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Show Positive Apraclonidine Test 36 Hours After Acute Onset of Horner Syndrome in Dorsolateral Pontomedullary Stroke Maud Lebas, MD, Julien Seror, MD, Thomas Debroucker, MD Abstract: A 40-year-old man developed a Horner syndrome as part of a dorsolateral medullary brainstem infarction. Thirty-six hours after the onset of the stroke, topical instillation of 0.5% apraclonidine produced reversal of anisocoria. This is the first case in which apraclonidine testing has been applied to a patient with a Horner syndrome caused by a lesion in the first segment of the oculosympathetic pathway and the shortest reported interval between clinical manifestations of the lesion and apraclonidine-induced reversal of anisocoria. A review of all reported cases of apraclonidine testing in Horner syndrome suggests that this is a promising diagnostic adjunct that must be validated in larger studies. Journal of Neuro-Ophthalmology 2010;30:12-17 doi: 10.1097/WNO.0b013e3181b1b41f 2010 by North American Neuro-Ophthalmology Society Where cocaine is not available, the topical apracloni-dine test may be used to replace it in the effort to pharmacologically distinguish Horner syndrome from physiologic anisocoria. The apraclonidine test is based on the development of denervation supersensitivity of a-1 receptors in the iris dilator muscle (1). Once that has occurred, instillation of apraclonidine will dilate the pupil on the side of a Horner syndrome but not the pupil of the unaffected eye. As a result, the anisocoria will reverse, with the miotic pupil becoming relatively mydriatic. The time needed for up-regulation of iris a-1 receptors is unknown, so that the usefulness of the apraclonidine test in diagnosis of acute Horner syndrome is still debated. We describe positive results for an apraclonidine test 36 hours after a patient had an acute brainstem stroke. We believe this interval to be the shortest yet reported. CASE REPORT A 40-year-old man with no past medical history complained of acute onset of dizziness, nausea, difficulty swallowing, pain around the right eye, and binocular diplopia. On examination, he was found to have full ductions and a comitant left hypertropia, constituting a skew deviation. He also manifested a counterclockwise right-beating horizontal-rotary nystagmus on right gaze and a counterclockwise left-beating horizontal-rotary nystagmus on left gaze. The palpebral fissure measured 7 mm in the right eye and 10 mm in the left eye. In darkness, pupils measured 6 mm in the right eye and 7 mm in the left eye. In bright light, both pupils were equal in size, measuring 3 mm. There was also a right lower motor neuron facial palsy and decreased sensation in the left face and arm. Results of the examination were otherwise normal. Diffusion MRI disclosed a very small area of high signal in the right dorsolateral pontomedullary junction with cor-responding low signal on the apparent diffusion coefficient (ADC) map (Fig. 1AB). MRA showed right vertebral stenosis without dissection (Fig. 1C). The patient received a diagnosis of acute right dorso-lateral pontomedullary infarction (Wallenberg syndrome variant). Thirty-six hours after the onset of symptoms, we instilled 1 drop of 0.5% apraclonidine into each ocular cul-de-sac. Forty-five minutes later, the right pupil became 8 mm with the left remaining 7 mm, thus demonstrating reversal of the anisocoria. DISCUSSION Because symptoms of a brainstem stroke are typically reported promptly, the delay between the onset of the Department of Ophthalmology (ML, JS) and Neurology (TD), Hoˆpital Delafontaine, Saint-Denis, France. Address correspondence to Maud Lebas, Department of Ophthal-mology, Hoˆpital Delafontaine, 2 rue du Docteur Pierre Delafon-t a ine , 93205 Sa i nt -Deni s Cedex, Fr ance ; E-ma i l : maudjacob@gmail.com 12 Lebas et al: J Neuro-Ophthalmol 2010; 30: 12-17 Original Contribution Horner syndrome in our patient and the performance of the apraclonidine test can be estimated reliably at 36 hours. Before our report, the shortest interval was 1 week (2). Although drawn from only one patient, our report of a delay of merely 36 hours suggests that supersensitivity of a-1 receptors occurs very quickly after sympathetic pathway damage. We add one more case to the list of positive results of 0.5% apraclonidine tests for pharmacologic diagnosis of Horner syndrome. (2-8). Apraclonidine testing has been used in 47 patients with Horner syndrome or suspected of having Horner syndrome in the reported literature (1-11). Among those, 43 (including ours) showed reversal of anisocoria, 3 did not (5,10,11), and 1 case was equivocal (1). Among 16 patients (3,4,9) with physiologic anisocoria [14 of which were cocaine proven (3,4)], none disclosed reversal of their anisocoria. Among 19 controls without anisocoria (4), one had 0.5 mm dilation on one side. The largest reported series in which apraclonidine was compared with cocaine included 10 patients with Horner syndrome and 10 patients with physiologic anisocoria (3). Among the patients with Horner syndrome, 7 showed reversal of anisocoria in both light and dark and 3 showed it only in light. None of the control subjects showed reversal of anisocoria. Of the 3 patients with negative apraclonidine results, 2 were thought to represent Horner syndrome of unknown origin (5,11), but neither had been tested with topical cocaine so that one may doubt the diagnosis. One patient who was considered by the authors to have positive results had not been tested with cocaine and had reversal of ptosis after 10 minutes but no pupil change (10). Although the test results were considered positive, ptosis reversal has been shown to occur in patients without Horner syndrome (4). Conversely, the pupil size was assessed a mere 10 minutes after apraclonidine instillation, perhaps too short a time to evaluate reversal of anisocoria. Finally, 1 patient (1) showed anisocoria greater in light than in dark, which was considered diagnostic of Horner syndrome, a conclusion that may be questioned. This is the first reported case in which the apraclonidine test has been positive in a patient with Horner syndrome caused by disruption of the first (central nervous system) segment of the sympathetic pathway. Among the other 42 patients with Horner syndrome considered to have positive results for apraclonidine testing, 9 were believed to have the lesion in the third segment (postganglionic), 3 were believed to have the lesion in the first or the second segment (preganglionic), 27 contained no lesion-localizing informa-tion, and 3 had a lesion of uncertain location. The supersensitivity that gives rise to the pupil dilation after apraclonidine instillation is based on up-regulation of iris sympathetic receptors, yet the lesion in our patient was located in the first segment, which was two synapses away. This makes the short delay in development of apraclonidine test positivity in our patient more interesting. Apraclonidine testing in a patient with Horner syndrome caused by brainstem stroke has not been described previously. The other reported etiologies of Horner syndrome in which results of the apraclonidine test have been positive include congenital (2 cases), birth trauma (3 cases), surgery (4 cases) (1 T2 ganglionectomy, 2 cervical spine surgery, and 1 unknown), neuroblastoma (2 cases), carotid artery dissection (2 cases), cluster headache (2 cases), and goiter (1 case) (Table 1). In 8 patients, a proper workup disclosed no etiology. In 14 patients, the etiology was not reported. In another 4 patients, the reported etiology was presumptively but questionably (owing to limited workup) head trauma (1 case), cervical disc disease (2 cases), and carotid stenosis (1 case). In 26 of 42 patients with Horner syndrome who had positive results of apraclonidine testing that were reported before our patient, the delay between the onset of Horner syndrome and apraclonidine positivity ranged from 1 week to 10 years (mean 30 months; SD 39 months). In only 3 patients was the delay less than 1 month (1 week [2 cases], 10 days [2 cases], and 14 days [6 cases]; postganglionic in all patients). In 9 additional patients, the delay between the onset of Horner syndrome and apraclonidine testing was FIG. 1. MRI performed within 48 hours of clinical onset shows high signal in the right dorsolateral pontomedullary junction (arrow) on the diffusion study (A) and a corresponding low signal on the apparent diffusion coefficient study (B). On MRA (C), the right vertebral artery appears narrowed. Original Contribution Lebas et al: J Neuro-Ophthalmol 2010; 30: 12-17 13 TABLE 1. Reported results of apraclonidine diagnostic testing for Horner syndrome Author No. Patients Tested and Suspected Diagnosis Failure of Cocaine-Induced Mydriasis Apraclonidine- Induced Reversal of Anisocoria Apraclonidine Concentration Cause of Horner Syndrome Damaged Segment of Sympathetic Pathway (1st, 2nd, or 3rd) Interval Between Diagnosis and Apraclonidine Testing Chen et al (3) 10 Horner 10 3 in bright light only, 7 in light and dark 0.5% Birth trauma: 3 NA 2.5, 8, and 1.5 years Idiopathic: 4 NA 3, 5, 10, and 10 years Head trauma: 1 NA 9 years Neuroblastoma: 1 NA 6 months Surgical trauma: 1 NA 2 years 10 Physiologic anisocoria 0 0 0.5% - - - Koc et al (4) 9 Horner 9 9 0.5% Diabetes and other unspecified conditions NA .3 months 4 Physiologic anisocoria 0 0 0.5% - - - 19 Control subjects with isocoria 0.5 mm dilation in 1 eye in 1 subject 0.5% - - - Bacal and Levy (9) 4 Horner NA 4 1% Left brachial plexus injury NA 2 months NA NA NA Neck MRI and chest X-ray negative NA 2 years Cervical neuroblastoma extending to the thyroid gland NA 1 month 2 physiologic anisocoria NA 0 1% - - - Brown et al (5) 3 Horner 3 3 0.5% Cervical goiter NA 4 months Unknown NA 9 months Unknown NA 8-12 months 5 Horner NA 0 0.5% Unknown 3rd* 9 years 4 0.5% Cervical disc degeneration 3rd* NA Possible cervical disc disease 3rd* 2 years Posterior T2 ganglionectomy Uncertain 10 months Original Contribution 14 Lebas et al: J Neuro-Ophthalmol 2010; 30: 12-17 TABLE 1. continued Author No. Patients Tested and Suspected Diagnosis Failure of Cocaine-Induced Mydriasis Apraclonidine- Induced Reversal of Anisocoria Apraclonidine Concentration Cause of Horner Syndrome Damaged Segment of Sympathetic Pathway (1st, 2nd, or 3rd) Interval Between Diagnosis and Apraclonidine Testing Carotid stenosis 3rd* 1 month Morales et al (1) 1 Horner 1 1 1% NA 3rd* NA 5 Horner NA 1 (but anisocoria greater in light) 1% NA 1st or 2nd* NA 4 1% Cluster HA Cluster HA NA 3rd* NA NA 3rd* NA NA 1st or 2nd* NA Bohnsack and Parker (6) 1 Horner NA 1 0.5% Traumatic carotid artery dissection from carotid artery bifurcation to the skull base 3rd (carotid artery dissection) 14 days Freedman and Brown (7) 2 Horner NA 2 0.5% Cervical discectomy for C6-C7 herniation 2nd (C6-C7 diskectomy) 5 months Congenital NA 5 years Garibaldi et al (2) 3 Horner NA 3 0.5% Cervical spinal surgery Uncertain 2 months Cluster HA 3rd* 1 week Carotid artery dissection 3rd* 10 days Mirzai and Baser (8) 1 Horner NA 1 0.5% Congenital; work-up negative (head, neck and thorax MRI; neck and abdomen ultrasound) 1st or 2nd (ipsilateral face anhydrosis) 7 months Chu and Byrne (10) 1 Horner NA 0 0.5% Neck surgery for cervical sympathetic chain schwannoma 1st or 2nd (ipsilateral face anhydrosis) 1 year (continued on next page) Original Contribution Lebas et al: J Neuro-Ophthalmol 2010; 30: 12-17 15 TABLE 1. continued Author No. Patients Tested and Suspected Diagnosis Failure of Cocaine-Induced Mydriasis Apraclonidine- Induced Reversal of Anisocoria Apraclonidine Concentration Cause of Horner Syndrome Damaged Segment of Sympathetic Pathway (1st, 2nd, or 3rd) Interval Between Diagnosis and Apraclonidine Testing Watts et al (11) 1 Horner NA 0 1% NA NA 4 months Lebas et al (present case) 1 Horner NA 1 0.5% Dorsolateral pontomedullary stroke 1st (brainstem stroke) 36 hours NA = not available. MRI = magnetic resonance imaging. CT = computerized tomography. US = ultrasound. 1stor 2nd*: central or pre-ganglionic location presumed on basis of pupil dilation following topical instillation of hydroxyamphetamine. 3rd* = postganglionic location presumed on basis of lack of pupil dilation following topical instillation of hydroxyamphetamine. HA = headache. The questionable cases for positivity or negativity of the apraclonidine test are underlined. The questionable location case is in italics. TABLE 2. Reported results and side effects of apraclonidine testing for Horner syndrome in children Author Age (months) No. of cases Apraclonidine Concentration Side Effects Bacal and Levy (9) 2 1 1% None Watts et al (11) 2.5 1 0.5% Drowsiness for 10 hours Bacal and Levy (9) 4 1 1% None Watts et al (11) 5 1 1% Lethargy, bradycardia, shallow respiration, oxygen desaturation H1-H8 after drop instillation Bacal and Levy (9) 5 1 1% None Bacal and Levy (9) 6 1 1% Sleepy all afternoon Watts et al (11) ,6 months 3 Unknown Drowsiness Mirzai and Baser (8), Chen et al (3), Freedman and Brown (7), Bacal and Levy (9) 7-204 14 0.5%: 12 cases 1%: 2 cases None Watts et al (11) Not reported 3 Unknown None Original Contribution 16 Lebas et al: J Neuro-Ophthalmol 2010; 30: 12-17 only mentioned as ‘‘greater than 3 months.'' In 7 patients the delay was not documented (Table 1). In the 3 patients suspected of having Horner syndrome in whom results of the apraclonidine test were reported as negative, the delay between the discovery of anisocoria and the apraclonidine testing was 4 months (11), 1 year (10), and 9 years (5). The article with the questionable case did not mention the delay between the discovery of anisocoria and the apraclonidine testing (1). There are no reported patients in whom results of the apraclonidine test were initially negative and later became positive. The use of apraclonidine in young children is limited by side effects related to blood-brain barrier immaturity. In infants younger than 6 months, drowsiness alone was the most common side effect (in 5 of 9 reported cases) after instillation of 1% apraclonidine, but bradycardia, shallow respiration, and oxygen desaturation have also occurred. These manifestations have been reported in a 5-month-old child after instillation of the 0.5% concentration (Table 2). Among 14 children tested when they were older than 6 months, there were no reported side effects (3,7-9). Therefore, apraclonidine testing can probably be safely applied in children who are 6 months of age or older. But if it is to be used in patients younger than 6 months of age, they should be observed for a period of at least 2 hours after instillation of the drops, with admission to a pediatric ward if lethargy, bradycardia, or a reduced respiratory rate occurs (11). REFERENCES 1. Morales J, Brown SM, Abdul-Rahim AS, et al. Ocular effects of apraclonidine in Horner syndrome. Arch Ophthalmol 2000;118:951-4. 2. Garibaldi DC, Hindman HB, Grant MP, et al. Effect of 0.5% apraclonidine on ptosis in Horner syndrome. Ophthalmic Plast Reconstr Surg 2006;22:53-5. 3. 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. 4. Koc F, Kavuncu S, Kansu T, et al. The sensitivity and specificity of 0.5% apraclonidine in the diagnosis of oculosympathetic paresis. Br J Ophthalmol 2005;89: 1442-4. 5. Brown SM, Aouchiche R, Freedman KA. The utility of 0.5% apraclonidine in the diagnosis of Horner syndrome. Arch Ophthalmol 2003;121:1201-3. 6. Bohnsack BL, Parker JW. Positive apraclonidine test within two weeks of onset of Horner syndrome caused by carotid artery dissection. J Neuroophthalmol 2008;28:235-6. 7. Freedman KA, Brown SM. Topical apraclonidine in the diagnosis of suspected Horner syndrome. J Neuroophthalmol 2005;25:83-5. 8. Mirzai H, Baser EF. Congenital Horner's syndrome and the usefulness of the apraclonidine test in its diagnosis. Indian J Ophthalmol 2006;54:197-9. 9. Bacal DA, Levy SR. The use of apraclonidine in the diagnosis of Horner syndrome in pediatric patients. Arch Ophthalmol 2004;122:276-9. 10. Chu EA, Byrne PJ. Pharmacologic reversal of Horner's syndrome-related ptosis with apraclonidine. Ear Nose Throat J 2007;86:270-3. 11. 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. Original Contribution Lebas et al: J Neuro-Ophthalmol 2010; 30: 12-17 17 |
