Conjugate Movements of the Brain (Eye Movements)

1. Types of Conjugate Eye Movements

• Goldman-Cecil Medicine, p. 4147

2. Horizontal Conjugate Eye Movements

Key Circuit

• Abducens nucleus (CN VI) - in the pons
• Oculomotor nucleus (CN III) - in the midbrain

The Abducens Nucleus as a Gaze Center

• Some neurons project to the ipsilateral lateral rectus (via CN VI)
• Other neurons project via the MLF to the contralateral oculomotor nucleus, activating the contralateral medial rectus

PPRF (Paramedian Pontine Reticular Formation)

3. Vertical Conjugate Eye Movements

• Upgaze center: dorsal region, near the posterior commissure
• Downgaze center: ventral region - the rostral interstitial nucleus of the MLF (riMLF) is the key nucleus here; other contributing nuclei include the nucleus of Darkschewitzh and the interstitial nucleus of Cajal

4. Cortical and Supranuclear Control

5. Clinical Correlations - Lesions of Conjugate Gaze

Summary of Important Lesions

• Neuroanatomy through Clinical Cases, 3rd Edition, pp. 612-617
• Goldman-Cecil Medicine, p. 4147

6. Vergence (Disconjugate) - For Contrast

• Convergence (adduction of both eyes): for near focus; mediated by the medial recti
• Divergence (abduction of both eyes): for far focus; mediated by the lateral recti
• Centers are in the midbrain reticular formation (separate pools for convergence and divergence), controlled by descending occipital and parietal cortex inputs
• These fibers do NOT travel in the caudal MLF, which is why convergence is often preserved in INO

Internuclear Ophthalmoplegia (INO) and External Ophthalmoplegia

PART 1: INTERNUCLEAR OPHTHALMOPLEGIA (INO)

Definition

Anatomy of the MLF Lesion

• The ipsilateral eye fails to adduct on attempted horizontal gaze (medial rectus does not receive the command)
• The contralateral eye abducts with nystagmus (ataxic/dysmetric nystagmus - an overshoot due to increased innervation compensating for the weak medial rectus, per Hering's Law of dual innervation)

Key rule: INO is named for the side of the adduction deficit = the side of the MLF lesion

• Neuroanatomy through Clinical Cases, p. 614
• Kanski's Clinical Ophthalmology, p. 7058

Clinical Features

• Most patients surprisingly have no symptoms
• When present: diplopia (horizontal), oscillopsia, blurred vision

Unilateral vs Bilateral INO

• Bilateral INO with bilateral exotropia (both eyes deviated laterally)
• Usually from a rostral midbrain lesion causing additional convergence deficit
• Bilateral INO + bilateral exotropia + abducting nystagmus
• Kanski's Clinical Ophthalmology, p. 7067
• Localization in Clinical Neurology, p. 615

Causes of INO

• Bradley and Daroff's Neurology, p. 914-944

Related Syndromes

One-and-a-Half Syndrome

• Lesion involves both the PPRF/abducens nucleus AND the ipsilateral MLF
• Result: Ipsilateral gaze palsy ("one") + ipsilateral INO ("half")
• The only remaining horizontal movement is abduction of the contralateral eye (with nystagmus)
• Vertical movements and convergence are preserved
• The contralateral eye is often exotropic (paralytic pontine exotropia)

Lutz Posterior INO (INO of Abduction)

• Rare; caused by rostral pontine or mesencephalic lesion (not the classic MLF)
• Abduction is impaired (not adduction); adducting eye may show nystagmus
• Mechanism: impaired inhibition of the antagonist medial rectus via uncrossed PPRF-oculomotor fibers

Workup & Treatment

• MRI with thin cuts through the brainstem (may miss isolated INO on standard cuts)
• Exclude MG unless obligatory brainstem signs are present (ice test, rest test, edrophonium)
• Treat the underlying cause (MS: immunotherapy; stroke: risk factor management)
• Persistent diplopia: strabismus surgery may be considered

PART 2: EXTERNAL OPHTHALMOPLEGIA

Concept: Internal vs External Ophthalmoplegia

Chronic Progressive External Ophthalmoplegia (CPEO)

• Ptosis is usually the first sign (levator palpebrae affected first)
• Followed by progressive, symmetric ophthalmoplegia (all extraocular muscles involved symmetrically)
• No diplopia in most cases (because both eyes are equally affected and remain aligned)
• Normal pupils and accommodation
• Eyes eventually become motionless in central position
• Hutchinsonian facies: head thrown back, frontalis muscle contracted to lift lids
• Orbicularis oculi weakness (eye closure AND opening weakness = hallmark myopathic sign)
• ~25% have additional weakness of facial muscles, masseters, sternocleidomastoid, deltoids, peronei

• Critical: Ptosis + limitation of ocular motility + normal pupils + orthophoric
• Other: Weak orbicularis, exposure keratopathy, limb/facial muscle weakness
• Adams and Victor's Principles of Neurology, p. 1408-1409

Causes of CPEO

1. Mitochondrial DNA Disorders (Most Common)

2. Nuclear Gene Disorders (Autosomal)

Kearns-Sayre Syndrome (KSS) - The Classic CPEO Syndrome

1. CPEO (onset before age 20)
2. Pigmentary retinopathy (salt-and-pepper appearance, not typical RP)
3. At least ONE of: cardiac conduction defect (heart block), cerebellar ataxia, or CSF protein >100 mg/dL

• Hearing loss, short stature, cognitive impairment, delayed puberty
• Nephropathy, vestibular abnormalities
• Ragged-red fibers on muscle biopsy (Gomori trichrome stain) - mitochondrial accumulation
• Cause: Sporadic single large mtDNA deletion (arising in mother's oocyte)
• Course: Progressive; many die in 3rd-4th decade from cardiac or CNS complications
• Pacemaker often required for AV block (risk of sudden death)
• Bradley and Daroff's Neurology, p. 1598

Differential Diagnosis of CPEO

• The Wills Eye Manual, pp. 690-691

Workup of CPEO

1. History: rate of onset (gradual = myopathic; sudden = CN disease), family history
2. Examine pupils and ocular motility carefully
3. Test orbicularis strength
4. Fundus: look for diffuse pigmentary changes (KSS)
5. Check swallowing (oculopharyngeal dystrophy)
6. Ice test / rest test / edrophonium to exclude MG
7. ECG (yearly) if KSS suspected - AV block can cause sudden death
8. Serum CK, lactate; CSF lactate and protein
9. Muscle biopsy: ragged-red fibers
10. Genetic testing: mtDNA deletion screen (blood if <20 yrs), POLG/Twinkle/ANT1 sequencing
11. Lipoprotein electrophoresis if abetalipoproteinemia suspected; serum phytanic acid if Refsum suspected

Key Comparison: INO vs External Ophthalmoplegia

Clinical Evaluation of Nystagmus

1. Definition

1. Systems maintaining steady gaze in primary position
2. The neural integrator (NI) - holds eyes in eccentric gaze positions
3. The vestibulo-ocular reflex (VOR) - maintains foveal fixation during head movement

• Adams and Victor's Principles of Neurology, p. 292

2. Classification by Waveform

Key rule: Pendular nystagmus = always central; Jerk nystagmus = peripheral OR central

• Bradley and Daroff's Neurology, p. 312

3. Clinical Examination Checklist (BOX 18.12)

1. Is nystagmus present in primary position, or only with eccentric gaze?
2. Is it binocular/conjugate, or dissociated (different in each eye)? - Dissociated = brainstem lesion (MLF)
3. Waveform: pendular or jerk? - If jerk, what direction is the fast phase?
4. Plane: Horizontal / vertical / torsional / mixed?
5. Is there a latent component? (intensifies when one eye covered = latent nystagmus)
6. Is there a torsional component?
7. Does direction alternate spontaneously? - Periodic alternating nystagmus (PAN)
8. Is there a null zone? (direction where nystagmus is minimal) - suggests congenital nystagmus
9. Does convergence damp or alter the nystagmus?
10. Is it positional? (Dix-Hallpike, supine roll)
11. Provocative maneuvers: elimination of fixation (Frenzel glasses), head shaking, hyperventilation, mastoid vibration
12. Effect of optokinetic stimulation (paradoxical in INS - fast phase goes with slow target)
13. Associated rhythmic movements: palate (oculopalatal myoclonus), limbs, face

• Bradley and Daroff's Neurology, p. 312-313

4. Peripheral vs Central Nystagmus - Key Differentiation

Important rule: Purely vertical nystagmus always indicates brainstem dysfunction (central)

• Scott-Brown's Otorhinolaryngology, p. 837
• Bradley and Daroff's Neurology, p. 4101

5. The HINTS Exam (for Acute Vestibular Syndrome)

A negative HIT + direction-changing nystagmus + skew deviation = "HINTS positive" = HIGH risk of stroke

• Tintinalli's Emergency Medicine, p. 1191

6. Localizing Value of Specific Nystagmus Syndromes

7. Key Nystagmus Types in Detail

A. Gaze-Evoked Nystagmus (GEN)

• Present only on eccentric gaze, in the direction of gaze
• Most common cause: drugs (phenobarbital, phenytoin, alcohol, benzodiazepines)
• Also: MS, myasthenia gravis, cerebellar atrophy
• Asymmetric GEN with larger amplitude on one side (Bruns nystagmus) = cerebellopontine angle lesion (lesion on side of larger amplitude nystagmus)
• Rebound nystagmus: GEN that reverses direction when eyes return to primary position = specific for cerebellum

B. Downbeat Nystagmus

• Slow upward drifts + fast downward resets; worsened in lateral gaze and head-hanging
• Most common: idiopathic; Arnold-Chiari malformation; cerebellar degeneration; drugs (lithium, anticonvulsants, amiodarone)
• Perverted nystagmus (downbeat after horizontal head shaking) = definite CNS disease
• Treat: 4-aminopyridine/dalfampridine, clonazepam, chlorzoxazone; base-out prisms if convergence damps it

C. Upbeat Nystagmus

• Spontaneous; fast phase upward in primary position; increases on upgaze
• Most common: Wernicke encephalopathy, MS
• Upbeat converting to downbeat = specific for Wernicke
• Bilateral pontomesencephalic lesions affecting perihypoglossal nuclei

D. Periodic Alternating Nystagmus (PAN)

• Nystagmus that spontaneously reverses direction every ~90-120 seconds
• Localization: nodulus/uvula of cerebellum; Arnold-Chiari
• Treatment: baclofen (very effective)

E. Peripheral Vestibular (Labyrinthine) Nystagmus

• Mixed horizontal + torsional (horizontal component dominant due to horizontal canal asymmetry)
• Unidirectional - never changes direction
• Alexander's Law: nystagmus increases looking toward fast phase, decreases looking toward slow phase
• Suppressed by fixation
• Associated with severe vertigo, nausea, hearing loss, tinnitus

F. Pendular Nystagmus (Acquired)

• Most common cause: multiple sclerosis (horizontal or elliptical, 3-5 Hz)
• Also: brainstem vascular disease, Whipple disease, Pelizaeus-Merzbacher disease, toluene abuse
• Mechanism: disruption of cerebellar nuclear feedback to neural integrators; inferior olive instability
• Treatment: memantine, gabapentin, clonazepam

G. Congenital/Infantile Nystagmus Syndrome (INS)

• High frequency, pendular waveform; null zone present (position of least nystagmus)
• Horizontal even on vertical gaze; absent in sleep
• Increasing velocity exponential slow phase on oculography
• Paradoxical OKN response (fast phase toward slow-moving target)
• Patients often unaware of it despite wide amplitude

H. Positional Nystagmus - BPPV

• Dix-Hallpike test: patient sits, head turned 45° toward affected ear, then quickly lowered to head-hanging position
• Posterior canal BPPV: upbeat + torsional nystagmus toward the affected (lower) ear
• Latency: 1-5 sec after positioning
• Duration: <1 minute
• Fatigues with repeated testing
• Horizontal canal BPPV (roll test): horizontal nystagmus beating toward the ground (geotropic) or away from the ground (apogeotropic) in the lateral head position

8. Oscillopsia

• Coarse nystagmus of any type
• Impaired VOR (aminoglycoside toxicity) - oscillopsia only during movement (walking, riding)
• Superior oblique myokymia - episodic, monocular, brief torsional oscillopsia

9. Summary: Quick Diagnostic Framework

NYSTAGMUS
    |
    ├── Pendular → CENTRAL (MS, brainstem/cerebellar lesion, congenital, visual loss)
    |
    └── Jerk
         |
         ├── Purely Vertical (up/downbeat) → ALWAYS CENTRAL (brainstem/cerebellum)
         |
         ├── Unidirectional, horizontal-torsional, suppressed by fixation
         |         → PERIPHERAL VESTIBULAR (labyrinth or VIII nerve)
         |
         ├── Direction-changing with gaze → CENTRAL
         |
         ├── Only on eccentric gaze (gaze-evoked) → NI dysfunction (drugs, cerebellum)
         |
         └── Positional (Dix-Hallpike) → BPPV (torsional-upbeat + latency + fatigues)

• Goldman-Cecil Medicine, p. 4148
• Bradley and Daroff's Neurology, pp. 312-316