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This article includes discussion of Horner syndrome, Bernard syndrome, Bernard-Horner syndrome, Claude Bernard syndrome, Horner’s syndrome, Horners syndrome, and subclinical Horner syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The authors provide an updated clinical review of Horner syndrome. The most current recommendations regarding pharmacologic diagnosis and radiographic evaluation are highlighted. Important issues regarding the evaluation of Horner syndrome in children are also reviewed.
• Horner syndrome is caused by an interruption of sympathetic nerves to the head, eye, and neck.
• The hallmark of Horner syndrome is ptosis and miosis on the same side.
• When Horner syndrome is suspected, pharmacologic testing with cocaine or apraclonidine should be performed to confirm the diagnosis as there are other causes of ptosis and miosis.
• Use of hydroxyamphetamine to localize the lesion is no longer recommended because it is unreliable.
• The use of selective or nonselective imaging to evaluate for an underlying cause is based on the presence of localizing clinical features.
Horner syndrome is an eponym used to describe the clinical triad of ptosis, miosis, and anhidrosis caused by interruption of the ipsilateral first-, second-, or third-order sympathetic neurons to the head, eye, and neck. It is named after the Swiss ophthalmologist Johann Friedrich Horner, but he was not the first to describe this syndrome. In 1727, Pourfour du Petit reported ptosis, miosis, and enophthalmos after cutting the vagosympathetic nerve trunk in dogs (73). Edward Selleck Hare reported similar signs in a published letter to the London Medical Gazette in 1838 (38), in which he described a 40-year-old man with ptosis, miosis, and arm dysesthesias from a tumor involving the structures of the left neck. However, he was unable to relate the eye findings to the structural involvement by the tumor.
Although other physiologists such as Ruete and Budge worked to establish the sympathetic innervation of the eye and pathways of these fibers, additional animal experiments in rabbits by Claude Bernard, published in 1852, finally led to the most complete description of the effects of severing the cervical sympathetic fibers and the first hypothesis that sympathetic nerves regulated the vasomotor response in blood vessels (08; 28; 70; 74). Given his important contribution, the syndrome is sometimes called Bernard syndrome or Bernard-Horner syndrome.
In 1864, S Weir Mitchell described the first full human account of ocular and facial findings attributed to injury of the sympathetic trunk in a 24-year-old man with a gunshot wound to the neck. It was not until 1869 that Johann Friedrich Horner famously reported the findings of ptosis, miosis, and enophthalmos in a 40-year-old peasant woman (39). He also observed increased skin temperature and dryness of the ipsilateral face. He pharmacologically confirmed the impairment of sympathetic innervation to the eye after noting poor dilation of the affected pupil following instillation of atropine and preserved pupillary constriction to the parasympathomimetic agent calabar.
The clinical manifestations of Horner syndrome are caused by interruption of the first-, second-, or third-order sympathetic neurons supplying the head, eye, and neck.
Ptosis. Upper and lower eyelid ptosis are key clinical findings in Horner syndrome. Ptosis of the upper eyelid is caused by paralysis of Müller’s muscle, a small band of sympathetically innervated smooth muscle originating on the underside of the levator palpebrae and inserting on the superior tarsal plate. It normally functions to further widen the palpebral fissure during states of excitement or arousal. Interruption of the sympathetic fibers to this muscle results in ptosis of at most 2 mm. The eyelid should not obscure the pupil or interfere with vision. This small amount of ptosis is in contrast to the more dramatic ptosis resulting from an oculomotor nerve palsy causing paresis of the levator palpebrae superioris. Interruption of sympathetic fibers to the lower eyelid will cause an elevation of the lid margin and loss of the normal scleral rim between the cornea and lower eyelid. This lower eyelid elevation has been called “upside-down” ptosis (66). Ptosis may rarely be absent in Horner syndrome (58).
Miosis. The affected pupil will be smaller and will not dilate properly owing to interruption of sympathetic fibers traveling to the iris dilator. The degree of anisocoria is usually small (2 mm or less) and may be difficult to appreciate in bright or even ambient light conditions when the intact parasympathetically innervated iris sphincter muscle is maximally stimulated. Therefore, the anisocoria is best appreciated in dim illumination when the effect of sympathetic tonic innervation of the pupil is more evident. Rather than comparing the difference in pupil measurements in bright and dim illumination, as suggested by some authors, we recommend that pupils be examined first in dim light, observing the size of the pupils by illuminating the patient’s eyes from below. In Horner syndrome, anisocoria will be present in dim illumination, but the pupils will constrict briskly to bright light, ruling out a parasympathetic innervational deficit and suggesting a possible interruption of the sympathetic fibers to the smaller pupil. Additional pharmacologic testing can confirm the presence of Horner syndrome. If anisocoria is present in dim illumination and one or both pupils do not constrict normally to bright light, then the cause of the anisocoria is not Horner syndrome, and additional examination of the pupils should be performed as discussed in the MedLink article on pupillary abnormalities.
In Horner syndrome, the miotic pupil dilates slowly (dilation lag) when light is withdrawn, a phenomenon that can be observed clinically by illuminating the patient’s eyes from below and quickly extinguishing room light. The degree of anisocoria should be greatest at 5 seconds after the light is withdrawn (47). However, this phenomenon is difficult to document without pupillography, and its absence does not therefore rule out Horner syndrome (18). On the other hand, observation of a dilation lag favors a diagnosis of Horner syndrome and rules out physiologic anisocoria.
Rarely, anisocoria may be absent in a patient with Horner syndrome (79). In this scenario, the miosis from Horner syndrome is eliminated by the preexisting physiologic mydriasis, occurring on the same side or instillation of a sympathomimetic eye drop (71). Anisocoria may also occur intermittently (54; 62; 65).
Anhidrosis. Interruption of sympathetic fibers to the head and neck can lead to loss of ipsilateral vasomotor and sudomotor functions in these areas. If the first- or second-order neuron is interrupted, the signs and symptoms will extend from the head to the clavicle. Interruption of the third-order neuron may result in signs and symptoms on the medial forehead and nose. Loss of vasomotor control causes dilation of blood vessels resulting in flushing, conjunctival hyperemia, and increased skin temperature. Loss of sudomotor function results in anhidrosis. Vasomotor and sudomotor dysfunction are best detected by history, as there are no practical and reliable clinical tests of these functions. If necessary, anhidrosis can be tested objectively by thermoregulatory sweat testing using alizarin powder (96).
Iris heterochromia. Iris melanocytes require sympathetic stimulation during prenatal development and infancy. Loss of this stimulation leads to depigmentation of the ipsilateral iris (43; 47). Although hypochromia is considered a hallmark feature of congenital Horner syndrome, it may be absent and has even been reported in chronic acquired Horner syndrome (22).
The ptosis of Horner syndrome may rarely cause a mild obscuration of vision and may be cosmetically unacceptable. Ptosis and miosis may, however, resolve over time, depending on the underlying cause.
A 65-year-old woman presented with double vision for 6 months. She described horizontal binocular diplopia particularly when looking to the left. She also noticed constant left eyelid droop. Visual acuity was normal. She had incomplete abduction of the left eye consistent with a cranial nerve VI palsy on the left. Ptosis of 2 mm was present. In dim illumination, pupils measured 6 mm on the right and 4 mm on the left. Both pupils constricted briskly to light. Pharmacologic testing with apraclonidine 0.5% showed resolution of the ptosis and reversal of the anisocoria (right pupil 6 mm and left pupil 7 mm), confirming the presence of a left Horner syndrome. The combination of a left cranial nerve VI palsy and Horner syndrome suggested a left cavernous sinus lesion. MRI brain with and without contrast with attention to the cavernous sinuses disclosed a left cavernous meningioma. Given the mild nature of her symptoms, she was not a candidate for surgery or radiation therapy. She was given apraclonidine to palliate her ptosis.
The cause of Horner syndrome depends on whether the first-, second-, or third-order neuron is affected (Table 1).
First-order (central) Horner syndrome. First-order neurons arise in the posterolateral hypothalamus and descend through the dorsolateral brainstem (58; 05). There are likely connections with the insular cortex (05).
Once in the spinal cord, the neurons travel in the intermediolateral gray column until reaching the lower cervical/upper thoracic spinal cord. The first-order neuron synapses with the second-order neuron at the ciliospinal center of Budge-Waller (C8-T1).
First-order (central) Horner syndrome rarely occurs in isolation. Accompanying neurologic signs aid in localizing the central interruption. Horner syndrome is a key finding in lateral medullary stroke (Wallenberg syndrome). Lesions in the midbrain and pons may also rarely include Horner syndrome. The combination of Horner syndrome and contralateral trochlear nerve palsy localizes to the dorsal midbrain ipsilateral to the Horner syndrome (36).
Lesions of the spinal cord caused by trauma, demyelination, stroke, or tumors have all been associated with central Horner syndrome. Cervical spinal cord syrinx is a reported cause of an isolated central Horner syndrome (72) and has been associated with bilateral Horner syndrome (15). In the rare patients with Horner syndrome that alternates from one side to the other, medullary demyelinating lesions, cervical spinal cord lesions, and systemic dysautonomias have been implicated (29; 99; 01).
Second-order (preganglionic) Horner syndrome. The cell bodies of second-order oculosympathetic neurons are located in the ciliospinal center of Budge-Waller. After exiting the spinal cord at C8-T1, the neurons travel over the pulmonary apex, through the stellate ganglion, and in the common carotid artery sheath. These neurons synapse in the superior cervical ganglion, located at the skull base. Second-order (preganglionic) Horner syndrome is frequently iatrogenic, resulting from procedures on neck vessels such as jugular vein cannulation, and surgeries of the neck and chest. Tumors of the thorax and neck are less common causes.
Third-order (postganglionic) Horner syndrome. After synapsing in the superior cervical ganglion, the sudomotor and vasomotor fibers of the neck and face travel with the external carotid artery after the bifurcation of the common carotid artery. The fibers traveling to the orbit (oculosympathetic pathway) continue with the internal carotid artery and enter the cavernous sinus. These neurons briefly travel with cranial nerve VI, then with the first division of cranial nerve V, later entering the orbit through the superior orbital fissure on the nasociliary branch of V1. Two or three long ciliary nerves arise from the nasociliary nerve and travel with the lateral and medial suprachoroidal vascular bundles to finally reach the iris dilator.
Disorders affecting the internal carotid artery at the skull base and intracranially, or affecting the cavernous sinuses, are the most common causes of third-order (postganglionic) Horner syndrome. In fact, Horner syndrome is the most common ophthalmologic sign of carotid dissection, occurring in 38.5% to 44% of all patients with dissection (11; 76; 56), but it may also be present intermittently (54; 65; 35). Additionally, Horner syndrome is commonly associated with trigeminal autonomic headache syndromes, including cluster headache and, rarely, migraine.
• stroke (ischemic or hemorrhagic)
• anterior cervical discectomy and fusion
• coronary artery bypass grafting
• first rib fractures
• jugular vein cannulation
• jugular vein thrombosis (Lemierre syndrome)
• lumbar epidural anesthesia
• lung and mediastinal surgery
• neck surgery
• pacemaker placement
• paraganglioma of the head and neck
• paravertebral contusion
• paravertebral primitive neuroectodermal tumor
• subclavian artery aneurysm
• sympathetic chain schwannoma
• thyroid tumors
• tumors/masses of the lung apex, mediastinum, and neck
Internal carotid artery
• arteriovenous malformation
• stroke (ischemic or hemorrhagic)
• tumor (meningioma, pituitary tumor)
• cluster headache
• giant cell arteritis
• intraoral anesthetic
• skull base fracture/tumor
(68; 33; 67; 55; 90; 14; 07; 80; 84; 49; 06; 78; Biousse et all 1995; 30; 97; 50; 23; 27; 69; 53; 86; 93; 59; 95; 41; 77; 16; 37; 24; 34; 64; 02; 13; 25; 40; 88; 09; 31).
Special consideration—infants. Although many of the causes of acquired Horner syndrome in children are similar to those in adults, most have no identifiable etiology (57). However, special consideration must be given to congenital causes typically detected during infancy.
Birth trauma is a common cause by 2 mechanisms: (1) injury to the lower trunk of the brachial plexus, and (2) tractional forces applied to the carotid artery during a forceps delivery (94). Agenesis of the carotid artery and orbital hemangioma have also been reported as causes of congenital Horner syndrome (75; 26; 51; 91).
Neuroblastoma is a common solid cancer of infancy and childhood that presents with an isolated Horner syndrome in 2% of cases (63). It causes Horner syndrome through direct disruption of the sympathetic fibers in the neck and thorax, but may rarely arise in the abdomen and cause a Horner syndrome by uncertain mechanisms (63; 32).
Horner syndrome is caused by interruption of the ipsilateral first-, second-, or third-order sympathetic neurons supplying the head, eye, and neck.
There are no epidemiologic data regarding Horner syndrome in adults. However, there is a single epidemiologic study of Horner syndrome in children with cases collected from the Olmsted County database (81). Over a 40-year period, 20 children were diagnosed with Horner syndrome. The age-adjusted and sex-adjusted incidence was 1.42 per 100,000 patients under 19 years old. Eleven of the 20 cases were congenital, a birth prevalence of 1 in 6250 (95% CI 3333 to 10,000). Most of the children had birth trauma as the cause of Horner syndrome; none had neuroblastoma.
Horner syndrome describes signs referable to interruption of the oculosympathetic pathway due to various mechanisms and, therefore, there is no primary prevention.
The presence of ptosis and miosis on the same side is highly suggestive of Horner syndrome. Anhidrosis is least helpful and only variably present. In a retrospective single institutional study of 450 cases of Horner syndrome, miosis was present in 98%, ptosis in 88%, and anhidrosis in only 4% (58). Although ptosis and miosis are the hallmark of Horner syndrome, they may be subtle or even transient (54; 62; 65). Therefore, specific questions regarding anisocoria and ptosis should be asked when Horner syndrome is suspected but not observed.
Not all patients with ptosis and miosis on the same side have Horner syndrome (87). Therefore, detailed pupillary examination and pharmacologic testing are necessary to establish the diagnosis.
Miosis. When confronted with anisocoria, the first step is to determine which pupil is the abnormal one. Pupils should always be examined first in dim lighting, observing the size of the pupils by illuminating the patient’s eyes from below. A bright light is then shined into each pupil from below (so as not to stimulate a near response) to observe the constriction to light. If anisocoria is present in dim illumination and both pupils constrict normally to light, then the abnormal pupil is the smaller one or the patient has physiologic (“benign,” “essential”) anisocoria. The distinction between pathologic and physiologic anisocoria is best determined with pharmacologic testing. Physiologic anisocoria, limited to 1.5 mm, occurs in approximately 20% of the population (47). Patients with physiologic anisocoria will often report that the smaller pupil changes from side to side. Topical medications with parasympathomimetic properties, such as those used in the treatment of glaucoma (pilocarpine), may also cause miosis and at least partially preserve pupil constriction to bright light.
If anisocoria is present in dim illumination and one of the pupils does not constrict briskly to light, then the nonconstricting pupil is the abnormal one. If the smaller pupil does not constrict briskly to light, then the most likely cause of the miosis is a chronic tonic (Adie) pupil or iris abnormality. During the acute phase, the tonic pupil will be the larger one. Over time, it will become miotic, owing to constant parasympathetic impulses to the reinnervated segments of the iris (45). Direct physical injury to the eye, inflammation (iritis), or eye surgery (eg, cataract surgery) may result in unequal or irregularly shaped pupils. A careful history will usually uncover those causes. If the larger pupil does not constrict briskly to light, cranial nerve III palsy is the chief consideration. See the MedLink article on pupillary abnormalities for further discussion.
Ptosis. This is a relatively common finding, and its differential diagnosis is beyond the scope of this article. The first step is to determine if the ptosis is congenital or acquired. Acquired causes of ptosis can be further differentiated into myogenic causes (myotonic dystrophy, chronic progressive external ophthalmoplegia), neuromuscular junction causes (myasthenia gravis), neurogenic causes (Horner syndrome, oculomotor nerve palsy), mechanical causes (inflammation, tumor), levator dehiscence (aging, contact lens wear), and pseudo-ptosis (enophthalmos, dermatochalasis). The history and a detailed eye exam will nearly always lead to the correct diagnosis. Examining old photographs may be helpful to establish chronicity when the clinical history is lacking.
Pharmacologic testing. When the physical examination suggests a diagnosis of Horner syndrome, it should be confirmed with pharmacologic testing, considering that there are other causes of miosis and ptosis.
Cocaine. Cocaine is a sympathomimetic agent that has traditionally been used to confirm the diagnosis of Horner syndrome. It blocks the re-uptake of norepinephrine in the presynaptic sympathetic nerve terminal, leading to a relative increase in norepinephrine available to the postsynaptic receptors located on the iris dilator. Instillation of cocaine drops into the normal eye leads to mydriasis and widening of the palpebral fissure. When the sympathetic pathway is disrupted, there is a decrease in the amount of norepinephrine released into the synapse and, therefore, a blunted effect on cocaine-induced mydriasis. Consequently, the Horner pupil will not dilate to the same degree as the contralateral normal pupil.
We recommend evaluating patients with cocaine in the following way. Instill a single drop of 10% cocaine solution into the right eye, then the left eye. After waiting for 1 to 5 minutes, instill a second drop, first in the left eye, then the right eye. Reversing the order of instillation ensures that equal amounts of cocaine reach the eyes, particularly in a child who may be uncooperative. Wait 40 to 60 minutes before examining the pupils. If neither pupil dilates, repeat the procedure or consider that the cocaine drops may have expired. The cocaine test should be considered positive for Horner syndrome if the miotic pupil remains smaller than the normal pupil by at least 1 mm (46). Patients should be counseled that a urine drug screen may be positive for at least 2 days after cocaine testing (42), but that there are no psychoactive effects.
Apraclonidine. For many physicians, cocaine testing is impractical. Cocaine drops are hard to obtain, expensive, and must be secured in a locked cabinet (44). For these reasons, apraclonidine drops are frequently used instead. Apraclonidine is primarily an alpha-2 receptor agonist with some weak alpha-1 activity. Disruption of the sympathetic pathway is believed to cause upregulation (denervation hypersensitivity) of the postsynaptic alpha-1 receptors on the iris dilator (60). This phenomenon leads to reversal of the anisocoria following instillation of apraclonidine in the 2 eyes; the Horner pupil becomes the larger pupil. The eyelid of the involved eye will also elevate. To perform this test correctly, instill a single drop of apraclonidine 0.5% to 1.0% in each eye (12). After waiting 30 to 60 minutes, observe the pupils for reversal of the anisocoria and/or elevation of the ptotic eyelid.
There are some limitations to using apraclonidine. First, the sensitivity and specificity of this test are unknown. Second, denervation hypersensitivity takes time to develop and the test may, therefore, be falsely negative in the acute phase. Although positive apraclonidine tests have been reported as early as 3 hours after the clinical onset of Horner syndrome, such a short interval may not always apply (21; 17). Third, strict adherence to absolute reversal may lead to false negatives (48). Last, caution should be used when using apraclonidine in children under 1 year of age, as it can precipitate an acute dysautonomia (92; 61). In fact, we use only cocaine drops in the diagnosis of Horner syndrome in children under 1 year of age.
Hydroxyamphetamine. The traditional use of this agent to localize the site of the lesion is unreliable (58). Furthermore, hydroxyamphetamine is difficult to obtain, and the testing must be performed at least 24 hours after cocaine testing, making it impractical. The use of this agent is, therefore, no longer recommended.
Imaging evaluation. If Horner syndrome is confirmed by pharmacologic testing or remains a strong clinical consideration despite negative pharmacologic testing, the next step is to decide on imaging. The need for selective or nonselective imaging is based on the presence of localizing clinical features (03; 89).
Selective imaging (nonisolated Horner). The selection of the imaging modality should be based on the presumed location of the lesion and its nature. For example, if a patient develops arm pain, weakness and numbness, or myelopathic features, imaging should be directed at the lung apex, brachial plexus, and cervical spine. In this setting, MRI is frequently best. If a patient with a Horner syndrome also has acute face or neck pain, or headache, vessel imaging to evaluate for a carotid dissection should be performed promptly. When there is accompanying hearing loss or ear pain, MRI should be performed to evaluate the temporal bone and carotid canal (83). In the setting of an ipsilateral abducens palsy, special attention should be focused on the cavernous sinus. Lastly, in patients with ataxia or nystagmus, MRI can be used to evaluate the brainstem.
Nonselective imaging (isolated Horner). When Horner syndrome is isolated, imaging should include the region between the skull base and the T1 spinal level. Such a study will ensure adequate imaging of the preganglionic and postganglionic segments. Both MRI/MRA and CT/CTA will provide adequate resolution of the soft tissues in the neck and excellent vascular imaging. However, MRI is easily degraded by motion and may be difficult to obtain urgently.
Special consideration—children. A history of birth trauma or the finding of heterochromia does not negate the need for imaging in children. An isolated Horner syndrome in a child, even if presumably congenital, should always be evaluated with imaging (98; 89; 04) because there are reports of congenital Horner syndrome from neuroblastoma (63; 32). Intermittent ptosis has also been observed (63). When evaluating for neuroblastoma as a potential cause of an isolated Horner syndrome, we and others recommend MRI of head, neck, and chest (57). Palpation of the neck, axilla, and abdomen to check for masses should also be performed to further direct imaging (57).
Laboratory testing. Prior studies have demonstrated that urine catecholamines are elevated in approximately 90% of children with neuroblastoma and that tumor burden seems to correlate with the degree of urine catecholamine elevation (52; 85). However, other studies have suggested that urine catecholamines are detected in only 60% to 70% of patients with neuroblastoma and Horner syndrome, particularly in those with stage 1 or 2 disease (19; 82). Given the low sensitivity of the test, some authors have suggested that in children with idiopathic Horner syndrome, greater emphasis should be placed on physical examination (to detect masses) and/or appropriate imaging of the head, neck, and thorax. Other authors continue to advocate urine testing (57; 81). There is consensus that the absence of urine catecholamines does not to rule out neuroblastoma.
In the setting of a nonisolated Horner syndrome, the results of the diagnostic imaging will usually establish the cause, which will determine further management. For isolated Horner syndrome, an etiology is rarely discovered (03; 89). An acute, isolated, painful Horner syndrome warrants urgent imaging to evaluate for carotid dissection. However, patients with Horner syndrome and carotid dissection are less likely to present with stroke or transient ischemic attack when compared to those patients without Horner syndrome in the setting of carotid dissection (56). When strokes do occur, as a result of carotid dissection, it is typically less severe and occurs within hours to 1 month after the clinical onset of Horner syndrome (56; 10); one-third of strokes occur in the first 24 hours (20) and 88% within the first 7 days of symptom onset (10). Some authors suggest that in chronic isolated Horner syndrome in adults, imaging need not be performed, given the low diagnostic yield (04).
For patients bothered by the appearance of ptosis, apraclonidine 0.5% or surgery may palliate symptoms.
Lindsey B De Lott MD
Dr. De Lott of the University of Michigan has no relevant financial relationships to disclose.See Profile
Jonathan D Trobe MD
Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.See Profile
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