Medial longitudinal fasciculus syndrome (MLF syndrome) appears with lesions of the medial longitudinal fasciculus (MLF) and is also called internuclear ophthalmoplegia (INO) because the lesion lies between the abducens nucleus and the oculomotor nucleus.
One-and-a-half syndrome (OHS) is a condition in which the lesion extends to the ipsilateral MLF in addition to the PPRF or abducens nucleus. Both adduction and abduction of the affected eye are impaired, leaving only abduction of the contralateral eye. OHS was first described and named by Charles Miller Fisher in 1967 as a pattern of ocular muscle palsy in patients with pontine lesions.
The MLF is a highly myelinated nerve fiber bundle that extends from the midbrain to the spinal cord. It is located ventral to the cerebral aqueduct or fourth ventricle and runs very close to the midline, so the bilateral MLFs are adjacent, making bilateral INO more likely.
The pathway for horizontal eye movements is as follows. Stimuli from the PPRF are transmitted via interneurons to the abducens nucleus, then via the abducens nerve to the ipsilateral lateral rectus muscle, and immediately cross to ascend the contralateral MLF to enter the oculomotor medial rectus nucleus, reaching the contralateral medial rectus muscle via the oculomotor medial rectus branch. Depending on the site of damage in this pathway (PPRF → abducens nucleus → MLF → contralateral oculomotor medial rectus nucleus), three clinical conditions arise: INO, horizontal gaze palsy, and OHS.
Onset due to cerebrovascular disease is common at ages 62–66, more frequent in the elderly.
Onset due to MS is common in young people under 45 years of age.
Isolated OHS is rare; it is associated with contralateral hemiparesis (30%) and hemisensory disturbance (35%).
QWhat is the origin of the name internuclear ophthalmoplegia?
A
It is named “internuclear ophthalmoplegia” because the lesion is in the MLF, which lies “between the nuclei” of the abducens nerve (CN VI) and the oculomotor nerve (CN III). The characteristic feature is that the lesion is in the internuclear pathway, not in the nuclei themselves.
Adduction deficit of the affected eye (incomplete to complete): Characterized by marked slowing of adduction saccades. Slowing often persists even after the adduction limitation resolves. Subtle slowing can be detected with an OKN drum.
Dissociated nystagmus of the contralateral (healthy) eye on abduction: Monocular nystagmus on abduction. This is an adaptive phenomenon due to Hering’s law of equal innervation in response to the adduction deficit of the affected eye.
Convergence preservation: Even if adduction is impaired during horizontal gaze, convergence is usually possible. Convergence is preserved because it is mediated by pathways that do not pass through the MLF. In lesions near the oculomotor nucleus, convergence may also be impaired.
Other related syndromes include WEMINO (a rare subtype with unilateral MLF lesion causing exotropia), Half-and-Half syndrome (INO + ipsilateral CN VI fascicular lesion), and Lutz posterior internuclear ophthalmoplegia (reverse picture with abduction limitation).
QWhy is adduction impaired while convergence is preserved?
A
The convergence pathway does not pass through the MLF; it is directly regulated near the oculomotor nucleus, so convergence is preserved even when the MLF is damaged. In contrast, adduction in horizontal conjugate gaze travels via the MLF, so MLF lesions selectively impair adduction saccades.
The causes of INO and OHS include any pathology affecting the brainstem or MLF. In both conditions, infarction of the inferior pontine tegmental branch arising from the basilar artery accounts for the majority, but pontine hemorrhage, pontine tumors such as cavernous hemangioma, and head trauma can also be causes.
Multiple sclerosis (MS): Young patients under 45 years old. Usually bilateral. Demyelination of the MLF can occur at any segment. INO may be the initial symptom of MS.
Cerebrovascular accident (CVA): Elderly patients. Usually unilateral. Infarction of the perforating branches of the basilar artery (paramedian arteries), especially the inferior pontine tegmental branch, accounts for the majority. Hypertension, diabetes, and smoking are risk factors.
Wernicke encephalopathy (thiamine deficiency): Caution is needed in cases of alcoholism, poor dietary intake, and post-gastrectomy. Pernicious anemia is also a cause.
Metabolic diseases: Maple syrup urine disease, hepatic encephalopathy, Fabry disease.
Tumors: Fourth ventricle/brainstem tumors (medulloblastoma, pontine glioma, metastatic melanoma). In children with INO, tumors and ventricular enlargement are common.
Trauma: Head injury.
Drug toxicity: Lithium, propranolol, tricyclic antidepressants, narcotics, phenothiazines.
Other demyelinating diseases: NMO (neuromyelitis optica/Devic’s disease) and MOGAD (anti-AQP4 antibody/anti-MOG antibody-associated diseases).
Paraneoplastic brainstem encephalitis: INO is included in the clinical spectrum of anti-Ri antibody-positive PNS. It is often associated with breast cancer (79% of women) and lung cancer (25% of men) 1).
QCan the cause be inferred from whether it is unilateral or bilateral?
A
Unilateral INO is more common in cerebrovascular disease (87% of infarction cases are unilateral), while bilateral INO is more common in multiple sclerosis (73% of MS cases are bilateral). However, this trend is only a reference, and definitive diagnosis requires further examination such as MRI.
Clinical diagnosis is made by testing the eye’s conjugate movement ability.
Saccade velocity test: Check for adduction lag on the affected side during horizontal saccades. It is easier to observe immediately after rapidly looking toward the healthy side.
OKN drum/OKN tape: Useful for detecting subtle disconjugate saccades.
Convergence test: Adduction with convergence may not be observable in early stages and is not essential for diagnosis.
Quantitative infrared oculography: Improves diagnostic accuracy in subtle cases. It has been reported that 71% of physicians could not identify INO in cases with mild adduction slowing.
Paralytic pontine exotropia in primary position (in OHS) is an important finding.
MRI: Superior to CT for evaluating INO and OHS. DWI (diffusion-weighted imaging) is useful for detecting brainstem infarcts not visible on T2 alone, and can identify infarcts within 4.5 hours of onset. For detecting MLF lesions in MS, proton density-weighted imaging is preferred over T2/FLAIR.
CT: Used for screening acute hemorrhage and tumors. Diagnosis of pontine hemorrhage or pontine tumors is relatively easy, but infarcts in the inferior pontine tegmentum are rarely visible.
Characteristic imaging findings by lesion: In MS, characteristic findings are seen around the lateral ventricles; in Wernicke encephalopathy, around the mammillary bodies and periaqueductal region.
Differentiation from the following diseases is important. Medial longitudinal fasciculus syndrome must be differentiated from oculomotor nerve palsy, and the key differentiating point is preserved convergence.
Oculomotor nerve palsy: There is adduction slowing but no limitation of elevation or depression. It is differentiated from INO by the absence of internal ophthalmoplegia such as ptosis, mydriasis, and decreased light reflex.
Pseudo-internuclear ophthalmoplegia (myasthenia gravis): May mimic OHS. In INO and OHS, adduction with convergence is preserved, whereas in MG, adduction impairment does not improve with convergence. It can also be differentiated by the absence of diurnal variation and lack of improvement with Tensilon test.
Fisher syndrome (variant of Guillain-Barré syndrome): Triad of areflexia, ataxia, and ophthalmoplegia. It is differentiated by not being bilaterally symmetric and by the absence of truncal ataxia causing unsteadiness.
Progressive supranuclear palsy (PSP): Accompanied by parkinsonism. It is differentiated from INO by the ability to overcome eye movement abnormalities with the oculocephalic reflex.
Anti-ganglioside antibody-related ophthalmoplegia: There are case reports of complex ophthalmoplegia with positive anti-GD1a antibodies. It responds to IVIg but tends to relapse 2).
Thyroid eye disease: If thyroid eye disease is suspected, thyroid function tests should be performed.
QHow is differentiation from myasthenia gravis performed?
A
Myasthenia gravis (MG) can present with pseudo-internuclear ophthalmoplegia that mimics INO or OHS. In INO/OHS, adduction is preserved during convergence, whereas in MG, adduction impairment is not improved even with convergence. Additionally, the absence of diurnal fluctuation and lack of improvement with the Tensilon test are grounds for differentiation. Differentiation from Fisher syndrome is made by the absence of bilateral symmetric involvement and lack of truncal ataxia.
Within 4.5 hours of onset: After confirming infarction on MRI DWI, thrombolytic therapy (t-PA intravenous: alteplase 0.6 mg/kg) is indicated. If recanalization does not occur after t-PA, consider endovascular treatment with a stent retriever device.
Within 24 hours of onset: Intravenous infusion of the neuroprotective drug Radicut (edaravone) is also an option.
Actual outpatient practice: Hyperacute treatment is rarely performed for isolated ocular motor abnormalities; often, observation is done with mecobalamin tablets 500 μg 3 tablets + kallikrein tablets 10 units 3 tablets (each divided into 3 doses) (both off-label).
Wernicke encephalopathy: Vitamin B1 therapy (in cooperation with neurology). With early treatment, ocular motor abnormalities resolve within 1–2 weeks.
Pontine hemorrhage/pontine tumor: Neurosurgery takes the lead.
Fresnel membrane prism: Useful for alleviating residual diplopia symptoms.
Eye patch / monocular occlusion: Useful for immediate management of diplopia.
Strabismus surgery (extraocular muscle recession with adjustable sutures): Considered when conservative treatment fails.
Botulinum toxin injection: Particularly effective for oscillopsia due to ataxic nystagmus. Although temporary, it is suitable for management during rehabilitation.
Cerebrovascular disease: Relatively good. Mild infarction cases without detectable lesions on imaging may resolve within a few days.
Wernicke encephalopathy: With early treatment, ocular motility abnormalities disappear within 1–2 weeks.
Multiple sclerosis: Symptoms do not completely disappear, often leaving mild limitations. However, the prognosis of MS itself presenting with ocular motility abnormalities is considered good.
OHS due to pontine hemorrhage: Complete recovery within 6 months has been reported3).
Even after improvement of adduction deficit, reduced adduction velocity often persists.
QWhat is the prognosis?
A
It depends on the cause. In cerebrovascular disease, the prognosis is relatively good, and mild cases may resolve within a few days. In MS, symptoms rarely disappear completely, and mild reduction in adduction velocity often persists. In Wernicke encephalopathy, early vitamin B₁ treatment can lead to recovery within 1–2 weeks. Complete recovery within 6 months has also been reported for OHS due to pontine hemorrhage.
The MLF is a highly myelinated nerve fiber bundle extending from the midbrain to the spinal cord. It runs in the dorsomedial brainstem tegmentum of the midbrain and pons, very close to the midline. Therefore, both MLFs are adjacent, making bilateral INO common. Vascular supply: the lower pons (near CN VI nucleus) is supplied by paramedian arteries (small perforating branches) from the basilar artery, and the midbrain (near CN III nucleus) is supplied by small perforating branches from the P2 segment of the posterior cerebral artery.
The center for horizontal gaze is the PPRF (paramedian pontine reticular formation). Saccade signals are transmitted via the pathway: frontal eye field (area 8, contralateral saccade) → PPRF → ipsilateral CN VI nucleus. From the CN VI nucleus, output goes in two directions.
Ipsilateral lateral rectus: abduction (CN VI proper)
Contralateral CN III medial rectus subnucleus: fibers from the CN VI nucleus cross and ascend in the MLF to reach the contralateral oculomotor medial rectus subnucleus → contralateral medial rectus adducts
Normal horizontal gaze involves three pathways: saccadic (frontal eye field → contralateral PPRF), smooth pursuit (occipital area 19 → ipsilateral PPRF), and vestibular (semicircular canals → vestibular nucleus → directly to contralateral abducens nucleus without passing through PPRF).
The PPRF, CN VI nucleus, and MLF are located close together in the dorsal tegmentum of the lower pons, so subtle differences in lesion location cause different eye movement abnormalities.
INO (MLF lesion): Signal transmission from CN VI nucleus to CN III medial rectus subnucleus is blocked. Adduction saccade velocity is reduced in the ipsilateral eye. Abduction nystagmus in the contralateral eye is an adaptive phenomenon based on Hering’s law of equal innervation. Convergence is preserved (convergence pathways do not pass through the MLF).
Horizontal gaze palsy (PPRF/abducens nucleus lesion): Horizontal eye movements toward the ipsilateral side are limited in both eyes. In the acute phase, there may be conjugate gaze deviation toward the contralateral side in primary position.
OHS (PPRF/abducens nucleus + ipsilateral MLF lesion): When both the PPRF and MLF on one side are damaged, horizontal gaze palsy impairs ipsilateral abduction and contralateral adduction, and the MLF lesion also impairs ipsilateral adduction.
Damage to both the ipsilateral abducens nucleus and PPRF
Damage to the ipsilateral abducens nucleus alone
Damage to the ipsilateral PPRF only
Damage to the ipsilateral abducens nerve root fibers and contralateral MLF due to two separate lesions
Differences based on the site of PPRF lesion:
Lesion rostral to the abducens nucleus: Saccades and pursuit movements are impaired, but vestibular-induced reflex horizontal eye movements are preserved.
Lesion at the level of the abducens nucleus: Both voluntary and vestibular-induced reflex movements are lost.
Damage to the abducens nucleus: All ipsilateral horizontal eye movements, including voluntary and reflex, cease.
Relationship between anterior/posterior INO and convergence
Anterior INO (midbrain, CN III nucleus level): May be accompanied by convergence impairment.
Posterior INO (below CN III nucleus): Convergence is preserved (typical INO).
Mechanism of convergence preservation: Convergence, pupillary light reflex, and vertical eye movements do not pass through the MLF, so they are usually preserved (unless the lesion extends to the midbrain).
In addition to horizontal gaze, the MLF is involved in the vestibulo-ocular reflex, vertical pursuit movements, and optokinetic nystagmus (OKN). The riMLF (rostral interstitial nucleus of the medial longitudinal fasciculus) generates vertical and torsional saccades. Damage to fibers from the inner ear passing through the MLF can cause vertical nystagmus, torsional nystagmus, and skew deviation.
Rodrigo-Gisbert et al. (2023) reported a case of subacute ophthalmoplegia and ataxia in an 82-year-old woman 1). It was anti-Ri antibody-positive paraneoplastic neurological syndrome (PNS), and internuclear ophthalmoplegia occurred as part of the clinical spectrum of paraneoplastic brainstem encephalitis. Anti-Ri antibody-positive PNS is often associated with breast cancer (79% of women) and lung cancer (25% of men), and in cases of unexplained internuclear ophthalmoplegia, a search for malignancy may be necessary.
McKean et al. (2021) reported a case of immune-mediated ophthalmoplegia in a 23-year-old woman with strongly positive anti-GD1a antibodies (also positive for anti-GM1/GM2/GD1b antibodies) 2). She presented with bilateral abduction deficits, upgaze limitation, and convergence-retraction nystagmus, which posed a differential diagnosis from INO. Complete remission was achieved with IVIg (2 g/kg over 5 days), but relapse occurred within 2 weeks, and maintenance was achieved with IVIg every 4 weeks.
Case of OHS due to pontine hemorrhage and prognosis
Nathan et al. (2024) reported a case of a 42-year-old woman with untreated hypertension who was brought to the emergency department with right hemiparesis, dizziness, and projectile vomiting 3). Complete horizontal gaze palsy in the left eye and nystagmus on abduction of the right eye were observed, and CT confirmed hemorrhage in the left midbrain and upper pons. She was managed with antihypertensive treatment, and at 2.5-year follow-up, eye movements had improved and she was able to perform daily activities.
It has been suggested that INO may be used as a biomarker of axonal and myelin integrity in MS. Objective assessment using quantitative infrared oculography may contribute to improved diagnostic accuracy in subtle INO cases. Additionally, the systematization of numbered syndromes (such as 8.5, 9, 13.5, 15.5, and 16.5 syndromes) centered on OHS has been increasingly organized in recent years.
Rodrigo-Gisbert M, Llaurado A, Baucells A, Auger C, González V. Clinical Reasoning: An 82-Year-Old Woman With Subacute Ophthalmoparesis and Ataxia. Neurology. 2023;101(5):e570-e575.
McKean N, Chircop C. Immune-mediated ophthalmoparesis with anti-GD1a antibodies. BMJ Case Rep. 2021;14:e244273.
Nathan B, Rajendran A, G E. One-and-a-Half Syndrome in a Case of Brainstem Bleed. Cureus. 2024.
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