What causes non-reactive pupils?

Causes of Non-Reactive Pupils

Life-Threatening Causes Requiring Immediate Action

Non-reactive pupils most commonly indicate either increased intracranial pressure with brain stem compromise, opioid toxicity, or third nerve palsy from compressive lesions such as aneurysm. 1, 2

Increased Intracranial Pressure

• Brain stem ischemia (blood flow <40 ml/100g/min) is the primary mechanism causing pupillary non-reactivity in severe head injury, rather than mechanical compression alone 2
• Decreased pupillary reactivity precedes peak ICP elevation by an average of 15.9 hours, making it an early warning sign 1
• Patients with non-reactive pupils have mean peak ICP of 33.8 mmHg versus 19.6 mmHg in those with normal reactivity 1
• Bilateral fixed dilated pupils following traumatic brain injury carry 88% mortality, though survivors may have favorable outcomes without persistent vegetative state 3

Third Nerve Palsy with Pupillary Involvement

• A dilated, non-reactive pupil accompanied by ptosis or ophthalmoplegia represents a pupil-involving third nerve palsy requiring emergent neuroimaging (MRI with gadolinium and MRA or CT angiography) to rule out posterior communicating artery aneurysm 4, 5
• Unilateral fixed dilated pupil in traumatic brain injury shows ipsilateral CT abnormality in only 34% of cases, with 49% showing diffuse injury and 9% showing contralateral pathology 3
• 72% of survivors with fixed dilated pupils develop permanent ophthalmological deficits 3

Opioid Toxicity

• Pupils measure 1-2mm (pinpoint) and may be difficult to visualize without magnification in opioid intoxication 6
• Response to naloxone is both diagnostic and therapeutic 6

Acute Angle-Closure Attack

During or immediately following acute angle-closure crisis, pupils become mid-dilated, asymmetric or oval, and non-reactive due to pressure-induced ischemia of the pupillary sphincter. 7

• Pupillary non-reactivity occurs when IOP is markedly elevated, making parasympathomimetic therapy ineffective 7
• Associated findings include conjunctival hyperemia, corneal edema, and anterior chamber inflammation 7
• Gonioscopy should be performed to evaluate for peripheral anterior synechiae and angle closure 7

Neurological Causes

Horner Syndrome

• Presents with miosis (not mydriasis), ptosis, and anhidrosis 5
• Requires urgent MRA/CTA for carotid dissection when combined with ptosis 5
• Represents sympathetic pathway disruption rather than parasympathetic dysfunction 5

Brain Stem Pathology

• Pontine lesions cause bilateral pinpoint pupils that may appear non-reactive 6
• Bilateral presentation suggests toxic/metabolic cause or pontine pathology, while unilateral suggests Horner syndrome 6

Pharmacological Causes

• Anticholinergic medications (including topical mydriatics, systemic anticholinergics, ipratropium bromide, phenothiazines) cause dilated, non-reactive pupils 7
• Pharmacological mydriasis must be distinguished from third nerve palsy through history and pilocarpine testing 8

Iris and Local Causes

Adie's Tonic Pupil

• Dilated pupil that is non-reactive to light but constricts strongly to near target with slow redilation 8
• Dilute pilocarpine 0.1% causes constriction in affected eye but not normal eye (denervation supersensitivity) 8
• Represents postganglionic parasympathetic denervation 8

Iris Trauma

• Iris sphincter tears from trauma cause irregular, dilated, non-reactive pupils 8
• Direct mechanical damage prevents pupillary constriction 8

Iris Atrophy

• Diffuse or focal iris atrophy following previous angle-closure attacks causes abnormal pupillary function 7
• Posterior synechiae may mechanically prevent pupillary movement 7

Critical Assessment Algorithm

When evaluating non-reactive pupils, immediately assess: 6, 4

1. Symmetry: Bilateral suggests toxic/metabolic or pontine pathology; unilateral suggests third nerve palsy or Horner syndrome 6

2. Size:

   • Dilated (>6mm) with ptosis/ophthalmoplegia = third nerve palsy requiring emergent imaging 4, 5
   • Mid-dilated (4-6mm) = consider acute angle-closure 7
   • Pinpoint (1-2mm) = opioid toxicity or pontine lesion 6

3. Associated signs:

   • Elevated IOP, corneal edema = angle-closure 7
   • Ptosis, ophthalmoplegia = third nerve palsy 4
   • Decreased consciousness, head injury = increased ICP 1, 2

Common Pitfalls

• Do not delay neuroimaging when pupillary abnormalities accompany ptosis, as this represents potential neurosurgical emergency 4, 5
• Do not confuse anisocoria with abnormal pupillary light response, as these represent different pathophysiologic processes 6
• Do not assume microvascular etiology if extraocular muscle involvement is partial, even with normal pupil 5
• Parasympathetic hypersensitivity can occur with both postganglionic (Adie's) and preganglionic (third nerve palsy) lesions 9