The brainstem consists of three parts: the midbrain, pons, and medulla oblongata. Each part contains the nuclei of the oculomotor nerve (CN III), trochlear nerve (CN IV), and abducens nerve (CN VI), as well as the reticular formation, medial longitudinal fasciculus (MLF), and cerebellar connecting pathways. Because these structures are densely packed, even a small lesion in the brainstem can simultaneously damage multiple cranial nerve nuclei or pathways, resulting in various eye movement disorders and spontaneous abnormal eye movements including nystagmus.
“Combined cranial nerve palsy” or “multiple cranial neuropathy” is a general term for clinical syndromes in which multiple cranial nerves are simultaneously affected due to brainstem lesions. It is not a single disease name but a conceptual framework that presents diverse clinical pictures depending on the lesion site and underlying cause 1,2.
The brainstem contains not only the nuclei and pathways involved in eye movements but also numerous neural pathways related to sensory, motor, and autonomic functions. Since eye movement disorders and nystagmus are often accompanied by neurological signs such as limb paralysis, sensory disturbances, and cerebellar ataxia, these associated symptoms provide important clues for estimating the location of the responsible lesion.
Within the brainstem, there are the oculomotor nucleus (CN III), trochlear nucleus (CN IV), and abducens nucleus (CN VI), as well as the paramedian pontine reticular formation (PPRF) that controls horizontal eye movements, the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) that controls vertical eye movements, and the medial longitudinal fasciculus (MLF) and posterior commissure (PC) that connect these nuclei. Because these structures involved in eye movements are densely packed, even a very limited brainstem lesion can simultaneously damage multiple oculomotor structures, resulting in characteristic complex syndromes.
Symptoms vary depending on the lesion site. Characteristic findings by location are shown below.
Midbrain Lesions
Vertical diplopia: The main complaint is separation of images in the vertical direction.
Oculomotor nerve palsy: Typical triad includes downward and outward deviation of the eye, pupillary dilation, and ptosis.
Upward gaze palsy (Parinaud syndrome): Presents with inability to look upward in both eyes and convergence-retraction nystagmus.
VOHS (Vertical one-and-a-half syndrome): A characteristic complex sign with upward gaze palsy plus downward gaze palsy in one eye.
Pontine Lesions
Horizontal diplopia: The main symptom is separation of images in the horizontal direction.
Abducens nerve palsy: Causes horizontal diplopia due to limited abduction on the affected side.
Facial nerve palsy: Ipsilateral facial muscle weakness and inability to close the eye occur.
Ipsilateral sensory disturbance: May be accompanied by decreased facial pain and temperature sensation due to trigeminal nucleus involvement.
One-and-a-half syndrome: A characteristic syndrome combining inability to gaze horizontally toward the affected side and inability to adduct the contralateral eye 3.
Medullary and Cerebellar Peduncle Lesions
Nystagmus: Abnormal eye movements occur due to cerebellar peduncle lesions.
Blurred vision: Patients often complain of visual oscillation due to nystagmus.
Wallenberg syndrome: A complex syndrome caused by lateral medullary infarction, including ipsilateral facial pain and temperature loss, nystagmus, Horner syndrome (miosis, ptosis), contralateral limb pain and temperature loss, and ipsilateral cerebellar ataxia 5.
Dysphagia and hoarseness: Occur due to involvement of the glossopharyngeal and vagus nerve nuclei.
Some cases present only with eye movement disorders and nystagmus. However, since many neural pathways other than those for eye movement run through the brainstem, accompanying symptoms such as limb paralysis, sensory disturbances, and limb ataxia can help identify the responsible lesion. Systematic evaluation of the presence and combination of these neurological signs is essential for estimating the lesion site and differentiating the underlying cause.
Due to unilateral pontine lesions involving the PPRF (paramedian pontine reticular formation) and abducens nucleus, horizontal gaze toward the affected side is completely lost (the “one” part). Additionally, involvement of the ipsilateral MLF (medial longitudinal fasciculus) prevents adduction of the ipsilateral eye during horizontal gaze to the opposite side (the “half” part). As a result, the only possible horizontal eye movement is abduction of the contralateral eye. Responsible lesions include pontine tumors, demyelination, infarction, and hemorrhage.
The causes of brainstem disorders vary greatly depending on the patient’s age group.
| Cause | Common site | Features |
|---|---|---|
| Brainstem glioma | Pons | Common in children to young adults. Infiltrative lesion on MRI. |
| Metastatic tumor | Entire brainstem | History of cancer. Often associated with multiple lesions. |
| Head trauma | Entire brainstem | Clear mechanism of injury. |
| Brainstem cavernous hemangioma | Pons and midbrain | Recurrent rebleeding. Hemosiderin deposition on MRI. |
In young individuals (up to 40s), inflammatory (brainstem encephalitis, neuro-Behçet disease) and demyelinating (MS, NMOSD) diseases are the main causes. In elderly individuals, vascular disorders (infarction, hemorrhage, dissection) of the vertebrobasilar system, often with underlying hypertension, diabetes, and dyslipidemia, are most common. Additionally, tumors, trauma, and cavernous hemangiomas can occur at any age.
A detailed medical history is the starting point for diagnosis. Confirm the onset time, course (acute, subacute, chronic), and accompanying symptoms. Acute onset suggests vascular disorders, while subacute to chronic course suggests inflammatory or neoplastic lesions.
Neurological examination evaluates the following:
| Test | Features and uses |
|---|---|
| Brain CT | Useful for detecting brainstem hemorrhage. Difficult to detect inflammatory lesions or hyperacute infarction. |
| Brain MRI (axial + coronal) | Essential for detecting brainstem tegmental lesions. T2WI and FLAIR detect demyelination and inflammation. |
| Diffusion-weighted imaging (DWI) | Detects acute cerebral infarction. May be false negative shortly after onset; repeat imaging may be needed. |
| MRA | Evaluation of stenosis, occlusion, or dissection of the vertebrobasilar system. |
When detecting brainstem tegmental lesions, it is important to request coronal sections in addition to axial sections. Also, in acute cerebral infarction, DWI may not show high signal intensity shortly after onset, so if cerebral infarction is clinically suspected, repeat MRI should be performed.
Lesions outside the brainstem can also present with multiple cranial nerve palsies, making differential diagnosis important.
First, systematically evaluate eye movement disorders, nystagmus, and associated neurological signs through neurological examination to estimate the lesion site (midbrain, pons, medulla oblongata). Then, perform brain CT for screening, and promptly add brain MRI (T2WI, FLAIR, DWI) and MRA. In acute onset with suspected cerebral infarction, confirm the time of onset to consider eligibility for t-PA administration, and make an emergency consultation with the stroke team.
Treatment is selected based on the underlying cause. If cerebral infarction is diagnosed, emergency management is required.
Cerebral Infarction
Intravenous t-PA therapy: Administer alteplase (Activacin®) 0.6 mg/kg intravenously within 4.5 hours of onset.
Endovascular treatment: If recanalization is not achieved with intravenous t-PA, consider mechanical thrombectomy using a stent retriever device.
Antiplatelet/Anticoagulant therapy: Initiated for secondary prevention after the acute phase.
Brainstem Hemorrhage
Conservative treatment: Blood pressure management and cerebral edema management are the mainstays.
Surgical intervention: In cases of massive hemorrhage with life-threatening risk, emergency collaboration with neurosurgery is performed.
Inflammatory Diseases
Brainstem encephalitis: Administer antibiotics or antivirals according to the causative microorganism, and use steroids to suppress inflammation.
Neuro-Behçet’s disease: Use steroids and immunosuppressants (cyclophosphamide, azathioprine).
Demyelinating Diseases (MS, NMOSD)
Acute phase: Intravenous methylprednisolone 1,000 mg/day for 3 days (steroid pulse therapy).
Relapse prevention: Introduction of disease-modifying drugs. In NMOSD, if anti-AQP4 antibody positive, consider inebilizumab, satralizumab, etc.
Ophthalmology contributes to the care of patients with brainstem disorders in the following aspects:
Many cases improve with appropriate treatment of the underlying disease. In acute exacerbations of brainstem encephalitis or multiple sclerosis, eye movements often recover within weeks to months after steroid pulse therapy. In cerebral infarction, early recanalization treatment affects the prognosis. On the other hand, when the lesion is extensive or relapses occur, oculomotor disorders and nystagmus may persist as sequelae.
Horizontal saccadic eye movements are generated by the paramedian pontine reticular formation (PPRF) located in the pons. Signals from the PPRF are transmitted to the ipsilateral abducens nucleus, causing contraction of the ipsilateral lateral rectus muscle. At the same time, interneurons within the abducens nucleus send signals via the medial longitudinal fasciculus (MLF) to the medial rectus subnucleus of the contralateral oculomotor nucleus, achieving conjugate horizontal eye movements.
Mechanism of one-and-a-half syndrome: When the unilateral PPRF and abducens nucleus in the pons are damaged, horizontal gaze toward the ipsilateral side becomes completely impossible. Additionally, if the ipsilateral MLF is also damaged, adduction of the ipsilateral eye during horizontal gaze to the contralateral side becomes impossible. As a result, the only remaining horizontal eye movement is abduction of the contralateral eye.
The control center for vertical eye movements is located from the midbrain to the thalamus.
Upward gaze signals originate from the riMLF, pass through the posterior commissure (PC), and reach the bilateral oculomotor nuclei. Downward gaze signals travel directly from the riMLF to the ipsilateral oculomotor nucleus and trochlear nucleus.
A unilateral lesion of the riMLF alone does not cause upward gaze palsy in both eyes. Upward gaze palsy becomes apparent only when combined with a PC lesion.
The responsible lesion for VOHS is a unilateral riMLF + PC lesion in the midbrain, caused by midbrain infarction, midbrain hemorrhage, or demyelinating lesions. On the other hand, since the horizontal eye movement system is intact, horizontal gaze is often preserved4,6.
Prognosis varies greatly depending on the underlying disease and the extent of the impairment.
