HS was first reported by Claude Bernard in 1854. However, Johann Friedrich Horner described this syndrome in detail for the first time in 1869 and suggested that it originated from oculosympathetic paresis [2].
Despite advances in neuroimaging and other diagnostic tests, in some patients with HS an underlying etiology cannot be identified. In a study by Wilhelm et al [5]., this rate was reported as 28% in preganglionic HS. Sabbagh et al [6]. demonstrated that a cause was identified in 61% of patients with apraclonidine-confirmed HS. Similarly, Maloney et al [7]. found a detectable cause in only 65% of patients. The authors reported that preganglionic (44%) and postganglionic (43%) causes were found in similar rates, whereas central lesions (13%) were very infrequent [7]. In a large series reported by Thompson et al [8]., malignancy was responsible from approximately 25% of the preganglionic HS cases. The most common tumor associated with preganglionic lesions have been reported as breast and lung cancers. This syndrome may rarely be the first presentation of the malignancy, but it usually occurs long after the diagnosis of cancer [2]. In our study, we did not find any etiology that could be related HS in 40% of the cases. This rate was similar to previous reports in the literature. We, however, reported that the rate of central lesions between the identifiable causes was higher than postganglionic lesions in contrast to the literature.
In posterior cavernous sinus or brainstem involvement, HS may be accompanied by abducens paralysis. This condition, also called Parkinson's syndrome [9], was observed in two cases. One was cavernous sinus invasion due to nasopharyngeal tumor and the other one was brain stem metastasis.
Apraclonidine, an alpha-2 adrenergic agonist with weak alpha-1 adrenergic activity, is used for decreasing intraocular pressure in glaucoma patients. Although it has no obvious effect on pupil's size, iris dilation is observed due to supersensitivity of the postsynaptic alpha-1 adrenergic receptors located on the dilator muscle affected by oculosympathetic paresis. [1,10]. It is still so controversial which test used in the diagnosis of HS is more reliable. In a research conducted by Bremner [11], apraclonidine was found to have higher sensitivity (93%) when compared with cocaine (40%). Similarly, apraclonidine sensitivity was determined as 87% by Koc et al [12]. The other disadvantages of cocaine are it’s being more expensive and less available. Therefore, it is recommended that apraclonidin should be the “gold standard” pharmacological test for diagnosing HS [11]. However, the test must be performed cautiously within hours after symptom onset, and infants under 1 year of age [11]. There are two main issues restricting the clinical use of apraclonidine. The first issue is the potential side effects, especially in children. In a study conducted by Watts et al [13]., drowsiness and unresponsiveness has been reported in infants under the age of 6 months after topical administration of 1% apraclonidine. Furthermore, hypotension, bradycardia, somnolence, and lethargy have been reported as other side effect related to alpha-adrenergic receptor agonism [2,13-15]. Although there are limited reports on the safety of apraclonidine in children younger than 10 years old [16,17], it is still the preferred drug diagnosing HS in infants and young children [1,18]. Another concern associated with topical apraclonidine usage is that the test results are negative in the early period after interruption of the sympathetic innervation. Because upregulation of the postsynaptic adrenergic receptors may require a certain period after sympathetic denervation, pupil dilation may not be achieved in an acute case [19]. The apraclonidine test can be positive between 1 month and 10 years after sympathetic interruption [7,20-27]. In our study, we found a high rate of apraclonidine positivity (92.5%) similar to Bremner's study. When we evaluated apraclonidine negative cases, we noticed that 2 patients were idiopathic and 1 patient was related to a central metastasis. However, the test was positive in all patients with second and third order neuron involvement. As the clinical picture was very typical we did not perform further evaluation such as cocaine test in 3 patients who had negative response to 0.5% apraclonidine.
This study has some limitations. First, it has limited statistical power due to relatively small sample size. Second, cocaine test was not used as a diagnostic test. We therefore could not compare the two agents. Third, we could not detect whether the apraclonidine test became positive after the acute period in patients who had a negative response initially. Fourth, our findings do not reflect the entire population as we only evaluated adult HS patients.