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Cocaine and Phenylephrine Eye Drop Test for Parkinson Disease
To the Editor: While there is no specific diagnostic test for Parkinson disease (PD), recent studies using iodine 123–metaiodobenzylguanidine (MIBG) have shown that cardiac sympathetic innervation is reduced in patients with PD.1-2  -Synuclein aggregations are found in the sympathetic ganglions as well as in the midbrain dopaminergic neurons.3 It is possible that sympathetic innervation to the pupillary dilator muscle in PD is reduced because it is innervated by the cervical sympathetic ganglia. We studied sympathetic dysfunction in the pupils as a possible diagnostic marker of PD by comparing responses to cocaine eye drops and phenylephrine eye drops. Cocaine blocks norepinephrine uptake, and cocaine-induced mydriasis is dependent on the sympathetic nerve terminal density. In contrast, phenylephrine acts directly on the adrenergic receptor to cause mydriasis.
Methods
Participants included patients with PD (according to the criteria of the United Kingdom Parkinson’s Disease Society Brain Bank4), controls (patients reporting symptoms including headache, dizziness, or back pain, but with no evidence of active neurological diseases), and patients with multiple system atrophy (MSA). Of the 38 patients with PD, 16 (42%) were men (mean [SD] age, 69.5 [9.0] years). Of the 20 age-matched control participants, 10 (50%) were men (mean [SD] age, 66.7 [13.5] years). Of the 10 patients with MSA, 2 (20%) were men (mean [SD] age, 61.3 [10.5] years). All participants provided written informed consent and the protocol was approved by the Ethic Committee of Kyoto University Hospital. Exclusion criteria were a history of diabetes mellitus, polyneuropathy, or glaucoma and use of selegiline, an -blocker, or dihydroxyphenylserine.
The pupil diameter of both eyes was recorded using an infrared videocamera in fixed daylight brightness, and the mean value was calculated. Next, 40 µL of 1% phenylephrine solution was applied to both eyes of each participant using an eye dropper, and the mean pupil diameter was recorded 60 minutes later. After at least 72 hours, 40 µL of 5% cocaine solution was applied to each participant’s eyes using an eye dropper, and the mean pupil diameter was recorded 60 minutes later. The difference between phenylephrine-induced mydriasis and cocaine-induced mydriasis was calculated as a measure of the relative amount of phenylephrine-induced mydriasis compared with cocaine-induced mydriasis.
For the isotope examination, 3 mCi (111 MBq) of MIBG was administered intravenously to the 35 participants with PD, 4 healthy controls, and 8 patients with MSA who consented to this examination. The ratio of the MIBG cardiac accumulation to the upper mediastinum accumulation (late heart–mediastinum ratio) was determined using a gamma camera 3 hours later.
The mean value of the pupil diameter and extent of mydriasis were analyzed using the Kruskal-Wallis and Bonferroni tests. The correlation between late heart–mediastinum ratio and difference between phenylephrine- and cocaine-induced mydriasis was analyzed using the Spearman rank correlation test (StatView 4.58 for Windows; SAS Institute Inc, Cary, NC). Area under the receiver operating characteristic curve was calculated using ROC Analyzer version 6 (Centor and Keightley, Richmond, Va).
Results
Phenylephrine-induced mydriasis was a mean (SD) of 2.29 (0.84) mm in patients with PD, 1.83 (1.1) mm in controls, and 1.38 (0.65) mm in patients with MSA. There was no statistically significant difference between the PD group and the control or MSA groups. Cocaine-induced mydriasis was a mean (SD) of 0.79 (0.63) mm in patients with PD, 1.20 (0.63) mm in controls, and 1.25 (0.66) mm in patients with MSA. Cocaine-induced mydriasis in patients with PD was significantly less than that in the control and MSA groups, and there was no statistically significant difference between the control and the MSA groups. The mean (SD) difference between phenylephrine- and cocaine-induced mydriasis was 1.50 (0.82) mm in patients with PD, 0.605 (1.08) mm in controls, and 0.125 (1.02) mm in patients with MSA. The difference was significantly greater in the PD group than in the control and MSA groups (Figure 1).
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Figure 1. Difference Between Phenylephrine- and Cocaine-Induced Mydriasis
The top and bottom of the boxes represent the 25th and 75th percentiles, respectively. The horizontal line inside the boxes represents the median. Error bars represent the 10th and 90th percentiles. Outliers are shown as circles.
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Late heart–mediastinum ratio was significantly reduced in patients with PD compared with the controls (mean [SD], 1.65 [0.47] vs 2.45 [0.40], respectively; P<.001). There was a significant negative correlation between the difference between phenylephrine- and cocaine-induced mydriasis and late heart–mediastinum ratio (R = –0.522, P<.001). Using a cutoff point of 1.0 mm, the sensitivity and specificity of phenylephrine- and cocaine-induced mydriasis difference for diagnosis of PD were 0.80 (95% confidence interval [CI], 0.65-0.94) and 0.79 (95% CI, 0.67-0.94), respectively. The corresponding positive likelihood ratio was 3.87 (95% CI, 1.44-10.4) and negative likelihood ratio was 0.25 (95% CI, 0.10-0.65). The area under the receiver operating characteristic curve was 0.83 (95% CI, 0.72-0.93) (Figure 2).
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Figure 2. Receiver Operating Characteristic Curve of Diagnosis of Parkinson Disease by Cutoff in Difference Between Phenylephrine- and Cocaine-Induced Mydriasis
Values labeled on the curve indicate the difference between phenylephrine- and cocaine-induced mydriasis in millimeters.
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Comment
The use of a tropicamide eye drop as a diagnostic test for Alzheimer disease has been proposed5 but this has been controversial.6 Although eye drop tests can be affected by several factors, including corneal permeability and age, these variations are consistent within an individual patient, and the difference between phenylephrine- and cocaine-induced mydriasis can be a good measure of pupillary sympathetic innervation. In this study, the difference between phenylephrine- and cocaine-induced mydriasis was significantly correlated with the reduction of MIBG cardiac accumulation in patients with PD and showed reasonable diagnostic accuracy. While these results need to be replicated, this study indicates the potential value of using phenylephrine- and cocaine-induced mydriasis, a marker of systemic reduction of sympathetic innervation, to aid in the diagnosis of PD.
Financial Disclosures: None reported.
Funding/Support: This work was supported by grants-in-aid for scientific research from the Japan Society for the Promotion of Science (Drs Sawada and Shimohama) and from the Ministry of Health, Labor and Welfare of Japan (Dr Shimohama).
Role of the Sponsor: The Japan Society for the Promotion of Science and the Ministry of Health, Labor and Welfare of Japan had no role in the design and conduct of the study; collection, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Hideyuki Sawada, MD, PhD;
Kentarou Yamakawa, MD;
Hodaka Yamakado, MD
Department of Neurology
Kyoto University Hospital
Kyoto, Japan
Ryohei Hosokawa, MD, PhD;
Muneo Ohba, MD
Department of Cardiology
Kyoto University Hospital
Kazuaki Miyamoto, MD, PhD
Department of Ophthalmology
Kyoto University Hospital
Takashi Kawamura, MD, PhD
Kyoto University Center for Student Health
Shun Shimohama, MD, PhD
i53367{at}sakura.kudpc.kyoto-u.ac.jp
Department of Neurology
Kyoto University Hospital
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ABSTRACT
Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2005;293:932-934.
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