MRI
First choice: The primary imaging modality providing the highest resolution.
T2-weighted imaging: Useful for confirming unilateral tongue atrophy due to chronic CN XII palsy.
Key evaluation site: Focus on signs of malignancy in the clivus.
Godfredsen syndrome
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Godtfredsen syndrome?
Section titled “1. What is Godtfredsen syndrome?”Godtfredsen syndrome is a rare syndrome characterized by simultaneous paralysis of the sixth cranial nerve (abducens nerve) and the twelfth cranial nerve (hypoglossal nerve). It was first reported in 1946 by Danish ophthalmologist Erik Godtfredsen in association with metastatic nasopharyngeal carcinoma. The original report was a case series of nine patients with nasopharyngeal carcinoma, and both direct intracranial invasion by the tumor and retropharyngeal lymph node metastasis were hypothesized as causes.
The original definition referred to an infiltrative tumor of the cavernous sinus causing ipsilateral blindness, trigeminal neuralgia, external ophthalmoplegia, and hypoglossal nerve palsy, but it has since been expanded to include any lesion compressing the sixth and twelfth cranial nerves. Modern imaging techniques have revealed that most cases of this syndrome are localized to lesions of the clivus.
The exact epidemiology is unknown. It is considered a rare disease with few literature reports, but underreporting is possible. A literature review over the past 20 years has accumulated nine cases 1). This syndrome due to clival chondrosarcoma was first reported in 2022 1).
Q
How rare is Godtfredsen syndrome?
A
The exact epidemiology is unknown. Only nine cases have been reported in the literature over the past 20 years, suggesting it is an extremely rare disease. However, underreporting due to lack of awareness has also been noted.
2. Main symptoms and clinical findings
Section titled “2. Main symptoms and clinical findings”Subjective Symptoms
Section titled “Subjective Symptoms”- Horizontal diplopia: The most common symptom. Binocular horizontal diplopia that worsens when looking toward the affected side.
- Abnormal head posture: To reduce diplopia, the patient may adopt a face turn toward the paralyzed side.
In a representative case, a 22-year-old man complained of gradually worsening horizontal binocular diplopia over one year, with the most severe symptoms on right gaze1).
Clinical Findings (Findings Confirmed by Physician Examination)
Section titled “Clinical Findings (Findings Confirmed by Physician Examination)”- Abducens nerve (CN VI) palsy: Impaired abduction due to lateral rectus muscle paresis. The affected eye shows esotropia in primary position. Diplopia is homonymous and increases in the direction of abduction of the paretic eye.
- Hypoglossal nerve (CN XII) palsy: When the tongue is protruded, it deviates toward the affected side. This occurs because innervation to the genioglossus muscle on the affected side is lost, and the action of the contralateral genioglossus becomes relatively stronger.
- Tongue atrophy: Chronic CN XII palsy causes unilateral atrophy on the affected side. This can be confirmed on T2-weighted MRI.
It is diagnostically important to distinguish between primary and secondary deviation using the cover test and cover-uncover test. On the Hess chart, the pattern shrinks in the direction of the affected eye’s abduction during primary deviation. In a representative case, the right eye was unable to abduct beyond the midline for 6 years1).
Q
Why does tongue deviation occur?
A
When the hypoglossal nerve (CN XII) is paralyzed, innervation to the genioglossus muscle on the affected side is lost. When the tongue is protruded forward, the action of the contralateral genioglossus becomes relatively stronger, causing the tongue to deviate toward the paralyzed (affected) side.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”Any lesion causing local compression of the VIth and XIIth cranial nerves can be a cause. When this syndrome is observed, neoplastic complications should be considered, and imaging should be performed promptly.
The number of reported cases by cause is shown below.
| Cause category | Number of reported cases |
|---|---|
| Nasopharyngeal tumor | 13 cases |
| Primary tumor | 9 cases |
| Metastatic disease | 8 cases |
| Subdural hematoma | 1 case |
A literature review of the past 20 years (9 cases) found that 55.5% (5/9 cases) were metastatic disease to the clivus, and 66.7% (6/9 cases) were neoplastic 1). Specific etiologies reported include clival chordoma, prostate metastasis, pancreatic metastasis, ovarian metastasis, leiomyoma metastasis, rectal adenocarcinoma metastasis, spontaneously resolving multiple cranial neuropathy, anaerobic mastoiditis, and posterior clival subdural hematoma 1).
The abducens nerve emerges from the pons, ascends along the sphenoid clivus, passes through the cavernous sinus and superior orbital fissure, and reaches the lateral rectus muscle. Due to its long course and anatomical proximity to the clivus, it is susceptible to compression by local lesions. Abducens nerve palsy is more frequently caused by tumors compared to oculomotor and trochlear nerve palsies.
Q
What should be suspected when Godfredsen syndrome is present?
A
This syndrome is most commonly caused by neoplastic disease. In the literature review, more than two-thirds were neoplastic, with metastatic disease accounting for the majority 1). When this syndrome is confirmed, it should be considered an oncological complication, and imaging (MRI) focusing on malignant tumors of the clivus should be performed immediately.
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”Imaging Diagnosis
Section titled “Imaging Diagnosis”Positron Emission Tomography (PET)
Indication: Useful for evaluating more active lesions, such as metastatic disease.
Role: Used adjunctively for primary tumor search and systemic evaluation.
CT
Indications: Can be used in urgent cases or for evaluating bone destruction.
Limitations: Soft tissue resolution is inferior to MRI.
In a representative case, MRI showed a lesion in the right spheno-occipital clivus with adjacent bone destruction 1). Postoperative MRI at 8 months confirmed residual tumor extension into the cavernous sinus 1). Head imaging should evaluate the brainstem, skull base, cavernous sinus, and orbital region; consultation with neurology or neurosurgery should be considered.
Differential Diagnosis
Section titled “Differential Diagnosis”The following should be considered in the differential diagnosis of this syndrome.
- Cavernous sinus syndrome: CN III, IV, V1, and VI are affected. It presents with painful ophthalmoplegia and requires differentiation from Tolosa-Hunt syndrome (idiopathic cavernous sinus granuloma). CN XII is usually not affected.
- Orbital apex syndrome: Presents with total ophthalmoplegia, sensory disturbance in the trigeminal nerve V1 distribution, and optic nerve involvement.
- Superior orbital fissure syndrome: Presents with total ophthalmoplegia and sensory disturbance in the trigeminal nerve V1 distribution, but without optic nerve involvement.
- Fisher syndrome: Presents with the triad of acute external ophthalmoplegia, ataxia, and areflexia. Anti-GQ1b antibody positivity rate is over 80%.
- Abducens nerve palsy as a false localizing sign: CN VI palsy due to increased intracranial pressure is often interpreted as a false localizing sign. However, in Godfredsen syndrome, it is important that it becomes a true localizing sign due to direct compression of the clival lesion1).
5. Standard Treatment
Section titled “5. Standard Treatment”Treatment of Primary Lesion
Section titled “Treatment of Primary Lesion”The first step in treatment is addressing the primary lesion. For neoplastic lesions, surgical resection, radiation therapy, and chemotherapy are options.
In a representative case, tumor debulking was performed via right supraorbital craniotomy, and for recurrence 5 years later, right orbitozygomatic craniotomy with tumor resection and 33 sessions of radiation therapy were performed, but CN VI and XII palsy did not improve over 6 years1).
Symptomatic Treatment for Diplopia and Strabismus
Section titled “Symptomatic Treatment for Diplopia and Strabismus”Alongside treatment of the primary lesion, management of diplopia due to abducens nerve palsy is performed.
- Eye patch: Covering the affected eye can immediately resolve binocular diplopia. This is the simplest symptomatic treatment.
- Prism glasses: Effective for improving subjective symptoms of diplopia in cases of mild strabismus.
- Botulinum toxin injection: Injecting the affected medial rectus muscle causes temporary paralysis and improves eye alignment.
- Extraocular muscle surgery: Considered when there is no improvement and subjective diplopia is severe.
In abducens nerve palsy due to reversible conditions such as peripheral circulatory disorders, spontaneous improvement is common. Conservative observation with vitamin and circulation-improving medications is typically performed for about 6 months.
The indication and surgical technique for extraocular muscle surgery depend on the degree of palsy.
| Degree of paralysis | Recommended procedure |
|---|---|
| Mild to moderate (eye crosses midline) | Lateral rectus resection + medial rectus recession |
| Severe (does not cross midline) | Vertical rectus muscle transposition (minimally invasive full-width transposition) |
The goal of surgery is to improve eye alignment in primary gaze and eliminate diplopia. Residual diplopia on lateral gaze is inevitable, and thorough preoperative explanation is necessary.
Q
What symptomatic treatments are available for diplopia due to abducens nerve palsy?
A
Symptomatic treatments for diplopia include occlusion of the affected eye with a patch, prescription of prism glasses, botulinum toxin-induced paralysis of the ipsilateral medial rectus muscle, and extraocular muscle surgery. Extraocular muscle surgery is indicated when there is no improvement and symptoms are severe, and the surgical technique is selected according to the degree of palsy (see section “Standard Treatments”).
6. Pathophysiology and Detailed Mechanism of Onset
Section titled “6. Pathophysiology and Detailed Mechanism of Onset”The anatomical basis of Godfredsen syndrome lies in the course of the abducens nerve and hypoglossal nerve near the clivus.
- Course of the abducens nerve (CN VI): It emerges from the pontomedullary sulcus and runs in the cisternal portion on the surface of the clivus. Then it ascends along the sphenoid clivus, passes through the cavernous sinus and superior orbital fissure, and reaches the lateral rectus muscle.
- Course of the hypoglossal nerve (CN XII): Exits from the preolivary sulcus and enters the hypoglossal canal.
Both run along the medial part of the clivus and are located medial to cranial nerves V, VII, VIII, IX, and X1). Therefore, midline clival lesions can affect only CN VI and CN XII while sparing other cranial nerves1). Abducens nerve palsy is often interpreted as a false localizing sign due to increased intracranial pressure, but in this syndrome, it results from direct compression by a clival lesion and represents a true localizing sign1).
This anatomical proximity explains why various clival lesions, such as nasopharyngeal tumors, clival tumors, and metastatic diseases, produce the same pattern of CN VI and XII palsy. Although clival chondrosarcomas often affect multiple adjacent cranial nerves, cases limited to CN VI and XII as this syndrome have been reported1).
7. Latest Research and Future Perspectives (Research-stage Reports)
Section titled “7. Latest Research and Future Perspectives (Research-stage Reports)”Wai et al. (2022) reported the first case of Godfredsen syndrome caused by clival chondrosarcoma 1). A 22-year-old male underwent two surgeries and 33 radiotherapy sessions, but CN VI and XII palsy did not improve over 6 years. Histopathologically, the initial surgery showed low-grade (Grade 1) chondrosarcoma (S100-positive, D2-40-positive), but at recurrence it progressed to Grade 2 with strong S100 positivity. The recurrent tumor compressed the right internal carotid artery.
This case is the 10th in a literature review over the past 20 years and the first report showing clival chondrosarcoma as a cause of this syndrome 1). Due to its rarity, large-scale studies are difficult, and future case accumulation and evaluation of treatment outcomes by cause are challenges.
8. References
Section titled “8. References”- Wai YZ, Chong YY, Dusa NM, Lai YP, Lim LT. Godtfredsen syndrome – recurrent clival chondrosarcoma with 6 years follow up: a case report and literature review. BMC Neurology. 2022;22:134.
- Yu DL, Yang TC, Chi HY. Contralateral Godtfredsen Syndrome Combined with Internal Carotid Artery Occlusion: One Case Challenge. Neurol India. 2024;72(5):1105-1106. PMID: 39428795.
- Amalnath SD. Teaching NeuroImages: Godtfredsen syndrome due to retroclival subdural hematoma. Neurology. 2018;91(10):e999-e1000. PMID: 30177537.