Differential Diagnosis in Neurology

Topic 5. Cranial Nerves

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5.3. Cranial Nerve III

Anatomical Features:
- Ipsilateral and contralateral innervation of the superior rectus
- Dorsal neurons of lateral nucleus (inferior rectus) intermediate neurons of lateral nucleus (inferior oblique) Ventral neurons of lateral nucleus (medial rectus)
- Central caudal nucleus-levator muscles of both eyes
- Edinger–Westphal nucleus-dorsal rostral portion of the oculomotor complex:
  - Anteromedian nucleus and EW: preganglionic parasympathetic
  - Post ganglion sympathetic fibers reach the eye by the short ciliary nerves
  - 3–3.5% of ocular parasympathetic axons supply the iris sphincter; greater than 90% supply the ciliary muscle and medicate accommodations
  - Pressure sensitive axons for pupillary contraction occupy form medial margins of IIIrd nerve; may be spread equally throughout the nerve; fibers for accommodation may be with pupillomotor fibers
  - Fascicular; cavernous; orbital portion (through) the S.O.F. and the annulus of Zinn
  - IIIrd separate into two divisions either within the anterior cavernous sinus or the orbit:
    - Superior division: SR, levator of the lids
    - Inferior division: MR; IR; IO; parasympathetic fibers (with the branch to the IO)
  - Blood supply:
    - Small arteries from the posterior cerebral and basilar arteries
    - Artery of the inferior cavernous sinus (branch of meningohypophyseal trunk)
    - Recurrent branched from ophthalmic artery to orbital portions of the nerve
IIIrd nerve nuclear complex:
- Ipsilateral and contralateral innervation of the superior rectus
- Dorsal neurons of the lateral nucleus innervate the inferior rectus; intermediate neurons of the lateral nucleus (inferior oblique) ventral neurons of the lateral nucleus (medial rectus)
- Central caudal nucleus innervates the levator muscles of both eye lids
- Edinger–Westphal nucleus overlies the dorsal rostral portion of the oculomotor complex:
  - Anteromedian nucleus and EW: preganglionic parasympathetic axons to the ciliary ganglion
  - Post ganglionic sympathetic fibers reach the eye by the short ciliary nerves
  - 3–3.5% of ocular parasympathetic axons supply the iris sphincter; >90% supply the ciliary muscle and mediate accommodation
  - Pressure sensitive axons for pupillary contraction occupy dorsomedial margin of the IIIrd nerve alternatively they may spread equally throughout the nerve; fibers for abomination course with pupillomotor fibers
  - Fascicular; cavernous; orbital portion (through the S.O.F. and the annulus of Zinn) syndromes occur clinically
  - IIIrd separates into two divisions either within the anterior cavernous sinus or the orbit:
    - Superior division: SR, levator of the lid
    - Inferior division: MR; IR; I.O: parasympathetic fibers (with the branch to I.O.)
  - Blood supply to the IIIrd nerve:
    - Small arteries form the posterior cerebral and basilar arteries (IIIrd nerve complex)
    - Artery of the inferior cavernous sinus (branch of meningohypophyseal trunk)
    - Recurrent branches from ophthalmic artery to orbital portions of the nerve

Vascular IIIrd Nerve Syndromes

Nuclear IIIrd nerve syndrome:
- Intrapeduncular branch of the PI division of the PCA (often involved)
- Bilateral ptosis
- Bilateral pupillary dilatation
- Bilateral superior rectus palsy
- Rarely a partial syndrome occurs
Fascicular IIIrd nerve/intraparenchymal lesions:
- Weber's syndrome: ipsilateral IIIrd (may or may not be pupil sparing) crossed hemiparesis; awake patient
- Benedict's syndrome: ipsilateral IIIrd nerve with contralateral movement disorder
- Claude's membrane: ipsilateral IIIrd contralateral nerve with cerebellar outflow
- Subdural Hematoma: ipsilateral IIIrd nerve; involved pupil; spastic hemiparesis; headache with lethargy
Cavernous IIIrd nerve lesion:
- Involved with IV, VI and first division of V₁
- Superior division involved anteriorly in the sinus (superior rectus and levator palpebrae)
Orbital IIIrd nerve lesion:
- Involved with IV, VI and first division of V
- Superior division: SR and levator palpebrae
- Inferior division: pupillary involvement; medial rectus, inferior rectus, and inferior oblique
- Intermediolateral limb of the external carotid (ILL) is the blood supply
Nuclear III and IV nerve (Masugi's syndrome):
- Posterior lateral choroidal artery from the terminal PCA (P4)
- Simultaneous nuclear IIIrd and IVth nerve paralysis
- Crossed hemisensory deficit
- Rare mild internal capsule type motor deficit
Hematoma of the midbrain:
- Lethargy to obtundation (periaqueductal grey)
- Failure of vertical gaze
- Large 3–4 or 4–5 mm pupils; sluggishly reactive
- Quadriparesis (if pressure on the cerebral peduncles)
- Nystagmus retractorius
- Rare: convergent nystagmus
- Hydrocephalus
Vascular Malformation of the midbrain:
- Cavernous hemangioma
- Capillary telangiectasia (rare: usually pons or cortex)
- Arteriovenous malformation:
  - Different clinical manifestations due to size, recurrent bleeding, and exact location
  - Arterial venous malformations in association with Wyburn–Mason and Von Hippel Lindau malformations
  - Cavernous hemangiomas rebleed repeatedly (specific MRI appearance: hemosiderin ring and increased signal intensity on T1 weighted image (old blood)
  - Capillary telangiectasia (asymptomatic and rare)
IIIrd nerve involvement from emboli or infarction secondary to "top of the basilar syndrome"

Aneurysmal Involvement of the Third Nerve

Pain behind the eye
Pupil involved early (vulnerability of location of pupillomotor fibers; dorsomedial part of the nerve, 3–4 micron small pressure sensitive fibers; may be spared:
- P-COM (third nerve affected alone)
- Carotid artery (third with contralateral face, arm and leg involvement)
- Between the posterior cerebral and superior cerebellar artery (usually IIIrd nerve alone)
- Giant aneurysm at the top of the basilar artery (IIIrd nerve involved in the interpeduncular fossa; hydrocephalus and contralateral spastic hemiparesis)
- Cercoid posterior cerebral artery (elongated; tortuous)
- Retroorbital pain more severe and prolonged than in diabetic neuropathy
- Intracavernous aneurysm may erode into the sphenoid sinus and present with a profuse nose bleed; usually gradual VIth nerve weakness and V1 facial pain

Ischemia of the Intracavernous Internal Carotid Artery

Inferolateral trunk of the ECA (external carotid artery):
- Superior or tentorial branch
- Anteromedial branch
The anterolateral branch of the ILT (inferolateral trunk of the ECA) anastomosis with the distal portion of the internal maxillary artery and the posterior branch anastomosis with the accessory and middle meningeal arteries
The IIIrd and IVth nerves are supplied by the superior or tentorial branch of the ILT
Cranial nerves III, IV, VI supplied by the anteromedial branch
The vascularization of the IIIrd nerve depends on the specific territory of the ILT; the nerve is supplied predominantly by the superior or tentorial components or the anteromedial branch
Clinical presentation of ischemia of the IIIrd nerve from external carotid artery disease:
- Isolated IIIrd nerve
- IIIrd nerve associated with Vth nerve
- IIIrd nerve associated with Vth, IVth, and VIth nerve
- IIIrd and IVth involved together
Blood supply of the IIIrd nerve:
- Region of the posterior perforated substance, artery from the basilar, causes isolated IIIrd
- Supracavernous region; artery of the tentorium; IIIrd, IVth nerve
- Intracavernous; ILT of the ECA; IIIrd, IVth VIth and Vth and VIth; rarely IInd and VIIth
- Ischemia affects the central portion of the nerve

Congenital Defects

Congential absence of IIIrd nerve nuclei in association with absence of other cranial nerves
Congential abnormalities of innervation; fascicles of IIIrd nerve may innervate Vith nerve
In association with Möbius syndrome. (Facial diplegia and ptosis.)

Trauma

Head trauma: occasionally III and IV nerve are injured simultaneously
IIIrd trapped:
- Between the posterior cerebral and the superior cerebellar arteries
- At the tentorial edge
- Damaged in the cavernous sinus
- Disrupted orbital wall
- Compression by the uncus of the hippocampal genus; tentorial edge or under the posterior cerebral artery by herniation from edema or mass lesions
Aberrant regeneration:
- Classic misdirection syndrome; engagement of the IIIrd nerve induces pathological lid retraction; no up or down movement of the globe (simultaneous innervation of the superior or inferior rectus muscles); adduction of the eye and pupillary constriction are intact
- Fully developed misdirection syndrome; minimal retraction of the globe, slight enophthalmos, droop of the upper lid on abduction

Neoplasm

Accounts for approximately 20–25% of IIIrd nerve paralysis
Midbrain tumors involving intraparenchymal portion of IIIrd: glioma, medulloblastoma, hemangiomas, metastatic lesions
Parinaud's syndrome:
- Paralysis of upward and downward gaze
- Dissociated vertical and horizontal gaze with opticokinetic nystagmus
- Pupillary abnormalities (large, poorly reactive; 3–4 mm dissociated light and accommodation pupillary response)
- Bilateral hearing loss
- Failure of convergence
- Nystagmus retractorius
Tumors of the quadrigeminal plate (gliomas) do not produce motility disorders until they extend beyond the tectal plate
Mild head trauma: may precipitate IIIrd nerve palsy from parasellar or clival tumor (to be ruled out if there is no fracture or the palsy lasts longer than 1–2 months)
Pituitary adenoma:
- May spread into cavernous sinus; compression of the nerve against the dura at the entrance of the sinus
- Pituitary apoplexy (associated with headache, sudden loss of vision, cranial nerve palsy) may have unilateral or bilateral IIIrd nerve palsy; CT and MRI demonstrate more benign clinical picture of pituitary apoplexy than formerly taught
- Intermittent signs and symptoms may be present with pituitary tumors
Nasopharyngeal tumors:
- May affect IIIrd nerve in the cavernous sinus
- Origin at the fossa of Rosenmüller; extend into the middle fossa through the foramen lacerum or ovale
- Squamous cell CA, lymphoepithelioma and lymphosarcoma may present similarly
Sphenoid sinus tumor:
- May produce cavernous sinus syndrome

Tumors of the IIIrd Nerve (Intrinsic)

Schwannoma
Neurofibroma
Fibroblastic tumors

Metastatic Tumors

Intracranial metastasis constitute about 30% of neoplasm that affect the IIIrd nerve
Nasopharynx most frequent metastatic tumor
Breast, thyroid, lung and lymphoid tumors
Most frequently affects the nerve by direct invasion
10–25% of late stage lymphoma invade the CNS; affects the nerve by involvement of the meninges and direct extension

Orbital Tumors

Metastatic:
- Breast, lung, melanoma of the choroid, lacrimal gland, lymphosarcoma, lymphoma leukemia, hypereosinophilia syndrome
- Intraorbital mass
  - Hemangioblastoma (conus)
  - Dermoid
  - Pseudotumor
  - Meningioma

Pupillary Involvement of the IIIrd Nerve

Internal carotid disease:
- Fibromuscular dysplasia, dissection, carotodynia, ischemia (atherosclerosis or arteritis) all may cause sympathic paresis. The internal carotid artery vasovasorum feed the internal branch of the sympathetic innervation to the eye
- Complete Horner's syndrome:
  - Myosis
  - Ptosis (sympathetic innervation of the tarsal muscles of the upper and lower lid); the upper lid droops while the lower lid rises)
  - Decreased sweating of the face (if the common carotid bifurcations and or external branches are affected)
  - Apparent enophthalmos; decreased innervation of Mueller's muscle behind the globe
- Iris ischemia with large pupils in carotid disease (10% of patients)
- Argyll Robertson pupil:
  - Secondary to syphilis; pretectal lesions
  - Six components:
    - Small (1 mm)
    - Irregular
    - Does not respond to light
    - No response to ciliospinal reflex
    - Does not respond to mydriatics
    - Responds to accommodation
- Behr's pupil:
  - Dilated
  - Ipsilateral to optic tract lesions
- Holmes–Adie pupil:
  - Responds sluggishly to light and accommodation
  - May be unilateral
  - More common in young women
  - Associated with absent ankle jerks; occasionally loss of knee reflexes
  - Part of generalized small fiber neuropathy
- Wernicke's pupil:
  - Slit lamp directed at retina that subserves VF deficit from stroke; slower contraction of the pupil
- Elliptical pupil (cat's eye):
  - Pretectal lesion
  - Usually seen after severe head trauma
- Oval pupil:
  - Diabetes
  - Herniation with compression of the IIIrd nerve
  - Syphilis
- Light near dissociation:
  - Diabetes
  - Amyloid
  - Syphilis
  - Rarely pressure on the nuclear complex or pretectal area
- Anisocoria:
  - 25% of the population
  - Equally reactive to light and convergence

Muscle Disease Affecting the IIIrd Nerve

Oculopharyngeal dystrophy:
- Middle to older patients
- Bilateral ptosis (may be severe)
- French Canadian ancestry
- Rimmed vacuoles on muscle biopsy
Myotonic dystrophy:
- Severe ptosis
- AD; chromosome 17
- Multisystem disease: flat glucose tolerance curve, cardiac arrhythmia, high FSH/LH; small testicles; frontal bossing; 50% decreased intelligence
Mitochondrial diseases:
- Kearns–Sayre: complete ophthalmoplegia; heart block; hearing loss; diabetic glucose tolerance curve
- Progressive external ophthalmoplegia with ptosis; associated myopathy and symmetrical neuropathy
- Late onset mitochondrial myopathy; ptosis; short stature; VIIIth nerve involvement
Myotubular myopathy; primarily bilateral ptosis with minimal proximal muscle weakness
Thyroid muscle disease (Hoffman's syndrome):
- Inferior rectus muscle may enlarge first
- All muscles are thickened and enlarged
- Elevated long acting thyroid stimulating hormone
- Sclerae and the tendinous insertion of muscle are not involved (they are in pseudo tumor of the orbit)

Neuromuscular Junction Disease

Acquired myasthenia gravis:
- Asymmetric ptosis and IIIrd nerve involvement
- The pupil is not clinically involved
- May be associated with pseudo intranuclear ophthalmoplegia
- Rapid nystagmus
Congenital nystagmus
Tetanus:
- IIIrd nerve with pupillary involvement
- Systemic muscular involvement
- Opisthotonus
Botulinum toxin:
- Nausea and vomiting
- Bilateral ptosis
- Bilateral dilated pupils
Snake bite (Elapidae species)
- Nausea, vomiting, and vertigo
- Ptosis
- Diplopia; IIIrd nerve and other cranial nerve involvement
Lambert–Eaton syndrome:
- Asymmetrical ptosis
- IIIrd nerve and other cranial nerve involvement
- Impaired strength with exercise

Collagen Vascular Disease/Arteritis

In general the arteritic process affects the vascular supply to the nerve which affects the central rather than the peripheral part of the nerve. The pupillomotor fibers are on the peripheral dorsomedial part of the nerve.

SLE: affects the IIIrd and VIth nerve most commonly
Wegener's granulomatosis: affects the Vth nerve as well as the IIIrd and VIth most commonly
Tolosa–Hunt: (severely painful ophthalmoplegia):
- All eye muscles may be involved in the affected eye; III, IV, and VI
- V, II and periarterial sympathetic fibers may be involved
- Persists for days to weeks; remission and exacerbations are common
- Nonspecific granulomatous involvement in the cavernous sinus
- Steroid responsive
Periarteritis nodosa: IIIrd nerve involvement rare; usually mononeuritis multiplex
Hypereosinophilic syndromes (>20,000 eosinophile/mm³)
Granulomatous angiitis

Infections

Viral Infection:
- St. Louis, Eastern and Western Equine encephalitis; IIIrd nerve involvement is rare
- Polio and Von Economo IIIrd nerve palsy was occasionally reported
- Most viral illness: the IIIrd nerve palsy occurs 2–3 weeks after the febrile illness
- IIIrd nerve palsy may occur with: HZ, EBV, pertussis, measles, influenza and HIV
- HZ-ophthalmoplegia III > IV nerve; recovery occurs
Bacterial Infection:
- Acute bacterial meningitis III and VIth nerve frequently involved; transient and clears with recovery; perineural inflammation may extend into the nerve substance (most commonly seen with meningococcus, pneumococcus and haemophilus influenzae)
- IIIrd nerve involved in syphilitic basilar meningitis (pupillomotor and medical rectus muscle fibers are most vulnerable)
- Lyme disease: IIIrd nerve may be an initial manifestation
- Tuberculosis: tuberculous meningitis may affect the IIIrd nerve; pupillomotor fibers are vulnerable
Fungal infections:
- Mucormycosis (genus Rhizopus):
  - Occurs in severely immunocompromised patients; cancer, diabetic ketoacidosis, HIV, uremia
  - Underlying sinus infection
  - May concomitantly involve the venous sinuses with consequent infarction
  - Black palate syndrome (lateral and jugular sinus infarction)
- Cryptococcosis:
  - Accompanies HIV infection
  - Usually cranial nerve II involved greater than III
  - Indolent with headache and dementia
Systemic disease:
- Diabetes mellitus:
  - Painful or painless ophthalmoplegia; pain retroorbital or at times with peduncular lesions there is no pain
  - Pupil sparing
  - Recovery without "misdirection"
- Cranial amyloid:
  - Primary uveal veil (vitreous)
  - Associated with meningeal involvement
  - Light near dissociation
- Hypertrophic pachymeningitis:
  - Exuberant overgrowth of the meninges that traps cranial nerves
  - Differential diagnosis includes: sarcoid, lymphoma, tuberculosis
  - Patients afebrile, do not appear ill, IIIrd nerve involved
  - Pupil sparing
- Carcinomatosis of the meninges:
  - MRI reveals that it often is associated with minimal features; enhancement of cerebellar folia; base of the skull
  - III relatively commonly involved
- Wernicke-Korsakoff's Syndrome:
  - Cranial nerve II and VI frequently involved bilaterally
  - Associated with thiamine deficiency
  - Encephalopathy, ataxia and neuropathy associated
  - Ophthalmoparesis less common in black patients
- Sarcoid:
  - Meningeal involvement of IIIrd nerve

Immune Mediated

Multiple sclerosis

IIIrd nerve relatively uncommonly involved directly; extremely commonly involved as component of intranuclear ophthalmoplegia

Miller Fisher variant of GBS

GD1b or GQ1b epitopes
Ophthalmoparesis, areflexia, ataxia are concomitant neurological findings

Descending GBS

III, VI, and VIII nerves are involved concomitantly
Pharyngeal innervated cranial nerves involved (cervical-brachial pattern)

CIDP

Rarely associated IIIrd nerve palsy

Trauma

Orbital fracture injuring either the superior or inferior division of the nerve
Injured during uncal herniation or anterior temporal lobe lobectomy