Case
A 40 year old woman presents with neck pain and anisocoria after a motor vehicle accident. The visual acuity is normal bilaterally. There is 1 mm of ptosis and upside down ptosis on the right (OD). The right pupil measures 3 mm and the left pupil measures 4 mm in the light. In the dark the pupils measure 3.5 mm OD and 6 mm OS (i.e., the anisocoria increases in the dark with a dilation lag OD). The remainder of the eye exam is normal.
Clinical Diagnosis of Horner Syndrome. Horner syndrome results from disruption of sympathetic innervation to the eye. It is characterized clinically by unilateral miosis, facial anhidrosis, ipsilateral upper lid ptosis, and mild lower lid elevation (upside-down ptosis). The ptosis and upside-down ptosis are due to denervation of the Müller muscle in the upper lid and the analogous lower lid muscle, respectively. The combination of upper and lower lid ptosis may create a false impression of enophthalmos. In the acute phase, conjunctival hyperemia and ocular hypotony can also be present. Sometimes the presence of these features, as well as an observed reduced dilation in dim light, are enough to bypass pharmacologic pupil testing.
Pupillometry data from a patient with oculosympathetic paresis (Horner syndrome) in his right eye. (a) both pupils constrict normally following a brief (1 second) flash of light, but the right pupil is slow to redilate (arrow) following cessation of the stimulus. (b) in a second experiment, after a 10 second light stimulus (green bar), the left pupil redilates more quickly and shows a mydriatic response (startle response, SR+) to a loud noise; in contrast the right pupil is slower to redilate and the startle response is almost absent (SR−)
Causes of Pseudo-Horner syndrome
Physiologic anisocoria | Physiologic anisocoria plus levator disinsertion |
|---|---|
Chronic tonic pupil | A longstanding Adie’s pupil becomes smaller over time (little old Adie’s). Not only does the Adie’s pupil becomes smaller than the normal pupil, but it also dilates poorly in the dark due to aberrant regeneration of the iris sphincter muscle by accommodative parasympathetic nerves. In such cases, the inequality is greatest in the dark. |
Aberrant reinnervation | Aberrant reinnervation of the iris sphincter by accommodative or extraocular motor neurons. Usually associated with impaired light reflex. |
Argyll Robertson pupil | Pupillary abnormality suggestive of syphilis. Pupils are miotic, dilate poorly in the dark, and do not react to the light but exhibit a brisk near response (light-near dissociation). Argyll Robertson pupils can sometimes be asymmetrically affected, resulting in an anisocoria in dim light. |
Pharmacological miosis | Parasympathomimetics: carbachol, methacholine, organophosphate esters (flea collars of pets), physostigmine, pilocarpine |
Sympatholytics: α-2 agonists (brimonidine) | |
Acute iritis | Post-traumatic prostaglandin release |
Chronic iritis | Iris synechiae |
Pigmentary dispersion syndrome | Dilator muscle atrophy |
Pseudoexfoliation syndrome | Dilator muscle atrophy |
The presence of dilation lag is helpful in making the diagnosis of an oculosympathetic deficit, but in many cases, it can be subtle and equivocal. Most lesions causing Horner syndrome are partial and incomplete which may explain why the clinical signs of Horner syndrome can be subtle when only a small percentage of fibers are impaired. Furthermore, the effect of a sympathetic lesion on the dilator muscle, Mueller’s muscle, blood vessels and sweat glands may be disproportional, owing to the topographic segregation of the fibers innervating the various target tissues within the sympathetic nerve. For example, an incomplete lesion may damage more pupil dilator fibers than eyelid fibers or vice versa. The more subtle or equivocal cases often require topical pharmacological testing to confirm an oculosympathetic nerve deficit (see below).
There is not a significant difference between the US and UK approach towards diagnosing an oculosympathetic deficit on clinical observation. Some academic centers have access to computerized pupillometry, which is useful for quantifying the dynamics of dilation lag, but not necessary. Some clinicians have utilized low-cost video cameras that use infrared illumination to record the dynamics of dilation lag (low light level feature that many commercial video cameras have). One can also use a smartphone in video mode to record the pupil dynamics as many of the newer smartphones can also record the pupils in low light levels. However, infrared video is more ideal since dark irides reflect infrared light and appear light colored against the contrast of a dark pupil.
Effect of (a) 4% cocaine or (b) 0.5% apraclonidine drops on the pupil. The appearance of the pupils before exposure to these drugs is shown in the upper panels, and after in the lower panels. The side of the oculosympathetic paresis (Horner syndrome) is indicated with a red circle
Effect of 1% hydroxyamphetamine drops on the pupils of patients with oculosympathetic paresis caused by a pre-ganglionic lesion (a) and a post-ganglionic lesion (b). The appearance of the pupils before exposure to these drugs is shown in the upper panels, and after in the lower panels. The side of the oculosympathetic paresis (Horner syndrome) is indicated with a red circle
In both the UK and US, there is much less use of cocaine for pharmacologic diagnosis of Horner syndrome due to the regulation of cocaine as a controlled substance. Most outpatient clinical practices do not keep cocaine on hand for testing, as it must be stored in a locked, controlled and monitored storage area and usually has only a shelf life of 1 month. Thus the relative lack of ready availability of cocaine has limited its use in an outpatient clinical setting. Apraclonidine is not a controlled drug and therefore, is much more readily available and convenient to use. However, its use is limited by the potential CNS depression and respiratory depression when given topically to infants. Also, since adrenergic supersenstivity is required for the diagnostic efficacy of apraclonidine, it is not used in the setting of an acute Horner syndrome (less than 2 days duration) such as in a suspected carotid dissection.
Localization of Sympathetic Denervation . After the diagnosis of Horner syndrome is made with sufficient certainty, the next step is to search for the cause. In some cases, this may be obvious, based on the coexistence of other symptoms, signs and history. For example, acute Horner syndrome can occur after surgical trauma along the course of the ocular sympathetic nerve, which may be a complication of spinal cord surgery, thoracic surgery or surgery in the neck. Head trauma, including basilar skull fractures, may injure cranial nerves in combination with the sympathetic nerve. Acute facial, jaw and ear pain in association with a Horner syndrome is often a tip-off that a carotid dissection has occurred. Brainstem signs such as skew deviation, lateropulsion of the eyes with eyelid closure and hemisensory loss in combination with a Horner syndrome may signal a lateral medullary infarct, sometimes due to a vertebral artery dissection. In some patients (especially males), orbital pain which may be associated with lacrimation, headaches and Horner syndrome may represent a form of cluster headache. In most cases, the cause of Horner syndrome is uncertain and not obvious based on the patient’s history, symptoms and examination. The next step requires imaging of the ocular sympathetic nerve pathway. Narrowing down the site of the lesion to the first, second or third order neuron can help focus the neuro-imaging protocol and scan window for image acquisition. It also helps to focus attention to certain regions during radiographic interpretation.
A good understanding of the anatomy of the oculosympathetic pathway is critical when trying to localize and determine the cause of Horner syndrome. The sympathetic outflow to the iris dilator muscle is a paired (right and left), 3-neuron chain without decussation. The first-order neuron (central) originates in the hypothalamus and descends through the brainstem into the lateral column of the spinal cord, where it synapses at the cervicothoracic junction (level C7-T2). The second-order neuron (preganglionic) leaves the spinal cord and travels over the apex of the lung to synapse at the superior cervical ganglion at the level of the carotid artery bifurcation. The third-order neuron (postganglionic) follows a course along the internal carotid artery, passes through the cavernous sinus where the postganglionic fibers are briefly associated with the abducens nerve and then the ophthalmic nerve (V1). The fibers then travel with the long ciliary nerve through the superior orbital fissure, and end within the iris dilator muscle and the retractor muscles of the upper and lower eyelids (Müller muscles).
Causes and location of Horner syndrome
Causes | Other signs and symptoms | |
|---|---|---|
First-order | Infarction Wallenberg syndrome Hypothalamic, pontine, midbrain Neoplasm Hypothalamic, brainstem, spinal cord Demyelination Syringohydromyelia Trauma or disc herniation | Brainstem lesion: vertigo Sensory deficits, nystagmus Ataxia, diplopia, facial weakness Spinal cord lesion: quadra- or Paraparesis, sensory deficit Bladder and bowel difficulty Hyperreflexia |
Second-order | Trauma or surgery Neck Brachial plexus Heart Lung Neoplasm Pancoast tumor Thyroid tumor Neurofibroma, neuroblastic tumors Sympathetic schwannoma | Preganglionic Horner can be associated with ipsilateral arm pain, weakness, and numbness |
Third-order | Mediastinal or neck lymphadenopathy Compression Carotid dissection or thrombosis Cavernous sinus lesion Skull base, parasellar, and orbital lesions Head or orbital trauma Trigeminal autonomic syndromes Cluster headache Paroxysmal Hemicrania continua Petrositis or otitis media | Ipsilateral facial, neck, ear pain Ocular motor nerve palsy Trigeminal neuropathy Ipsilateral headache, periocular Pain, rhinorrhea, conjunctival Injection, tearing Ear pain, hearing loss, vertigo Diplopia, proptosis |
Following at least 72 hours after cocaine pharmacologic testing to confirm the diagnosis of Horner syndrome, 1% hydroxyamphetamine is applied topically to both eyes. Since cocaine blocks the reuptake of adrenergic substances into the nerve ending, residual cocaine may block the uptake of hydroxyamphetamine and confound the test if used within 72 hours of the cocaine test. If apraclonidine was initially used to confirm the diagnosis of Horner syndrome, then hydroxyamphetamine testing may be performed in 24 hours. The pupils are measured before and 40 to 60 minutes after the drops. In first- and second-order Horner syndrome, both pupils will dilate, and occasionally the involved pupil will dilate more than the normal one due to supersensitivity (see Figure 10.3a). In contrast, in third-order Horner syndrome (postganglionic), the involved pupil dilates less than the normal pupil, which manifests as an increase in the anisocoria post-hydroxyamphetamine (see Figure 10.3b). Hydroxyamphetamine may result in a false negative postganglionic result when used in the acute phase since it takes about a week after injury for the synaptic stores of norepinephrine to be depleted at the presynaptic terminal of the sympathetic nerves innervating the iris dilator muscle.
While hydroxyamphetamine may be useful, sometimes the change in anisocoria can be equivocal for localization to the pre or postganglionic site. A thorough history alone may determine the etiology of Horner syndrome. For example, if there has been previous accidental or surgical trauma to the chest, neck, or upper spine, no further work-up is typically necessary, although it is helpful to document that the Horner syndrome is temporally related to the surgery or trauma by checking old photographs. Associated signs and symptoms might help localize the lesion. In a central Horner syndrome, there will often be associated neurological findings. The presence of ataxia, skew deviation, nystagmus, and hemisensory deficit, for example, would strongly suggest a medullary lesion and magnetic resonance imaging (MRI) of the brain would be recommended. An acute Horner syndrome associated with ipsilateral facial or neck pain requires urgent imaging of the neck to exclude a carotid dissection or thrombosis. Trigeminal autonomic syndromes, such as cluster headache, should remain diagnoses of exclusion since carotid dissections can present in a similar fashion. Arm pain, weakness, and numbness would suggest a lesion near the lung apex, brachial plexus, or cervical spine. The presence of an ipsilateral sixth, third, or fourth nerve palsy or trigeminal dysfunction would suggest a lesion in the cavernous sinus and should be further evaluated with neuroimaging. Table 10.2 summarizes potential causes of Horner syndrome in adults.
Pediatric Horner Syndrome. As mentioned earlier, apraclonidine can be associated with CNS and respiratory depression when used in children younger than 1 year old. In cases of congenital or early onset Horner syndrome hydroxyamphetamine may yield false localizing results. This is due to orthograde transsynaptic degeneration at the superior cervical ganglion following early damage to the preganglionic neuron. Transsynaptic degeneration results in fewer postganglionic neurons, even in the absence of postganglionic injury, and therefore a false positive postganglionic hydroxyamphetamine test.
A diagnosis of Horner syndrome can be confirmed without pharmacologic testing in a child with suspected Horner syndrome who presents with one of the following: (1) hemifacial flush on the normally innervated side and facial blanching on the side of oculosympathetic defect (can be seen when the child is crying or nursing), (2) naturally curly hair on the normal side and straight hair on the affected side, (3) iris heterochromia with an ipsilateral lighter colored iris (might not be detected until the age of 9 to 12 months).
These findings are typically seen with congenital Horner syndrome or sympathetic damage within the first year of life, but rarely with oculosympathetic disruption acquired after 1 year of age. While a history of birth trauma or presence of heterochromia suggests a benign etiology, it does not entirely exclude the possibility of an underlying neoplasm. A mass lesion such as neuroblastoma is the main concern in the presence of Horner syndrome in a child of any age without a history of surgery in the area of the sympathetic chain [4]. Urine catecholamine levels alone cannot rule in or out neuroblastoma. Emphasis should be placed on a thorough physical examination and imaging studies of the brain, neck, and chest. MRI is the imaging modality of choice in the pediatric population.
Neuroimaging for Evaluation of Horner Syndrome
In most cases, neuro-imaging is an integral part of the evaluation of Horner syndrome [5], unless the history, symptoms and exam provide an unequivocal cause. There are a number of studies that advocate for a systematic approach to localization of the oculosympathetic lesion in Horner syndrome using associated signs and symptoms, and then performing sub-sequent anatomically focused imaging with either MRI or computed tomography (CT) with angiography. Digre and colleagues [6] separated patients based on preganglionic and postganglionic lesions with pharmacologic testing or clinical localization, and imaged the region. Davagnanam and colleagues [7] developed an imaging algorithm separating patients based on the localization to first, second and third order neuron lesions. In their algorithm, first-order neuron lesions were imaged with MRI, including the brain, cervical spinal cord, and upper thoracic spinal cord. Second and third order neuron lesions were imaged with CT angiography from the orbits to T4 to T5. However, as previously stated, most cases of Horner syndrome are isolated and cannot be readily localized to the first, second or third order neuron prior to imaging.
Patients with isolated Horner syndrome do not lend themselves to decision trees of traditional neurologic localization and have a wide variety of potentially serious causes [8]. An isolated Horner syndrome is present if the patient does not have other clinical signs to aid in localization following a thorough history and physical examination. This includes patients with pain or headache, since most of the time the pattern of pain does not provide certain localization. Of the 88 patients who did have imaging [8], 18 patients (20%) were found to have a causative lesion for their isolated Horner syndrome (Table 10.1). The most common causative lesion was a carotid artery dissection (7/88 patients). One of the imaged patients was found to have a primary malignancy, an orbital extranodal marginal zone lymphoma, and underwent focal radiation therapy. Additionally, 1 patient with known metastatic disease had a new metastatic lung lesion. Five (6%) of the 88 patients were noted to have an incidental finding on imaging, unrelated to the oculosympathetic defect, which often required additional workup.
In patients with isolated Horner syndrome in whom the diagnosis is not apparent from clinical history or examination, imaging of the oculosympathetic pathway is usually pursued. Our study found a causative lesion on imaging in 20% of patients with isolated Horner with unknown etiology [8]. Almog and colleagues [9] evaluated nine patients with isolated Horner syndrome and found a causative lesion in one patient, who had a thyroid carcinoma. Mollan and colleagues [10] reviewed cases of clinically isolated Horner syndrome and found causative lesions in 25 (54%) of 47 patients, with the most common identified etiology being carotid artery dissection in 11 of 47 patients. Chen and colleagues [11] found that 41% of all patients with Horner syndrome had an identifiable cause; however, this study did not require the presentation to be clinically isolated.
The most common cause of an isolated Horner syndrome in our study was a carotid artery dissection (7/88 patients) [8]. Carotid artery dissection has previously been reported as the most common identifiable cause of Horner syndrome [10]. In our study, of the seven patients in whom a carotid artery dissection was found, all but one patient presented with an acute-onset painful Horner syndrome. We suggest that, unless there is associated pain at the time of presentation, emergent imaging is usually not indicated. Carotid artery dissections are the leading cause of ischemic stroke in individuals younger than 45 years, which underscores the importance of making this diagnosis. A recent review in the radiology literature suggested that MRI with MRA is the imaging modality of choice to demonstrate an intramural hematoma secondary to a carotid artery dissection. Classic radiologic findings of a carotid artery dissection seen with an MRI/MRA include a hyperintense T1-weighted eccentric “crescent sign” or narrowing of the carotid artery on MRA, as noted in the imaging from a 44-year-old man from our study.
We found only one isolated Horner syndrome secondary to a primary malignancy and one patient with growth of a known metastatic neoplasm as a cause in our review. Other studies have found higher percentages of patients with Horner syndrome caused by a neoplasm, with 1 study reporting that approximately 17% of patients have a neoplasm as the cause [9].
The root of this study’s question was to help determine the value of imaging in patients with isolated Horner syndrome [8]. Imaging identified a causative lesion in 20% of patients with a clinically isolated Horner syndrome. We found that 6% of patients had an incidental finding on imaging, unrelated to the cause of the oculosympathetic defect, which underscores the advantage of localization with pharmacologic testing to assist with radiologic interpretation [7].
From the Beebe et al. study it has become more readily apparent that patients with isolated Horner benefit from radiologic investigation [8]. Given these results for patients with isolated Horner syndrome, our institution chooses to image the entire oculosympathetic pathway and use pharmacologic localization as a mean to focus interpretation of imaging, rather than to determine the modality or extent of imaging. MRI with angiography has been the modality of choice, providing imaging of the entire oculosympathetic pathway. Patients with isolated Horner syndrome should be counseled that a significant, yet small, percentage of patients are found to have a causative lesion with imaging. Patients and clinicians are often concerned about Horner syndrome being caused by a malignancy. This study found only one patient with a new primary malignancy presenting as an isolated Horner syndrome. Finally, it is currently not known whether patients with isolated Horner syndrome with unrevealing imaging need to be followed over time. Presently, these patients are usually discharged and are asked to follow up only if any new signs or symptoms develop. We are currently studying the long-term outcome of these patients to determine whether there are cases in which the cause ultimately became apparent.
If a Horner syndrome is felt to be truly isolated without accompanying cranial nerve palsy, and pharmacologically localizes to the postsganglionic location, then chest and neck imaging should be performed. An adequate neck protocol should go as far up as the skull base. Computed tomography and CT angiography (CTA) of the neck is a good choice since CT offers excellent resolution of the soft tissues of the neck and CTA provides good views of the carotid artery lumen. Alternatively, MRI/MRA of the neck (including the skull base) along with a chest CT would also provide a thorough anatomical evaluation of an isolated Horner syndrome to help determine its cause. While the presence of anisocoria in old photographs can be reassuring, it does not exclude the possibility of underlying pathology.
Imaging approaches to isolated Horner syndrome do not differ significantly between the US and UK. Imaging differences primarily vary based on accessibility for emergent or urgent need and financial constraints of different regions. Because the availability of hydroxyamphetamine eye drops for localization to pre versus post-ganglionic Horner syndrome is no longer widely available, most imaging windows include both the preganglionic and postganglionic locations of the sympathetic nerve distribution.