Horner syndrome (HS) was first noted in 1852 by Claude Bernard but was first described as a syndrome in 1869 by Johann Friedrich Horner. The syndrome is caused by any disruption along the oculosympathetic pathway (OSP) and is characterized by ipsilateral blepharoptosis, pupillary miosis, and facial anhidrosis (1). The preganglionic OSP extends from the posterolateral hypothalamus, down through the brainstem to the cervical (C8) and thoracic (T1–T2) spinal levels, and finally back up along the cervical sympathetic chain to reach the superior cervical ganglion. After synapsing at the superior cervical ganglion, the postganglionic portion begins and neurons travel with the carotid artery enter the cavernous sinus and eventually enter the orbit for final innervation destinations. Because this pathway is long and complex, there are many opportunities for disruptive pathology to result in HS, and clinicians must be cognizant of the broad list of benign and life-threatening etiologic possibilities.
Determining the cause of HS requires a thorough clinical examination and evaluation. Cocaine 10% drops, which inhibit norepinephrine reuptake, are traditionally used to confirm the diagnosis of HS, although in recent years the use of apraclonidine has become more popular mainly because it is cheaper and more readily available. After the diagnosis is confirmed, localization using hydroxyamphetamine, which stimulates norepinephrine release from postganglionic fibers, helps determine whether the pathology is preganglionic (first- or second-order neuron HS) or postganglionic (third-order neuron HS). Although imaging is an important and often used method for evaluating patients with HS, extensive imaging is costly and frequently unrevealing.
Utilization of pharmacologic localization and imaging recommendations is controversial (2). In a new era in which CT and MRI are widely available and used, there has been a major shift toward broad, nontargeted imaging for every HS patient with or without pharmacologic localization. In our study, we present a retrospective series of 200 patients with HS evaluated over the course of 22 years to determine 1) the etiology of HS, and 2) the yield of localization-guided imaging. We provide our recommendations for pharmacologic localization and imaging for patients with HS.
A retrospective chart review was performed on all patients with HS examined in an outpatient setting by 1 neuro-ophthalmologist (K.C.G.) at Cincinnati Eye Institute (CEI) between 1994 and 2016. Institutional review board approval from the University of Cincinnati was obtained.
The study population included all patients older than 18 years with a diagnosis code of HS. Inclusion criteria required that the patient had anisocoria with or without ptosis, pharmacologic confirmation of HS using 10% cocaine drops, and a full neuro-ophthalmic evaluation.
Confirmation of HS using 10% cocaine drops was considered positive if there was at least 1 mm of anisocoria 30 minutes after topical instillation or any increase in the amount of anisocoria. This was usually followed by pharmacologic testing using 1% hydroxyamphetamine drops a week later to localize the syndrome as preganglionic or postganglionic whenever possible. Hydroxyamphetamine testing was not performed if the patient already had head and neck imaging before their visit, symptoms occurred immediately after a neck procedure, symptoms were determined to be congenital or urgent imaging was needed because of concern for internal carotid artery dissection.
Patients with preganglionic HS, determined by pharmacologic localization, were recommended to undergo contrast-enhanced MRI of the entire OSP.
Patients were considered to have a “complete workup” if they received pharmacologic testing with both cocaine and hydroxyamphetamine and had the appropriate imaging protocol as described.
Data collected included age, sex, medical history, relevant information from history and physical examination, duration of symptoms, laterality, hydroxyamphetamine testing results whenever available, and imaging results.
Patient data analysis was performed using Microsoft Excel 2013 (MSO 32-bit part of Microsoft Office Professional Plus 2013).
We initially reviewed 259 charts with the coded diagnosis of HS between years 1994 and 2016. Two hundred charts met our inclusion criteria. The other 59 were excluded because patients were younger than 18 years, lost to follow-up for additional testing or imaging, or had missing required information (Fig. 1).
Of the 200 patients included in the study, 114 (57%) were female, 86 (43%) were male, and the mean age was 52.4 years (range 18–82 years). Laterality was fairly even with 103 (51.5%) involving the right side and 97 (48.5%) the left. Most patients, 175 (87.5%), had both anisocoria and ptosis. Twenty-one (10.5%) had only anisocoria without ptosis, and 4 (2%) were believed to have anisocoria by the referring physician but only had ptosis on presentation.
Of the 200 patients, 137 (68.5%) were tested with hydroxyamphetamine drops, and 132 (96.4%) of those tested received imaging and, therefore, considered to have a complete workup (Fig. 1). The remaining 5 patients tested with hydroxyamphetamine did not have imaging done because old photographs proved that their anisocoria and ptosis were longstanding. Sixty-three patients (31.5%) did not receive hydroxyamphetamine drops because they already had head and neck imaging before their visit, symptoms occurred immediately after a neck procedure, symptoms were determined to be congenital, or urgent imaging was needed because of concern for carotid artery dissection.
Of the 132 patients who had a complete workup, 86 (65.2%) had postganglionic HS and 46 (34.8%) had preganglionic HS, determined by pharmacologic testing. Most cases of both postganglionic (70 patients, 81.4%) and preganglionic (33 patients, 71.7%) HS had no identifiable cause on history, examination, and/or imaging and were considered idiopathic. Various other etiologies for HS were determined in both preganglionic and postganglionic categories (Table 1). Of those who received a complete workup, targeted imaging resulted in an otherwise unknown diagnosis in 10 (21.7%) of the 46 patients with preganglionic HS and 7 (8.1%) of the 86 patients with postganglionic HS (Table 2).
Among the 63 patients who did not receive hydroxyamphetamine testing, 47 (74.6%) had imaging of the entire OSP. Imaging in this group of patients resulted in findings in 7 (14.9%) cases, ipsilateral to the side of the HS and along the OSP, including 3 internal carotid artery dissections, 2 strokes, 1 brain mass, and 1 neck mass. Thirty (47.6%) of the 63 cases with imaging but no pharmacologic testing were classified as idiopathic. The other 16 (25.4%) did not have hydroxyamphetamine testing or imaging, for reasons including longstanding anisocoria and ptosis proven by old photographs, symptoms noted by the patient immediately after a neck procedure, and intermittent ptosis/anisocoria associated with cluster headaches. None of the cases within this subgroup were classified as idiopathic. The remaining diagnoses given to patients with HS without hydroxyamphetamine testing are summarized in Table 1.
A majority consisting of 147 of our 200 patients (73.5%) noticed their anisocoria and/or ptosis before physical examination, ranging from 3 days prior to many years. Fifty-three (26.5%) patients had never noticed any pupil or lid abnormality before examination by the referring physician. In this subset of 53 patients, 11 (20.8%) had positive imaging, including 4 with neck mass, 1 with brain mass, and 3 previously treated for carotid artery dissection. In this group, the 2 patients with arterial dissection and 2 patients who had experienced a stroke were not tested with hydroxyamphetamine drops because they had head and neck imaging done before their presentation. All these patients had their lesions ipsilateral to the side of HS and along the OSP. All the other patients had hydroxyamphetamine eyedrop testing.
Eighteen of the 200 (9.0%) patients had pathology considered to be serious, including carotid artery dissection, brain, or neck mass. Of the 7 patients with artery dissections, 4 had sudden onset ptosis/anisocoria with pain after straining and 3 were referred after diagnosis and treatment of the dissection. Those patients had other systemic and neurologic findings as well related to their stroke. Of the 3 patients with a brain mass, 2 had acute onset of ptosis/anisocoria. The other patient was asymptomatic with a pituitary macroadenoma that was compressing the cavernous sinus and, although unusual, could have been the cause of HS in this patient. Of the 8 neck masses, duration of anisocoria and/or ptosis was unknown, and no pain was reported. All remaining patients denied other symptoms or relevant history, except for patients with acute pain and those who had a stroke. All other patients had no other clinical findings.
Correctly diagnosing HS and proceeding with an appropriate evaluation is critical because HS may be the initial presentation of life-threatening conditions. However, there is controversy regarding what constitutes appropriate evaluation when it comes to pharmacologic localization and imaging (2–4).
Several groups have made various recommendations despite only using a small population size analysis (2–4). These are primarily based on either preganglionic or postganglionic neuronal localization (5), imaging specific to suspected pathologies (3), or imaging of the entire OSP on every patient with HS (2). Although imaging often is at the forefront of physician minds, pan-imaging is often unnecessary for patient evaluation resulting in high medical costs and inappropriate use of medical resources.
Before the modern imaging era, Maloney et al (6) and Giles and Henderson (7) studied 450 and 260 patients, respectively, with HS to determine the etiology based on history, and examination and surgical findings. Both studies included inpatients and outpatients. Maloney et al found that 40% of HS cases were idiopathic, whereas Giles et al reported head and neck masses to be the most common cause. Keane (8) found in their inpatient population of 100 patients that stroke was the most common cause. The variation among these studies stems mainly from the diversity of the studied populations—inpatient vs. outpatient, ophthalmology vs. neurology clinics, and the means used to determine etiology.
Now in the era of modern imaging, our study and others (2–4) have shown that idiopathic HS in adults is the most common etiology in an outpatient setting. However, the diagnostic yield of imaging in these reports differed from ours. Almog et al (3) had a 64% positive imaging yield in nonisolated HS and 11% in isolated HS. Both inpatients and outpatients were included, and patient workup was based on history and the suspected etiology at presentation. Digre et al (4) used localizing pharmacologic drop testing and showed a positive imaging yield of 33% in 33 patients. Chen et al (2) used imaging of the entire OSP in 27 patients, which resulted in a yield of 22%. The latter 2 studies only looked at outpatients. Imaging technology has advanced significantly over the span of our study period (20 years), and this factor likely influenced our imaging yield results.
Several reports have addressed whether or not pharmacologic localization is a necessary part of the HS workup. Almog et al (3) recommended imaging based on the patient's history and clinical examination without performing any localizing testing, arguing that two-thirds of their patients with HS had a known etiology on initial presentation. They believed that the majority of the remaining patients had enough clinical information permitting targeted imaging and only a minority required imaging of the entire OSP. Al-Moosa and Eggenberger (9) reviewed the literature on HS and suggested that, in adults, it may be possible to defer imaging of isolated HS, especially if there is evidence of chronicity. Although we agree that some clinical presentations may predict etiology, it can be dangerous to solely rely on clinical symptoms in a patient with HS.
In our group of patients, of the 53 patients who never before recognized their own anisocoria and/or ptosis, 8 (15.1%) had serious pathology on imaging. This finding reflects the importance of a thorough evaluation for all patients regardless of duration or acuteness of symptoms. In addition, 19 (9.5%) had what we considered to be serious pathology, including a brain mass, neck mass, or carotid artery dissection. In this subset of patients, pain and/or acute onset of symptoms were present in only 6 (31.5%) of these patients.
In our study, the overall yield in discovering new pathology in patients with HS was 13.4%. The yield in patients who obtained a complete workup was 21.7% in preganglionic lesions, and 8.1% in postganglionic lesions. Of patients with imaging but without hydroxyamphetamine testing, the yield was 14.9% but may be biased, as some of these patients had forgone pharmacologic localization because of urgent concern for serious pathology. Patients who were otherwise asymptomatic and never previously noticed their anisocoria and/or ptosis demonstrated a higher than expected imaging yield of 22.6% (Table 2).
The financial burden of radiological imaging in the era of cost-cutting practice of medicine supports our targeted imaging approach. There is no doubt that routinely imaging the entire OSP poses a financial cost to both the patient and the health care system.
This study is limited by many factors including 1) its retrospective nature, 2) the improvements in MRI technology over the study period and the variation among the different imaging centers, 3) the argument of possible false localization (false-negative hydroxyamphetamine testing) because not every patient got a complete workup, and 4) the applicability and availability of pharmacologic testing at different institutions and community settings. In addition, we are aware of the time constraints imposed for correctly administering and interpreting topical eyedrop tests (10). Also, there are limitations to the sensitivity of pharmacologic testing (11).
In conclusion, because both benign and life-threatening processes are associated with HS, a thorough clinical evaluation is required regardless of duration of symptoms and patient presentation. Once a lesion is localized clinically through a combination of physical examination results and pharmacological testing, the radiologic examination can be tailored appropriately. For postganglionic HS, MRI of the head should be adequate. For preganglionic HS, we recommend imaging the entire OSP.
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© 2017 by North American Neuro-Ophthalmology Society
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