Horner syndrome (HS) results from the interruption of the sympathetic supply to the eye (the oculosympathetic pathway). Throughout its long and circuitous route, it covers the entire ipsilateral anatomy of the head, neck, and upper chest. Therefore, before discussing the etiologic causes of HS, it is imperative to briefly outline in detail the three-neuron course of the sympathetic pathway until it reaches the eye and its adnexa.⁴ A deep understanding of the anatomy will not only accurately confirm the location of the lesion, and condense the differential diagnosis, but would also help the physician choose the appropriate investigative tool.⁸

The first-order neuron (central neuron) originates in the posterolateral nuclei in the hypothalamus. It descends caudally through the tegmentum of the midbrain and pons in a diffuse manner. At the pontomedullary junction, the fibers merge into a discrete bundle and take an abrupt anterior turn to lie ventral to the inferior olivary nucleus of the medulla. The fibers course down the spinal cord, to terminate in the intermediolateral cell column (the ciliospinal center of Budge-Waller) between C8 and T2.³,⁴,⁵,⁹

The second-order neuron, or the preganglionic sympathetic fibers, takes a complicated course through the upper chest and neck. Most of these fibers exit the spinal cord rostrally through the ventral rami or anterior roots at the level of T1, although some fibers exit the ventral roots at C8 or T2. These anteriorly exiting neurons arch over the apex of the lung, before starting their ascent by joining the paravertebral sympathetic chains. The latter are paired bundles of nerve fibers that lie parallel to the vertebral bodies along the entire length of the spinal column. The fibers then pass through
the inferior cervical ganglion without synapsing. In 80% of individuals, the inferior cervical ganglion is found to be fused with the first thoracic ganglion to form the stellate or cervicothoracic ganglion.⁹,¹⁰ The stellate ganglion is anteromedial to the vertebral artery, posteromedial to the common carotid artery and jugular vein, and lateral to the trachea and esophagus and is related inferiorly to the apex of the lung.¹¹,¹² After they leave the inferior cervical/stellate ganglion, the oculosympathetic fibers split around the anterior subclavian artery into two separate tracts to form a complete loop. The first tract passes anterior to the subclavian artery, whereas the second tract loops posteriorly and encircles the vessel forming the ansa subclavia. The fibers then rejoin again and ascend uninterrupted through the middle cervical ganglion, which lies at the level of the C6 vertebra, to terminate and synapse in the superior cervical ganglion roughly at the level of the carotid bifurcation.² The superior cervical ganglion is the largest cervical sympathetic ganglion, as it may reach up to 2.5 to 3 cm in length.⁸,¹⁰ It is situated anterior to the transverse processes of the C2 and C3 vertebrae, is roughly 1.5 cm posterior to the palatine tonsil, and lies directly posterior to the internal carotid artery and sheath.²,⁸,¹⁰,¹² To sum up the relevant surface anatomical landmarks, the stellate ganglion lies at the level of the neck of the first rib, the middle cervical ganglion is marked by the cricoid cartilage, whereas the level of the superior cervical ganglion is roughly approximated either by the hyoid bone or the angle of the jaw because it is a considerably longer structure.¹²

Each preganglionic neuron synapses with about 15 postganglionic or third-order neurons within the superior cervical ganglion.⁸ A small number of these postganglionic fibers, the so-called sudomotor fibers, leave the main bulk of the axons with the sheath of the external carotid artery to supply the sweat glands on the face. However, most of the axons remain within the internal carotid artery sheath in their path toward the cavernous sinus. They exit the superior cervical ganglion via the internal carotid nerve, which ascends along the petrous segment of the internal carotid artery, and then branch into several bundles or two main branches, a larger lateral or anterosuperior bundle, and a smaller medial or posteroinferior one.¹³,¹⁴ These bundles may stay separate or join the nerve plexus around the internal carotid artery.¹³,¹⁴,¹⁵ Although the internal carotid nerve plexus is derived largely (but not exclusively) from the sympathetic nervous system, it also receives contributions from parasympathetic and sensory fibers.¹⁴,¹⁶

Although the topography, composition, and connections of the nerve plexus within the cavernous sinus have been extensively investigated, there is considerable disagreement about the exact course and relationships of the sympathetic fibers both within and beyond the cavernous sinus.¹⁴,¹⁷ This disagreement may simply stem from the substantial variability of the course the sympathetic fibers take from this point onward to the orbit.¹⁴ What has repeatedly been demonstrated is that within the cavernous sinus the greater part of the sympathetic nerve plexus along the internal carotid artery gives off filaments that either briefly hitchhike along the abducens nerve (VI), only to leave the nerve several millimeters later to join the ophthalmic division of the trigeminal nerve (V1),⁹,¹⁴,¹⁵ or the fibers continue in their course uninterrupted along with the abducens nerve to the orbit.¹⁴

The fibers traveling along V1 join the nasociliary nerve, which is one of its three terminal branches, and enters the orbit through the superior orbital fissure, then pass on to the long ciliary nerves (2-3 in number), which penetrate the sclera adjacent to the optic nerve to supply the dilator pupillae muscle.²,¹⁷ Alternatively, the ciliary ganglion may receive a tiny sympathetic rootlet within the orbit, which passes through the ganglion without synapsing and joins the short ciliary nerves before reaching their final destination to innervate the dilator pupillae muscle.¹⁴,¹⁷,¹⁸ Sympathetic fibers may directly follow the course of cranial nerves III, IV, or V1, or they may accompany the ophthalmic artery. Therefore, sympathetic fibers may enter the orbit both through the superior orbital fissure or the optic canal, although access through the optic canal is controversial.¹⁶,¹⁷,¹⁹,²⁰,²¹

Exactly how the unmyelinated postganglionic sympathetic efferent nerve fibers reach the Müller muscle in the upper lid or the inferior tarsal muscle in the lower lid is not entirely clear, but it appears that sympathetic fibers to both muscles also follows the motor and sensory nerves of the orbit (cranial nerves III, IV, V1, and VI),¹⁷,¹⁹,²² although some authors insist that the sympathetic supply to Müller muscle reaches its destination through the superior division of the oculomotor nerve.⁸ It remains controversial whether or not sympathetic fibers extend along the infraorbital nerve to the inferior sympathetic tarsal muscle.¹⁷,¹⁹ It should be noted that, besides giving off the orbital branches, the sympathetic plexus around the internal carotid artery contributes to the autonomic supply of sweat glands in the medial part of the forehead probably via the supraorbital nerve, in contrast to the lateral part of the forehead, which, like the rest of the face, is supplied by the sympathetic plexus around the external carotid artery.¹⁴,²¹,²³

HS can be congenital or acquired. Congenital causes of HS include labor trauma resulting from brachial plexus injury, which is exceedingly rare nowadays; malformations of the internal carotid artery; or congenital tumors along the course of the sympathetic chain.²⁴,²⁵ An upper thoracic or cervical neuroblastoma is the most common occult malignancy associated with HS in children as well as in congenital HS and is the presenting sign in 2% of individuals with neuroblastoma.²⁵,²⁶,²⁷ In adults, any lesion along the unusually long course of the oculosympathetic pathway can result in HS. The injury could be due to mechanical, traumatic, vascular, inflammatory, or neoplastic disorders near, or directly involving, any of the structures related to this U-shaped three-neuron pathway.⁸,²⁸ Central HS usually occurs as a result of vascular occlusion or a tumor, whereas preganglionic lesions are usually associated with iatrogenic injuries or an apical lung mass and postganglionic HS is usually associated with a pathology involving the internal carotid artery.²
It should be realized that, in up to 40% of patients, no cause is ever established and the condition is labeled idiopathic HS.²⁵,²⁹,³⁰

The main presenting symptom of HS is a unilateral mild drooping of the upper eyelid, although observant parents may notice that their child has unequal pupils or hemifacial sweating abnormalities.³¹,³² In congenital HS, a history of birth trauma may be elicited, whereas in adults as well as in children without a congenital onset, inquiring about prior trauma or neck or chest surgery is important. As we shall see later, some specific symptoms may help localize the lesion; for example, the association of HS with acute pain may suggest the possibility of a dissecting carotid aneurysm. Patients should also be asked about the presence of palpable masses in the neck, axilla, and abdomen.²⁵