report described a functional movement disorder comprising ataxia, dysarthria, chorea, and tremors following propofol exposure, with avoidance of propofol preventing recurrence during subsequent anesthetics underscoring a triggering role in susceptible individuals. ¹⁵ Movement disorders reported in children after general anesthesia are not confined to a single phenotype. Budde et al ¹⁶ described a 10-year-old girl who underwent outpatient foot/orthopedic surgery and, approximately 2.5 hours after emergence, developed sleep onset–triggered rhythmic movements that ceased with arousal and resolved spontaneously over several days, a case suggesting that delayed motor phenomena can occur in children in the post-anesthetic period, yet are often self-limited. In addition, systematic reviews indicate that tramadol can precipitate visual and auditory hallucinations. ¹⁷ Taken together, these data imply that propofol may exacerbate hyperkinesias, whereas tramadol may amplify agitation, hallucinations, and hyperexcitability; accordingly, co-exposure in a susceptible child could plausibly increase symptom severity.

Our case departs from the sequence reported in most published pediatric cases, namely, movement disorder first, behavioral phenomena second. In our patient, agitation and hallucinations began at approximately 24 hours, whereas choreiform movements emerged around 36 hours. This inversion of timing suggests that, in the post-anesthetic setting, distinct network conduction mechanisms (GABAergic/basal-ganglia circuits) may be engaged sequentially but differentially, and that with propofol and tramadol co-exposure the timing and intensity of symptom clusters may be heterogeneous.^4,11,16 Mechanistically, classic primate work showed that microinjection of the GABA_A antagonist bicuculline into the lentiform complex produced contralateral chorea and myoclonus, implicating pallido-thalamo-cortical disinhibition, a biologically plausible scaffold for our patient's delayed, antipsychotic refractory hyperkinesia. ¹⁸ Finally, sevoflurane-related emergence agitation typically occurs in the early postoperative window and would not alone account for a 24-36-hour delay. ⁴

By contrast, a clinical relationship between rocuronium-sugammadex, paracetamol, or a single prophylactic dose of cefazolin and chorea would not be expected. The possibility of midazolam paradoxical reaction supports minimizing premedication or considering dexmedetomidine alternatives in children with prior paradoxical responses.^6,7

In the differential diagnosis, Sydenham chorea must be prioritized on the basis of age and phenotype; accordingly, ASO/anti-DNase B testing and echocardiography for carditis are appropriate. ³ In our case, these were negative, and the rapid, complete recovery makes an infectious/autoimmune etiology unlikely. Autoimmune encephalitis is also not supported given normal MRI/CSF, electroencephalogram normal, negative antibodies, and rapid resolution. ¹⁹ The index procedure did not involve cardiopulmonary bypass or any maneuver likely to cause perioperative hypoxia/asphyxia; thus, a post-pump–like mechanism is unlikely. Throughout the perioperative period and hospitalization, arterial blood pressure remained within the normotensive range, arguing against hypertensive encephalopathy as a contributor. Although initial MRI and CSF are reasonable at first presentation, in similar cases featuring a strong anesthesia time link and dramatic response to benzodiazepine infusion, a stepwise, cost-conscious strategy at relapse is preferable.^1,5,6

Conclusion

Given the potential of the propofol-tramadol combination to potentiate hyperkinetic responses within basal ganglia networks, caution is warranted with coadministration, and avoidance is advisable when feasible. In this case of delayed-onset, haloperidol-refractory acute chorea after orthopedic surgery, a continuous midazolam infusion achieved rapid and sustained control. Agent-level appraisal supports contributions from tramadol and possibly propofol to the movement-disorder component, and a paradoxical midazolam effect to the behavioral component. For this patient at future anesthetics, we will plan tramadol-free multimodal analgesia, minimal or alternative premedication, and anesthetic strategies with a lower risk of emergence agitation; more broadly, a similar approach may be reasonably adopted in comparable cases, with avoidance of propofol with tramadol co-use considered.

Limitations

Although perioperative agents are listed in detail, minute-by-minute intraoperative dose and timing data are not available, which limits a high-resolution analysis of time-effect relationships. In addition, CYP2D6 phenotyping/genotyping and tramadol/O-desmethyltramadol serum levels were not obtained; similarly, no drug-level monitoring was performed for midazolam or propofol. These gaps constrain our ability to clarify individual susceptibility to tramadol (eg, ultrarapid metabolizer phenotype) and to delineate agent-specific contributions. The concomitant use of multiple perianesthetic agents further limits attribution of causality to any single drug, and because no re-challenge was undertaken and agent-specific triggerability cannot be proven. Finally, with respect to discharge strategy, a benzodiazepine taper would have been a reasonable alternative, whereas we elected short-term oral haloperidol maintenance given the high presenting symptom burden and concern for early relapse.

Supplemental Material

Supplemental Material