Reversible pupillary dilation following botulinum toxin injection to the lateral rectus

Sir,

Low-dose botulinum toxin (BT) is being widely used in ophthalmology including the management of strabismus,¹ congenital entropion,² nystagmus,³ blepharospasm,⁴ and aberrant regeneration of the facial nerve.⁵ Previously reported complications following injection to the horizontal recti muscles include ptosis,⁶ permanent muscle damage,⁷ globe perforation,⁸ necrotising fasciitis,⁹ and angle closure glaucoma.¹⁰ We report a case of a middle-aged man who developed a reversible pupillary dilation following injection of BT to the lateral rectus (LR) muscle.

Case report

A 69-year-old man was referred to us with a longstanding history of horizontal diplopia following a cerebrovascular accident. The diplopia remained uncontrolled with Fresnel prisms. Examination revealed a 16° right alternating exotropia at 33 cm, increasing to 20° at 6 m. Visual acuity was 6/6 in the right eye (RE) and 6/5 in the left eye (LE). Both pupils were equal sized, reactive, with no relative afferent pupillary defect (RAPD). He was noted to have horizontal hypometric saccades (secondary to his cerebrovascualar accident). Rest of the ocular examination was unremarkable.

Following informed consent, 1.25 international units (IU) of BT (Botox^®, Botulinum Toxin Type A, Allergan pharmaceuticals, Ireland) was injected to the LR muscle of the RE under electromyographic guidance. A similar dose was repeated a month later. Following this, the ocular deviation was reduced to 4° BI for near and 2° BI at distance and his symptoms resolved. A similar dose (1.25 IU) of BT injection to the LR muscle was repeated twice at quarterly intervals. On review, 3 months later he was noted to have anisocoria (Figure 1). The right pupil measured 6 mm and was fixed, with no direct or consensual response to light and it failed to dilate further in scotopic conditions. There was no RAPD. The left pupil measured 3 mm with brisk direct and consensual light response. There was limitation of the RE in abduction and no diplopia, consistent with a prolonged action of BT. There was no other neurological abnormality. At this stage it was presumed that the dilated right pupil was secondary to effect of BT and a decision was made to withhold further BT injections to the RE. At review, 2 months later, the right pupil returned to its original size and the anisocoria had completely resolved (Figure 2). The RE had become more divergent and there was intermittent diplopia. The patient remains under follow-up.

Figure 1

Clinical photograph showing anisocoria. Note the dilated right pupil.

Figure 2

Note the reversal of anisocoria.

Discussion

BT is a protein produced by the anaerobic bacillus Clostridium botulinum. It works primarily on peripheral cholinergic synapses where it inhibits the release of the neurotransmitter acetylcholine. The exotoxin possesses two subunits, one of which bind to a membrane receptor and are responsible for cellular specificity. By this means the toxin enters the cell, where the other subunit exerts a toxic effect by inactivating specific enzymes. BT is believed to inactivate actin, a protein involved in exocytosis, by this mechanism.¹¹ Clinically it produces a transient paresis of the injected muscle by the above mechanism.

Reported complications of BT following horizontal recti muscle injection include ptosis, vertical muscle involvement,⁶ permanent extra ocular muscle damage,⁷ globe perforation,⁸ necrotising fasciitis,⁹ and angle closure glaucoma.¹⁰ A Medline and a PubMed search showed no previous clinical reports of reversible pupillary dilation secondary to BT injection to the extraocular muscles. However, retrobulbar injection of BT in rats has been shown to cause mydriasis at a dose of 1.5 ng.¹² In this rat model, the mydriasis resolved in 12 weeks. In our case, the mydriasis resolved by 20 weeks. It is likely that the BT would have affected the ciliary ganglion, which is located in the intraconal space between the optic nerve and the LR muscle. We speculate that the toxin would have reached the ciliary ganglion by diffusion from the LR muscle, given the proximity of the ciliary ganglion to the LR. Although there was a good audible response with the EMG machine confirming the intramuscular location of the needle, it is possible that the needle could have advanced beyond the muscle into the intraconal space. Alternatively, its action could be at the parasympathetic neuromuscular junctions in the sphincter pupillae of the iris, although this is unlikely as it would require an intraocular injection or an idiosyncratic reaction to the BT. Tonic pupils have also been reported in patients with systemic botulism.¹³ There have been no documented cases in the literature of pupillary abnormalities following botulinum toxin injection, although it has been postulated that this may precipitate acute closed angle glaucoma following treatment of blepharospasm.¹⁰ To the best of our knowledge, this is the first documented clinical case of pupillary abnormality following BT injection. Although pupillary changes following BT injection are a rare phenomenon, the treating physician should be aware of this side effect. The pupillary changes are reversible as shown in this case.