Horner Syndrome

Horner syndrome is a condition resulting from an interruption of the sympathetic innervation of the eyes. The syndrome is usually idiopathic but can be directly caused by head and neck trauma, cerebrovascular disease, or a tumor of the CNS. Horner syndrome is classified as 1st-order (central), 2nd-order (preganglionic), or 3rd-order (postganglionic) based on the location of the lesion along the sympathetic pathway. Partial ptosis, miosis, and facial anhidrosis are the classical signs of Horner syndrome, making up a characteristic triad. Other associated neurologic signs may also be present, depending on the location of the lesion and can aid in determining the cause. The syndrome is diagnosed by using cocaine, apraclonidine, or hydroxyamphetamine eye drops. Management of Horner syndrome requires treatment of the underlying condition.

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Overview

Definition

Horner syndrome, also known as oculosympathetic paresis, is a condition resulting from the interruption of the sympathetic supply to the eyes. The syndrome is characterized by the classic triad of: 

  • Partial ptosis (drooping or inability to raise the upper eyelid)
  • Miosis (constricted pupil)
  • Facial anhidrosis (absence of sweating)

Epidemiology

  • Can affect any age, sex, or ethnicity
  • Frequency: approximately 1 per 6000 individuals

Neuroanatomy

Horner syndrome can result from a lesion anywhere on the 3-neuron sympathetic pathway supplying the eye. The nerve supply starts from the posterolateral hypothalamus and ends as the long ciliary nerves that supply the iris dilator and Müller muscles (superior tarsal muscle).

  • 1st-order neuron: originates in the hypothalamus and descends to the first synapse in the cervical spinal cord, located at levels C8–T2 (also called the ciliospinal center of Budge).
  • 2nd-order neuron: Preganglionic pupillomotor fibers exit the spinal cord at T1, travel through the brachial plexus, over the lung apex, ascending to the superior cervical ganglion located near the angle of the mandible and the bifurcation of the common carotid artery. 
  • 3rd-order neuron: Pupillomotor fibers ascend along the internal carotid artery and enter the cavernous sinus where it is in close relation with the abducens nerve (cranial nerve (CN) VI). These fibers enter the orbit with the ophthalmic branch (V1) of the trigeminal nerve (CN V) via the long ciliary nerves, which innervate the iris dilator and Müller muscles.
Sympathetic pathway of eye

Sympathetic pathway of the eye

Image by Lecturio. License: CC BY-NC-SA 4.0

Classification

  • 1st-order, or central, Horner syndrome: caused by lesions of the sympathetic tracts in the brain stem or cervicothoracic spinal cord
  • 2nd-order, or preganglionic, Horner syndrome: caused by lesions that involve the spinal cord, thoracic outlet, or lung apex. These lesions are usually acquired through trauma, surgery, or malignancy (e.g., Pancoast tumor).
  • 3rd-order, or postganglionic, Horner syndrome: caused by lesions of the internal carotid artery, such as arterial dissection, thrombosis, cavernous sinus aneurysm, or injuries acquired during carotid artery stenting

Etiology

Most cases of Horner syndrome are idiopathic. Of the identified causes, the etiology depends on the location of the lesion. The causes vary between adult and pediatric populations. 

1st-order syndrome (central)

  • Hypothalamus:
    • Stroke 
    • Tumor
  • Brain stem:
    • Stroke
    • Demyelination (e.g., multiple sclerosis)
    • Tumor
  • Spinal cord:
    • Neck trauma 
    • Pituitary tumor
    • Myelitis
    • Syringomyelia
    • Demyelination (e.g., multiple sclerosis)
    • Arteriovenous malformation (AVM)
    • Infarction
  • Arnold-Chiari malformation
  • Encephalitis

2nd-order syndrome (preganglionic)

  • Apical lung tumor (e.g., Pancoast tumor)
  • Subclavian artery lesions
  • Mediastinal tumors
  • Cervical rib
  • Thyroid malignancies
  • Birth trauma with injury to lower brachial plexus
  • Mandibular tooth abscess
  • Lesions of the middle ear (e.g., acute otitis media)
  • Iatrogenic (e.g., central venous catheterization, chest tube placement, thoracic surgery)

3rd-order syndrome (postganglionic)

  • Internal carotid artery dissection
  • Carotid cavernous fistula
  • Trauma
  • Herpes zoster
  • Nasopharyngeal carcinoma, lymphoma
  • Cluster or migraine headache

Etiology of Horner syndrome in children

  • Congenital (diagnosed 4 weeks after birth):
    • Trauma to the neck and brain stem during birth
    • Congenital infections
    • Neuroblastoma
    • Idiopathic
  • Acquired:
    • Neuroblastoma
    • Rhabdomyosarcoma
    • Brain stem AVMs
    • Brain stem tumors (glioma)
    • Demyelination (brain stem)
    • Carotid artery thrombosis
    • Neck trauma
    • Postsurgical (e.g., after jugular cannulation, thoracic surgery, or neck surgery)

Pathophysiology

Horner syndrome is the result of the disruption of the sympathetic supply to the eye. The symptoms depend on the location of the lesion, and the severity depends on the severity of denervation. 

  • Denervation of the nerves that supply the Müller muscle (superior tarsal muscle) causes ptosis. Partial ptosis can occur because the levator palpebrae superioris muscle is unaffected.
  • Denervation of the nerves that supply the iris dilator muscle causes miosis of the affected side: 
    • Upon exam, anisocoria and a lag of pupil dilation can be seen. 
    • The light and accommodation pupillary reflexes remain normal. 
  • Denervation of the nerves that supply the facial sweat glands causes anhidrosis:
    • Depends on the degree of disruption of the sympathetic supply
    • Seen in 1st- or 2nd-order lesions, but not a prominent feature of 3rd-order lesions

Clinical Presentation

  • Classic triad of Horner syndrome: 
    • Ptosis
    • Miosis
    • Anhidrosis
  • Ocular signs:
    • Pupils: 
      • Miosis on the affected side
      • Anisocoria (difference in the pupillary size) that is more prominent in the dark.
      • Dilation lag (the constricted pupil takes 15–20 seconds longer to dilate when a light source is moved away from the eye.)
    • Eyelids:
      • Mild (< 2 mm) ptosis of the upper eyelid
      • Inverse ptosis of the lower eyelid (lower lid rests at a higher level than normal) 
      • Combined: decreased palpebral aperture compared to the other eye
    • Extraocular movements may be affected in lesions of the brain stem or the cavernous sinus.
  • Associated neurologic signs:
    • Signs of brain stem lesions:
      • Ataxia
      • Diplopia
      • Lateralized weakness
      • Vertigo
    • Signs of spinal cord (myelopathic) lesions:
      • Ipsilateral weakness
      • Long tract signs
      • Bowel and bladder impairment
      • Spasticity
    • Brachial plexopathy: pain and weakness in the arm or hand
    • Cranial neuropathy 
  • In infants and children, the Harlequin sign (facial flushing) is more apparent than anhidrosis. 
  • Iris heterochromia (different-colored irides) may be seen in children with congenital Horner syndrome. In these cases, the affected eye has lighter color. 
Horner syndrome

Right-sided miosis and ptosis suggestive of Horner syndrome

Image: “Myosis and eyelid ptosis were noted on the right side” by Case Reports in Endocrinology. License: CC BY 4.0

Diagnosis and Management

Clinical diagnosis

  • Horner syndrome is clinically diagnosed by the presence of ptosis and dilation lag in the affected eye. 
  • Anhidrosis is also usually observed on the same side as the affected eye but is not necessary for diagnosis. 
  • Painful acute anisocoria is highly suggestive of Horner syndrome. 

Pharmacologic tests

  • Topical cocaine can be used to confirm the diagnosis of Horner syndrome:
    • Cocaine blocks reuptake of norepinephrine from the synaptic cleft and will cause dilation of the pupil in case of an intact sympathetic pathway. Cocaine has no effect on eyes with impaired sympathetic innervation.
    • 1 hour after the application of 2 drops of 10% cocaine, a normal pupil dilates more than the Horner pupil, increasing the degree of anisocoria.
    • Anisocoria ≥ 1 mm after cocaine administration is considered a positive result.
  • Topical apraclonidine is used as an alternative agent to confirm Horner syndrome: 
    • An α-adrenergic agonist that causes pupillary dilation in the Horner pupil and mild pupillary constriction in the normal eye by down-regulating norepinephrine
    • A reversal of anisocoria after the application of 2 drops of 0.5% apraclonidine is suggestive of Horner syndrome.
    • Apraclonidine should not be used in infants.
  • Topical hydroxyamphetamine is used to differentiate 1st-order and 2nd-order Horner syndrome: 
    • Hydroxyamphetamine causes a release of norepinephrine from intact adrenergic nerve endings, causing pupillary dilation.
    • 1 hour after the application of 1% hydroxyamphetamine eye drops, dilation of both pupils indicates a lesion of the 1st- or 2nd-order neuron. 
    • If the miotic pupil fails to dilate, it indicates a 3rd-order Horner syndrome.
    • Pholedrine can be used as an alternative to hydroxyamphetamine. The test is performed using 1% pholedrine.

Imaging

  • Imaging is used in conjunction with medical tests to confirm the etiology and locate the site of the lesion.
  • MRI of the brain and spinal cord is indicated in cases with signs indicative of spinal lesions. 
  • Head CT is also advised in cases of Horner syndrome with a history of or clinical signs suggesting stroke. 
  • Chest X-ray followed by a CT scan must be performed in patients when pulmonary malignancy is suspected. 

Management

  • Depends on the underlying cause
  • Prompt recognition of the condition and diagnosis of the underlying etiology is necessary to reduce worsening of the condition. 
  • The acute painful onset of Horner syndrome should be considered a medical emergency, as it might indicate a carotid artery dissection.
  • Vascular surgical care is necessary in cases of carotid artery dissection. 
  • Neurologic care should be provided in cases of Horner syndrome related to aneurysms. 

Differential Diagnosis

  • Adie pupil: disorder of parasympathetic denervation of the pupil that results in poor light constriction but better accommodation. Adie pupil is mostly idiopathic. The affected pupil initially appears abnormally dilated at rest and has a poor pupillary constriction in bright light. Patients complain of difficulty adapting to dark conditions and photophobia. No treatment is required, but topical physostigmine may provide relief. 
  • Argyll-Robertson pupil: characterized by small and irregular pupils that constrict briskly to near targets but react with little to no constriction to light. Argyll-Robertson pupil is frequently associated with iris atrophy and is a highly specific sign of neurosyphilis and is treated by managing the underlying cause. 
  • Chronic anterior uveitis: condition that affects the anterior uvea, iris, and ciliary body. The symptoms of uveitis are pain, redness, and photophobia. The symptoms respond well to antiinflammatory drugs. Chronic anterior uveitis occurs in association with other chronic inflammatory conditions. 
  • Pupillary sphincter tear: occurs because of trauma and can cause unilateral or bilateral mydriasis. Patients report glare, haloes in brightly lit conditions, and trouble reading. Patients with atonic, mydriatic pupils report worse glare at night and inability to focus on near objects. The tear requires surgical repair. 
  • Aponeurotic ptosis: most common type of acquired ptosis. Aponeurotic ptosis occurs because of outstretching of the levator muscle and is usually seen in elderly patients. Patients usually present with asymmetrical ptosis or partial vision loss. Surgical treatment is required. 
  • Ocular myasthenia: ocular representation of myasthenia gravis. Ocular myasthenia results in ocular muscle fatigue and weakness. In myasthenia, antibodies that block the acetylcholine receptor are produced, resulting in muscle fatigue and paralysis in some cases. Diagnosis relies on an edrophonium sodium test. Treatment involves anticholinesterase agents. 

References

  1. Kedar, S., Biousse, V., Newman, N.J. (2018). Horner syndrome. UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/horner-syndrome
  2. Khan, Z., Bollu, P.C. (2021). Horner syndrome. StatPearls. Retrieved June 24, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK500000/
  3. Bardorf, C.M. (2019). Horner syndrome. Emedicine. Retrieved June 24, 2021, from https://emedicine.medscape.com/article/1220091
  4. Kanagalingam, S., Miller, N.R. (2015). Horner syndrome: clinical perspectives. Eye and Brain 2015:35–46. https://doi.org/10.2147/EB.S63633 

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