Parinaud syndrome (dorsal midbrain syndrome)

Key points at a glance

Key points of this disease

• Parinaud syndrome (dorsal midbrain syndrome) is a syndrome caused by a lesion in the dorsal midbrain, characterized by light-near dissociation and vertical gaze palsy.
• The six components are: ① light-near dissociation, ② upward gaze palsy, ③ convergence palsy, ④ convergence-retraction nystagmus, ⑤ Collier sign, and ⑥ skew deviation.
• Main causes include pineal tumor (in young patients), hydrocephalus, brainstem vascular disorders, and demyelinating diseases.
• The pupil is moderately dilated with loss of light reflex, but the near reflex is preserved (light-near dissociation).
• When accompanied by aqueductal stenosis, it may be complicated by papilledema and is also called midbrain aqueduct syndrome.
• Differentiation from Argyll Robertson pupil (miosis + light-near dissociation) and Adie pupil (unilateral mydriasis) is important.
• Treatment is primarily directed at the underlying disease (e.g., tumor treatment, shunt surgery), and prognosis varies depending on the cause.

1. What is Parinaud syndrome?

Parinaud syndrome, also called dorsal midbrain syndrome, is a syndrome caused by a lesion in the dorsal midbrain. The main findings are tectal pupil (light-near dissociation) and vertical gaze palsy (especially upward saccadic impairment).

Light-near dissociation (Parinaud pupil) is a pupillary abnormality caused by lesions in the dorsal midbrain that disrupt the pupillary light reflex pathway through the pretectal area and posterior commissure. Pineal tumors are a well-known cause, but they account for only a minority of cases.

The components of this syndrome consist of the following six items.

1. Light-near dissociation (loss of light reflex with preserved near reflex)
2. Vertical gaze palsy: especially impairment of upward saccades
3. Convergence paralysis: impaired convergence during near vision
4. Convergence-retraction nystagmus: characteristic finding of both eyes retracting on attempted upward gaze
5. Collier sign: Bilateral lid retraction observed during forward gaze or upward gaze
6. Skew deviation: Vertical misalignment of the eyes

In a 25-year review of 40 adult cases, vertical gaze palsy was present in all cases, but the classic triad including convergence-retraction nystagmus and light-near dissociation was found in only 65%, indicating that not all components are necessarily present¹.

When obstruction of the cerebral aqueduct occurs, it is complicated by papilledema and is called sylvian aqueduct syndrome.

Q Are Parinaud syndrome and sylvian aqueduct syndrome the same disease?

A

They essentially refer to the same syndrome, but are sometimes strictly distinguished. Sylvian aqueduct syndrome refers to the condition where, in addition to the findings of Parinaud syndrome, there is increased intracranial pressure and papilledema due to obstruction of the cerebral aqueduct. The presence or absence of papilledema is the main distinguishing point.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The main subjective symptoms reported by patients are as follows.

• Vertical diplopia: Double vision in the vertical direction due to impaired eye movement when looking upward
• Photophobia: Discomfort in bright environments due to impaired pupillary light reflex
• Visual fluctuation and difficulty with near work: Difficulty focusing when accompanied by convergence paralysis or accommodation disorders
• Headache: Caused by increased intracranial pressure due to hydrocephalus or tumor

Clinical Findings (Findings Confirmed by Physician Examination)

Pupillary Findings

• Loss of light reflex: The light reflex pathway is interrupted due to damage to the pretectal area and posterior commissure
• Preserved near response: Fibers for the near response run ventrally to the light reflex pathway and are less susceptible to damage, resulting in light-near dissociation
• Moderate mydriasis: Initially, pupil size may be normal, but gradually bilateral moderate mydriasis develops

Ocular motility findings

• Vertical gaze palsy: Upward saccadic eye movements are particularly impaired. Downward gaze is often relatively preserved.
• Convergence-retraction nystagmus: When attempting upward gaze, both eyes retract and exhibit nystagmoid movements. This finding is characteristic of Parinaud syndrome.
• Convergence palsy: Adduction of both eyes during near vision (convergence) is impaired.

Eyelid findings

• Collier sign (lid retraction): Bilateral eyelid retraction observed during primary gaze or upward gaze. It is thought to be caused by disinhibition of the levator palpebrae superioris due to a lesion of the posterior commissure.

Other Findings

• Skew deviation: Vertical misalignment of the eyes. One eye is elevated and the other is depressed.
• Papilledema: Occurs when there is increased intracranial pressure due to aqueductal stenosis.

Q What is convergence-retraction nystagmus?

A

When attempting upward gaze, the lateral rectus muscles contract simultaneously, causing both eyes to retract into the orbit and exhibit rapid nystagmoid movements. This is thought to result from abnormal activation of the convergence system during attempted upward gaze. It is a characteristic finding of Parinaud syndrome, and observation with a slit lamp or video nystagmography is useful for diagnosis.

3. Causes and Risk Factors

The causes of Parinaud syndrome are diverse. Any lesion that compresses or directly damages the posterior commissure, pretectal area, or dorsal midbrain can be a cause.

Main causative diseases

• Pineal tumors: Common in young people, best known as a cause of Parinaud syndrome. Germinoma is the most frequent histological type, often seen in males around puberty²
• Hydrocephalus: Compression of the posterior commissure leads to the syndrome. Obstructive hydrocephalus in children is a typical example.
• Brainstem vascular disorders: Infarction or hemorrhage in the dorsal midbrain. More common in elderly onset.
• Demyelinating diseases: When demyelinating lesions such as multiple sclerosis (MS) occur in the dorsal midbrain.

Frequency of Causes

In adult studies, midbrain lesions (hemorrhage 30%, infarction 20%, tumor 15%) are the most common, and pineal region tumors account for about 30% ¹. In children, pineal region tumors are the leading cause ³. Imaging diagnosis is essential for identifying the cause.

Characteristics in Children

In pediatric Parinaud syndrome, pineal region germinoma may be the cause. Pineal tumors are more common in children and young adults than in adults, and tumor markers (AFP, β-HCG) and head MRI are important for evaluation. In a study of 35 pediatric pineal region tumors, about half (51%) developed dorsal midbrain syndrome, with the most common symptom being upward gaze limitation (89%), followed by pupillary abnormalities (83%), and convergence-retraction nystagmus (50%) ³.

4. Diagnosis and Examination Methods

Clinical Diagnosis

Clinical diagnosis is possible based on the combination of the following findings.

• Light-near dissociation (loss of light reflex, preserved near response)
• Vertical gaze palsy (especially upward gaze limitation)
• Convergence-retraction nystagmus and convergence palsy
• Collier sign (bilateral eyelid retraction)

The syndrome may present with only some components, and should be suspected even when the typical six findings are not all present.

Differential Diagnosis

It is important to differentiate diseases that present with light-near dissociation.

Tectal Pupil (Parinaud Syndrome)

Lesion: Dorsal midbrain (pretectal area, posterior commissure)

Pupil size: Moderate dilation (bilateral)

Laterality: Bilateral

Associated findings: vertical gaze palsy, convergence-retraction nystagmus, Collier sign

Argyll Robertson pupil

Lesion: midbrain pretectal area (neurosyphilis)

Pupil size: bilateral severe miosis

Laterality: bilateral

Associated findings: miosis, irregular pupil, history of syphilis infection

Adie pupil (tonic pupil)

Lesion: Ciliary ganglion (peripheral)

Pupil size: Moderate dilation

Laterality: Usually unilateral (about 80%)

Associated findings: Tonic miosis and areflexia (Holmes-Adie syndrome)

Light-near dissociation without miosis is called pseudo Argyll Robertson pupil and presents similarly to tectal pupil. In neurosyphilis, miosis is always present, which helps in differentiation.

Required Tests

• Head MRI/CT: Confirms pineal region tumors, hydrocephalus, and brainstem lesions. Diffusion-weighted and contrast-enhanced MRI are useful for tumor evaluation. Intrinsic midbrain T2/FLAIR hyperintensity (intrinsic midbrain signal abnormality, IMSA) is a highly sensitive finding for Parinaud syndrome in pineal region lesions ⁴⁵
• Eye movement evaluation: Quantification of upward gaze limitation. Recording of convergence-retraction nystagmus using video-oculography
• Visual acuity and visual field tests: Assessment of optic nerve compression
• Tumor markers: Measurement of AFP, β-HCG, and PLAP in serum and cerebrospinal fluid if pineal tumor is suspected

Q What is the difference from Argyll Robertson pupil?

A

The biggest difference is pupil diameter. Argyll Robertson pupils are characterized by bilateral small pupils that show extreme miosis even in dark conditions, and are strongly associated with neurosyphilis. Tectal pupils (Parinaud syndrome) present with moderate mydriasis, and accompanying findings such as vertical gaze palsy, convergence-retraction nystagmus, and Collier sign also serve as clues for differentiation.

5. Standard Treatment

The basic treatment strategy for Parinaud syndrome is treatment of the underlying disease. Ophthalmic treatment for the syndrome itself is symptomatic, and removing the cause leads to fundamental improvement.

Treatment Strategies by Cause

Pineal tumor

• Radiation therapy, chemotherapy, or surgical resection is selected depending on the histological type.
• Germ cell tumors are highly radiosensitive, and radiotherapy is effective.
• Multidisciplinary collaboration with neurosurgery and oncology is essential.

Hydrocephalus

• V-P shunt (ventriculoperitoneal shunt): the most common surgical treatment.
• Endoscopic third ventriculostomy (ETV): indicated for obstructive hydrocephalus.
• In many cases, Parinaud syndrome findings improve after shunt surgery.

Brainstem vascular disorder

• Acute management in the neurology department
• Antiplatelet therapy and risk factor management (hypertension, diabetes, dyslipidemia)
• Some degree of spontaneous recovery can be expected in vascular lesions

Demyelinating lesions (multiple sclerosis, etc.)

• Acute treatment with steroid pulse therapy (methylprednisolone)
• Long-term management with disease-modifying therapy (DMT) in neurology

Symptomatic treatment

For vertical diplopia, prescription of prism glasses may be considered as a temporary symptomatic treatment. It can be useful for maintaining quality of life until the underlying disease responds to treatment. In adult studies, conservative management with observation, occlusion, and prisms was sufficient in about 88% of cases, and strabismus surgery for refractory diplopia improved symptoms in 80% of cases¹.

About the medical care system

Parinaud syndrome cannot be fundamentally treated by ophthalmology alone. Depending on the nature of the underlying disease, collaboration with neurosurgery, neurology, oncology, etc., is essential. Ophthalmology plays an important role in evaluating and following up pupils, eye movements, visual acuity, and visual fields, and serves as a starting point for diagnosis.

Q Is there any ophthalmologic treatment for Parinaud syndrome itself?

A

There is no curative ophthalmic treatment. The goal is to improve symptoms by treating the underlying disease. If vertical diplopia interferes with daily life, prism glasses may be chosen as symptomatic therapy. Ophthalmology handles diagnosis, follow-up, and symptomatic treatment, while causal treatment is performed in collaboration with each specialist.

6. Pathophysiology and Detailed Mechanism

Each component finding of Parinaud syndrome is explained by neuroanatomical damage to the dorsal midbrain, centered on the posterior commissure and pretectal area.

Anatomy of the Posterior Commissure and Pretectal Area

The pretectal area is located rostral and dorsal to the cerebral aqueduct, and the posterior commissure is a white matter commissure continuing caudally. Pineal tumors or dilation of the posterior third ventricle due to hydrocephalus compresses and damages this area, causing Parinaud syndrome.

Neuroanatomical Mechanism of Light-Near Dissociation

The afferent pathway of the light reflex follows the route: optic nerve → optic chiasm → optic tract → pretectal area → posterior commissure → contralateral Edinger-Westphal nucleus → oculomotor nerve → ciliary ganglion → pupillary sphincter.

In contrast, the supranuclear fibers that control the near response (convergence miosis) run more ventrally (anteriorly) than the light reflex pathway. Therefore, when the pretectal area or posterior commissure is affected, the light reflex pathway is interrupted, but the near response pathway is preserved. This is the anatomical basis for light-near dissociation ².

Pathogenesis of each component finding

Finding	Neuroanatomical mechanism
Upward gaze palsy	Posterior commissure lesion → interruption of pathway to riMLF (rostral interstitial nucleus of medial longitudinal fasciculus)
Convergence-retraction nystagmus	Abnormal firing of the convergence system (lateral rectus) during attempted upward gaze
Collier sign	Disinhibition of the levator palpebrae due to posterior commissure lesion
Skew deviation	Asymmetric impairment of the vestibulo-ocular reflex pathway
Loss of light reflex	Blockade of the afferent pathway of the light reflex at the pretectal area and posterior commissure

Factors affecting prognosis

Prognosis varies greatly depending on the underlying disease.

• Associated with hydrocephalus: If intracranial pressure improves with shunt surgery or ETV, compression of the pretectal area may be relieved and symptoms may recover.
• Brainstem vascular lesions: Some degree of spontaneous recovery can be expected. The size and location of the lesion influence the prognosis.
• Pineal tumors: Depends on the treatment effect (shrinkage/disappearance) of the tumor. Germ cell tumors are often radiosensitive and have a good prognosis.
• Demyelinating diseases: The course varies depending on the response to steroid therapy.

7. Latest Research and Future Prospects

For patients: Please be sure to read

The following content is currently in the research stage or under clinical trials, and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Expansion of Indications for Endoscopic Third Ventriculostomy (ETV)

The usefulness of endoscopic third ventriculostomy (ETV) as an alternative to V-P shunt for Parinaud syndrome associated with hydrocephalus is attracting attention. ETV is advantageous in avoiding shunt-related complications (infection, malfunction), and its indications are expanding for obstructive hydrocephalus. Further evidence accumulation is awaited regarding how much early relief of hydrocephalus contributes to visual function improvement in Parinaud syndrome.

Multimodal treatment for pineal tumors

For pineal germ cell tumors, multimodal treatment combining radiotherapy and chemotherapy (carboplatin, etoposide, etc.) is becoming standardized. Optimization of the indications for craniospinal irradiation and the intensity of chemotherapy is under continuous study.

Visual function improvement through early intervention

In hydrocephalus-associated Parinaud syndrome, early relief of intracranial pressure may quickly reduce compression on the pretectal area, contributing to improvement in visual function and eye movements. Development of methods to quantitatively track the course of upward gaze palsy is also progressing.

8. References

Footnotes

1. Shields M, Sinkar S, Chan W, Crompton J. Parinaud syndrome: a 25-year (1991-2016) review of 40 consecutive adult cases. Acta Ophthalmol. 2017;95(8):e792-e793. PMID: 27778456. doi:10.1111/aos.13283 ↩ ↩² ↩³

2. Ortiz JF, Eissa-Garcés A, Ruxmohan S, et al. Understanding Parinaud’s Syndrome. Brain Sci. 2021;11(11):1469. PMID: 34827468. PMC: PMC8615667. doi:10.3390/brainsci11111469 ↩ ↩²

3. Hoehn ME, Calderwood J, O’Donnell T, Armstrong GT, Gajjar A. Children with dorsal midbrain syndrome as a result of pineal tumors. J AAPOS. 2017;21(1):34-38. PMID: 28069468. doi:10.1016/j.jaapos.2016.09.024 ↩ ↩²

4. Vuppala AA, Hura N, Sahraian S, Beheshtian E, Miller NR, Yousem DM. MRI findings in Parinaud’s syndrome: a closer look at pineal masses. Neuroradiology. 2019;61(5):507-514. PMID: 30684115. doi:10.1007/s00234-019-02166-4 ↩

5. Hura N, Vuppala AD, Sahraian S, Beheshtian E, Miller NR, Yousem DM. Magnetic resonance imaging findings in Parinaud’s syndrome: comparing pineal mass findings to other etiologies. Clin Imaging. 2019;58:124-130. PMID: 31377440. doi:10.1016/j.clinimag.2019.07.010 ↩