Raeder syndrome (Raeder paratrigeminal syndrome)

Key Points at a Glance

Key Points of This Disease

• Raeder syndrome is a rare condition characterized by unilateral postganglionic Horner syndrome and ipsilateral trigeminal symptoms.
• Facial sweating is often preserved, indicating that the lesion is distal to the carotid bifurcation.
• MRI/MRA is essential to rule out serious underlying conditions such as internal carotid artery dissection, aneurysm, or middle cranial fossa tumor.
• Confirm Horner syndrome with pharmacological testing (apraclonidine eye drop test) and investigate the cause with imaging.
• Group I (with parasellar nerve involvement) has a prognosis dependent on the underlying disease; Group II (without involvement) often resolves spontaneously within weeks to months.
• Treatment prioritizes the underlying disease; idiopathic cases are managed symptomatically.

1. What is Raeder syndrome?

Raeder paratrigeminal syndrome (RPS) is a rare neurological disorder characterized by unilateral oculosympathetic palsy (Horner syndrome) accompanied by ipsilateral sensory and motor abnormalities in the trigeminal nerve distribution. It is often described as a painful, postganglionic, incomplete Horner syndrome. Defined as a condition presenting with trigeminal neuralgia and postganglionic Horner syndrome, the core pathology involves a lesion near the trigeminal ganglion.

RPS is largely a diagnosis of exclusion. Because middle cranial fossa or cavernous sinus lesions and internal carotid artery dissection can mimic RPS, neuroimaging is essential.

History and Subtype Classification

In 1924, Norwegian ophthalmologist Johan Georg Raeder reported five cases presenting with unilateral oculosympathetic palsy and ipsilateral trigeminal symptoms. Four of the five cases had no sweating disorder and no involvement of other cranial nerves, localizing the lesion to the middle cranial fossa, which he termed “paratrigeminal neuralgia.”

After the subtype classification (Group I and II) by Boniuk and Schlezinger in 1962, Grimson and Thompson (1980) revised it into the following three subtypes (Goadsby 2002, Mokri 1982).

Below is an overview of the three subtypes currently widely referenced.

Subtype	Features	Prognosis
Group I	Involvement of parasellar region (with other cranial nerve disorders)	Depends on underlying disease
Group II	No involvement (cluster headache + isolated ocular sympathetic palsy)	Good, self-limiting
Group III	Painful postganglionic Horner with V1 involvement	Depends on underlying disease

In modern times, all subtypes are considered exclusion diagnoses that meet IHS criteria. Mokri argues that only Group I should be considered true Raeder syndrome, and many reports have noted that it was vascular headache (such as migraine).

Epidemiology

The exact incidence is unknown, and it is a rare disease. It is most common in middle-aged men.

Q What is the difference between Group I and Group II of Raeder syndrome?

A

Group I involves other cranial nerves near the parasellar region, requiring investigation for underlying diseases (e.g., tumors, vascular lesions). Group II has no other cranial nerve involvement and a good prognosis, with symptoms usually resolving spontaneously within weeks to months. Both are diagnoses of exclusion, requiring imaging to rule out underlying conditions.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Unilateral headache or facial pain: Often around the ipsilateral eye or retro-orbital area, may be limited to V1 or extend to V2 (cheek, teeth).
• Pain characteristics: Severe lancinating pain radiating to the face, resembling trigeminal neuralgia.
• Persistent pain: Typically lasts from hours to weeks to months. May also present with cluster headache-like attack patterns.
• Ptosis and miosis: Accompanied by ipsilateral ptosis and miosis, resulting in narrowing of the palpebral fissure.
• Diplopia and hearing loss: May occur when other cranial nerves are involved.

Clinical Findings (Findings Confirmed by Physician Examination)

Findings of Horner syndrome

• Miosis (anisocoria): More pronounced in dim light. Accompanied by delayed dilation.
• Ptosis: Mild ptosis on the same side and elevation of the lower eyelid (inverse ptosis). Causes narrowing of the palpebral fissure.
• Normal pupillary light reflex: Because the sphincter pupillae is affected, the light reflex is preserved despite miosis.
• Apparent enophthalmos and low intraocular pressure: Mild decrease in intraocular pressure or apparent enophthalmos may be observed.
• Conjunctival injection and lacrimation: Seen in some cases.

Findings of trigeminal nerve dysfunction

• Facial sensory loss: Asymmetry in touch and pain/temperature sensation in the V1 and V2 distributions.
• Decreased corneal reflex: due to V1 (ophthalmic branch) involvement.
• Allodynia: a hypersensitive state where mild stimuli cause pain.
• Weakness of masticatory muscles: occurs when the motor branch of the trigeminal nerve is affected.

Characteristic findings related to sweating

• Preserved facial sweating: absence of anhidrosis is a characteristic finding of RPS. Since sympathetic fibers involved in facial sweating travel along the external carotid artery, sweating is preserved in postganglionic lesions along the internal carotid artery. If decreased sweating is present in postganglionic lesions, it is limited to the medial forehead and tip of the nose (Santos 2016).

Q Why is there no sweating disorder despite Horner syndrome?

A

Sympathetic nerve fibers involved in facial sweating run along the external carotid artery after passing the carotid bifurcation. In RPS, because the lesion is distal (postganglionic) to the carotid bifurcation, the sweating fibers that branch to the external carotid artery are not affected, and facial sweating is preserved. Preserved sweating is a useful finding for localizing the lesion site.

3. Causes and Risk Factors

The causes of RPS are diverse. Although many cases are idiopathic, systematic evaluation is necessary because serious underlying diseases may be present.

Internal carotid artery abnormalities (priority for evaluation)

• Internal carotid artery dissection: Oculosympathetic palsy with hemicrania is recognized as a symptom of idiopathic internal carotid artery dissection. Early recognition is important due to the risk of acute ischemic neurological sequelae (Lyrer 2014).
• Internal carotid artery aneurysm: This requires mandatory evaluation. Dissecting aneurysms require urgent management.
• Others: occlusion, inflammation, fibromuscular dysplasia, congenital anomalies, or traumatic changes of the internal carotid artery.

Neoplastic lesions

• Middle cranial fossa tumors and nasopharyngeal tumors: direct involvement of the Gasserian ganglion, local invasion, metastasis, lymphoma.

Inflammatory and infectious lesions

• Dental abscess and chronic sinusitis: spread to the trigeminal nerve region (Pritchett 2015).

Trauma and iatrogenic causes

• Basilar skull fracture, iatrogenic injury to the Gasserian ganglion, gunshot wound.
• There are reports of cases after embolization of giant cavernous carotid artery aneurysms (sympathetic nerve compression due to balloon placement).

Related diseases

• Cluster headache, SUNCT syndrome, ophthalmic herpes zoster, hemicrania continua, Tolosa-Hunt syndrome, vasculitis, hypertension, head trauma, migraine, Lyme disease.

Prevention and daily care

There are reports that pain worsens after consuming alcoholic beverages. During the active phase of the disease, it is recommended to avoid triggers that may cause vasodilation, such as alcohol.

4. Diagnosis and Examination Methods

IHS Diagnostic Criteria

The diagnosis of RPS requires meeting all of the following four criteria.

1. Persistent, unilateral headache (meeting criterion C)
2. Imaging evidence of underlying disease in the middle cranial fossa or ipsilateral carotid artery
3. Evidence of a causal relationship (temporal association + localization in the trigeminal V1 distribution, worsening with eye movement)
4. Cannot be explained by other ICHD-3 diagnoses

Pharmacological testing

Used to confirm Horner syndrome and estimate the lesion site. The main tests are shown below.

Test agent	Mechanism	Interpretation
Apraclonidine 1%	Denervation supersensitivity increases α1 receptors → dilation of affected pupil	Anisocoria reverses 30–60 minutes after instillation (sensitivity 88–100%)
Cocaine 10%	Inhibits norepinephrine reuptake	Normal pupil dilates; affected pupil does not dilate
Hydroxyamphetamine 1%	Release of norepinephrine from postganglionic nerve endings	In postganglionic disorders, the affected pupil does not dilate

Apraclonidine (Iopidine®) is not covered by insurance. Cocaine is classified as a narcotic and is difficult to obtain; a 5-fold dilution of 1% phenylephrine hydrochloride (Neo-Synephrine®) can be used as a substitute. Many experts recommend discontinuing pharmacological testing and directly performing imaging of the entire oculosympathetic pathway based on clinical diagnosis. Caution is needed for eye drops in eyes with narrow angles.

Imaging tests

• MRI/MRA: Head to T2 level of the neck. Aimed at excluding compressive and vascular lesions (e.g., internal carotid artery dissection, aneurysm). Coronal and axial sections are obtained; gadolinium contrast is useful for differentiating inflammatory and neoplastic diseases.
• CT/CTA: Check for orbital, cavernous sinus, and skull base bone destruction, and confirm sinus lesions. CTA is useful for differentiating vascular lesions such as aneurysms.
• Chest imaging: Performed preferentially to rule out lung cancer and mediastinal tumors.
• Blood tests: Peripheral blood, ESR, CRP, antinuclear antibody, ANCA, ACE, β-D-glucan, etc. Used to differentiate infectious and autoimmune diseases.

Differential Diagnosis

• Tolosa-Hunt syndrome: Painful extraocular muscle palsy due to cavernous sinus lesions. Differentiated by rapid response to steroids within 1–2 days with marked pain improvement.
• Cavernous sinus syndrome: Oculomotor, trochlear, abducens, and trigeminal nerves are affected in various combinations, presenting with diplopia, proptosis, and conjunctival edema.
• Cluster headache, migraine, SUNCT syndrome, hemicrania continua: Differentiate based on headache characteristics, duration, and periodicity.
• Giant cell arteritis (GCA): In new-onset Horner syndrome in elderly patients, consider the possibility of giant cell arteritis.

Q How is the apraclonidine eye drop test performed?

A

Instill 1% (or 0.5%) apraclonidine in both eyes and check pupillary diameter changes after 30–60 minutes. If ocular sympathetic denervation hypersensitivity is present, the affected eye’s α1 receptors are increased, causing the affected pupil to dilate and reverse anisocoria. Sensitivity is reported as 88–100%, but it is not covered by insurance, and it is necessary to confirm that the eye does not have a narrow angle before instillation.

5. Standard Treatment

Treatment depends entirely on the underlying disease. Treatment of the primary disease is the highest priority.

For internal carotid artery dissection

• Emergency management is necessary to prevent embolic events and progression of dissection.
• Antiplatelet therapy: A common choice.
• Anticoagulation therapy: Selected in some cases.
• Surgical intervention: Rarely indicated when ischemia is refractory or there are high-risk features.

When no intracranial cause is found (symptomatic treatment)

• NSAIDs, aspirin, codeine compounds: Useful for controlling head and facial pain.
• Ergotamine, steroids, intensive vitamin B therapy: Reported to be effective in reducing pain in some cases.

Management of ptosis associated with Horner syndrome

• Observation: If no other systemic findings are present, observation is sufficient.
• Privine® eye drops: May be effective for peripheral ptosis when denervation supersensitivity is acquired (off-label use).
• Levator aponeurosis repair: Effective for ptosis of about 2 mm.

Prognosis

Depends on the underlying disease. In Group I, prognosis varies depending on the underlying condition. Group II has a very good prognosis, with symptoms usually resolving within weeks to months. In a reported case (50-year-old male) where the condition transitioned to persistent unilateral headache 10 months after onset, indomethacin was effective.

Precautions in treatment

There are reports of pain worsening after alcohol consumption. During the active phase of the disease, it is recommended to avoid triggers such as alcohol and vasodilators. Additionally, if internal carotid artery dissection is suspected, emergency response is necessary; self-monitoring should be avoided, and prompt consultation with a specialist is required.

Q Does idiopathic Raeder syndrome require treatment?

A

If no intracranial cause is identified, symptomatic treatment is the main approach. Pain management with NSAIDs or aspirin is performed while monitoring the course. Cases corresponding to Group II usually resolve spontaneously within weeks to months. However, it is essential to reliably exclude serious underlying diseases such as internal carotid artery dissection or tumors through imaging.

6. Pathophysiology and Detailed Pathogenesis

Anatomy of the Ocular Sympathetic Pathway

The efferent pathway of the ocular sympathetic nerve consists of three neurons.

• First-order neuron (central): Descends from the posterolateral hypothalamus to the Budge ciliospinal center (C8-T2).
• Second-order neuron (preganglionic): From the intermediolateral column of the spinal cord → apex of the lung and sympathetic trunk → superior cervical ganglion (SCG).
• Third-order neuron (postganglionic): Originates from the SCG, enters the cranium along the internal carotid artery, and proceeds to the cavernous sinus. Within the cavernous sinus, it leaves the internal carotid artery, runs briefly with the abducens nerve (CN VI), then joins the ophthalmic division of the trigeminal nerve (V1) and enters the orbit through the superior orbital fissure. Finally, it innervates Müller’s muscle (upper eyelid), the sympathetic tarsal muscle of the lower eyelid, and the dilator pupillae muscle.

Why Sweating Is Not Impaired

Sympathetic fibers involved in facial sweating branch off from the main trunk after the carotid bifurcation and run along the external carotid artery. In RPS, because the lesion is in the postganglionic region along the internal carotid artery, the sweating fibers on the external carotid side are not affected, and facial sweating is preserved. Preservation of sweating indicates that the lesion is distal to the carotid bifurcation. If sweating is reduced in a postganglionic disorder, it is limited to the medial forehead and the tip of the nose.

Mechanism of Pain

• Even if trigeminal nerve fibers from the ophthalmic branch (V1) or parasympathetic fibers of the oculomotor nerve (CN III) are not affected, pain may occur without sensory disturbance.
• A hypothesis has been proposed that pain arises from synapses between the pterygopalatine ganglion and the lateral sellar plexus.
• Periorbital pain in carotid artery dissection may be referred pain originating from general visceral afferent fibers.

Anatomical relationship with the cavernous sinus

Within the cavernous sinus, the abducens nerve (CN VI) is adjacent to the internal carotid artery, oculosympathetic nerve, oculomotor nerve (CN III), trochlear nerve (CN IV), and trigeminal nerve V1. Carotid aneurysms or inflammatory cavernous sinus lesions may be complicated by Horner syndrome (Adult Strabismus PPP).

8. References

• Goadsby PJ. Raeder’s syndrome: paratrigeminal paralysis of the oculopupillary sympathetic system. J Neurol Neurosurg Psychiatry. 2002;72(3):297-299. doi:10.1136/jnnp.72.3.297. PMID: 11861683.
• Mokri B. Raeder’s paratrigeminal syndrome. Original concept and subsequent deviations. Arch Neurol. 1982;39(7):395-399. doi:10.1001/archneur.1982.00510190013004. PMID: 7103769.
• Santos M, Burton K, McGillen B. Raeder’s paratrigeminal syndrome: headache and Horner’s lacking anhidrosis. J Gen Intern Med. 2016;31(9):1102-1103. doi:10.1007/s11606-016-3642-1. PMID: 26902244.
• Lyrer PA, Brandt T, Metso TM, et al. Clinical import of Horner syndrome in internal carotid and vertebral artery dissection. Neurology. 2014;82(18):1653-1659. doi:10.1212/WNL.0000000000000381. PMID: 24727317.
• Pritchett CV, Zacharek MA. Raeder syndrome: paratrigeminal oculosympathetic syndrome presenting as a manifestation of chronic sinusitis. Ear Nose Throat J. 2015;94(12):E22-E25. PMID: 26670762.
• American Academy of Ophthalmology. Adult Strabismus Preferred Practice Pattern.