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Long lasting choreiform dyskinesia
after spinal anesthesia and ondansetron.

- A case report and review of the literature -

Yen-Mie Lai, M.D.1,2 ; Martijn Mertens, M.D., Ph.D.2 ; Casper van der Hoeven, M.D.2 ; Stephan A. Loer, M.D., Ph.D.1 ; Lothar A. Schwarte, M.D., Ph.D.1

Affiliations:
1 Dept. of Anesthesiology, VU university medical center, Amsterdam, The Netherlands
2 Dept. of Anesthesiology, Spaarne Hospital, Hoofddorp, The Netherlands

Introduction

Involuntary leg movements are a known side effect during recovery from spinal anesthesia1,2. Additionally, several drugs routinely used in the per-operative period are also reported to occasionally induce involuntary leg movements. Here we report the youngest patient so far, presenting the extremely rare complication of a long-persisting choreiform dyskinesia (≥1 week), starting during recovery from spinal anesthesia and administration of ondansetron.

The Case

A 13-year old athletic girl, 177 cm, 58 kg, BMI 18.5, ASA-1, presented for elective arthroscopy of the right knee. She had an empty medical history, e.g., no reports of allergies or other adverse drug reactions. Occasionally she took acetaminophen (paracetamol) for pain treatment.
Spinal anesthesia was performed uneventfully with a 25-gauge Whitacre needle via the L3/L4 interspace, yielding freely dripping clear liquor. Spinal anesthesia was then induced with 60 mg hyperbaric articaine (5%). Prior to actual surgery 1.5 mg midazolam (Dormicum®, Roche, Basel, Switzerland) i.v. was administered for sedation upon patient’s request. Apart from moderate vasoactive support (ephedrine, 3x 5 mg) to maintain systolic blood pressure > 100 mmHg, the intra-operative course was uneventful. Total duration of surgery was 15 minutes.
Thereafter, the patient was transferred to the recovery room. For treatment of nausea 4 mg ondansetron (Zofran®, GlaxoSmithKline, London, Great Britain) was administered intravenously. About 10 min later the patient experienced involuntary movements (rhythmic, convulsion-like muscle contractions) starting in both legs. The movement progressed from the legs to the abdominal muscles and subsequently to the upper limbs. These involuntary movements were best characterized as choreiform dyskinesia. There was no involvement of the cervical, lingual or ocular muscles. The patients remained conscious and communicated adequately. However, the patient became anxious and concomitantly the heart rate increased to 120/min (from 60/min pre-operatively). Pulseoxymetric SpO2 decreased to 92% (from 99% pre-operatively) and therefore supplemental oxygen was administered (FiO2 0.4, via facemask). The leg movements further intensified as the spinal block receded. To treat the involuntary movements and anxiety, additional 2 mg midazolam were injected. Hereon the movements weakened but did not disappear. A subsequent injection of 1 mg clonazepam (Rivotril®, Roche, Basel, Switzerland) abolished the movements, however, returning after about 2 min. Both a hospital pharmacist and neurologist were consulted. After searching a pharmacological database, the pharmacist classified this episode as very rare side-effect of ondansetron. The neurologist found, except for the choreiform dyskinesia, no abnormalities during thorough neurological examination. As advised by the neurologist 25 mg promethazine (hospital pharmacy prepared) was administered intravenously. Subsequently, the involuntary movements diminished within minutes. For further observation the patient was admitted at the intensive care unit (ICU). After absence of these involuntary movements for several hours, the patient was transferred to the paediatric ward.
On the 2nd postoperative day the patient reported severe muscle pain attributable to the multifocal dyskinetic muscle contraction during the choreatic attacks. To exclude an atypical epilepsy, an electroencephalogram was performed on the 3rd postoperative day, demonstrating no abnormalities. To maintain the anti-choreatic therapy, 2 mg biperidene per os (Akineton®, Abbott, Illinois, USA) was administered twice a day. Still from the 4th to the 6th postoperative day the patient had involuntary twitches in both legs. With remission of the twitches, biperidene was phased out and finally stopped. The patient was finally discharged from hospital on the 10th postoperative day in complete absence of choreiform dyskinesia. Telephone interviews 8 and 12 months later revealed that no more episodes of dyskinesia had occurred after hospital discharge.

Discussion

We report the youngest patient so far developing the extremely rare complication of long lasting (≥1 week) acute choreatic dyskinesia following spinal anesthesia and/or administration of a single dose ondansetron.
For the agents used intra-operatively in the present case (i.e., articaine, midazolam and ephedrine), no reports of chorea-like adverse reactions have been published yet. However, single cases of similar reactions have been reported after other types of spinal anesthesia1-8 and also similar reactions occur very rarely after administration of ondansetron, which was postoperatively given in the present case. Other drugs and medical conditions, reported to induce chorea-like symptoms, are compiled in Table 2.
During recovery from spinal anesthesia, harmless involuntary leg movements occur regularly, however mostly unrecognized. Högl et al.1 report an incidence of ~9% developing transitory restless leg movements after spinal anesthesia. Herein, Watanabe et al.2 suggest that spinal anesthesia preferentially blocks inhibitory spinal neurons, enabling an unopposed excitation of spinal interneurons, a concept supported by Tergau et al.3 and Bara-Jimenez et al.4. In addition, involuntary movements during recovery from spinal anesthesia may occur after transient spinal chord hypoperfusion due to spinal anesthesia induced hypotension. Herein, the caudal spinal chord appears more sensitive, with motor neurons being more vulnerable than sensory neurons of the same spinal level.5,6 In addition, hypotension following spinal anesthesia may also induce basal ganglia dysfunction and lead to hemi-chorea, as suggested by Itoh et al.8
Furthermore the pathophysiology could also involve dopaminergic and possibly opoidergic mechanisms.7
Besides these direct (local anesthetic) and indirect (hypotension) possible contributions of spinal anesthesia to the observed choreatic attacks, also the postoperative administration of ondansetron could contribute. Although postoperative nausea and vomiting (PONV) is more frequent after general anesthesia with incidences between 25-30%9,10, it may also occur and demand therapy after spinal anesthesia, as in the present case with incidences up to 20%.11 Ondansetron is the first choice drug in the treatment of PONV, with greater efficacy and favourable side-effect profile compared with other antiemetics, e.g., metoclopramide.12,13 Ondansetron acts as 5-HT3 receptor antagonist, with little direct effects on dopamine receptors. 5-HT3 receptors are located both peripherally and centrally (e.g., chemoreceptor trigger zone of the area postrema; nucleus tractus solitarius) and are crucial within the vomiting reflex. Although the central mechanisms of ondansetron are complex, blockade of central 5-HT3 receptors and of dopaminergic transmission within the nucleus accumbens appear crucial.14 Extra-pyramidal reactions to ondansetron are extremely rare.15,16,17 Moreover, in the few cases reported, ondansetron was usually dosed markedly higher than in our case. Only four reports describe extra-pyramidal reactions after per-operative application of ondansetron.18,19,20,21 Tolan et al.20 suggest an interaction of ondansetron with dopamine D2-receptors, explaining the extrapyramidal reactions. Herein, serotonergic innervations of the basal ganglia (and the limbic system) modulate the central D2-receptor motor inhibitory activities. In line, pathophysiology of chorea likely involves basal ganglia dysfunction with reduction of impulses to the sub-thalamic nucleus.
Duncan et al.21 describes an obstetric patient with severe chorea following administration of ondansetron, the movements lasted for five days postoperative. This last case-report is one which has similarities with our case. In line with our case, all patients reported so far are women. It has been reported that dopamine hypersensitivity occurs due to post-synaptic modifications in elevated oestrogen states.22
This case report stresses, that even in ASA-1 patients a lege artis performed procedure for a minimal surgical procedure (here: 15 min arthroscopy) may still result in significant medical and economic sequels (ambulatory scheduled procedure, resulting in 10 days hospital admission, including temporary ICU-utilization).
In conclusion, we report the youngest patient so far developing severe and long-lasting (≥1 week) choreiform dyskinesia after spinal anesthesia and/or administration of a single dose of ondansetron. Herein, spinal anesthesia may contribute both directly and indirectly, e.g., by inducing transient hypotension and thus spinal cord or cerebral hypoperfusion. Alternatively, ondansetron is another, rare trigger of this adverse effect. Whether the choreatic dyskinesia in the present case was induced by spinal anesthesia or ondansetron (or both) remains speculative. We would like to reaffirm that this complication exists, and that it should be differentiated from similar clinical appearances, such as epileptic convulsion. This may improve patient care, e.g., by preventing repeat doses of possible triggers such as ondansetron in affected patients. Finally, drugs to control choreatic dyskinesia should be known and readily available.

Acknowledgements to:

Christa Boer Ph.D., Assistant Professor Anesthesiology, VU University medical center, Amsterdam, The Netherlands, for their advice and suggestions in the process.

References

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First Published September 2010.

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