Internuclear Ophthalmoplegia & Supranuclear Gaze Palsies
Supranuclear and internuclear ocular motor disorders are among the most localizing findings in clinical neurology. Unlike cranial nerve palsies that affect individual muscles, these disorders disrupt the complex brainstem and cortical networks that coordinate conjugate eye movements. Internuclear ophthalmoplegia (INO) is the hallmark of medial longitudinal fasciculus pathology, while supranuclear gaze palsies reflect lesions of the cortical and brainstem centers that generate horizontal and vertical gaze commands. A systematic understanding of horizontal and vertical gaze circuitry allows precise anatomical localization from bedside examination alone — a skill that remains essential in the era of advanced neuroimaging.
Bottom Line
- INO: Impaired adduction on the side of the MLF lesion with abducting nystagmus in the contralateral eye; convergence is preserved — distinguishing it from CN3 palsy
- INO etiology: MS is the most common cause in young patients (often bilateral); stroke is the most common cause in elderly patients (typically unilateral)
- One-and-a-half syndrome: Ipsilateral CN6 nucleus lesion + ipsilateral MLF damage = ipsilateral horizontal gaze palsy + INO; only the contralateral eye can abduct
- Cortical gaze deviation: Frontal eye field (FEF) lesion → eyes deviate toward the lesion (away from hemiparesis); pontine lesion → eyes deviate away from the lesion (toward hemiparesis)
- Parinaud syndrome (dorsal midbrain): Upgaze palsy + light-near dissociation + convergence-retraction nystagmus + eyelid retraction (Collier sign) — caused by pinealoma, MS, stroke, hydrocephalus, or midbrain compression
- PSP: Vertical supranuclear gaze palsy (downgaze affected before upgaze) with slow vertical saccades as the earliest sign; falls within the first year; poor response to levodopa
- Skew deviation: Supranuclear vertical misalignment from brainstem or cerebellar lesion; distinguished from CN4 palsy by the alternating cover test (comitant misalignment) and negative Bielschowsky head tilt test
Anatomy of Conjugate Gaze Pathways
Horizontal Gaze Circuit
Conjugate horizontal eye movements require coordinated activation of the lateral rectus of one eye and the medial rectus of the other eye. This coordination is achieved through a well-defined brainstem circuit:
Horizontal Gaze Pathway
- Frontal eye field (FEF): Contralateral saccade command center; located in the posterior part of the middle frontal gyrus (Brodmann area 8); projects contralaterally to the PPRF
- Paramedian pontine reticular formation (PPRF): The horizontal gaze center; generates the burst signal for ipsilateral horizontal saccades; projects to the ipsilateral CN6 nucleus
- CN6 nucleus: Contains two neuron types:
- Abducens motor neurons: Innervate the ipsilateral lateral rectus via the CN6 nerve
- Internuclear neurons: Project via the contralateral medial longitudinal fasciculus (MLF) to the CN3 medial rectus subnucleus, activating the contralateral medial rectus for conjugate adduction
- Result: Activation of the right PPRF → right CN6 nucleus → right lateral rectus (abduction) + left medial rectus (adduction via MLF) = rightward conjugate gaze
Vertical Gaze Circuit
Vertical gaze is controlled by midbrain structures that are less discretely organized than the horizontal gaze circuit:
- Rostral interstitial nucleus of the MLF (riMLF): Located in the midbrain, generates vertical and torsional saccades; projects bilaterally to CN3 and CN4 nuclei
- Interstitial nucleus of Cajal (INC): Controls vertical gaze holding (neural integrator for vertical eye position) and vertical vestibular integration
- Posterior commissure: Carries decussating fibers essential for upgaze; lesions here produce selective upgaze palsy (dorsal midbrain syndrome)
- MLF (rostral): Carries signals for vertical vestibulo-ocular reflex and vertical gaze coordination
| Structure | Location | Function | Lesion Effect |
|---|---|---|---|
| FEF | Frontal lobe (area 8) | Contralateral saccade generation | Eyes deviate toward the lesion |
| PPRF | Paramedian pons | Ipsilateral horizontal saccade burst | Ipsilateral horizontal gaze palsy |
| CN6 nucleus | Dorsal pons (floor of 4th ventricle) | Lateral rectus motor neurons + interneurons for contralateral MR | Ipsilateral conjugate gaze palsy |
| MLF | Paramedian brainstem (pons to midbrain) | Connects CN6 interneurons to contralateral CN3 MR subnucleus | INO (impaired adduction on lesion side) |
| riMLF | Midbrain (rostral to CN3 nucleus) | Vertical and torsional saccade generation | Vertical saccadic palsy |
| INC | Midbrain (rostral to CN4 nucleus) | Vertical gaze holding (neural integrator) | Vertical gaze-evoked nystagmus, skew deviation |
| Posterior commissure | Dorsal midbrain | Upgaze fibers decussation | Upgaze palsy (dorsal midbrain syndrome) |
Internuclear Ophthalmoplegia (INO)
Pathophysiology
INO results from a lesion of the medial longitudinal fasciculus (MLF) between the CN6 nucleus in the pons and the CN3 subnucleus in the midbrain. The MLF carries signals from CN6 interneurons that activate the contralateral medial rectus for conjugate horizontal gaze. When this pathway is interrupted, the medial rectus cannot be activated for conjugate gaze, but can still function during convergence (which uses a separate supranuclear pathway).
Clinical Features
Clinical Signs of INO
- Impaired adduction: Slowed or incomplete adduction of the eye ipsilateral to the MLF lesion during contralateral horizontal gaze; ranges from mild slowing of adducting saccades to complete loss of adduction
- Abducting nystagmus: Dissociated nystagmus of the contralateral (abducting) eye — thought to result from adaptive increase in the neural signal to overcome the impaired yoking, with consequent overshoot of the abducting eye
- Convergence preserved: The medial rectus responds normally to convergence commands (which bypass the MLF and use a direct midbrain convergence pathway) — this distinguishes INO from CN3 palsy
- Skew deviation: May accompany INO; typically the ipsilateral eye is hypotropic (on the side of the MLF lesion)
- Naming convention: An INO is named for the side of the adduction deficit (i.e., the side of the MLF lesion): a left INO means impaired left eye adduction due to a left MLF lesion
Bilateral INO (WEBINO)
Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) occurs when both MLFs are damaged, producing bilateral adduction impairment with exotropia at rest:
- Bilateral adduction deficit on horizontal gaze in both directions
- Abducting nystagmus bilaterally
- Exotropia ("wall-eyed") at primary position due to bilateral medial rectus underaction
- Convergence may or may not be preserved
- Most common cause in young patients: Multiple sclerosis (demyelinating lesion in the paramedian pons or midbrain)
- Most common cause in elderly patients: Brainstem stroke (small vessel basilar artery branch occlusion)
Etiology of INO
| Etiology | Key Features | Typical Laterality |
|---|---|---|
| Multiple sclerosis | Young patient; often bilateral; may be the presenting sign of MS; high recovery rate | Bilateral > unilateral |
| Brainstem stroke | Elderly patient; acute onset; vascular risk factors; associated brainstem signs | Unilateral > bilateral |
| Brainstem tumor | Progressive; additional brainstem signs | Variable |
| Wernicke encephalopathy | Thiamine deficiency; confusion, ataxia, nystagmus | Often bilateral |
| Drug intoxication | Phenytoin, carbamazepine, barbiturates, opioids, benzodiazepines | Often bilateral |
| Infection | Brainstem encephalitis (Listeria, CMV, TB) | Variable |
| Trauma | Diffuse axonal injury affecting brainstem | Variable |
One-and-a-Half Syndrome
The one-and-a-half syndrome is a distinctive brainstem localization that combines an ipsilateral horizontal gaze palsy with an INO, producing severe limitation of horizontal eye movements:
One-and-a-Half Syndrome
- Lesion location: Ipsilateral paramedian pons, involving BOTH the CN6 nucleus (or PPRF) AND the ipsilateral MLF
- The "one": Ipsilateral horizontal conjugate gaze palsy — neither eye can look toward the side of the lesion (loss of ipsilateral lateral rectus activation + loss of contralateral medial rectus activation via the CN6 nucleus interneurons)
- The "half": INO on contralateral gaze — the ipsilateral eye cannot adduct (because the MLF is also damaged), while the contralateral eye can abduct normally
- Net result: The only remaining horizontal movement is abduction of the contralateral eye
- Common causes: Pontine stroke (small perforating branch occlusion), MS, pontine hemorrhage, tumor
- May be accompanied by: Facial nerve palsy (CN7 fascicle wraps around CN6 nucleus), exotropia of the contralateral eye ("paralytic pontine exotropia")
| Eye Movement | Right One-and-a-Half Syndrome |
|---|---|
| Right gaze | Neither eye moves right (gaze palsy from right CN6 nucleus lesion) |
| Left gaze — left eye | Abducts normally (intact left CN6) |
| Left gaze — right eye | Cannot adduct (right MLF lesion = INO) |
| Convergence | Both medial recti may still function (bypasses MLF) |
Horizontal Gaze Palsies
Supranuclear Horizontal Gaze Palsies
| Lesion Site | Eye Deviation | Mechanism | Key Feature |
|---|---|---|---|
| Frontal eye field (FEF) | Eyes deviate toward the lesion (away from the hemiparesis) | Loss of contralateral saccade drive; the intact opposite FEF drives the eyes toward the damaged hemisphere | "The eyes look at the lesion" — classic stroke teaching point; overcomes with doll’s eye maneuver (VOR intact) |
| Pontine (PPRF or CN6 nucleus) | Eyes deviate away from the lesion (toward the hemiparesis if there is one) | Loss of ipsilateral gaze drive; the intact contralateral PPRF drives the eyes away from the lesion | "The eyes look away from the lesion" — does NOT overcome with doll’s head (infranuclear pathway involved) |
| Epileptic focus (FEF seizure) | Eyes deviate away from the seizure focus (contralateral to the discharging cortex) | Active FEF discharge drives saccades contralaterally | Opposite of destructive FEF lesion; version away from the lesion during seizure |
| "Wrong-way eyes" (thalamic hemorrhage) | Eyes deviate away from the lesion (same direction as hemiparesis) | Pressure on the midbrain, disrupting ipsilateral gaze-holding pathways | Exception to the cortical rule; suggests thalamic or upper midbrain involvement |
Distinguishing Cortical from Pontine Gaze Palsy
- Doll’s eye maneuver (oculocephalic reflex): A cortical (supranuclear) gaze palsy can be overcome by the vestibulo-ocular reflex (VOR) — turning the head drives the eyes past midline because the brainstem pathways are intact
- Pontine (nuclear/infranuclear) gaze palsy: Cannot be overcome by the VOR because the final common pathway is damaged
- This distinction is critical in the comatose patient: eyes that do not move with oculocephalic or caloric testing suggest brainstem damage rather than cortical injury
- Caloric testing: Cold water irrigation of the ear canal (or ice water calories) drives a slow conjugate eye deviation toward the irrigated ear; absence of this response indicates brainstem dysfunction
Vertical Gaze Palsies
Dorsal Midbrain Syndrome (Parinaud Syndrome)
The dorsal midbrain (Parinaud) syndrome is the most recognizable vertical gaze disorder and results from compression or infiltration of the dorsal midbrain at the level of the posterior commissure and superior colliculus.
Clinical Features of Dorsal Midbrain Syndrome
- Upgaze palsy: Impaired or absent upward saccades (supranuclear — can be overcome with doll’s head or Bell phenomenon initially); upward pursuit may be relatively preserved early
- Light-near dissociation of the pupils: Bilateral mid-dilated pupils that constrict poorly to light but react to accommodation/convergence; due to disruption of the pretectal light reflex pathway with preservation of the more ventral convergence-accommodation pathway
- Convergence-retraction nystagmus: On attempted upgaze, the eyes converge and retract into the orbits; best elicited with a downward-moving OKN drum; results from co-contraction of the medial recti and other extraocular muscles
- Eyelid retraction (Collier sign): Bilateral lid retraction producing a "staring" appearance; due to involvement of the posterior commissure fibers that normally inhibit the levator
- Setting sun sign: Tonic downward deviation of the eyes, particularly in hydrocephalus; due to impaired upgaze tone
- Skew deviation: May accompany other features
| Etiology | Key Features | Age Group |
|---|---|---|
| Pineal region tumor (pinealoma, germinoma) | Most common mass cause; direct compression of tectal plate | Children/young adults |
| Hydrocephalus | Dilated third ventricle/aqueduct compressing dorsal midbrain; setting sun sign | Any age (especially infants) |
| Stroke | Midbrain infarction (top of the basilar syndrome) | Elderly |
| Multiple sclerosis | Demyelinating plaque in dorsal midbrain | Young adults |
| Midbrain hemorrhage | Hypertensive, vascular malformation | Any age |
| Tumor (other) | Thalamic glioma, metastasis, tectal glioma | Variable |
Progressive Supranuclear Palsy (PSP)
PSP (Steele-Richardson-Olszewski syndrome) is the most important neurodegenerative cause of vertical gaze palsy and a critical differential diagnosis in any patient presenting with vertical gaze limitation and parkinsonism.
Ocular Motor Features of PSP
- Slow vertical saccades: The earliest eye movement abnormality; may precede vertical gaze restriction by months to years; tested by asking patient to make rapid vertical saccades to command
- Downgaze palsy: Characteristically affected before upgaze (distinguishing PSP from normal aging, which affects upgaze); progressive limitation of volitional vertical saccades followed by smooth pursuit loss
- Supranuclear nature: Vertical gaze palsy can initially be overcome by the VOR (doll’s head maneuver), confirming the supranuclear localization; as disease advances, even VOR-driven movements become impaired
- Eventual horizontal gaze involvement: Late-stage PSP involves horizontal saccades as well, leading to global ophthalmoplegia
- Square wave jerks: Small, involuntary saccadic intrusions during fixation; common in PSP
- Eyelid abnormalities: Decreased blink rate, blepharospasm, eyelid opening apraxia (difficulty initiating eyelid opening)
- Absent convergence-retraction nystagmus: Distinguishes PSP from dorsal midbrain syndrome
| Feature | PSP | Parkinson Disease |
|---|---|---|
| Vertical gaze palsy | Early, prominent (downgaze > upgaze) | Mild upgaze limitation (normal aging overlap) |
| Saccade velocity | Markedly slow vertical saccades | Hypometric but normal velocity |
| Falls | Early (within first year), typically backward | Late (after years of disease) |
| Axial rigidity | Prominent, with retrocollis (neck extension) | Mild; antecollis more common |
| Tremor | Absent or minimal | Rest tremor characteristic (4–6 Hz) |
| Levodopa response | Poor or absent | Excellent (at least initially) |
| Cognition | Early frontal-subcortical dysfunction (apathy, impulsivity) | Cognitive decline later in course |
| MRI | "Hummingbird sign" (midbrain atrophy on sagittal view); "morning glory sign" (axial midbrain atrophy) | Typically normal or nonspecific |
Other Causes of Vertical Gaze Palsy
- Niemann-Pick type C: Vertical supranuclear gaze palsy (downgaze > upgaze) in a child or young adult; hepatosplenomegaly, ataxia, dementia; diagnosis by filipin staining or genetic testing
- Whipple disease: Vertical gaze palsy with oculomasticatory myorhythmia (convergent eye movements synchronous with jaw contractions) — pathognomonic; diagnosed by PAS staining of duodenal biopsy or PCR for Tropheryma whipplei
- Normal aging: Mild upgaze limitation is common in elderly patients (≥70 years) and does not indicate pathology unless accompanied by other signs
- Corticobasal degeneration: May show vertical gaze abnormalities later in disease; distinguished by asymmetric apraxia, cortical sensory loss, and alien limb phenomenon
Skew Deviation
Skew deviation is a vertical misalignment of the eyes caused by a supranuclear (brainstem or cerebellar) imbalance in the otolithic (gravity-sensing) pathways. It is important to distinguish from CN4 palsy because the management differs fundamentally.
Features of Skew Deviation
- Vertical misalignment: One eye is higher than the other; the hypertropic eye is typically contralateral to a pontine/medullary lesion or ipsilateral to a midbrain/cerebellar lesion
- Comitant or near-comitant: The vertical deviation tends to be relatively constant across gaze positions, unlike CN4 palsy which varies
- Ocular tilt reaction (full triad): Skew deviation + head tilt + ocular torsion (ipsilateral incyclotorsion of the hypertropic eye); represents disruption of the utricular otolithic pathway
- Alternating skew: Hypertropia switches sides depending on gaze direction; classic in lateral medullary (Wallenberg) syndrome
- Bielschowsky head tilt test: Typically negative (does not worsen with head tilt to either side), unlike CN4 palsy — this is the key bedside distinction
| Feature | CN4 Palsy | Skew Deviation |
|---|---|---|
| Vertical deviation pattern | Incomitant: worse in contralateral gaze and ipsilateral tilt | Comitant or near-comitant: relatively constant |
| Bielschowsky head tilt | Positive (worsens on tilt toward paretic side) | Usually negative |
| Torsion pattern | Excyclotorsion of the affected eye | Incyclotorsion of the hypertropic eye |
| Head tilt direction | Toward the unaffected side | Toward the hypotropic eye |
| Cause | CN4 injury (trauma, microvascular, congenital) | Brainstem or cerebellar lesion |
| Other brainstem signs | Absent (unless fascicular) | Often present (INO, nystagmus, ataxia) |
Supranuclear vs Nuclear vs Infranuclear: Summary Framework
| Feature | Supranuclear | Nuclear | Infranuclear (Nerve/NMJ/Muscle) |
|---|---|---|---|
| Movement type affected | Conjugate gaze (both eyes move together) | Conjugate gaze or individual muscle (depends on nucleus) | Individual muscle(s) |
| VOR (doll’s head) | Overcomes the deficit (vestibular pathway intact) | Does not overcome (nuclear final common pathway involved) | Does not overcome |
| Pupils | May show light-near dissociation (dorsal midbrain) | May be involved (Edinger-Westphal) | Involved if CN3 affected; spared in NMJ/muscle |
| Examples | FEF stroke (gaze deviation), Parinaud syndrome, PSP | CN6 nuclear lesion (conjugate gaze palsy), nuclear CN3 palsy | CN3/4/6 palsy, myasthenia gravis, orbital myositis, thyroid eye disease |
| Eye deviation pattern | Cortical: toward lesion; Pontine: away from lesion | Variable by nucleus involved | Pattern of individual muscle weakness |
| Associated findings | Hemiparesis, aphasia (cortical); long tract signs (brainstem) | Adjacent brainstem signs (CN7, long tracts) | May be isolated or have orbital/NMJ signs |
Diagnostic Approach
Bedside Examination of Supranuclear and Internuclear Disorders
- Saccades: Test horizontal and vertical saccades to command and to target; assess velocity, accuracy, and range; slow saccades suggest PSP or brainstem disease
- Smooth pursuit: Have patient follow a slowly moving target; pursuit is often preserved longer than saccades in supranuclear palsies
- Convergence: Test with a near target; preserved convergence with impaired adduction on lateral gaze is the hallmark of INO
- VOR (doll’s head): Passive head rotation to test whether gaze limitation can be overcome; distinguishes supranuclear from nuclear/infranuclear
- OKN (optokinetic nystagmus): A downward-moving OKN drum elicits convergence-retraction nystagmus in dorsal midbrain syndrome
- Pupils: Light-near dissociation suggests dorsal midbrain pathology
- Alternating cover test: Quantifies vertical misalignment; comitant pattern suggests skew deviation
- Head tilt test: Differentiates CN4 palsy (positive) from skew deviation (negative)
Neuroimaging
- MRI brain with thin-section brainstem protocol: The study of choice for all suspected brainstem eye movement disorders; includes DWI for acute stroke
- MRA: For suspected vascular etiology (top of the basilar syndrome, vertebrobasilar dissection)
- MRI with contrast: For suspected tumor, MS, or inflammatory process
- CT head: Urgent initial study for suspected hemorrhage or acute raised ICP
Treatment Considerations
- INO (MS): Acute MS-related INO typically improves with IV methylprednisolone and disease-modifying therapy; most patients recover significant adduction function
- INO (stroke): Recovery is variable; small pontine infarcts may have excellent recovery; larger lesions may have persistent deficits
- Dorsal midbrain syndrome: Treat the underlying cause (CSF diversion for hydrocephalus, tumor resection/radiation for pineal tumors)
- PSP: No disease-modifying therapy available; supportive care including fall prevention, speech therapy, and treatment of blepharospasm; prism glasses may help for reading with downgaze palsy
- Skew deviation: Usually resolves or improves with treatment of the underlying brainstem/cerebellar lesion; persistent skew may be managed with prism correction
- Residual strabismus from INO or gaze palsy: Strabismus surgery may be considered for stable, persistent misalignment after ≥6 months
References
- Leigh RJ, Zee DS. The Neurology of Eye Movements. 5th ed. Oxford University Press; 2015.
- Keane JR. Internuclear ophthalmoplegia: unusual causes in 114 of 410 patients. Arch Neurol. 2005;62(5):714-717.
- Frohman EM, Frohman TC, Zee DS, McColl R, Galetta S. The neuro-ophthalmology of multiple sclerosis. Lancet Neurol. 2005;4(2):111-121.
- Wall M, Wray SH. The one-and-a-half syndrome — a unilateral disorder of the pontine tegmentum: a study of 20 cases and review of the literature. Neurology. 1983;33(8):971-980.
- Pierrot-Deseilligny C, Milea D. Vertical nystagmus: clinical facts and hypotheses. Brain. 2005;128(Pt 6):1237-1246.
- Baloh RW, Furman JM, Yee RD. Dorsal midbrain syndrome: clinical and oculographic findings. Neurology. 1985;35(1):54-60.
- Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology. 1996;47(1):1-9.
- Boxer AL, Yu JT, Golbe LI, Litvan I, Lang AE, Hoglinger GU. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 2017;16(7):552-563.
- Brodsky MC, Donahue SP, Vaphiades M, Brandt T. Skew deviation revisited. Surv Ophthalmol. 2006;51(2):105-128.
- Sharpe JA, Kim JS. Midbrain disorders of vertical gaze: a quantitative re-evaluation. Ann N Y Acad Sci. 2002;956:143-154.
- Halmagyi GM, Gresty MA, Leech J. Reversed optokinetic nystagmus (OKN): mechanism and clinical significance. Ann Neurol. 1980;7(5):429-435.
- Chen CM, Huang SH, Lin TK, Lu CS, Shan DE. Conjugate eye deviation with head version and ipsilateral shoulder elevation in seizures. Neurology. 1999;52(7):1498-1500.
- Wong AM. Understanding skew deviation and a new clinical test to differentiate it from trochlear nerve palsy. J AAPOS. 2010;14(1):61-67.
- Rucker JC, Lavin PJ. Neuro-ophthalmology: ocular motor system. Continuum (Minneap Minn). 2019;25(5):1176-1193.
- Cogan DG. Internuclear ophthalmoplegia, typical and atypical. Arch Ophthalmol. 1970;84(5):583-589.