Horner syndrome

INTRODUCTION — 

The signs of a Horner syndrome include miosis, ptosis, and anhidrosis. Also called oculosympathetic paresis, a Horner syndrome can be produced by a lesion anywhere along the sympathetic pathway that supplies the head, eye, and neck.

Causes of Horner syndrome range from benign to serious, requiring a methodologic approach to diagnostic evaluation. The differential diagnosis differs in children and adults, leading to differences in the diagnostic approach.

This topic reviews Horner syndrome. Other causes of anisocoria and ptosis are reviewed separately:

●(See "Approach to the patient with anisocoria (unequal pupil size)".)

●(See "Approach to ptosis".)

NEUROANATOMY — 

Horner syndrome can result from a lesion anywhere along a three-neuron sympathetic (adrenergic) pathway that originates in the hypothalamus (figure 1):

●The first-order neuron descends caudally from the hypothalamus to the first synapse, which is located in the cervical spinal cord (levels C8-T2, also called ciliospinal center of Budge).

●The second-order neuron travels from the sympathetic trunk, through the brachial plexus, over the lung apex. It then ascends to the superior cervical ganglion, located near the angle of the mandible and the bifurcation of the common carotid artery.

●The third-order neuron then ascends within the adventitia of the internal carotid artery, through the cavernous sinus, where it is in close relation to the sixth cranial nerve [1]. The oculosympathetic pathway then joins the ophthalmic (V1) division of the fifth cranial nerve (trigeminal nerve).

In the orbit and the eye, the oculosympathetic fibers innervate the iris dilator muscle as well as Müller's muscle, a small smooth muscle in the eyelids responsible for a minor portion of the upper lid elevation and lower lid retraction.

CLASSIFICATION AND ETIOLOGY

Adults — The etiology of Horner syndrome in adults relates to the lesion location (table 1).

In one case series, 40 percent of 450 cases of Horner syndrome had an unknown diagnosis [2]. In the remaining 270 patients, 13 percent were related to a first-order (central) lesion, 44 percent to a second-order (preganglionic) lesion, and 43 percent to a third-order (postganglionic) lesion.

First-order syndrome — Lesions of the sympathetic tracts in the brainstem or cervicothoracic spinal cord can produce a first-order Horner syndrome (table 1).

●Lateral medullary infarction – The most common cause is a lateral medullary infarction, which produces a Horner syndrome as part of the Wallenberg syndrome. Typically, the patient presents with vertigo and ataxia, which overshadow the Horner syndrome. Other neurologic symptoms and signs include abnormal eye movements, ipsilateral limb ataxia, and a dissociated sensory loss (loss of pain and temperature sensation on the ipsilateral face and contralateral trunk). Hoarseness and dysphagia are also often present. (See "Posterior circulation cerebrovascular syndromes", section on 'Lateral medullary infarction'.)

●Other causes – Strokes, tumors, and demyelinating lesions affecting the sympathetic tracts in the hypothalamus, midbrain, pons, medulla, or cervicothoracic spinal cord are other potential causes of a central Horner syndrome [3]. Syringomyelia and cervical cord trauma can also produce a Horner syndrome when the intermediolateral columns are affected.

These central nervous system lesions are usually associated with other neurologic signs and symptoms such as weakness, sensory deficit, homonymous hemianopia, diplopia, or ataxia. Similarly, myelopathic features (unilateral or bilateral long tract signs, sensory level) indicate a lesion in the cervical or thoracic spine [4].

Second-order syndrome — A variety of pathologies in the spinal cord, thoracic outlet, or lung apex can produce a second-order or preganglionic Horner syndrome (table 1). Trauma and surgery involving these regions are common causes. Other cases are related to malignancy in these locations, which can be occult at the time of presentation with the Horner syndrome [3,5]. Ipsilateral axillary or arm pain often accompanies the Horner syndrome in these cases [2].

Lumbar epidural anesthesia can also produce a Horner syndrome due to pharmacologic disruption of the preganglionic neuron as it exits the spinal cord [6,7]. This is most often described in association with obstetric procedures; in such cases, a Horner syndrome may indicate high sympathetic blockade. (See "Overview of neuraxial anesthesia", section on 'High or total spinal anesthesia' and "Overview of neuraxial anesthesia", section on 'Subdural injection'.)

Rare cases of a second-order Horner syndrome caused by infection and/or inflammation in the neck have also been reported [3].

Third-order syndrome — Third-order Horner syndromes often indicate lesions of the internal carotid artery such as an arterial dissection, thrombosis, or cavernous sinus aneurysm [3]. Carotid endarterectomy and carotid artery stenting can also produce a Horner syndrome. (See "Complications of carotid endarterectomy", section on 'Nerve injury'.)

●Carotid dissection – An acute Horner syndrome with neck or facial pain should be presumed to be caused by cervical internal carotid dissection until proven otherwise [8,9]. Between 25 and 60 percent of patients with internal carotid artery dissections present with an isolated, painful third-order Horner syndrome [10-12]. Patients often have an antecedent history of neck trauma, but this can be subtle, and a number of carotid dissections are spontaneous events. Patients with acute carotid dissection are at a high risk for cerebral infarction, which usually occurs within the first few weeks, often within days, after onset of the Horner syndrome [13,14]. Emergent diagnostic tests should be obtained (see 'Neuroimaging to identify etiology' below). Carotid dissection is discussed separately. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".)

●Cluster headache – Horner syndrome is a common feature of cluster headache, occurring with unilateral eye or temple pain and lacrimation, generally lasting no more than an hour or two [3,15,16]. (See "Cluster headache: Epidemiology, clinical features, and diagnosis", section on 'Clinical features'.)

●Other causes – Other causes of postganglionic Horner syndrome include neck masses, otitis media, and pathology involving the cavernous sinus [3]. Abnormalities of eye movements, particularly a sixth nerve palsy, commonly occur when the cavernous sinus is involved [17]. Horner syndrome has also been described in the context of reversible cerebral vasospasm syndrome [18].

Children — The etiology of Horner syndrome in infants and children differs from that in the adult population (table 2) [19,20]. Classic causes include birth trauma, neuroblastoma, vascular anomalies of the large arteries, and chest surgery.

The most common cause is delivery-related trauma to the neck and shoulder damaging the sympathetic pathway. Associated injury to the lower brachial plexus can produce weakness in the ipsilateral forearm and hand (Klumpke's paralysis).

In the absence of a clear history of birth trauma, an acquired Horner syndrome in a child should prompt evaluation for a tumor, particularly a paraspinal neuroblastoma, which can present with a Horner syndrome [20-24].

CLINICAL FEATURES

Signs of Horner syndrome — The classic signs of a Horner syndrome are ptosis, miosis, and anhidrosis (picture 1).

●Anisocoria – The degree of anisocoria is more marked in the dark than in light. There is associated dilation lag, an asymmetry in the rate of pupillary dilation between the two eyes when the light source is moved away from the eye [25]. The Horner pupil will dilate more slowly (by 15 to 20 seconds) than the normal pupil.

●Ptosis – The ptosis is mild (less than 2 mm) and occurs as a result of paralysis of Müller's muscle, which is innervated by the sympathetic pathway, and provides only a minor component of upper eyelid elevation. The levator palpebrae superioris, which provides the major component of upper eyelid elevation, is unaffected; weakness of this muscle produces the more profound upper lid ptosis seen in third cranial nerve palsies.

In Horner syndrome, the lower eyelid is elevated as a result of weakness of the lower eyelid retractors, producing the so-called "upside-down ptosis." This further narrows the palpebral fissure.

●Anhidrosis – Anhidrosis is present in central or preganglionic (first-order or second-order) lesions (figure 1). The sympathetic fibers responsible for facial sweating and vasodilation branch off at the superior cervical ganglion along the external carotid artery and its branches. The remainder of the oculosympathetic pathway contains a few sudomotor fibers, which supply a very small strip of skin along the ipsilateral forehead. Thus, anhidrosis is not a prominent feature of postganglionic or third-order lesions [26] and is frequently not apparent to patients or clinicians, even in first-order or second-order lesions.

●Other clinical features – In infants and children, impaired facial flushing (Harlequin sign) is often more apparent than anhidrosis [27]. Acute features of sympathetic disruption can also include ipsilateral conjunctival injection, nasal stuffiness, and increased near point of accommodation [28].

A congenital Horner syndrome should be suspected when anisocoria is associated with heterochromia (unequal iris color, with the affected iris being lighter). Heterochromia occurs because formation of iris pigment in the first several months of age is under sympathetic control. Heterochromia may be apparent only if the natural iris color is relatively dark.

Associated symptoms and signs — Associated neurologic symptoms and signs can be useful in localizing the origin of the Horner syndrome:

●Brainstem signs (diplopia, vertigo, ataxia, lateralized weakness) suggest a brainstem localization.

●Myelopathic features (bilateral or ipsilateral weakness, long tract signs, sensory level, bowel and bladder impairment) suggest involvement of the cervicothoracic cord.

●Arm pain and/or hand weakness, typical of brachial plexus lesions, suggest a lesion in the lung apex.

●Ipsilateral oculomotor cranial nerve palsies, especially sixth nerve palsy, in the absence of other brainstem signs localize the lesion to the cavernous sinus.

●An isolated Horner syndrome accompanied by neck or head pain suggests an internal carotid dissection.

EVALUATION AND DIAGNOSIS

Pharmacologic confirmation of Horner syndrome — Because there are numerous causes of anisocoria and ptosis, pharmacologic tests are often useful to confirm the diagnosis of Horner syndrome.

Indications — Whether to take the time to test the pupils pharmacologically to confirm a Horner syndrome mostly depends on the clinical setting.

For example, pharmacologic testing is indicated for:

●Incidental finding in an outpatient – When a patient presents to an outpatient clinic with incidentally found isolated anisocoria, it is helpful to confirm the Horner syndrome before obtaining potentially costly and unnecessary tests.

By contrast, pharmacologic testing is not indicated in the following settings:

●Acute-onset, painful anisocoria – When a patient is seen in an emergency department with acute painful anisocoria highly suggestive of Horner syndrome, it is essential to immediately obtain appropriate investigations to look for a cervical artery dissection or a cavernous sinus lesion.

In this setting, the diagnosis of Horner syndrome is usually obvious, and pharmacologic testing would only delay appropriate testing and management.

●Known cause of a Horner syndrome – When there has been a preceding procedure on the neck, chest, skull base, or paraspinal region that could reasonably have damaged the oculosympathetic pathway, confirmation of the diagnosis may not be required.

Testing agents and procedures — Pharmacologic testing with apraclonidine or cocaine drops can confirm the diagnosis of Horner syndrome [29,30]. This can also be used to distinguish a Horner syndrome from a pseudo-Horner syndrome that is due to other causes of anisocoria or ptosis [31].

●Apraclonidine, a direct alpha-adrenergic receptor agonist, can confirm the diagnosis of Horner syndrome. Apraclonidine has weak alpha-1 and strong alpha-2 activity; the former mediates pupillary dilation, while the latter downregulates norepinephrine release at the neuromuscular junction [32].

One to two drops of 0.5% apraclonidine instilled in both eyes causes a reversal of anisocoria and ptosis in patients with Horner syndrome. In a Horner pupil, denervation supersensitivity to the alpha-1 receptor will cause that pupil to dilate (usually by approximately 2 mm), while alpha-2 stimulation in the normal eye will cause that pupil to constrict slightly (usually by <1 mm).

This test compares favorably with cocaine in the diagnosis of Horner syndrome and can be positive shortly after the onset of Horner syndrome [33,34]. False negatives are reported, especially within a few days of onset (before denervation supersensitivity has time to develop), but appear to be rare [35].

Apraclonidine should not be used in young children (less than one year old) because of potentially severe side effects including sedation, bradycardia, and respiratory distress. Recommendations for the use of apraclonidine drops in children vary among countries.

●Cocaine is an alternative to apraclonidine; it blocks the reuptake of norepinephrine at the sympathetic nerve synapse and causes pupillary dilation in eyes with intact sympathetic innervation. Cocaine has no effect in eyes with impaired sympathetic innervation, regardless of the lesion location.

After instillation of two drops of cocaine 10%, a normal pupil dilates more than the Horner pupil, increasing the degree of anisocoria; anisocoria of 1 mm or more one hour after cocaine administration is considered a positive result [30]. Cocaine drops can be used safely in children. Both false negatives and false positives have been reported [35].

●Hydroxyamphetamine drops previously used to help localize the lesion along the sympathetic pathways are now difficult to obtain and are not used [36]. Hydroxyamphetamine releases stored norepinephrine from the postganglionic adrenergic nerve endings.

One hour after instillation of 1% hydroxyamphetamine, a normal pupil and a first- or second-order Horner pupil will dilate, whereas a third-order Horner pupil will not dilate as well as the normal pupil (picture 2). The test is positive for postganglionic Horner lesions when the anisocoria increases by at least 1 mm. However, hydroxyamphetamine is not available anymore, and therefore, pharmacologic localization of the lesion is usually not performed [36].

●Pholedrine, a derivative of hydroxyamphetamine, may be more available than hydroxyamphetamine in some locations. The test using 1% pholedrine is performed in the same manner as with hydroxyamphetamine [37].

Neuroimaging to identify etiology — While many cases of Horner syndrome have no identified etiology even after extensive investigation, the possibility of a life-threatening condition dictates that some evaluation take place [2,38].

Most cases of Horner syndrome require imaging, usually with magnetic resonance imaging (MRI), unless it occurs in the setting of obvious trauma or after a surgical procedure.

For a child, unless there is a clear history of birth trauma, an acquired Horner syndrome should prompt evaluation for a tumor, particularly a paraspinal neuroblastoma, which can present with a Horner syndrome [21-24]. Testing will often include imaging studies, such as MRI of the head, neck, chest, and abdomen, as well as measurement of urinary catecholamines. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Diagnostic evaluation'.)

In adults, associated neurologic findings help identify high-yield sites of imaging investigation [35]:

●Brainstem symptoms or signs – A lateralized weakness or sensory deficit, homonymous hemianopia, diplopia, ataxia, or other cranial neuropathy indicate a brain MRI.

Depending on the age of the patient and the most likely underlying condition, specific techniques will increase sensitivity: diffusion-weighted imaging for acute cerebrovascular disease (image 1), proton-density and fluid-attenuated inversion recovery (FLAIR) sequences for demyelinating disease, and gadolinium enhancement for potential tumor.

●Myelopathic features – Ipsilateral or bilateral long tract signs and/or a sensory level indicate a cervical spinal cord MRI [4].

●Associated pain in the neck or face – An acute Horner syndrome associated with pain in the neck or face indicates prompt evaluation for carotid artery dissection by cervical and cranial MRI with T1-weighted, fat-suppressed sequences and magnetic resonance angiography (MRA) (image 2 and image 3) [39]. Alternatively, a noncontrast head computed tomography (CT) with CT angiography (CTA; which requires injection of contrast media) of the head and neck can be ordered.

Although CT and MRI can detect most internal carotid artery dissections, conventional angiography may be indicated if noninvasive vascular imaging is normal and suspicion for dissection remains. This matter is discussed in detail separately. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Choice of neuroimaging study'.)

●Ipsilateral ophthalmoparesis – A Horner syndrome with ipsilateral ophthalmoparesis, particularly involving the sixth cranial nerve, indicates a brain MRI and MRA with attention to the cavernous sinus.

●Preganglionic second-order Horner syndrome – Patients with ptosis, miosis, and anhidrosis without neurologic symptoms localizing the lesion to the central nervous system should have an MRI or CT scan of the chest to evaluate the lung apex and paravertebral area (image 4) [40]. Ipsilateral axillary or arm pain also indicate this evaluation.

●No associated ophthalmic or neurologic abnormalities – When there are no associated ophthalmic or neurologic abnormalities, the imaging evaluation cannot be so focused. In adults, imaging should extend across the paraspinal region, chest, and neck with MRI/MRA or CT and CTA to cover the region between the upper thoracic cord and the cranial base [40]. Children should also have abdominal imaging as mentioned above.

SUMMARY AND RECOMMENDATIONS

●Neuroanatomy and classification – Horner syndrome can be caused by a lesion anywhere along the three-neuron sympathetic (adrenergic) pathway that originates in the hypothalamus (figure 1). (See 'Neuroanatomy' above.)

●Causes – The common etiologies of Horner syndrome are categorized by which of the three neurons is affected. The differential diagnosis is also distinct in children versus adults (table 1 and table 2). (See 'Classification and etiology' above.)

●Clinical features – Classic signs of a Horner syndrome include miosis, ptosis, and anhidrosis (picture 1).

•Miosis is typically mild, associated with a dilation lag, and most prominent in dim light.

•Ptosis is mild; the lower lid may be slightly elevated.

•Anhidrosis occurs only with first-order or second-order lesions and is often difficult to identify. (See 'Clinical features' above.)

●Diagnosis – Horner syndrome should be confirmed pharmacologically with apraclonidine; cocaine is used in young children because apraclonidine is unsafe in infants.

One to two drops of 0.5% apraclonidine instilled in both eyes causes a reversal of anisocoria and ptosis in patients with Horner syndrome. (See 'Testing agents and procedures' above.)

●Evaluation for underlying cause – Imaging is required when the cause of a Horner syndrome is not known. Imaging can be targeted according to accompanying abnormalities. As examples:

•Brainstem symptoms or signs (eg, lateralized weakness or sensory deficit, homonymous hemianopia, diplopia, ataxia, or other cranial neuropathy) indicate a brain MRI.

•Pain in the neck or face indicates an urgent evaluation for carotid artery dissection by neck MRI with T1-weighted, fat-suppressed sequences and magnetic resonance angiography (MRA).

When the Horner syndrome is an isolated abnormality, imaging with MRI or CT must extend from the cranial base to the upper thoracic cord; in children, it should include the abdomen because of the concern for neuroblastoma. (See 'Neuroimaging to identify etiology' above.)