Horner syndrome and tonic pupil

Horner Syndrome (Oculosympathetic Paresis)

Clinical Tetrad & Cardinal Manifestations

Horner syndrome results from interruption of the three-neuron oculosympathetic pathway at any point along its anatomical trajectory:

1. Mild Ptosis (1 to 2 mm): Paresis of the superior tarsal muscle of Müller (smooth muscle innervated by sympathetics, supplying 1-2 mm of lift). The ptosis is distinctly milder than the profound ptosis seen in CN III palsy.
2. 'Upside-Down Ptosis' (Reverse Ptosis): Slight elevation of the lower eyelid due to paresis of the inferior tarsal smooth muscle. The combination of upper lid ptosis and lower lid elevation narrows the palpebral fissure, creating an illusion of enophthalmos (apparent enophthalmos).
3. Miosis & Dilation Lag: Pupillary constriction resulting from unopposed parasympathetic tone, with characteristic dilation lag in darkness.
4. Anhidrosis: Loss of facial sweating. In first-order lesions, anhidrosis involves the entire ipsilateral hemibody; in second-order lesions, it affects the entire ipsilateral hemiface; in third-order lesions (postganglionic, distal to the carotid bifurcation), anhidrosis is restricted to the medial forehead and nose or is completely absent.
5. Heterochromia Iridis: A lighter-coloured, hypochromic iris on the affected side. This is seen in congenital Horner syndrome or lesions acquired before age 2, because sympathetic stimulation is obligatory for the migration and pigmentation of stromal melanocytes during early ocular development.

Pharmacological Diagnostic Ladder

1. Step 1: Pharmacological Confirmation (Apraclonidine vs. Cocaine):
   • Apraclonidine 0.5% (First-Line): A topical alpha-2 adrenergic agonist with weak alpha-1 activity. In a normal pupil, its alpha-2 effect dominates, causing no change or mild pupillary constriction. In a denervated Horner pupil, sympathetic interruption causes upregulation of post-synaptic alpha-1 receptors (denervation supersensitivity). Apraclonidine stimulates these supersensitive receptors, causing the Horner pupil to dilate dramatically while simultaneously elevating the ptotic upper eyelid. This produces a reversal of anisocoria (the smaller Horner pupil becomes larger than the fellow normal pupil).

• Paediatric safety: Avoid apraclonidine below six months and use extra caution below two years under specialist guidance; early negative testing does not exclude acute Horner.
  • Cocaine 4% to 10% (Historical Gold Standard): Blocks the reuptake of noradrenaline at postganglionic sympathetic terminals. In a normal eye, basal noradrenaline release accumulates, producing brisk pupillary mydriasis. In a Horner pupil of any order, baseline noradrenaline release is diminished or absent, so the Horner pupil fails to dilate. A substantial post-cocaine anisocoria supports Horner syndrome, but timing, baseline anisocoria, drug availability and examination conditions influence interpretation. Do not delay urgent vascular imaging in an acute painful presentation for drop testing.

1. Step 2: Anatomical Localisation (Hydroxyamphetamine):
   • Hydroxyamphetamine 1%: Stimulates the release of stored noradrenaline from viable postganglionic (third-order) nerve endings:
   • First-Order (Central) or Second-Order (Preganglionic) Lesion: The third-order neuron is anatomically intact and maintains normal stores of noradrenaline. Hydroxyamphetamine triggers transmitter release, causing the Horner pupil to dilate normally or excessively, matching or exceeding the fellow pupil.
   • Third-Order (Postganglionic) Lesion: The third-order nerve endings have degenerated and are depleted of noradrenaline. Hydroxyamphetamine fails to induce mydriasis, and the Horner pupil fails to dilate (anisocoria increases by $\ge 1.0\text{ mm}$).

Clinical Emergencies Associated with Horner Syndrome

• Acute Painful Horner Syndrome: An Internal Carotid Artery (ICA) Dissection until proven otherwise! The oculosympathetic plexus travels within the adventitia of the ICA. Mural expansion and haematoma dissecting the carotid wall stretch and compress the sympathetic fibers, presenting with acute neck, periorbital, or jaw pain and Horner syndrome. It carries an immediate risk of thromboembolic stroke. Mandates emergent CT angiography (CTA) or magnetic resonance angiography (MRA) of the head and neck extending from the aortic arch to the skull base.
• Second-Order (Preganglionic) Horner: Most concerning for a Pancoast tumour (apical lung bronchogenic carcinoma invading the sympathetic chain and brachial plexus, presenting with Horner syndrome and shoulder/arm pain), mediastinal masses, or thoracic surgical trauma.
• First-Order (Central) Horner: Associated with Wallenberg lateral medullary syndrome (posterior inferior cerebellar artery [PICA] stroke: Horner syndrome, ipsilateral limb ataxia, vertigo, nystagmus, ipsilateral facial numbness, and contralateral loss of pain and temperature sensation).

Adie Tonic Pupil & Holmes-Adie Syndrome

Pathophysiology & Aberrant Regeneration

Adie tonic pupil is an acquired neuro-ophthalmic disorder resulting from denervation of the postganglionic parasympathetic nerve supply originating in the ciliary ganglion or short ciliary nerves:

• Etiology: Most cases are idiopathic (presumed viral ciliary ganglionitis). Secondary causes include orbital trauma, orbital surgery, herpes zoster ophthalmicus, and diabetes mellitus.
• Demographics: Strong predilection for young adults, with an 80% female preponderance (peak age 20 to 40 years). It presents unilaterally in 80% of patients, although the fellow eye becomes involved over time at a rate of ~4% per year.
• The Aberrant Regeneration Paradigm: Following ciliary ganglion injury, postganglionic axons regenerate. Many more ganglion fibres serve accommodation than the sphincter. As regenerating fibers randomly re-innervate the globe, fibers originally destined for accommodation overwhelmingly miswire to the iris sphincter muscle. This produces the characteristic clinical phenomenon of light-near dissociation.

Cardinal Clinical Signs

1. Unilateral Mydriasis in Ambient Light: Anisocoria is distinctly greater in bright illumination.
2. Absent or Sluggish Light Reaction: Poor or absent pupillary constriction to direct and consensual light stimulation.
3. Tonic, Prolonged Near Constriction: On sustained near fixation, the pupil constricts slowly and powerfully. Upon refixating at distance, the pupil exhibits remarkably slow, tonic redilation.
4. Vermiform (Worm-Like) Iris Movements: On high-magnification slit-lamp biomicroscopy, the iris sphincter exhibits sectoral paralysis with focal, rhythmic, writhing contractions along the pupillary margin.
5. Accommodative Paresis: Difficulty focusing at near, which typically recovers over several months.
6. Holmes-Adie Syndrome: The association of an Adie tonic pupil with diminished or absent deep tendon reflexes (particularly Achilles and patellar reflexes) secondary to concurrent dorsal root ganglionopathy.

Pharmacological Confirmation: Dilute Pilocarpine

• Mechanism: Denervation of the postganglionic parasympathetic nerve terminal induces an upregulation of muscarinic M3 receptors on the post-synaptic iris sphincter muscle membrane (cholinergic denervation supersensitivity).
• Testing: Use a correctly prepared dilute pilocarpine solution under a clinical protocol. Supersensitivity supports parasympathetic denervation but may be absent early or occur with other chronic lesions. Do not improvise a 1:10 dilution of either 1% or 2% stock: those stocks produce different concentrations.
• Interpretation: A disproportionate response can support denervation but is not diagnostic alone; normal pupils and other chronic denervation can respond, and recent tonic pupils may not yet show supersensitivity.