The College has recently received a report from NHS Improvement of a severe adverse reaction in a six month old child with anisocoria who had been administered apraclonidine 1% to help exclude Horner syndrome. Two drops of apraclonidine 1% were administered to each eye, 30 minutes apart. Ninety minutes later the child had an acute collapse outside of the ophthalmic facility and was taken to the emergency department, where they were found to be bradycardic, apnoeic and hypoxic. The child required intubation, ventilation and admission to the paediatric intensive care unit.
Why is topical apraclonidine used in the diagnosis of Horner syndrome?
Topical apraclonidine hydrochloride (Iopidine, Novartis Pharmaceuticals UK Ltd) is an a-adrenergic agonist with strong a-2 and weak a-1 activity, used most commonly to lower intra-ocular pressure. It is also used in the pharmacological testing of Horner syndrome. A lack of sympathetic innervation to the eye results in upregulation of a-1 receptors in the iris (“denervation supersensitivity”). As a result, instillation of topical apraclonidine in an eye with Horner syndrome causes mydriasis with no effect in normally innervated eyes. A positive test is therefore denoted by a reversal of anisocoria in patients with unilateral Horner syndrome.
What is the concern regarding topical apraclonidine?
There are several reports of topical apraclonidine being associated with cardiovascular instability in infants. Bacal and Levy report an early paediatric case series of 6 children from the age of 2 months to 14 years (mostly infants), describing the utility of topical apraclonidine 1% in testing for Horner syndrome, where one infant was noted to be drowsy following instillation of the drop1.
Apraclonidine 0.5% has been suggested as a potentially safer option to aid in the diagnosis of Horner syndrome. In a study of 10 children, Chen et al have shown that apraclonidine 0.5% resulted in a positive test in 10 children with known Horner syndrome, but only when viewed in high ambient lighting conditions2. A study of 75 children, with a mean age of 5.3 months and a mean of 15 exposures per child to apraclonidine 0.5%, did not report any life-threatening adverse events3 with this preparation. Lethargy was noted in 3 children (all below 4 months of age) and reduced appetite in another 4 month old.
The potentially life-threatening side-effects of apraclonidine are detailed by Watts et al, who describe 5 infants below the age of six months that became drowsy following instillation of apraclonidine as part of the work-up for suspected Horner syndrome. Two very young infants (4 and 10 weeks old) were known to have required hospital admission, with one child becoming bradycardic and apnoeic4. It is noted that the symptoms took 8-10 hours to resolve. One child had received apraclonidine 1% and the other 0.5%.
The incidence of significant side effects in infants and young children with topical apraclonidine is uncertain, with a number of anecdotal but unpublished reports of cardiovascular instability existing. Several of these reports describe drowsiness lasting 12 hours or more. Given the retrospective nature of these reports, it is often not clear which concentration of apraclonidine was used in testing.
Anisocoria and diagnosis
Physiological anisocoria in children is very common5, and most cases of anisocoria will not have any neurological or serious cause. Congenital Horner syndrome in most cases has no serious or malignant cause, although acquired or progressive Horner syndrome is a more concerning finding that requires investigation6.
Apraclonidine is not licensed for use in children; its summary of product characteristics (SmPC) states that it is contraindicated in children. At present there are no large studies of either apraclonidine 1% or 0.5% in the diagnosis of Horner syndrome, either in adults or in children. The false positive and false negative rates of this test are unknown in the paediatric population. There is no evidence to suggest that apraclonidine 1% offers a diagnostic advantage over the use of the weaker formulation, although it has often been used for this purpose as it is available in a single-use formulation. However theoretically the higher concentration 1% may carry increased risk of side -effects.
It should be emphasised that apraclonidine testing does not replace a thorough history and examination of a child with suspected Horner syndrome. Most cases of anisocoria and most cases of Horner syndrome are able to be diagnosed clinically without the use of drop testing. The risk versus the benefit of this test should be carefully considered in children, particularly the very young. Phenylephrine 1% may represent a safer alternative but its utility in the diagnosis of paediatric Horner syndrome has not been studied.
Advice and recommendations
- Apraclonidine 1% should not be used in the diagnosis of paediatric Horner syndrome.
- Apraclondine 0.5% should not be used in children below the age of 6 months old in the diagnosis of Horner syndrome and used with extra caution in children below the age of 2 years.
- All children under the age of 2 years should remain in the facility for 2 hours following administration of the agent2.
If considering the use of apraclonidine 0.5% for this purpose, all clinicians need to remember the drug is not licenced for children and its use is contraindicated according to the drug’s Summary of Product Characteristics. Therefore the decision to use apraclonidine needs careful weighing of the risks and benefits of the test, which should be discussed with patients/parents and documented in the records along with the fact that the drug’s use will be off license (see GMC guidance) We recommend giving parents an information sheet or written documentation outlining possible side effects and clear instructions to attend an emergency department if there is abnormal drowsiness or concern the child is unwell.
The use of apraclonidine drops in paediatric glaucoma is a separate issue and this advice does not pertain to that area, where there is a greater track record of safety and a greatly different risk-benefit balance.
- Bacal DA, Levy SR. The use of apraclonidine in the diagnosis of Horner syndrome in pediatric patients. Arch Ophthalmol. 2004; 122: 276–9
- Chen, PL, Hsiao CH, Chen JT et al. Efficacy of apraclonidine 0.5% in the diagnosis of Horner syndrome in pediatric patients under low or high illumination. Am J Ophthalmol 2006; 142: 469–74
- Wright TM, Freeman SF. Exposure to topical apraclonidine in children with glaucoma. J Glaucoma 2009;18: 395-8
- Watts P, Satterfield D, Lim MK. Adverse effects of apraclonidine used in the diagnosis of Horner syndrome in infants. J AAPOS 2007; 11: 282-3
- Suh S, Suh D, Benson C. The degree of anisocoria in paediatric patients with Horner syndrome when compared to children without disease. J Pediatr Ophthalmol Strabismus 2016; 53: 186-9
- George N, Gonzalez G, Hoyt C. Does Horner syndrome in infancy require investigation? Br J Ophthalmol 1998; 82: 51-4