Skull Base Syndromes

Skull base syndromes are patterned combinations of cranial neuropathies caused by lesions of the skull base or adjacent structures. Each is localised by the foramina and compartments involved, and the clinical value lies in identifying the site and directing imaging and urgent treatment.

Key anatomy

• Anterior fossa: cribriform plate (CN I).
• Middle fossa: optic canal (CN II, ophthalmic artery), superior orbital fissure (CN III, IV, V1, VI, ophthalmic veins), foramen rotundum (V2), foramen ovale (V3), foramen spinosum (middle meningeal artery), cavernous sinus (III, IV, V1, V2, VI, ICA, sympathetic plexus), and petrous apex (Meckel cave, abducens within Dorello canal).
• Posterior fossa: internal acoustic meatus (VII, VIII), jugular foramen (IX, X, XI, internal jugular vein), hypoglossal canal (XII), and foramen magnum (medulla, vertebral arteries, spinal accessory roots).

Causes

• Neoplastic: skull base metastases (breast, prostate, lung, myeloma), nasopharyngeal carcinoma, lymphoma, meningioma, schwannoma, chordoma, chondrosarcoma, paraganglioma (glomus jugulare), pituitary macroadenoma, craniopharyngioma, perineural spread of head and neck cancers, and leptomeningeal disease.
• Infective: skull base osteomyelitis (malignant otitis externa), invasive fungal sinusitis (mucormycosis and aspergillosis), petrous apicitis, cavernous sinus thrombosis, and tuberculosis.
• Vascular: intracavernous carotid aneurysm, carotid-cavernous fistula, cavernous sinus thrombosis, and pituitary apoplexy.
• Inflammatory: Tolosa-Hunt syndrome, sarcoidosis, IgG4-related disease, granulomatosis with polyangiitis, giant cell arteritis, and hypertrophic pachymeningitis.
• Traumatic and bony: basilar skull fractures, fibrous dysplasia, Paget disease, and craniovertebral junction abnormalities.

Named syndromes

• Foster Kennedy: ipsilateral optic atrophy with contralateral papilloedema and anosmia (olfactory groove or sphenoid wing mass).
• Superior orbital fissure syndrome: CN III, IV, V1, VI with ophthalmoplegia and forehead sensory loss. Adding CN II gives orbital apex syndrome.
• Cavernous sinus syndrome: CN III, IV, VI, V1, often V2, and oculosympathetic fibres.
• Gradenigo syndrome: petrous apicitis with abducens palsy, ipsilateral facial pain and ear discharge.
• Raeder paratrigeminal neuralgia: V1 pain with an oculosympathetic palsy and preserved facial sweating (middle fossa lesion).
• Jacod (petrosphenoidal) syndrome: CN II to VI, usually from a nasopharyngeal or middle fossa mass.
• Cerebellopontine angle syndrome: CN V, VII, VIII with ataxia.
• Jugular foramen syndromes: Vernet (IX, X, XI), Collet-Sicard (IX to XII), Villaret (IX to XII with Horner syndrome), Tapia (X and XII), Schmidt (X, XI), and Jackson (X, XI, XII).
• Occipital condyle syndrome: unilateral occipital pain, neck stiffness, and hypoglossal palsy, typically from condylar metastasis.
• Garcin syndrome: progressive unilateral involvement of many cranial nerves without brainstem or raised ICP signs, characteristic of nasopharyngeal carcinoma.

Clinical clues are specific to the compartment

• Cavernous sinus: painful ophthalmoplegia, ptosis, dilated or normal pupil, V1 and V2 sensory loss, chemosis, proptosis, and venous congestion. In septic thrombosis there is fever, rapid bilateral spread, and a facial or sinus source.
• Orbital apex: similar ophthalmoplegia with visual loss and a relative afferent pupillary defect.
• Petrous apex: deep facial or retro-orbital pain, diplopia from abducens palsy, and otitis media.
• Cerebellopontine angle: progressive unilateral sensorineural hearing loss, tinnitus, facial numbness, facial weakness and gait unsteadiness.
• Jugular foramen: dysphagia, hoarseness, palatal deviation, loss of taste in the posterior third of the tongue, trapezius and sternocleidomastoid weakness, with additional tongue deviation in Collet-Sicard syndrome.
• Occipital condyle: severe occipital pain worsened by neck flexion, followed by tongue atrophy and deviation.
• Nasopharyngeal carcinoma: unilateral hearing loss from middle ear effusion, nasal obstruction, epistaxis, neck mass, and multiple cranial neuropathies (V, VI most common).

Red flags requiring urgent evaluation

• Diabetes, ketoacidosis, neutropenia or other immunosuppression with sinus symptoms, facial pain, black eschar, or visual loss (mucormycosis).
• Fever with periorbital oedema and rapidly progressive ophthalmoplegia (septic cavernous sinus thrombosis).
• Pulsatile proptosis and an orbital bruit (carotid-cavernous fistula).
• Sudden headache, visual loss and ophthalmoplegia (pituitary apoplexy).
• A known cancer with new cranial neuropathies or occipital pain.
• Otalgia with otorrhoea in an elderly diabetic patient (skull base osteomyelitis).

Causes of isolated painful ophthalmoplegia that should be separated include diabetic cranial neuropathy, posterior communicating artery aneurysm, orbital pseudotumour, and ophthalmoplegic migraine.

Define the compartment by careful cranial nerve examination, including visual acuity, fields, pupils, eye movements, corneal sensation, facial sensation and strength, hearing, palate, tongue and trapezius.

Imaging

• MRI of the brain and skull base with gadolinium, including fat-suppressed thin section sequences through the orbits, cavernous sinus, cerebellopontine angle and nasopharynx. It demonstrates tumours, perineural spread, thrombosis, marrow replacement and inflammation.
• High resolution CT of the skull base shows bone erosion, hyperostosis, foraminal widening, fractures and sinus disease.
• CT or MR venography for sinus thrombosis. CT angiography, MR angiography or catheter angiography for aneurysm and carotid-cavernous fistula.
• PET CT for staging and primary tumour search.

Laboratory evaluation

• CBC, ESR, CRP, glucose, HbA1c, renal function and blood cultures.
• ACE, ANCA, ANA, IgG4, treponemal serology, HIV, Lyme serology and interferon gamma release assay.
• Beta-D-glucan, galactomannan and fungal culture where invasive fungal infection is a concern.
• Pituitary hormone profile for sellar masses.
• Plasma or urinary metanephrines before surgery for paragangliomas.
• EBV DNA for suspected nasopharyngeal carcinoma.

Procedures

• Nasopharyngoscopy and endoscopic biopsy for nasopharyngeal masses and sinus disease. Urgent nasal endoscopy and debridement with histology for suspected mucormycosis.
• Audiometry and ophthalmological assessment with visual fields.
• Lumbar puncture after imaging for leptomeningeal disease (cytology and flow cytometry) and infection.
• Tissue biopsy for diagnosis of masses and for inflammatory conditions that do not respond to treatment.

Treat the underlying cause urgently and protect vision.

Septic cavernous sinus thrombosis

• Ceftriaxone 2 g IV every 12 hours, with vancomycin 15 to 20 mg/kg IV every 8 to 12 hours and metronidazole 500 mg IV every 8 hours, for 3 to 4 weeks (longer with intracranial extension).
• Drain the source (sinus, dental or facial infection). Therapeutic anticoagulation with enoxaparin 1 mg/kg twice daily is commonly used.

Invasive fungal sinusitis (mucormycosis)

• Liposomal amphotericin B 5 to 10 mg/kg IV daily, with urgent and repeated surgical debridement.
• Correct hyperglycaemia and acidosis, reverse neutropenia, and stop immunosuppression where possible.
• Step-down therapy after response with isavuconazole (200 mg isavuconazole equivalent, 372 mg isavuconazonium sulfate, every 8 hours for 6 doses, then 200 mg daily) or posaconazole 300 mg twice daily on day 1 then 300 mg daily. Duration is typically months.

Skull base osteomyelitis (malignant otitis externa)

• Antipseudomonal therapy for 6 to 12 weeks: ciprofloxacin 750 mg orally twice daily, or ceftazidime 2 g IV every 8 hours or piperacillin-tazobactam 4.5 g IV every 6 hours for severe or resistant cases.
• Strict glycaemic control, local debridement, and surgery for sequestra or abscess.

Petrous apicitis (Gradenigo syndrome)

• Ceftriaxone 2 g IV every 12 hours with metronidazole 500 mg IV every 8 hours (add vancomycin for resistant organisms), and mastoidectomy or petrous apex drainage.

Tolosa-Hunt syndrome and other inflammatory causes

• Tolosa-Hunt syndrome is a diagnosis of exclusion. Prednisolone 60 to 80 mg daily for 3 to 14 days with a taper over 4 to 8 weeks produces pain relief within 72 hours. Biopsy is needed if there is no response.
• Sarcoidosis, IgG4-related disease and vasculitis: prednisolone 0.5 to 1 mg/kg daily plus steroid-sparing agents (methotrexate, rituximab, azathioprine) according to the disease.

Vascular lesions

• Carotid-cavernous fistula: endovascular transvenous or transarterial embolisation with coils or liquid embolics.
• Intracavernous carotid aneurysm: flow diverter stent or coil occlusion after balloon test occlusion.
• Pituitary apoplexy: hydrocortisone 100 mg IV then 50 mg every 6 hours, fluid and electrolyte correction, and urgent transsphenoidal decompression for visual loss or ophthalmoplegia.

Neoplastic causes

• Nasopharyngeal carcinoma: IMRT to 70 Gy in 33 to 35 fractions with concurrent cisplatin 100 mg/m2 every 3 weeks for 3 cycles (or 40 mg/m2 weekly), with induction chemotherapy for advanced disease.
• Skull base metastases: palliative radiotherapy (30 Gy in 10 fractions or stereotactic radiosurgery) with dexamethasone 4 mg every 6 hours for pain and oedema, and systemic therapy for the primary tumour.
• Meningioma, schwannoma, chordoma, chondrosarcoma: endoscopic endonasal or open skull base surgery. Proton beam radiotherapy (about 74 Gy RBE) after chordoma resection.
• Glomus jugulare tumours: preoperative embolisation, resection or stereotactic radiosurgery. Alpha-blockade with phenoxybenzamine 10 mg twice daily, titrated, before surgery for secreting tumours.
• Leptomeningeal metastases: intrathecal methotrexate 12 mg or radiotherapy to symptomatic sites.

Trauma

• Basilar skull fracture with CSF leak: head elevation, avoidance of nose-blowing, and surgical repair if persistent beyond 1 to 2 weeks. Prophylactic antibiotics are not recommended.
• Traumatic optic neuropathy and cranial nerve palsies are managed conservatively, with decompression for selected cases.

Symptomatic and supportive care

• Eye protection for exposure keratopathy (lubricating drops every 1 to 2 hours, ointment at night, tarsorrhaphy), prisms or patching for diplopia, and strabismus surgery after 6 to 12 months of stable deficit.
• Dysphagia assessment, swallow therapy and enteral feeding, vocal fold medialisation (injection or thyroplasty) for vagal palsy, and tracheostomy for airway compromise.
• Neuropathic facial pain with carbamazepine 200 mg twice daily titrated, gabapentin or pregabalin.
• Audiological rehabilitation (hearing aids, cochlear implantation where appropriate) for hearing loss.
• Multidisciplinary skull base team review, regular imaging follow-up, and rehabilitation.