Jugular Foramen Syndrome

Etiology

The following etiologies of jugular foramen syndrome have been described in the literature:

• Congenital 
  • Primary cholesteatoma [2]
• Vascular 
  • Asymmetry and enlargement of the jugular foramen
  • High or protruding jugular bulb
  • Internal jugular vein thrombosis [3]
  • Parapharyngeal internal carotid or vertebral artery aneurysms causing mass effect on the jugular foramen [4]
  • Jugular diverticulum
• Inflammatory
  • Giant cell arteritis
  • Immunoglobulin G4-related disease of the skull base
  • Wegener granulomatosis 
• Infectious
  • Varicella-Zoster virus (VZV) infection (recent literature refers to lower-cranial-nerve VZV palsy as a Ramsay Hunt type II variant rather than mechanical compression) [5][6]
  • Herpes virus infection [7]
  • Parapharyngeal abscess [8]
  • Acute otitis media: indirectly causing thrombosis or vascular reaction of the jugular bulb [9]
• Neoplastic
  • Benign
    • Paraganglioma [10]
    • Lower cranial nerve schwannoma
    • Meningioma [11]
    • Aneurysmal bone cyst [12]
    • Neurofibroma
    • Temporal bone chordoma [13]
  • Malignant
    • Metastasis [14]
    • Squamous cell carcinoma [15]
    • Multiple myeloma
    • Chondrosarcoma
    • Lymphoma
    • Mucoepidermoid carcinoma of the parotid gland [16] 
    • Nasopharyngeal adenocarcinoma [17] 
    • Metastatic conjunctival malignant melanoma [14]
• Traumatic
  • Penetrating trauma
  • Fractures involving the posterior skull base [18][19]

Epidemiology

The exact incidence of jugular foramen syndrome is challenging to estimate due to its rarity. Metastatic disease is the most common cause of jugular foramen syndrome, but it is often underdiagnosed.[20] Skull base metastasis is typically regarded as a manifestation of systemic malignancy. The most common primary cancers that are likely to metastasize to the jugular foramen are those of the breast, lung, kidney, and prostate.[21] Paragangliomas are the most frequent primary lesions, followed by schwannomas and meningiomas.[22] Recent literature suggests that primary lesions are more common than metastases.[23] This discrepancy arises because metastatic disease is more common in oncology cohorts, whereas primary tumors (especially paragangliomas and schwannomas) predominate in skull-base referral centers.

Pathophysiology

Cranial nerve IX is primarily sensory, receiving general visceral and special sensory input from the tonsils, larynx, middle ear, posterior one-third of the tongue, and carotid bodies. This nerve has a small general motor efferent to the stylopharyngeus muscle, which aids in elevating the larynx and pharynx. Cranial nerve X has a wide range of functions and controls heart rate, peristalsis, speech phonation, elevation of the palate, respiration, and autonomic visceral reflexes. Cranial nerve XI is a pure motor efferent supplying the ipsilateral sternocleidomastoid and trapezius muscles. Derangement in the functions of these nerves occurs when they become compressed in jugular foramen syndrome. The proximity of the jugular bulb and sigmoid sinus explains why venous thrombosis or jugular bulb pathology can mimic mass-related jugular foramen syndrome.

Although most cases of jugular foramen syndrome result from compression of structures within the jugular foramen, other mechanisms are implicated in viral infections. These factors can lead to the spread of the virus into the lower cranial nerves, which are as follows:

• Interconnections between upper and lower cranial nerves (spinal accessory nerve plexus)
• Simultaneous reactivation of VZV in multiple ganglia and inter-connecting nerves
• Viral spread through a common blood supply [24]

History and Physical

The most common presenting symptom of jugular foramen syndrome is hoarseness of voice or dysphagia. Pain is also a common associated symptom (persistent unilateral periauricular pain and headache).

Clinical features depend on the structures affected by jugular foramen syndrome:

• Vagus nerve
  • Vagal compression initially causes paralysis of the laryngeal muscles, resulting in hoarseness and a nasal timbre. If the nerve is further compressed, it results in unilateral paralysis of the soft palate and deviation of the uvula toward the normal side.
• Glossopharyngeal nerve
  • Loss of sensation to the posterior ipsilateral aspect of the tongue
  • Dysphagia due to reduced pharyngeal constriction
  • Reduced secretions from the ipsilateral parotid gland
  • Loss of the ipsilateral gag reflex 
• Accessory nerve
  • This manifests as drooping of the shoulder, difficulty abducting the ipsilateral arm, and contralateral rotation of the head due to weakness of the sternocleidomastoid and trapezius muscles.
• Obstruction of the traversing venous sinuses and veins
  • Headache and papilledema due to intracranial venous congestion leading to cerebral edema and raised intracranial pressure [25]

The clinician should specifically note the following findings in the case of jugular foramen syndrome:

• Nasal regurgitation of liquids and aspiration are key early clinical clues of vagal dysfunction.
• Palatal and gag reflexes
• Drooping of the shoulder
• Unilateral vocal cord palsy: the most reliable sign of vagal nerve involvement
• Power of the sternocleidomastoid and trapezius muscles
• Fasciculation or winging of the scapula
• Other cranial nerves and brainstem involvement
• Cerebellar signs
• Examination of the mouth and external auditory canal for any vesicular rash or mass
• Ipsilateral palatal droop with loss of cough reflex → aspiration risk
• “Wet pillow sign” from nocturnal salivary pooling → subtle but highly specific for cranial nerve IX/X palsy

Some unique presentations include:

• Glossopharyngeal neuralgia syncope syndrome
• Pulsatile tinnitus [26][22]

Evaluation

The following investigations are aimed at diagnosing the etiology of jugular foramen syndrome:

• Magnetic resonance imaging (MRI) of the head with contrast
  • This is the investigation of choice when a patient presents with the clinical diagnosis of jugular foramen syndrome.
  • Magnetic resonance angiography and venography may provide additional information on tumor vascularization and local venous anatomy.
  • High-resolution 3-dimensional T2 sequences (constructive interference steady-state/fast imaging employing steady-state acquisition/sampling perfection with application-optimized contrasts using different flip-angle evolution) provide the best visualization of the lower cranial nerves within the jugular foramen.
• Digital subtraction angiography 
  • This is mandatory in patients with highly vascular lesions. Such cases may benefit from preoperative embolization.
• Computed tomography (CT) of the skull base with angiogram
  • This imaging will assess the extent of bony erosion and vascular invasion or infiltration, and is necessary to plan surgery.
• 18F-Fludeoxyglucose Positron Emission Tomography (FDG-PET) CT/positron emission tomography (PET)-MRI
  • This detects skull base metastases, recurrent paraganglioma, and multifocal schwannomas/neurofibromatosis.
  • Ga-68 DOTATATE PET and metaiodobenzylguanidine scans are essential for staging and guiding treatment of paragangliomas. 
• Indirect laryngoscopy
  • This modality assesses the extent of vocal cord palsy, which may indicate the need for postoperative tracheostomy. 
  • A fiberoptic speech/voice evaluation (stroboscopy) is recommended to quantify glottic insufficiency and aspiration risk.
• Laboratory tests
  • Total blood count, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, extractable-nuclear antigen antibodies, antineutrophil-cytoplasmatic antibodies
• Serum-protein electrophoresis
• VZV and herpes simplex virus
  • Immunoglobulins M and G
• Cerebrospinal fluid analysis
  • Checks for any hyperproteinorrachia, pleocytosis, or oligoclonal bands
  • Polymerase chain reaction to detect VZV
• Nerve conduction studies and electromyography of the sternocleidomastoid and trapezius muscles are performed if there is doubt regarding the diagnosis.
• Genetic testing for paragangliomas
  • SDHB mutation → malignant potential
  • SDHD mutation → multiple/bilateral tumors

The characteristic finding of glomus jugulare tumors is a ‘‘moth-eaten’’ pattern of destruction of the temporal bone (on CT), a ‘‘salt-and-pepper’’ pattern on long repetition time–long echo time images (on MRI), and a ‘‘dropout’’ phenomenon in time-intensity curves on contrast MRA.

• Paragangliomas displace nerves anteromedially.
• Schwannomas displace nerves laterally/posteriorly.

Treatment / Management

Treatment of jugular foramen syndrome depends on the etiology:

• Surgery
  • Safe resection is the treatment of choice and may be curative in schwannomas, meningiomas, noninfiltrative paragangliomas, and other benign tumors. However, stereotactic radiosurgery is preferred for paragangliomas less than 3.5 cm in size, with surgery reserved for young patients, rapidly growing tumors, and if there is evidence of brainstem compression. Subtotal removal may be necessary to preserve the integrity of vascular structures and the brainstem. An interprofessional approach is vital in the radical excision of large paragangliomas with intracranial extension.
  • Shunt procedure, venous sinus angioplasty, and stenting, or optic nerve sheath fenestration: these are for intracranial hypertension due to venous sinus stenosis.
• Radiotherapy
  • Stereotactic radiosurgery (eg, Gamma Knife, linear accelerator) is a valuable and safe treatment option for paragangliomas at this location when the diameter is less than approximately 3.5 cm (or <20 mL volume), thereby reducing morbidity.[27]
  • Fractionated stereotactic radiotherapy combines the precision of stereotaxy with dose fractionation for large tumors exceeding 3 to 4 cm in diameter that are not suitable for radiosurgery.
  • Postoperative radiotherapy is sometimes used to control the residual disease following subtotal resection.
• Embolization
  • Preoperative embolization may be helpful for extensively vascular tumors, such as paragangliomas, to reduce blood loss during surgery.
• Anticoagulants
  • Low molecular weight heparin or direct oral anticoagulants
    • Used for jugular vein thrombosis unless contraindicated by intracranial hemorrhage [3]
• Acyclovir and steroids (for viral infections)
(B2)

Differential Diagnosis

Clinical variants of jugular foramen syndrome include:

• Jackson syndrome
  • Dysfunction of IX, X, and XI cranial nerves from a medullary (brainstem) lesion
• Collet–Sicard syndrome
  • Dysfunction of cranial nerves IX, X, XI, and XII
• Villaret syndrome
  • Dysfunction of cranial nerves IX, X, XI, and XII, with sympathetics (causing an ipsilateral Horner syndrome)
• Tapia syndrome
  • Dysfunction of X and XII nerves
• Avellis syndrome
  • Vocal cord and palatal paralysis with contralateral dissociative hemianesthesia (loss of pain and temperature sensations, but with preservation of touch)
• Schmidt syndrome
  • A lesion of the vagal and both the bulbar and spinal accessory nuclei

Prognosis

Prognosis depends on the specific pattern of compression at the jugular foramen. Compression arising from a benign condition may allow curative resection. Survival in patients with metastatic compression depends on the status of the primary malignancy and the extent of additional systemic metastases.[28] Infectious and vascular causes often respond well to targeted therapy. Posttraumatic lower cranial nerve palsy frequently leads to incomplete recovery in most affected patients.[18]

Complications

The main complications that are likely to occur in patients with jugular foramen syndrome, especially in the postoperative period, include:

• Vocal cord paralysis
• Aspiration pneumonia
  • Prevented by delayed extubation, tracheostomy in selected cases, and early rehabilitation
• Exposure keratopathy, if the facial nerve is involved
  • May need tarsorrhaphy
• Cerebrospinal fluid leakage

Modern perioperative algorithm (skull base centers) to reduce aspiration-related mortality (the leading cause of death after surgery):

• Laryngoscopy and fibreoptic endoscopic evaluation of swallowing preoperatively
• Temporary nasogastric feeding rather than early percutaneous endoscopic gastrostomy 
• Early swallow therapy and vocal cord injection