Head drop after botox: Electrodiagnostic evaluation of iatrogenic botulinum toxicity

Abstract

Background:

Botulinum is a potent neurotoxin with increasing indications for neurologic disorders. While clinical benefit manifests primarily due to local actions at the neuromuscular junction, regional and systemic effects do occur. Rarely, systemic symptoms including weakness, dysarthria, dysphagia and other side effects occur as a result of iatrogenic botulinum neurotoxicity.

Case:

A 72 year-old female with right leg dystonia developed head drop, bulbar and systemic weakness following right lower extremity botulinum toxin injection. Routine nerve conduction studies were normal. Repetitive stimulation of the spinal accessory nerve showed decrement; electromyography (EMG) demonstrated slightly small units with subtle signs of denervation, and single fiber EMG revealed increased jitter with blocking, all of which are consistent with systemic botulism.

Conclusion:

This case highlights and reviews the important electrodiagnostic features of iatrogenic systemic botulinum neurotoxicity.

1. Introduction

Systemic weakness following botulinum neurotoxin injection is rare. Life-threatening cases of iatrogenic botulism have been reported following lethal doses of unlicensed preparations. In adults, iatrogenic botulism has been reported in hereditary spastic paraparesis, limb dystonia, hemiparesis, stroke, hyperhidrosis, and even following detrusor injection for neurogenic bladder [4,5]. In the majority of reported cases, clinical criteria have established the diagnosis ([1,6–8]). Few reports, however, have included electrodiagnostic (EDX) confirmation.

2. Report

A 72 year-old Caucasian female with Parkinson’s disease (PD) and peripheral neuropathy presented for evaluation of right foot dystonia. She was initially managed with oral medications without improvement and subsequently underwent botulinum toxin type A (i.e. BOTOX^® or onabotulinumtoxin A) injection twice at an outside facility (preparation and dose unknown). On presentation to our facility, examination revealed mild rigidity, bradykinesia, and severe gait disturbance with equinovalgus right foot dystonia. She tolerated botulinum toxin type A injection (400 units) into the right lower extremity. After repeat injection (botulinum toxin type A, 600 units) 5 months later, she reported minor generalized weakness and dysphagia one month after treatment. Otolaryngology work up was negative and symptoms resolved. Her fifth injection was performed after a 4 month interval (botulinum toxin type A, 600 total units: extensor hallucis longus: 50, flexor digitorum longus: 150, gastrocnemius: 150, peroneus longus: 150, soleus: 100).

She experienced right leg heaviness three days after injection. New intermittent horizontal diplopia and dysphagia developed at one week without other symptoms of autonomic involvement, and then head drop at 2 weeks. Evaluation revealed dilated, poorly reactive pupils, intact extraocular movements, mild dysarthria, 4/5 neck flexion and extension, 4+/5 deltoids bilaterally, 4+/5 triceps bilaterally, otherwise 5/5 in the upper extremities, 3/5 bilateral hip flexors, 5/5 knee flexion and extension, 3/5 bilateral dorsi- and plantar flexion. Right patellar and Achilles reflexes were absent but 2+ elsewhere. Sensory examination confirmed distal sensory deficits without proximal loss.

Electrodiagnosis: nerve conduction studies.

EDX evaluation was performed using a Nicolet Viking IV (Nicolet Biomedical Inc, Madison, WI) 21 days following injection. Right ulnar motor and sensory responses were normal, including F-wave. Spinal accessory compound motor action potential (CMAP) amplitude was 1.9 mV. Repetitive nerve stimulation of the right trapezius muscle at 3 Hz revealed a decremental response with maximal decrement of 14% at rest. Subsequent trains of 3 Hz repetitive stimulation following 1 min of exercise were not significantly different from baseline varying 12–20%. After 10 s of voluntary isometric activation of this muscle, no incremental response was observed. Stimulation at 20 Hz frequency was not performed to avoid patient discomfort. NCS of paraspinal muscles were not performed as the patient was on Coumadin (warfarin).

Needle EMG.

Electromyography (EMG) of the right deltoid and triceps was normal. Rare positive waves were observed in the right trapezius with low amplitude, short duration, and polyphasic motor unit potentials (MUPs). Voluntary single fiber EMG (SFEMG) of the left extensor digitorum (ED) was complicated by tremor. Eight pairs were analyzed with a mean jitter of 66.24 μs (upper limit of normal, 43.8 μs) and blocking in 2 pairs (Fig. 1B). Stimulated SFEMG of the left ED captured 16 potentials with a mean jitter of 52.74 μs (upper limit 25 μs) and blocking in 2 pairs.

Fig. 1.

Repetitive nerve stimulation and single fiber EMG results. (A) RNS at 3 Hz for a duration of 0.1 s performed 4 min after a 1 min maximum exercise demonstrating decremental CMAP amplitude with a maximum decrement of 20% (vertical axis increment 1 mV, horizontal axis increment 5 ms) and (B) voluntary SFEMG of the left EDC demonstrating mean jitter of 128.52 μs in 65 superimposed potentials with blocking (vertical axis increment 200 μV, horizontal axis increment 10 ms).

Laboratory assessment was within normal limits including sodium, potassium, calcium, magnesium, phosphorus, and creatinine kinase (123 U/L). Acetylcholine receptor and muscle-specific kinase antibodies were negative. The patient remained hospitalized for 3 days without deterioration or respiratory dysfunction; she was discharged with a diagnosis of systemic botulinum toxicity. Symptoms resolved after 7 weeks.

3. Discussion

Botulinum neurotoxin is an important therapy in many neurologic diseases, but local therapy can have distant effects. Underlying mechanisms of systemic neurotoxicity are unknown. Diffusion of botulinum toxin into adjacent muscles is well documented. Distant spread of neurotoxin may occur as a result of a shortened inter-dose interval, larger volume of fluid for injection, higher single injection doses, axonal transport, or other factors. Here we describe a case of iatrogenic botulism, and comprehensively detail the electrodiagnostic evaluation and SFEMG findings of prolonged mean jitter and frequent blocking.

In systemic non-iatrogenic botulism, EDX evaluation typically reveals normal conduction velocities. Diminished CMAP is a potential finding, but is often only apparent in proximal muscles and can be missed on routine evaluation. Low frequency RNS variably demonstrates a decremental response; high frequency RNS classically reveals a modest incremental response which is not always apparent. Needle EMG is useful for evaluating other causes of weakness and may reveal a reduction in MUP duration, polyphasia, reduced recruitment, and motor unit instability related to toxin induced denervation.

EDX evaluation is critical to the evaluation of patients with iatrogenic botulism. In the 7 reports of iatrogenic botulism, routine nerve conduction studies have been normal in 6 of 15 cases (including the current case) in which they were reported. RNS, documented in 6 cases, has shown a mean decrement of 17% (range, 10–26%). MUP’s in the majority of studies were low amplitude and short duration with denervation findings reported in 8 of 9 studies reporting EMG findings (supplemental Table 1). SFEMG has been rarely reported but as in this case a prolonged mean jitter and frequent blocking has been reported.

Symptoms have lasted an average of 12 weeks (range 4–24) and 5 of 11 patients who underwent electrodiagnostic testing were successfully re-challenged at lower doses with longer treatment intervals. Two patients experienced resolution of SFEMG abnormalities after one month. In 5 of the 15 reported patients, including our patient, antecedent systemic weakness was experienced following a prior injection and antecedent dysphagia in 1. While control data is unavailable and such symptoms are reported in many patients who do not develop subsequent toxicity, this raises the question of an underlying predisposition to susceptibility in these patients.

The mechanism of distant transport remains poorly understood; despite the standard practice of aspirating for blood before injection, toxin entry directly into the vascular system is a consideration. SFEMG in a rat model of iatrogenic botulism revealed increases in jitter, fiber density, and occasional blocking in muscles distant from the injection site. Persistent catalytic activity has been demonstrated at sites distant to local injection as a result of both anterograde and retrograde axonal transport [2]. In patients undergoing standard botulism neurotoxin therapy, a study of SFEMG analysis 1 month post-botulinum injection revealed abnormal results in 17.6% of asymptomatic control patients compared to 75% of patients experiencing symptoms of pseudobotulism (weakness in >1 muscle more than 1 joint from injection). Such results support the diffusion of toxin into muscles distant from the injection site even in asymptomatic patients, underscoring SFEMG as a pertinent tool to both characterize and support the mechanism of botulism toxicity [3]. While no cases of significant respiratory depression or death have been reported after FDA-approved regimens, post-injection toxicity is a concern. Supportive care remains the primary treatment mechanism.

4. Conclusion

Systemic botulinum neurotoxicity is a rare but recognized side effect of therapeutic botulinum toxin injections. Systemic botulinum neurotoxicity is a rare but recognized side effect of therapeutic botulinum toxin injections. EDX findings include decremental response on RNS and rare denervation potentials in addition to low amplitude and short duration motor unit morphology on EMG. Prompt clinical and electrodiagnostic evaluation is important. Findings suggest the pertinence of SFEMG to confirm abnormalities not found on routine nerve conduction studies. Assessment of antecedent weakness before administering subsequent injection should be considered as a means to screen for potential increased risk of future toxicity.

Abbreviations:

EMG

electromyography

EDX

electrodiagnosis

PD

Parkinson’s disease

CMAP

compound motor action potential

RNS

repetitive nerve stimulation

MUP

motor unit potential

SFEMG

single fiber EMG

ED

extensor digitorum