Horner Syndrome

Etiology

Horner syndrome is primarily an acquired condition secondary to systemic or local disorders or iatrogenic causes, although rare congenital and hereditary forms occur.[8][9] Sympathetic fibers follow an extensive course and can be interrupted during their extracranial, intracranial, or intraorbital traversal.[10][11][12] Disruption may occur centrally between the hypothalamus and the point at which the fibers exit the spinal cord at C8 through T2 or peripherally within the cervical sympathetic chain, superior cervical ganglion, or carotid artery pathway.[10] Preganglionic Horner syndrome can be an ominous sign because of its association with pulmonary malignant neoplasms. Overall, the causes of Horner syndrome can be categorized according to the anatomical location of the disruption. First-order neurons are mostly affected by intracranial conditions and include the following:

• Cerebrovascular accident
• Multiple sclerosis
• Arnold-Chiari malformation
• Encephalitis
• Meningitis
• Lateral medullary syndrome 
• Syringomyelia
• Intracranial tumors (pituitary or basal skull)
• Spinal trauma above the T2 through T3 levels
• Spinal cord tumors [13][14][15]

Second-order neurons traverse the thoracic region and are affected by the following:

• Malignant neoplasms involving the lung apex, including Pancoast tumors
• Cervical rib causing tractional injury
• Subclavian artery lesions, including aneurysms
• Mediastinal lymphadenopathy
• Trauma to the brachial plexus [11]
• Neuroblastoma of the paravertebral sympathetic chain [15]
• A dental abscess involving the mandibular region
• Iatrogenic injury associated with thyroidectomy, radical neck dissection, tonsillectomy, coronary artery bypass grafting, or carotid angiography [12][13][12][16][17]

Third-order neurons are in close proximity to the internal carotid artery and cavernous sinus and are affected by the following:

• Carotid-cavernous fistula
• Internal carotid artery dissection or an aneurysm [18]
• Cluster headaches or migraine
• Raeder paratrigeminal syndrome, characterized by unilateral facial pain, headache, and Horner syndrome
• Herpes zoster infection
• Temporal arteritis

Epidemiology

Horner syndrome is uncommon, with an estimated frequency of 1 in 6000 individuals. The condition may occur at any age and in any racial or ethnic group.[15][19]

Pathophysiology

Horner syndrome results from disruption of the sympathetic pathway. Clinical manifestations depend on the location of the lesion, whereas severity depends on the degree of denervation.[9] The superior tarsal muscle helps elevate the upper eyelid and receives sympathetic innervation. Denervation of this muscle causes ptosis, which is milder than the ptosis associated with oculomotor nerve palsy because the oculomotor nerve innervates the levator palpebrae superioris. The superior tarsal muscle maintains elevation of the upper eyelid after the levator palpebrae superioris raises it, accounting for the partial ptosis seen in Horner syndrome. The lower eyelid may be slightly elevated because of denervation of the lower eyelid muscle, which is analogous to the superior tarsal muscle.[20]

The sympathetic nervous system mediates pupillary dilation. Disruption of this pathway leaves parasympathetic innervation unopposed, resulting in pupillary constriction. Pupillary responses to light and accommodation remain normal because these systems do not depend on sympathetic innervation.[21] Ipsilateral anhidrosis, another classic manifestation, depends on the level of sympathetic interruption. First-order neuron lesions may cause anhidrosis involving the ipsilateral side of the body because these fibers arise centrally.[22] Second-order neuron lesions typically affect the ipsilateral face. Third-order postganglionic neuron lesions produce limited facial anhidrosis, usually confined to the area adjacent to the ipsilateral brow, because the vasomotor and sudomotor fibers have already branched from the pathway. Iris heterochromia, characterized by reduced pigmentation of the iris on the affected side, may occur in children younger than 2 years with congenital Horner syndrome.[9]

History and Physical

Accurate localization of the lesion in Horner syndrome is crucial for guiding subsequent evaluation and treatment. Therefore, a detailed history and physical examination are essential. Clinical assessment should address the following features:

• Balance impairment, hearing loss, sensory changes, or swallowing difficulties may indicate a central lesion involving first-order neurons.
• A history of trauma or a surgical procedure involving the head, face, neck, shoulder, or back may indicate second-order neuron involvement.[17]
• A detailed medical and medication history should assess for exposure to miotic or mydriatic agents.
• Headache, diplopia, facial numbness, or facial pain may indicate third-order neuron involvement.
• The presence and distribution of anhidrosis may assist with lesion localization.
• The characteristics and duration of any headache should be documented.
• Longstanding, stable symptoms may suggest a more benign cause, whereas recently progressive symptoms accompanied by weight loss, hemoptysis, low-grade fever, or lymphadenopathy raise concern for a serious underlying disorder.[23]
• Facial or orbital pain accompanied by miosis and ptosis may indicate Raeder paratrigeminal syndrome.[24]
• A history of skin lesions or previously diagnosed herpes zoster infection should be obtained.
• The severity and location of pain should be documented.

A detailed ocular examination is warranted and should include the following assessments:

• Pupillary reactivity to light and accommodation
• Measurement of pupillary diameter in dim and bright light
• Examination of the upper eyelid for ptosis and fatigability
• Evaluation of extraocular movements
• Assessment of visual acuity, color vision, and visual fields
• Slit-lamp examination for structural details 
• Evaluation of the presence of nystagmus

A detailed ocular examination may reveal a round, constricted pupil. The affected pupil demonstrates dilation lag, and anisocoria is typically more pronounced in darkness than in light. The ciliospinal reflex may also be absent. Additional findings may include partial ptosis, iris heterochromia, apparent enophthalmos, contralateral eyelid retraction, conjunctival injection, and unchanged or transiently reduced intraocular pressure.[17][25][17] A comprehensive systemic examination should also focus on the neurologic, pulmonary, and cardiovascular systems while accounting for the relevant differential diagnoses.

Evaluation

Laboratory Testing

• The initial workup should include a complete blood count, erythrocyte sedimentation rate, and serum chemistry panel.
• Urine or blood cultures may be ordered if an infectious agent is suspected.
• Testing for suspected neurosyphilis, HIV, thyroid function, vitamin B₁₂, and folate levels may be ordered if indicated following a detailed history and examination.
• Urine testing for elevated metabolic catecholamine metabolites is important in the pediatric population with suspected neuroblastoma.
• Purified protein derivative is warranted in suspected tuberculosis.

Imaging

• Chest radiography followed by CT of the chest should be performed when a pulmonary malignant neoplasm is suspected.
• Head CT and MRI are recommended when stroke is suspected.
• MRI is warranted and preferred over ultrasonography when carotid artery dissection is a possibility (particularly in painful Horner syndrome).[26]

Pharmacological Testing

Pharmacologic testing is the most useful modality for confirming Horner syndrome and assisting with lesion localization.[27] Pharmacologic testing for Horner syndrome includes the following:

• Topical cocaine test: Cocaine acts as an indirect sympathomimetic by inhibiting norepinephrine reuptake from the synaptic cleft. Cocaine solution at a concentration of 2% to 10% is instilled into both eyes. Pupillary responses are assessed after at least 30 min. Denervation causes the affected pupil to dilate poorly compared with the unaffected pupil. Anisocoria of 0.8 mm or more is considered diagnostic. However, the test does not localize the lesion. Additional disadvantages include the relatively high cost of cocaine, prolonged testing time, potentially ambiguous results, and detectable urinary cocaine metabolites.[28]
• Topical hydroxyamphetamine test: This test is particularly helpful for localizing the lesion. Hydroxyamphetamine stimulates the release of stored norepinephrine from postganglionic nerve terminals into the synapse. The test differentiates postganglionic third-order neuron lesions from first- or second-order neuron lesions. Two drops of a 1% hydroxyamphetamine solution are instilled into each eye. With a third-order neuron lesion, the affected pupil dilates less than the unaffected pupil. In patients with intact postganglionic fibers and first- or second-order neuron lesions, the affected pupil dilates equally or more than the unaffected pupil. Disadvantages include the inability to perform the test on the same day as the cocaine test and the possibility of false-negative results.[28] 
• Topical apraclonidine test: This test is considered the preferred pharmacologic test because of its sensitivity and practicality. Apraclonidine acts as a weak α₁-adrenergic agonist and strong α₂-adrenergic agonist and is categorized as an ocular hypotensive agent. Upregulation of α₁-adrenergic receptors in Horner syndrome produces denervation supersensitivity and an exaggerated response of the iris dilator muscle to apraclonidine.[29] A 0.5% to 1% solution is instilled into both eyes. The affected eye develops mydriasis, whereas the unaffected eye shows minimal dilation or constriction. Apraclonidine therefore reverses the anisocoria because its α₂-adrenergic activity predominates in the unaffected eye, whereas α₁-adrenergic receptor supersensitivity produces dilation in the affected eye. Disadvantages include false-negative results in acute cases, systemic adverse effects in children, inability to localize the lesion, and the relatively long half-life of the drug.

Other proposed pharmacologic agents have limited clinical relevance:

• Pholedrine: Pholedrine, an N-methyl derivative of hydroxyamphetamine, is approximately half as potent as hydroxyamphetamine and has produced comparable results. However, limited availability restricts its use.
• Epinephrine: Epinephrine is a direct-acting sympathomimetic with poor corneal penetration and variable sensitivity.
• Phenylephrine: Phenylephrine is a selective α₁-adrenergic agonist with poor corneal penetration and variable results depending on the degree of denervation.[30]

Treatment / Management

Treatment depends on identifying and treating the underlying cause. Timely diagnosis is critical and should be followed by referral to the appropriate specialist. Healthcare professionals should incorporate comprehensive ocular examinations into clinical practice when Horner syndrome is suspected. The indication for a surgical procedure and the appropriate approach largely depend on the underlying disorder. Surgical treatment options include the following:

• Neurosurgical evaluation and treatment for Horner syndrome associated with an aneurysm
• Vascular surgical evaluation and treatment for carotid artery dissection or aneurysm

Differential Diagnosis

Pain accompanying Horner syndrome may indicate a serious underlying cause and warrants thorough evaluation. Systemic symptoms such as weight loss and progressive fatigue may suggest an underlying malignant neoplasm. Furthermore, Horner syndrome can be an early manifestation of neuroblastoma in children. Carotid artery dissection may present with unilateral headache and facial or neck pain. Suspected carotid artery dissection requires urgent diagnostic evaluation and treatment. Raeder paratrigeminal syndrome may also present with headache but is accompanied by trigeminal nerve (cranial nerve V) impairment. Anisocoria or ptosis may result from numerous disorders, including Holmes-Adie syndrome, neurosyphilis with an Argyll Robertson pupil, oculomotor nerve palsy, and optic neuritis.

Prognosis

The long-term prognosis of idiopathic Horner syndrome appears to be benign. Symptoms generally do not worsen, and approximately half of affected patients no longer experience anisocoria. Almost one-third of patients with ptosis report spontaneous improvement or complete resolution after a mean of 7.9 years following diagnosis. In unilateral cases, the oculosympathetic defect does not progress to bilateral involvement. New medical disorders may develop 3 to 20 years after the diagnosis of Horner syndrome; however, these conditions are generally unrelated to the syndrome.[31]

Complications

Horner syndrome is almost always secondary to an underlying cause, such as a tumor, trauma, or infection, and is only rarely idiopathic. The complications associated with Horner syndrome are primarily related to the underlying cause. For instance, Horner syndrome resulting from multiple sclerosis may be associated with muscle stiffness or spasms, impaired bladder, bowel, or sexual function, and seizures. Similarly, ocular disorders associated with Horner syndrome may cause temporary or permanent visual impairment. Severe visual involvement may result in partial or complete vision loss.