The Case

A 5-year-old boy with a history of transverse myelitis with resultant spasticity of both lower extremities, gait abnormalities, neurogenic bladder, and neurogenic bowel presented to the rehabilitation medicine clinic for scheduled botulinum toxin (Botox) injections to his legs. He had been receiving Botox injections approximately every 3 months to his bilateral hamstrings, hip adductors, and gastrocnemius. Due to the patient's age and parent preference, he was given a dose of midazolam for sedation in the office prior to his injections.

The attending physician, fellow, and nurse went in the room to perform the injections. A time out was completed and the patient information, procedure, and sites were verified. About halfway through the 12 injections (2 to each muscle group on each side), the patient's mother said, "Wow, he is responding much better to the injections and sedating medications this time than he did 3 weeks ago." The attending and fellow were confused, as it had been 3 months since his last injections in the rehabilitation medicine clinic. Upon further questioning, the mother clarified that the clinicians in the urology clinic had had Botox injected 3 weeks earlier for management of the patient's neurogenic bladder. The scheduled injections were completed, followed by a long discussion held with the mother about the risk of antibody formation and decreased efficacy from too-frequent injections.

Despite the concerns, the patient had no adverse effects and experienced good results from the injections. However, after the procedure, the attending and fellow reviewed the electronic medical record (EMR) in an effort to understand how this error occurred. They realized that many specialties have begun to use Botox, and each one documented its use differently in the EMR. Whereas the rehabilitation medicine clinic entered a formal procedure note for each treatment, the urology clinic simply documented its injections in progress notes. Procedure notes appeared in a different area of the EMR and were not readily visible to clinicians accustomed to reviewing progress notes or test results.

Based on this review, clinic intake procedures were changed so that nurses now always ask about prior or recent Botox injections. In addition, the hospital's IT department created a clinical alert within the EMR that clearly states when the last order of Botox was given when a provider attempts to order Botox.

The Commentary

by Krishnan Padmakumari Sivaraman Nair, DM

Since its introduction in 1970s as a treatment for strabismus, the indications for use of botulinum neurotoxin continue to expand.(1) Currently there are at least four types of botulinum toxins licensed for therapeutic use in most countries. They are onabotulinum toxin A (Botox), abobotulinum toxin A (Dysport), incobotulinum toxin A (Xeomin), and rimabotulium toxin B (Myobloc/Neurobloc).(1) Even though the doses for all products are expressed as units of biological activity, the units of different toxins are not interchangeable. This case highlights the risks posed by the use of botulinum neurotoxin by different specialists for a range of indications; several of which are unlicensed (Table).

When injected into skeletal muscle, smooth muscle, or exocrine gland, botulinum neurotoxin selectively blocks the release of acetylcholine at the nerve endings. Therapeutic effects are realized in 7 to 10 days, peak in 4 to 6 weeks, and diminish by 12 weeks. If needed, one injection should be planned every 12 weeks.(2) Botulinum neurotoxin injections are generally well tolerated. Adverse events include dry mouth, injection site pain, focal muscle weakness, and fever. Rarely, the toxin can cause transient dysphagia, even requiring nasogastric feeding. Patients should receive counseling regarding these adverse events, and they should be instructed to seek medical help in case of signs and symptoms of toxin spread.(2)

Iatrogenic botulism and development of antibotulinum toxin antibodies are two potential consequences of too-frequent injections of botulinum neurotoxin. Botulism is a potentially lethal neuromuscular paralysis caused by toxins of the anaerobic bacteria Clostridium botulinum. Signs of botulism include ptosis, opthalmoplegia, dysphagia, pupillary dilatation, and generalized neuromuscular weakness requiring ventilation. Reports of botulism following therapeutic use of botulinum toxin are rare. Two author groups described cases of iatrogenic botulism after injections with unlicensed high-strength preparations of botulinum toxin.(3,4) Two separate cases of iatrogenic botulism in children following injections of higher than the recommended dose of botulinum toxin for treatment of spasticity also were reported.(5,6) Administration of botulinum toxin by different specialists may result in unwittingly exceeding the safe limit of the botulinum neurotoxin, causing iatrogenic botulism.

As with any foreign protein, the human body produces antibodies to botulinum neurotoxin. The immune response varies with the dose, frequency of administration, and type of the toxin used.(7) In typical clinical settings, doses up to 300 units of BOTOX (Allergan) or equivalent of the toxin are injected at intervals of no less than 12 weeks.(3) This makes the development of the antibodies less likely. Injections at more frequent intervals—intentionally or unintentionally—may increase the chance of development of an immune response. The effect of the neutralizing antibodies on therapeutic response to botulinum neurotoxin is controversial, but may result in development of resistance to treatment.(8,9)

Secondary loss of clinical responses to botulinum neurotoxin injections are more likely to be due to wrong injection techniques, problems in reconstitution and storage, poor muscle selection, comorbidities, and unrealistic expectations than to development of genuine resistance.(1) Recommendations include trying another injection of the same dose and injection into a small muscle with obvious effect (such as the extensor digitorum brevis in the foot or the abductor digiti minimi in the hand) before diagnosing therapeutic resistance.(1) In patients who develop genuine antibody-mediated resistance to botulinum neurotoxin, switching to another type of the toxin may help.

Like the child in this case, patients receiving botulinum neurotoxin for spasticity often have long-term neurological conditions requiring management by multiple specialists. They often have other symptoms like neurogenic bladder and sialorrhea that may require botulinum toxin injections from different specialists. The care of patients with complex, chronic illnesses is often poorly coordinated (10), leaving patients at risk for errors. In particular, prior studies (11) have shown that information exchange between multiple specialists caring for the same patient is often poor. Children may be particularly vulnerable to adverse drug events due to the need for weight-based dosing. In this case, poor communication between specialists and a nonstandardized documentation system put the patient at risk for a clinical adverse drug event.

Organizations should take specific steps to improve medication safety for patients (especially children) with chronic illnesses. A robust mechanism of documentation and communication is essential to ensure safety of the injections. Electronic medical records (EMRs) hold promise in this area, but thus far there is no clear evidence that EMRs alone can prevent errors related to communication between providers. Standardizing how procedures and medication administration are documented is a reasonable step and should improve communication. The implementation of an alert notifying prescribing clinicians about prior botulinum toxin doses is also a reasonable step to take in response to this incident; however, this step alone may not prevent similar errors, as the safety performance of warnings in CPOE systems is mixed, and alert fatigue is a potential consequence of a proliferation of similar alerts. Information about the indication, goals, adverse effects, type, and dose of botulinum toxin injections should be clearly recorded, and patients should be educated about these potential toxicities. In this case, the interventions implemented by the clinic—a combination of standardizing documentation, a CPOE alert, and a standardized screening question during the clinic intake process—represents a robust multifaceted approach that is more likely to prevent similar errors than a single intervention alone.

Take-Home Points

• Ever expanding therapeutic indications for botulinum neurotoxin injections put patients at risk of receiving multiple frequent injections from different specialists.
• Unintentional overdosing may result in iatrogenic botulism.
• Frequent high-dose injections may cause formation of neutralizing antibodies resulting in loss of therapeutic effect.
• Proper documentation and communications between the treating teams about the botulinum neurotoxin injections are essential to mitigate this risk.

Krishnan Padmakumari Sivaraman Nair, DM Consultant Neurologist with Special Interest in Disability Management Royal Hallamshire Hospital United Kingdom

References

1. Truong D, Hallett M. Pharmacology of botulinum neurotoxins. In: Truong D, Hallett M, Zachary C, Dressler D, eds. Manual of Botulinum Toxin Therapy. 2nd ed. Cambridge, UK: Cambridge University Press; 2013;12-15. ISBN: 9781107025356.

2. Nair KPS, Marsden J. The management of spasticity in adults. BMJ. 2014;349:g4737. [go to PubMed]

3. Chertow DS, Tan ET, Maslanka SE, et al. Botulism in 4 adults following cosmetic injections with an unlicensed, highly concentrated botulinum preparation. JAMA. 2006;296:2476-2479. [go to PubMed]

4. Souayah N, Karim H, Kamin SS, McArdle J, Marcus S. Severe botulism after focal injection of botulinum toxin. Neurology. 2006;67:1855-1856. [go to PubMed]

5. Partikian A, Mitchell WG. Iatrogenic botulism in a child with spastic quadriparesis. J Child Neurol. 2007;22:1235-1237. [go to PubMed]

6. Crowner BE, Brunstrom JE, Racette BA. Iatrogenic botulism due to therapeutic botulinum toxin A injection in a pediatric patient. Clin Neuropharmacol. 2007;30:310-313. [go to PubMed]

7. Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs. 2012;26:e1-e9. [go to PubMed]

8. Oshima M, Deitiker PR, Jankovic J, Duane DD, Aoki KR, Atassi MZ. Human T-cell responses to botulinum neurotoxin: proliferative responses in vitro of lymphocytes from botulinum neurotoxin A-treated movement disorder patients. J Neuroimmunol. 2011;237:66-72. [go to PubMed]

9. Lange O, Bigalke H, Dengler R, Wegner F, deGroot M, Wohlfarth K. Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing? Clin Neuropharmacol. 2009;32:213-218. [go to PubMed]

10. Schoen C, Osborn R, Squires D, Doty M, Pierson R, Applebaum S. New 2011 survey of patients with complex care needs in eleven countries finds that care is often poorly coordinated. Health Aff (Millwood). 2011;30:2437-2448. [go to PubMed]

11. van Walraven C, Taljaard M, Bell CM, et al. Information exchange among physicians caring for the same patient in the community. CMAJ. 2008;179:1013-1018. [go to PubMed]

Table

Table. Indications for Botulinum Neurotoxin.