Horner syndrome

INTRODUCTION — Horner syndrome is a classic neurologic syndrome whose signs 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 range from benign to serious, requiring a methodologic approach to diagnostic evaluation. The differential diagnosis also 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" and "Overview of 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 — The etiology of Horner syndrome in adults relates to the lesion location (table 1). In one large case series, 40 percent of 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.

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".)

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. 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 [3].

Second-order syndrome — Second-order or preganglionic Horner syndromes can occur with trauma or surgery involving the spinal cord, thoracic outlet, or lung apex. Other cases are related to malignancy, which can be occult at the time of presentation with the Horner syndrome [4]. 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 [5]. 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'.)

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. Carotid endarterectomy and carotid artery stenting can also produce a Horner syndrome [6]. (See "Complications of carotid endarterectomy", section on 'Nerve injury'.)

An acute Horner syndrome with neck or facial pain should be presumed to be caused by carotid dissection until proven otherwise [7,8]. Between 25 and 60 percent of patients with internal carotid artery dissections present with an isolated painful third-order Horner syndrome [9-11]. 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 [12,13]. Emergent diagnostic tests should be obtained (see 'Neuroimaging' below). Carotid dissection is discussed separately. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".)

Other causes of postganglionic Horner syndrome include neck masses, otitis media, and pathology involving the cavernous sinus. Abnormalities of eye movements, particularly a sixth nerve palsy, commonly occur when the cavernous sinus is involved [14].

A 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 [15,16]. (See "Cluster headache: Epidemiology, clinical features, and diagnosis", section on 'Clinical features'.)

Children — The etiology of Horner syndrome in infants and children differs from the adult population [17]  (table 2). 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 is known to present with a Horner syndrome [18-21]. Testing will often include imaging studies, such as magnetic resonance imaging (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 'Is there a role for neuroblastoma screening?'.)

CLINICAL FEATURES — The classic signs of a Horner syndrome are ptosis, miosis, and anhidrosis (picture 1 and picture 2).

●The degree of anisocoria is more marked in the dark than in light. There is associated dilation lag, an asymmetry in pupillary redilation between the two eyes when the light source is moved away from the eye [22]. The Horner pupil will redilate more slowly (by 15 to 20 seconds) than the normal pupil.

●The ptosis is minor (less than 2 mm) and occurs as a result of paralysis of the Müller's muscle, which is innervated by the sympathetic pathway. The lower as well as the upper lid is affected, producing the so-called "upside-down ptosis." This further narrows the palpebral fissure. The levator palpebrae superioris is unaffected; weakness of this muscle produces the more profound upper lid ptosis seen in third cranial nerve palsies.

●Anhidrosis is present in central or preganglionic (first- 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 forehead. Thus, anhidrosis is not a prominent feature of postganglionic or third-order lesions [23]. This sign is frequently not apparent to patients or clinicians.

In infants and children, impaired facial flushing (Harlequin sign) is often more apparent than anhidrosis [24]. Acute features of sympathetic disruption can also include ipsilateral conjunctival injection, nasal stuffiness, and increased near point of accommodation [25].

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

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 extraocular pareses, particularly a 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 tests — Pharmacologic tests can be useful to confirm the diagnosis of Horner syndrome and to localize the lesion.

Whether to take the time to test the pupils pharmacologically or not to confirm a Horner syndrome mostly depends on the duration of the anisocoria and the location of the consultation:

●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, pharmacologic testing would only delay appropriate testing and management.

●When a patient presents to an outpatient clinic with incidentally found isolated anisocoria, confirming the Horner syndrome before obtaining potentially costly and unnecessary tests is helpful. Unlike cocaine drops, apraclonidine drops are readily available, and are a very reliable way to confirm (or to rule out) a Horner syndrome in adults or even older children.

However, localization of the lesion along the sympathetic pathway with hydroxyamphetamine is much less often done, and many experts do not recommend its routine use prior to obtaining the work-up of a confirmed Horner syndrome. The test is poorly reliable in children, and the difficulty in obtaining such drops limits its use to very specialized centers in most cases. Additionally, it cannot be performed on the same day as the apraclonidine test, making it necessary for the patient to come back a few days later.

Confirmation of Horner syndrome — Pharmacologic testing with cocaine or apraclonidine drops can confirm the diagnosis of Horner syndrome in subtle cases [26,27]. This can also be used to distinguish a Horner syndrome from a pseudo-Horner syndrome due to physiologic anisocoria in the setting of mild eyelid asymmetry or aponeurotic ptosis [28]. If the diagnosis of Horner syndrome is clear clinically, then use of cocaine or apraclonidine drops to confirm the diagnosis can be avoided, as their administration will interfere with the hydroxyamphetamine test for localization.

Cocaine 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. One hour after instillation of two drops of cocaine (4 or 10 percent), a normal pupil dilates more than the Horner pupil, increasing the degree of anisocoria; anisocoria of 1 mm or more after cocaine administration is considered a positive result [27].

Apraclonidine, a direct alpha-adrenergic receptor agonist, has been proposed as an alternative to cocaine in confirming 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 [29]. 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). Thus, one to two drops of 0.5 percent apraclonidine instilled in both eyes causes a reversal of anisocoria in patients with Horner syndrome. Comparison testing in small series of patients suggests that this test compares favorably with cocaine in the diagnosis of Horner syndrome [30,31]. Apraclonidine should not be used in young children (less than one year old).

Localization of the lesion — Hydroxyamphetamine eye drops will differentiate between a lesion affecting the first- (brainstem or cervical cord) or second-order (chest or neck) neuron and one affecting the third-order or postganglionic neuron (above the superior cervical ganglion at the carotid bifurcation). There is no pharmacologic test to distinguish between first- and second-order lesions. Because cocaine may interfere with the uptake and efficacy of hydroxyamphetamine drops, it is recommended that 24 to 72 hours elapse between the two tests [32].

Hydroxyamphetamine releases stored norepinephrine from the postganglionic adrenergic nerve endings. One hour after instillation of 1 percent 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. This test has a sensitivity of 93 to 96 percent and a specificity of 84 percent for detecting postganglionic lesions [2,33,34]. This test is not reliable in children in whom transsynaptic degeneration occurs [24].

An alternative to hydroxyamphetamine is its derivative, pholedrine, which may be more available than hydroxyamphetamine in some locations. The test using 1 percent pholedrine is performed in the same manner as with hydroxyamphetamine [35].

Neuroimaging — 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 [2,36]. 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.

Associated neurologic findings and/or use of the hydroxyamphetamine test help identify high-yield sites of investigation:

●Brainstem symptoms or signs (eg, lateralized weakness or sensory deficit, homonymous hemianopia, diplopia, ataxia) 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, 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 will typically accompany cervicothoracic lesions [3]. When present, an MRI of the cervical spinal cord is indicated.

●An acute Horner syndrome associated with pain of the neck or face should prompt an emergent evaluation for carotid artery dissection. An axial MRI of the neck with T1-weighted, fat-suppressed sequences and magnetic resonance angiography (MRA) will detect most internal carotid artery dissections (image 1) [37]. However, conventional angiography remains the gold standard.

●A Horner syndrome with accompanying ophthalmoparesis, particularly involving the sixth cranial nerve with no other brainstem signs, should focus the neuroimaging study (usually MRI) on the cavernous sinus.

●Patients who have a preganglionic Horner syndrome (second-order syndrome) without neurologic symptoms localizing the lesion to the central nervous system should have an MRI or computed tomography (CT) scan of the chest to evaluate the lung apex and paravertebral area [38].

●A new Horner syndrome in a child without obvious birth or other traumatic association should initiate an evaluation for tumor, particularly neuroblastoma. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Is there a role for neuroblastoma screening?'.)

SUMMARY AND RECOMMENDATIONS

●Classic signs of a Horner syndrome include miosis, ptosis, and anhidrosis. The miosis is typically mild, associated with a dilation lag and most prominent in dim light. The ptosis is also mild and also involves the lower lid. Anhidrosis occurs with first- or second-order lesions only. (See 'Clinical features' above.)

●The presence of a Horner syndrome can be confirmed pharmacologically with either cocaine or apraclonidine eye drops. (See 'Confirmation of Horner syndrome' above.)

●A 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.)

●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.)

●Hydroxyamphetamine eye drops can help distinguish a third-order (postganglionic) Horner syndrome from either a first- or second-order syndrome. (See 'Localization of the lesion' above.)

●In the absence of a clear history of trauma as the cause of Horner syndrome, imaging studies will be required. High-yield sites of imaging can be identified based on accompanying signs and symptoms and/or the hydroxyamphetamine test. (See 'Neuroimaging' above.)