What are the broad categories and examples of causes of cranial nerve (CN) 3, 4, and 6 palsy?

Causes of Cranial Nerve 3,4, and 6 Palsies

For OSCE preparation, organize the causes of ocular motor nerve palsies using the mnemonic "VITAMIN-CD" (Vascular, Inflammatory/Infectious, Trauma, Autoimmune/Aneurysm, Metabolic, Idiopathic, Neoplasm, Congenital, Demyelinating), with vascular causes being the most common in adults over 50 years. 1, 2

Major Categories with Key Examples

1. Vascular (Most Common in Adults)

• Microvascular ischemia accounts for approximately 37% of isolated CN VI palsy cases and is the leading cause in adults over 50 years 2, 3
• Risk factors include diabetes mellitus, hypertension, and hyperlipidemia 1
• Giant Cell Arteritis (GCA) is a medical emergency in elderly patients presenting with scalp/temporal tenderness or jaw claudication—can cause permanent visual loss if untreated 1, 2
• Approximately 71% of vascular-cause palsies recover spontaneously, with most resolving within 6 months 4, 5
• Pupil-sparing CN III palsy typically suggests microvascular ischemia 6

2. Aneurysm (Emergency for CN III)

• Pupil-involving CN III palsy is a medical emergency requiring urgent neuroimaging with MRA or CTA to rule out posterior communicating artery aneurysm 6
• 90% of patients with isolated third nerve dysfunction caused by aneurysm have anisocoria 7
• Carotid artery aneurysms in the cavernous sinus may present with concomitant Horner's syndrome, CN III/IV palsies, or facial pain 1, 2

3. Trauma

• Accounts for 26.1% of cases in some series 5
• Usually self-evident with history of head injury, typically involving basilar skull fracture 1
• Acute rise in intracranial pressure from intracranial bleed 1
• Patients with trauma-related palsies are less likely to recover compared to vascular causes 4

4. Neoplasm

• May present insidiously or acutely 1
• Bilateral CN VI involvement suggests clival chordoma or increased intracranial pressure 1
• Look for associated neurologic deficits: facial/extremity motor weakness, other cranial nerve involvement, visual field defects, papilledema, proptosis 1
• Patients with neoplasm-related palsies have poor recovery rates 4

5. Demyelinating Disease

• Multiple sclerosis can cause isolated CN VI palsy 1, 2
• Pontine lesions typically produce other findings, most notably ipsilateral facial palsy (CN VII curves over CN VI nucleus) 1
• Neurosyphilis should be considered in young individuals with risk factors 2

6. Inflammatory/Infectious

• Idiopathic cranial nerve neuritis shows enhancement on high-resolution MRI and responds well to steroid treatment 8
• Postviral CN VI palsy is a diagnosis of exclusion, described with COVID-19 infection and post-vaccination 1
• CSF inflammation, infection, or meningeal processes can affect the subarachnoid space 1, 2

7. Congenital

• Accounts for 13.4% of cases 5
• Most congenital cases require extraocular muscle surgery with 80.9% success rate 5

8. Idiopathic/Undetermined

• Surprisingly high proportion (263 of 1,000 cases in one series) remain of undetermined cause despite modern imaging 4
• About 51% of patients with no known cause undergo spontaneous remission 4
• In patients with vasculopathic risk factors only, 10% were found to have other causes including midbrain infarction, neoplasms, inflammation, and pituitary apoplexy 3

Anatomic Localization Clues

Nuclear/Fascicular (Brainstem)

• CN VI nucleus lesions: ipsilateral facial paralysis or complete horizontal gaze deficit 1
• Pontine lesions involving CN VI: contralateral hemiparesis (corticospinal tract involvement) 1

Subarachnoid Space

• Susceptible to stretching from increased intracranial pressure 1, 2
• Vulnerable to CSF inflammation, infection, infiltration, or compression from clival tumors 1, 2

Cavernous Sinus

• Look for concomitant Horner's syndrome, CN III/IV/VI palsies together, or facial pain (CN V involvement) 1, 2
• Inflammatory cavernous sinus processes or structural lesions 1

Orbital

• Associated proptosis and optic neuropathy may be present 1
• Orbital infections, mass lesions, or inflammation can affect the nerve or muscle directly 1

Critical Distinguishing Features for OSCE

CN III palsy: Ptosis, pupillary abnormalities, limited adduction/elevation/depression, "down and out" eye position 6, 9

CN IV palsy: Vertical diplopia worse on downgaze and head tilt toward affected side (Parks-Bielschowsky three-step test) 6

CN VI palsy: NO ptosis, NO pupillary abnormalities, limited abduction only, esotropia, horizontal diplopia worse at distance 1, 2, 9

Common Pitfalls to Avoid

• Do not assume all palsies with vascular risk factors are microvascular—16.5% of patients over 50 had other causes including neoplasm, GCA, and brainstem infarction 3
• Vasculopathic risk factors were present in 61% of patients with non-microvascular causes 3
• In vascular cases with anisocoria, the pupillary diameter difference was <1.0 mm, whereas aneurysm cases typically have more pronounced anisocoria 7
• If no recovery is apparent by 6 months, approximately 40% of patients demonstrate serious underlying pathology warranting further evaluation 1
• Brain MRI and laboratory workup have a role in initial evaluation regardless of whether vascular risk factors are present 3