Horner Syndrome

Horner syndrome (Horner’s syndrome or oculosympathetic paresis) results from an interruption of the sympathetic nerve supply to the eye and is characterized by the classic triad of miosis (ie, constricted pupil), partial ptosis, and loss of hemifacial sweating (ie, anhidrosis), as well as enophthalmos (sinking of the eyeball into the bony cavity that protects the eye). The term Horner syndrome is commonly used in English-speaking countries, whereas the term Bernard-Horner syndrome is common in France. Von Passow syndrome is an association of Horner syndrome with iris heterochromia (heterochromia iridis).[1, 2]

Causes of Horner syndrome include the following:

• Lesion of the primary neuron

• Brainstem stroke or tumor or syrinx of the preganglionic neuron – In one study, 33% of patients with brainstem lesions demonstrated Horner syndrome[3]

• Trauma to the brachial plexus

• Tumors (eg, Pancoast) or infection of the lung apex

• Lesion of the postganglionic neuron

• Dissecting carotid aneurysm – In one study, 44% (65/146) of patients with internal extracranial carotid artery dissections had painful Horner syndrome, which remained isolated in half the cases (32/65)[4]

• Carotid artery ischemia

• Migraine

• Middle cranial fossa neoplasm

• Internal Jugular Vein Catheterization[5]

• Obstetric neuraxial blockade[6]

Horner syndrome is uncommon. No age, sexual, or racial predilections are known to exist. The prognosis and the complications to be expected depend on the underlying cause of the syndrome, as does treatment.

Sympathetic innervation to the eye consists of a 3-neuron arc. First-order central sympathetic fibers arise from the posterolateral hypothalamus, descend uncrossed through the midbrain and pons, and terminate in the intermediolateral cell column of the spinal cord at the level of C8-T2 (ciliospinal center of Budge). Second-order preganglionic pupillomotor fibers exit the spinal cord at the level of T1 and enter the cervical sympathetic chain, where they are in close proximity to the pulmonary apex and the subclavian artery.

The fibers ascend through the sympathetic chain and synapse in the superior cervical ganglion at the level of the bifurcation of the common carotid artery (C3-C4). Postganglionic pupillomotor fibers exit the superior cervical ganglion and ascend along the internal carotid artery. Shortly after the postganglionic fibers leave the superior cervical ganglion, vasomotor and sudomotor fibers branch off, traveling along the external carotid artery to innervate the blood vessels and sweat glands of the face.

The third-order pupillomotor fibers ascending along the internal carotid artery enter the cavernous sinus. The fibers then leave the carotid plexus briefly to join the abducens nerve (cranial nerve [CN] VI) in the cavernous sinus and enter the orbit through the superior orbital fissure along with the ophthalmic branch (V1) of the trigeminal nerve (CN V) via the long ciliary nerves. The long ciliary nerves then innervate the iris dilator and the Müller muscle.[1]

Horner syndrome may develop from lesions at any point along the sympathetic pathway.[7] Abnormalities found in all patients, regardless of the level of interruption, include the following:

• Mild-to-moderate ptosis, owing to denervation of the sympathetically controlled Müller muscle

• Slight elevation of the lower lid (upside-down ptosis), owing to denervation of the lower lid muscle (analogous to the denervation of the Müller muscle in the upper lid)

• Miosis and dilation lag, where pupillary dilation after psychosensory stimuli is slower in the affected pupil than in the unaffected pupil

Depending on the level of the lesion, impaired flushing and sweating may be found ipsilaterally. With central first-order neuron lesions, anhidrosis affects the ipsilateral side of the body. Lesions affecting second-order neurons may cause anhidrosis of the ipsilateral face. With postganglionic lesions occurring after vasomotor and sudomotor fibers have branched off the sympathetic chain, anhidrosis is either absent or limited to an area above the ipsilateral brow. The pupils react normally to light and accommodation.

Iris heterochromia (with the affected eye being hypopigmented) is seen in congenital Horner syndrome or Horner syndrome that occurs in children younger than 2 years. Iris heterochromia also may occur in long-standing Horner syndrome.[1]

Horner syndrome has a frequency of 1 per 6,250 population. It may occur at any age and in any ethnicity.[8]

Horner syndrome can be congenital, acquired, or purely hereditary (autosomal dominant). The interruption of the sympathetic fibers may occur centrally (ie, between the hypothalamus and the fibers’ point of exit from the spinal cord [C8 to T2]) or peripherally (ie, in cervical sympathetic chain, at the superior cervical ganglion, or along the carotid artery).[1, 9]

The common lesions that cause Horner syndrome interfere with preganglionic fibers as they course through the upper thorax. Virtually all lesions producing postganglionic sympathetic dysfunction are located intracranially or intraorbitally because the superior cervical ganglion is near the skull. Preganglionic Horner syndrome indicates a serious underlying pathology and is associated with a high incidence of malignancy. Postganglionic involvement has primarily benign causes (ie, usually a vascular headache).[1]

Causes of Horner syndrome may also be classified as involving first-order, second-order, or third-order neuron lesions. First-order neuron lesions that may give rise to the syndrome include the following:

• Arnold-Chiari malformation

• Basal meningitis (eg, syphilis)

• Basal skull tumors

• Cerebral vascular accident (CVA)/Wallenberg syndrome (lateral medullary syndrome)

• Demyelinating disease (eg, multiple sclerosis)

• Lesions in the hypothalamus or medulla

• Intrapontine hemorrhage

• Neck trauma (eg, traumatic dislocation of cervical vertebrae or traumatic dissection of the vertebral artery) - Horner syndrome occurring in association with spinal cord trauma suggests a high cervical cord lesion because it does not occur with lesions below T2 or T3

• Pituitary tumor

• Syringomyelia

Second-order neuron lesions that may give rise to Horner syndrome include the following[1] :

• Pancoast tumor (tumor in the apex of the lung, most commonly squamous cell carcinoma)

• Birth trauma with injury to lower brachial plexus[10]

• Cervical rib

• Aneurysm or dissection of the aorta

• Lesions of the subclavian or common carotid artery

• Central venous catheterization

• Trauma or surgical injury (eg, due to radical neck dissection, thyroidectomy,[11] carotid angiography, radiofrequency tonsil ablation,[12] chiropractic manipulation,[13] or coronary artery bypass grafting)

• Chest tubes

• Lymphadenopathy (eg, Hodgkin disease, leukemia, tuberculosis, or mediastinal tumors)

• Mandibular tooth abscess

• Lesions of the middle ear (eg, acute otitis media)

• Neuroblastoma[14]

Third-order neuron lesions that may give rise to Horner syndrome include the following[1] :

• Internal carotid artery dissection (associated with sudden ipsilateral face or neck pain)[15]

• Raeder syndrome (paratrigeminal syndrome) - Oculosympathetic paresis and ipsilateral facial pain with variable involvement of the trigeminal and oculomotor nerves

• Carotid cavernous fistula

• Cluster or migraine headache

• Herpes zoster

Patient history

Obtaining a careful history is very helpful in the localization of lesions causing Horner syndrome. The symptoms reported by the patient will depend on the underlying cause, as follows[1] :

• First-order neuron lesions – Hemisensory loss, dysarthria, dysphagia, ataxia, vertigo, and nystagmus

• Second-order neuron lesions – Prior trauma; facial, neck, axillary, shoulder or arm pain; cough; hemoptysis; previous thoracic or neck surgery; previous chest tube or central venous catheter placement; or neck swelling

• Third-order neuron lesions – Diplopia from sixth nerve palsy, numbness in the distribution of the first or second division of the trigeminal nerve (cranial nerve [CN] V), and pain

Although Horner syndrome is commonly an incidental finding related to a benign cause, it occasionally may be a manifestation of a serious and life-threatening disorder. Careful direction of the history to rule out such life-threatening disorders is vital.

Given that malignancy is a prominent feature of recently diagnosed preganglionic Horner syndrome, patients may avoid an unnecessary extensive workup for carcinoma if the lesion can be shown to be old or long-standing. To prove that a lesion is long-standing, inspect old photographs of the patient that might show ptosis or anisocoria. If the affected iris is blue and the other is brown, the lesion most likely was present at birth or during the first 2 years of life. (Of course, this color asymmetry will not occur in patients who are genetically blue-eyed.)

It is important to determine whether the patient has recently undergone an interventional procedure that has the potential to cause relevant neurologic damage. Iatrogenic Horner syndrome has been reported as a complication of a variety of chest, neck, and otolaryngologic procedures[16, 17, 18, 19, 20] ; for example, ptosis may rarely complicate injection of botulinum toxin for glabellar lines.[21]

Patients may not be able to open the affected eye completely and may not sweat on that side of the face. The presence, absence, or location of anhidrosis is an important localizing sign.

Patients with preganglionic lesions may have facial flushing. This symptom (ie, harlequin effect) occurs with physical exercise in some patients. Patients with postganglionic lesions may have ipsilateral orbital pain or a migrainelike headache.

Raeder described a combination of orbital pain, miosis, and ptosis and termed it paratrigeminal syndrome.[22] If this set of symptoms is associated with lesions of CNs III-VI on the ipsilateral side, a mass lesion in the middle cranial fossa (ie, type I Raeder paratrigeminal syndrome) should be suspected. A benign form characterized by episodic retrobulbar or orbital pain, with miosis and ptosis but without associated cranial nerve findings, is considered a migraine variant (ie, type II Raeder paratrigeminal syndrome).

Patients with carotid artery dissection may present with ipsilateral head, neck, or facial pain.

Physical examination

Important aspects of the physical examination include the following:

• Measurement of pupillary diameter in dim and bright light and the reactivity of the pupils to light and accommodation
• Examination for dilation lag of the pupil immediately after the room lights are dimmed
• Examination of the upper lids for ptosis
• Examination of the lower lids for upside-down ptosis (eg, the position of the lower lid with respect to the inferior limbus)
• Observation of extraocular movements
• Biomicroscopic examination of the pupillary margin and iris structure and color
• Confrontational visual field testing and testing of facial sensation
• Observation for the presence of nystagmus, facial swelling, lymphadenopathy, or vesicular eruptions

The pupil on the affected side may be round and constricted (ie, miosis). In individuals with Horner syndrome, the anisocoria is greater in darkness than in light. The affected pupil dilates more slowly than the normal pupil does because the affected pupil lacks the pull of the dilator muscle (ie, dilation lag). Patients may have a loss of the ciliospinal reflex (ie, afferent C2, C3), in which the pupil fails to dilate when the skin on back of the neck is pinched. (Most authors, however, consider this finding unreliable.)

Patients have dry skin (ie, anhidrosis) on the same side of their face as the affected pupil. The pattern of a patient’s inability to sweat may be helpful in localizing the lesion. If a patient has a lesion in the area of the common carotid artery, loss of sweating involves the entire side of the face. With lesions distal to the carotid bifurcation, the lack of sweating is confined to the medial aspect of the forehead and the side of the nose.

Other findings that may be noted include the following:

• Partial ptosis
• Apparent enophthalmos – Assertions to the contrary notwithstanding, true enophthalmos does not occur; the ptosis merely gives an illusion created by narrowing of the palpebral fissure, which results from weakness of the muscle of Müller in both the upper lid (causing partial ptosis) and the lower lid (causing slight elevation of lower eyelid)
• Increased amplitude of accommodation
• Iris heterochromia (heterochromia iridis) – The affected iris may remain blue when the other iris changes to brown; this may be present if the lesion is in a child younger than 2 years but is uncommon in older patients; iris pigmentation is under sympathetic control during development, which is completed by the age of 2 years
• Unilateral straight hair ipsilateral to the side affected by congenital Horner syndrome
• Paradoxical contralateral eyelid retraction
• Transient decrease in intraocular pressure and changes in tear viscosity
• Absence of a horizontal eyelid fold or crease in the ptotic eye, especially in patients with congenital Horner syndrome
• Red conjunctivae

Horner syndrome in the presence of pain merits special consideration.

Horner syndrome in the presence of axial, shoulder, scapula, arm, or hand pain may be indicative of compression by an apical lung tumor (Pancoast tumor).

Horner syndrome in the presence of acute-onset, ipsilateral facial or neck pain may indicate carotid artery dissection, which may be caused by cardiovascular disease, arteriopathy (eg, fibromuscular dysplasia or collagen disorders), or trauma (even minor trauma, such as results from quick head turns). If carotid artery dissection is suspected, especially if there are signs or symptoms of retinal ischemia, urgent neuroimaging studies (magnetic resonance imaging or magnetic resonance angiography) should be obtained along with neurologic consultation.

Postganglionic Horner syndrome associated with ipsilateral headache has several causes. Patients with spontaneous carotid artery dissection may present with Horner syndrome and ipsilateral headache. Patients with cluster headaches may develop ipsilateral Horner syndrome during an acute attack.

The term Raeder paratrigeminal syndrome is applied to patients, usually middle-aged males, who have Horner syndrome and daily unilateral head pain. In the original Raeder syndrome, the pain is trigeminal pain associated with hypoesthesia or anesthesia in the distribution of the trigeminal nerve (cranial nerve [CN] V). Pain related to Raeder syndrome can be distinguished from that related to cluster headaches or carotid disease in that the latter conditions occur without impairment of trigeminal nerve function.

Horner syndrome may be the first manifestation of neuroblastoma.

Conditions to be considered in the differential diagnoses include the following:

• Adie pupil
• Physiologic anisocoria and involutional ptosis
• Argyll Robertson pupil
• Holmes-Adie pupil (contralateral)
• Iris sphincter muscle damage
• Senile miosis
• Third nerve palsy

Unilateral use of miotic drugs or mydriatic drugs should also be considered in the differential diagnoses. Other medications to consider include local anesthetics (lidocaine, bupivacaine, etidocaine), acetophenazine, alseroxylon, butaperazine, carphenazine, chloroprocaine, chlorpromazine, deserpidine, diacetylmorphine, diethazine, ethopropazine, fluphenazine, guanethidine, influenza virus vaccine, levodopa, lidocaine, mesoridazine, methdilazine, methotrimeprazine, oral contraceptives, perazine, prilocaine, procaine, prochlorperazine, promazine, promethazine, propoxycaine, reserpine, thioproperazine, thioridazine, and trifluoperazine.

In general, laboratory studies do not play a significant role in the diagnosis and management of Horner syndrome. However, depending on the localization and suspected etiology, certain laboratory tests may be considered, as follows[1] :

• Urine test (ie, vanillylmandelic acid [VMA] and homovanillic acid [HVA]) in pediatric Horner syndrome to rule out neuroblastoma
• Complete blood count (CBC)
• Fluorescent treponemal antibody absorption (FTA-ABS) test
• Venereal Disease Research Laboratory (VDRL) test (for rare cases of syphilitic basilar meningitis or when Argyll Robertson pupil is suspected)
• Purified protein derivative (PPD) placement

Imaging studies may be ordered in conjunction with appropriate medical or surgical consultation, depending on the localization and suspected etiology.[1, 23]

A chest radiograph should be obtained; apical bronchogenic carcinoma is the most common cause of Horner syndrome. If stroke is suspected, computed tomography (CT) of the head should be performed.

Painful Horner syndrome should alert the physician to the possibility of carotid artery dissection, and the patient should undergo further testing (ie, magnetic resonance imaging [MRI]/magnetic resonance angiography [MRA] of the brain and neck) to exclude this possibility. Internal carotid artery dissection is life-threatening and carries a risk that the patient will experience a disabling stroke.

Ultrasonography may be considered but has not been found to be reliable for diagnosing carotid artery dissection in patients with isolated Horner syndrome.[24]

MIBG Scan is a nuclear imaging test to asist in the diagnosis and assessment of neuroendocrine tumors.[25]

Pharmacologic testing is very helpful in the diagnosis of Horner syndrome.[1, 26] The following pharmacologic tests document the presence or absence of an ocular sympathetic lesion and identify the level of involvement (ie, preganglionic or postganglionic). Localizing the lesion is important because preganglionic lesions are associated with a higher incidence of malignancy that necessitates extensive investigations.

Topical cocaine test

The basis for the topical cocaine test is the ability of cocaine to act as an indirect sympathomimetic agent by inhibiting the reuptake of norepinephrine from the synaptic cleft at the nerve ending.

The test is performed by instilling cocaine solution (2-4% or, according to some, 4-10%) into each eye. Cocaine instilled in an eye with intact sympathetic innervation causes the pupil to dilate. A sympathetically denervated pupil (such as is present in Horner syndrome) dilates poorly to cocaine, regardless of the level of the sympathetic interruption, because of the absence of endogenous norepinephrine in the synapse.

For optimal accuracy, test results should be evaluated 30 minutes or longer after cocaine is administered. The maximal response is seen 40-60 minutes after instillation of the drops. Postcocaine anisocoria greater than 0.8 mm is sufficient to diagnose Horner syndrome.

The disadvantages of the topical cocaine test are as follows:

• The drops are difficult to obtain because they must be made at a compounding pharmacy

• The drops are relatively expensive

• The test can yield equivocal results

• Cocaine metabolites may be detected in urine

Topical apraclonidine test

The topical apraclonidine test is a practical and reliable alternative to the topical cocaine test; it is readily available and adequately sensitive (87%) and is currently the test of choice.[27, 28, 29]

Apraclonidine is an ocular hypotensive agent that acts as a weak alpha1-agonist and a strong alpha2-agonist.[30, 27, 26, 31] Typically given in a 0.5% or 1% solution, it has little to no effect on a normal pupil but has a mydriatic effect on an abnormal pupil.

In Horner syndrome, upregulation of alpha1-receptors increases apraclonidine sensitivity and causes denervation supersensitivity of the iris dilator muscle. The denervation supersensitivity results in pupillary dilatation and lid elevation on the abnormal side but no response or mild miosis on the normal side from alpha2-activity after apraclonidine administration. Reversal of anisocoria occurs after bilateral instillation of apraclonidine.

In acute cases, false-negative test results may occur because the alpha1-receptor upregulation on which the effect of apraclonidine depends may take 5-8 days.[32, 33] Accordingly, a negative apraclonidine test result, especially in acute settings, does not exclude Horner syndrome. In such cases, a cocaine test should be performed to exclude Horner syndrome.

Apraclonidine 0.5% or 1% may cause lethargy, bradycardia, and respiratory depression in infants younger than 6 months as a consequence of the immaturity of the blood-brain barrier.[34]

Topical hydroxyamphetamine test

The localization of a lesion causing Horner syndrome may be aided by the use of the topical hydroxyamphetamine test. Hydroxyamphetamine stimulates the release of stored endogenous norepinephrine from the postganglionic axon terminals into the neuromuscular junction at the iris dilator muscles. This test may distinguish a postganglionic third-order neuron lesion from a presynaptic second-order or first-order neuron lesion.

To perform the test, 2 drops of 1% hydroxyamphetamine solution are instilled into each eye. A period of 24-48 hours must be allowed to elapse between the cocaine test and the hydroxyamphetamine test because cocaine has the ability to inhibit the uptake of hydroxyamphetamine into the presynaptic vesicles, thereby reducing the accuracy of the latter test.

Hydroxyamphetamine drops instilled into an eye with Horner syndrome with intact postganglionic fibers (ie, first- or second-order neuron lesions) dilate the affected pupil to an equal or greater extent than they do the normal pupil. However, hydroxyamphetamine drops instilled into an eye with Horner syndrome with damaged postganglionic fibers (ie, third-order neuron lesions) do not dilate the affected pupil as well as they do the normal pupil.

In general, appropriate treatment of Horner syndrome depends on the underlying cause. The goal of treatment is to eradicate the underlying disease process. In many cases, however, no effective treatment is known. Prompt recognition of the syndrome and expedient referral to appropriate specialists are vital.[1]

Whether surgical care is indicated and what type is appropriate depend on the particular cause of Horner syndrome. Potential surgical interventions include neurosurgical care for aneurysm-related Horner syndrome and vascular surgical care for causative conditions such as carotid artery dissection or aneurysm.

For optimal management of the underlying cause, the following specialist consultations may be required:

• Pulmonology

• Internal medicine

• Neurology or neuro-ophthalmology

• Interventional radiology (in cases of suspected carotid artery dissection)

• Surgery or oncology (as warranted by the particular etiology)

• Neurosurgery (in cases of suspected aneurysm)