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Horner syndrome is a rare condition classically presenting with partial ptosis (drooping or falling of the upper eyelid), miosis (constricted pupil), and facial anhidrosis (absence of sweating) due to a disruption in the sympathetic nerve supply. It is primarily acquired following damage to the sympathetic nerve supply, but rare cases of congenital forms have been seen. Treatment is centered around the identification and appropriate management of the underlying cause. This activity reviews the evaluation and management of Horner syndrome and highlights the role of the interprofessional team in the management of affected patients. Objectives: Identify the etiology of Horner syndrome. Describe the presentation of a patient with Horner syndrome. Outline the management options available for patients with Horner syndrome. Summarize interprofessional team strategies for improving care coordination and communication to advance the diagnosis and treatment of Horner syndrome and improve patient outcomes. Access free multiple choice questions on this topic.

Horner syndrome is a rare condition classically presenting with partial ptosis (drooping or falling of upper eyelid), miosis (constricted pupil), and facial anhidrosis (loss of sweating) due to a disruption in the sympathetic nerve supply. It is primarily acquired following damage to the sympathetic nerve supply, but rare cases of congenital forms have been seen. Therefore, treatment is centered around identifying and appropriately managing the underlying secondary cause. The syndrome has several names, including Bernard-Horner syndrome (French-speaking countries), Horner syndrome (English-speaking countries), oculosympathetic palsy, and Von Passow syndrome (Horner syndrome associated with iris heterochromia). The syndrome was first described by Francois Pourfour du Petit in 1727, following an animal experiment involving resection of intercostal nerves and subsequent changes in the ipsilateral eye and face.[1] It was outlined more thoroughly by the French physiologist Claude Bernard in 1852, followed by several physicians who offered different interpretations. The condition was formally described and later named after Swiss ophthalmologist Johann Friedrich Horner in 1869.[2][3][4][5] Anatomy

The syndrome was first described by Francois Pourfour du Petit in 1727, following an animal experiment involving resection of intercostal nerves and subsequent changes in the ipsilateral eye and face.[1] It was outlined more thoroughly by the French physiologist Claude Bernard in 1852, followed by several physicians who offered different interpretations. The condition was formally described and later named after Swiss ophthalmologist Johann Friedrich Horner in 1869.[2][3][4][5] Anatomy Understanding the sympathetic innervation of the eye is vital to understanding the features of this syndrome. The nerve supply is constituted by 3 different neurons, starting from the posterolateral hypothalamus and ending as the long ciliary nerves to supply the iris dilator and superior tarsal muscles (Müller muscle).[6] The first-order neurons originate from the hypothalamus and descend through the midbrain and pons uncrossed, terminating at the C8-T2 level of the spinal cord in the intermediolateral cell columns (ciliospinal center of Budge). Second-order preganglionic neurons exit at the T1 level of the spinal cord to enter the cervical sympathetic chain, where the fibers ascend to synapse in the superior cervical ganglion at the C3-C4 level.[7] Third-order, postganglionic fibers branch off into the sudomotor and vasomotor fibers, which follow the external carotid artery and innervate the sweat glands and blood vessels of the face. The remaining fibers ascend along the internal carotid artery in the carotid plexus to eventually enter the cavernous sinus, where they join the abducens nerve (CN VI). The fibers then exit the cavernous sinus to enter the orbit via the superior orbital fissure and the ophthalmic branch (V1) of the trigeminal nerve (CN V) as the long ciliary nerves.

Horner syndrome is primarily an acquired condition secondary to systemic/local diseases or iatrogenic causes, but may be congenital and purely hereditary in some rare cases.[8][9] Sympathetic fibers have an extensive course and can be interrupted during extracranial, intracranial, or intra-orbital traversal.[10][11][12] The sympathetic fibers may be interrupted centrally, between the hypothalamus and the exit point of fibers from the spinal cord (C8 to T2), or the discontinuation could be peripheral, in the cervical sympathetic chain, at the level of the superior cervical ganglion, or along the course of the carotid artery.[10] Preganglionic Horner syndrome can be an ominous sign due to its association with pulmonary malignancies. Overall, the causes of Horner syndrome can be divided into categories based on the anatomical location of disruption. First-order neurons are mostly affected by intracranial conditions and include the following: Cerebral vascular accidents (CVA) Multiple sclerosis Arnold-Chiari malformation Encephalitis Meningitis Lateral medullary syndrome Syringomyelia Intracranial tumors (pituitary or basal skull) Spinal trauma above the T2-T3 level Spinal cord tumors [13][14][15] Second-order neurons traverse the thoracic region and are affected by the following: Malignancies involving the apex of the lungs (Pancoast tumor) Cervical rib (tractional injury) Lesions of the subclavian artery (an aneurysm) Mediastinal lymphadenopathy Trauma to the brachial plexus [11] Neuroblastoma of the paravertebral sympathetic chain [15] A dental abscess involving the mandibular region Iatrogenic (including thyroidectomy, radical neck dissection, tonsillectomy, coronary artery bypass grafting, or carotid angiography) [12][13][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 migraines Raeder paratrigeminal syndrome (unilateral facial pain, headache, and Horner syndrome) Herpes zoster infection Temporal arteritis

As previously described, Horner syndrome is a consequence of sympathetic disruption. The symptomatology depends on the lesion's location, and the severity depends on the degree of denervation.[9] The superior tarsal muscle helps raise the upper eyelid and has a sympathetic nerve supply. Denervation of this muscle causes ptosis, which is milder than oculomotor (CN III) palsy, which supplies the levator palpebrae superioris. The superior tarsal muscle is responsible for keeping the upper eyelid in a raised position after the levator palpebrae superioris raises it. This explains the partial ptosis seen in Horner syndrome. The lower eyelid may be slightly elevated owing to the denervation of the lower lid muscle, which is analogous to the superior tarsal muscle.[20] The sympathetic nervous supply is responsible for pupil dilation (mydriasis). When disrupted, parasympathetic supply is uninhibited, and constriction of the pupil (miosis) ensues. The pupils' reaction to light and accommodation is normal, as these systems do not depend on sympathetic nerve supply.[21] Ipsilateral anhidrosis, another classic presentation, depends on the level of sympathetic interruption. Anhidrosis with first-order neuron lesions affects the ipsilateral side of the body due to sympathetic innervation from its central origin.[22] The ipsilateral face is involved in lesions involving the second-order neurons. Postganglionic third-order neuron lesions after the vasomotor and sudomotor fibers have branched off show very limited involvement of the face (area adjacent to the ipsilateral brow). Iris heterochromia (relevant deficiency of pigment in the iris on the affected side) is seen in children younger than 2 years and is the congenital form of Horner syndrome.[9]

Localization of the lesion in Horner syndrome is crucial in subsequent management. A detailed history and physical examination are, therefore, of vital importance. When evaluating, the following points need to be considered: Balance, hearing, sensory, and swallowing problems can point towards a more central process involving the first-order neurons. Prior history of trauma or surgical intervention involving the head, face, neck, shoulder, or back points towards the involvement of second-order neurons.[17] A detailed past medical and medication history to rule out the use of a miotic or mydriatic agent. A headache, double vision, facial numbness, or pain indicates third-order neuron involvement. The presence and location of anhidrosis can help with localization. A detailed history of a headache, if present. Longstanding symptoms point towards a more benign underlying cause versus recently progressive symptoms such as weight loss, hemoptysis, low-grade fever, and lymphadenopathy. Facial flushing suggests a preganglionic lesion.[23] Facial or orbital pain in combination with miosis and ptosis should point towards Raeder paratrigeminal syndrome.[24] History of skin lesions or previously diagnosed herpes zoster infection. Severity and location of the pain. A detailed examination of the eyes is warranted and should include the following: Reactivity of the pupils 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 Vision, including color vision and visual fields Slit-lamp examination for structural details Evaluation of the presence of nystagmus A detailed exam can reveal a round and constricted pupil. The affected pupil exhibits dilation lag (dilates more slowly), and the unequal pupils are appreciated more in darkness than in light. In addition, the ciliospinal reflex may be absent. Furthermore, partial ptosis, iris heterochromia, apparent enophthalmos, contralateral eyelid retraction, injected conjunctivae, and no change or a transient decrease in intraocular pressure may be seen.[17][18][25] It is important to perform a detailed systemic examination, paying specific attention to the neurological, pulmonary, and cardiovascular systems, and considering the various differentials discussed later.

Labs 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 B-12, and folate levels may be ordered if indicated following a detailed history and examination. Urine testing for elevated metabolic catecholamine by-products is important in the pediatric population with suspected neuroblastoma. Purified protein derivative is warranted in suspected tuberculosis. Imaging A chest x-ray followed by a computed tomography scan must be ordered in patients when pulmonary malignancy is suspected. Head computed tomography and magnetic resonance imaging (MRI) are advised in cases of possible stroke. MRI is warranted and preferred over ultrasonography when carotid artery dissection is a possibility (painful Horner syndrome).[26] Pharmacological Testing This is the most helpful testing modality for diagnostic localization.[27] Pharmacological testing for Horner syndrome includes: Topical Cocaine Test: Cocaine acts as an indirect sympathomimetic, inhibiting the reuptake of norepinephrine from the synaptic cleft. Cocaine solution (ranging from 2% to 10%) is instilled into both eyes. Both eyes are evaluated after at least 30 or more minutes for an optimal response. Denervation of the affected eye causes it to dilate poorly compared with the normal eye. Anisocoria of 0.8 mm or more is considered diagnostic. However, the test does not help in identifying the level of the lesion. The test has other disadvantages, such as comparatively high prices of the compound, time-consuming, test yielding ambiguous results, and the metabolites of cocaine can be detected in urine.[28]

Topical Cocaine Test: Cocaine acts as an indirect sympathomimetic, inhibiting the reuptake of norepinephrine from the synaptic cleft. Cocaine solution (ranging from 2% to 10%) is instilled into both eyes. Both eyes are evaluated after at least 30 or more minutes for an optimal response. Denervation of the affected eye causes it to dilate poorly compared with the normal eye. Anisocoria of 0.8 mm or more is considered diagnostic. However, the test does not help in identifying the level of the lesion. The test has other disadvantages, such as comparatively high prices of the compound, time-consuming, test yielding ambiguous results, and the metabolites of cocaine can be detected in urine.[28] Topical Hydroxyamphetamine Test: This test is particularly helpful for localizing the lesion. Hydroxyamphetamine stimulates the release of stored norepinephrine from the postganglionic terminals into the synapse. Postganglionic third-order lesions can be differentiated from presynaptic second-order or first-order ones. Two drops of a 1% hydroxyamphetamine solution are instilled into each eye. As a result, the affected eye (third-order lesion) does not dilate as well as the normal eye. In the case of intact postganglionic fibers (first and second-order lesions), the affected pupil dilates to an equal or greater extent. Disadvantages of this test include its inability to be performed on the same day as the cocaine test and false-negative results.[28]

Topical Hydroxyamphetamine Test: This test is particularly helpful for localizing the lesion. Hydroxyamphetamine stimulates the release of stored norepinephrine from the postganglionic terminals into the synapse. Postganglionic third-order lesions can be differentiated from presynaptic second-order or first-order ones. Two drops of a 1% hydroxyamphetamine solution are instilled into each eye. As a result, the affected eye (third-order lesion) does not dilate as well as the normal eye. In the case of intact postganglionic fibers (first and second-order lesions), the affected pupil dilates to an equal or greater extent. Disadvantages of this test include its inability to be performed on the same day as the cocaine test and false-negative results.[28] Topical Apraclonidine Test: This test is considered the test of choice due to its good sensitivity and overall practicality. Apraclonidine acts as a weak alpha1-agonist and strong alpha2-agonist. It is categorized as an ocular hypotensive agent. The upregulation of alpha1-receptors in Horner syndrome results in an exaggerated response of the iris dilators (denervation supersensitivity) to an agonist such as apraclonidine.[29] A 0.5-1% solution is instilled in both eyes. The affected eye shows mydriasis, while the normal eye is predominantly insensitive. Consequent instillation of the solution results in an evident reversal of anisocoria (the affected pupil dilates and the normal pupil constricts). This is because apraclonidine has stronger alpha-2 agonist activity than weaker alpha-1 agonist activity. Some disadvantages of this form of testing include false-negative results in acute cases, systemic side effects in the pediatric population, inability to localize the lesion, and the relatively long half-life of the drug. Other agents have been proposed but fall short of clinical relevance due to several reasons, such as: Pholedrine, an N-methyl derivative of hydroxyamphetamine, is roughly half as potent as hydroxyamphetamine and has shown comparable results, but due to limited availability, it has been restricted. Adrenaline, a direct-acting sympathomimetic, has also been proposed but has poor penetration through the cornea, and sensitivity to the drug is variable.

Pholedrine, an N-methyl derivative of hydroxyamphetamine, is roughly half as potent as hydroxyamphetamine and has shown comparable results, but due to limited availability, it has been restricted. Adrenaline, a direct-acting sympathomimetic, has also been proposed but has poor penetration through the cornea, and sensitivity to the drug is variable. Phenylephrine, a selective alpha1 agonist, has also been proposed but suffers from poor penetration through the cornea and varying results, depending on the degree of denervation.[30]

Treatment options are based on the diagnosis and management of the underlying cause. Timely diagnosis is critical, followed by referral to an appropriate specialist. Healthcare professionals are advised to incorporate the importance of eye examinations into their practice. Whether surgical intervention is indicated and what type is appropriate largely depends on the cause of the disease. Surgical treatment options include the following: Neurosurgical attention for aneurysm-related Horner syndrome Vascular surgical care for causes such as carotid artery dissection or aneurysm

As previously described, pain accompanied by Horner syndrome points towards a more insidious underlying cause and should be evaluated thoroughly. Systemic symptoms such as weight loss and progressive fatigue can indicate an underlying malignancy. Furthermore, Horner syndrome can be an early manifestation of neuroblastoma in the pediatric population. Carotid artery dissection can present with a unilateral headache and facial or neck pain. If suspected, urgent appropriate workup and treatment are warranted. Raeder paratrigeminal syndrome also can present with headaches but is accompanied by trigeminal nerve (CN V) impairment. Anisocoria and/or ptosis can be due to myriad diseases and conditions such as Holmes-Adie syndrome, neurosyphilis (Argyll Robertson pupil), third nerve palsy, or optic neuritis.

The long-term prognosis of idiopathic Horner syndrome appears to be benign. Clinically, patients do not generally become worse, and in fact, half of the patients no longer experience anisocoria. Almost a third of patients with ptosis notice spontaneous improvement or complete resolution in a mean duration of 7.9 years after Horner syndrome is diagnosed. In unilateral cases, the oculo-sympathetic defect does not progress to become bilateral. It is possible that new medical disorders later develop between 3 and 20 years after the diagnosis of Horner syndrome; none are usually related to Horner syndrome.[31]

Horner syndrome is almost always secondary to an underlying cause, such as a tumor, trauma, infection, etc, and is rarely idiopathic. The complications that result from Horner syndrome are essentially related to its cause. For instance, if Horner syndrome is secondary to multiple sclerosis, it could lead to muscle stiffness or spasms, impaired bladder, bowel, or sexual function, and seizures. Similarly, Horner syndrome-related eye problems can lead to vision problems that may be temporary or permanent. Visual involvement can lead to partial or complete blindness.

For the appropriate management of Horner syndrome and the underlying cause, the following consultations may be needed: Pulmonology Neurology Neurosurgery Interventional radiology Oncology Neuro-ophthalmology

Patients should be educated about the possible presentations of Horner syndrome. Parents of babies born with congenital Horner syndrome should be aware of the management options and follow-ups. Patients with Horner syndrome should be informed that it does not damage the eye or cause vision loss, but it may indicate damage to structures along the nerve. It is essential to explore the extent of the damage and its cause, as the underlying cause can be severe. F In addition, patients may complain of a gritty sensation and are prone to infection. Artificial tears and ointment are often enough; however, surgery may be needed in severe or more complicated cases.

There are many causes of Horner syndrome, and thus, the condition is best managed by an interprofessional team. The key is to determine the location of the eye defect. Thus, it is important to perform a detailed systemic examination, paying specific attention to neurological, pulmonary, and cardiovascular systems and considering various differentials discussed later. The outcomes depend on the cause.