Vestibular Schwannomatosis

Vestibular schwannomatosis is a distinct genetic tumour predisposition syndrome characterised by multiple, usually bilateral, schwannomas of the vestibular nerves along with other cranial, spinal and peripheral nerve tumours. It is also called schwannomatosis with vestibular involvement. The term NF2-related schwannomatosis applies to the disease with bilateral vestibular schwannomas.

The commonest form is NF2-related schwannomatosis, an autosomal dominant disorder caused by mutations of the NF2 gene on chromosome 22q12 (encoding merlin, a tumour suppressor). The incidence is 1 in 25,000 to 40,000. About 50 percent of cases arise from de novo mutations, and many are mosaic.

The hallmark is bilateral vestibular schwannomas (over 90 percent by age 30), with onset in the late teens and twenties (mean 18 to 24 years). Earlier onset is associated with severe disease (nonsense and frameshift mutations).

Associated tumours:

• spinal schwannomas
• meningiomas (cranial and spinal, in about 50 to 75 percent)
• ependymomas (spinal, 20 to 50 percent)
• peripheral schwannomas, and cutaneous schwannomas

Non-tumour features include juvenile posterior subcapsular lens opacities or cataracts (60 to 80 percent), retinal hamartoma, epiretinal membranes, and mononeuropathy.

Other forms are LZTR1-related and SMARCB1-related schwannomatosis. These are non-vestibular, and vestibular schwannomas are rare. Unilateral vestibular schwannoma may occur in LZTR1-related disease, the "vestibular schwannomatosis" subtype.

Complications: bilateral deafness, brainstem compression, hydrocephalus, cranial neuropathies (facial, trigeminal, lower cranial nerves), myelopathy, and premature death (median survival about 62 years, reduced in severe phenotypes).

• Progressive unilateral or bilateral sensorineural hearing loss (the commonest presentation in young adults), tinnitus, and imbalance; poor speech discrimination out of proportion to threshold.
• Children present with cutaneous schwannomas, cataract, mononeuropathy, or spinal tumour (weakness, scoliosis), before auditory symptoms.
• Facial numbness or weakness, diplopia, dysphagia, hoarseness with other cranial nerve schwannomas, and headache or hydrocephalus with large tumours.
• Spinal cord compression (myelopathy), radiculopathy and pain from spinal tumours; peripheral nerve masses.
• Skin plaque like or subcutaneous nodular lesions (schwannomas), and café-au-lait macules (fewer than in NF1).
• Visual impairment from cataracts, optic nerve sheath meningioma.

• Diagnostic criteria for NF2-related schwannomatosis, any one of:
  • bilateral vestibular schwannomas
  • a first degree relative with NF2 plus a unilateral vestibular schwannoma (before age 70) or any two of meningioma, glioma, schwannoma, juvenile cataract
  • unilateral vestibular schwannoma plus two other NF2-related tumours (meningioma, schwannoma, ependymoma, or cataract)
  • multiple meningiomas plus unilateral vestibular schwannoma or two other tumours
  • a pathogenic NF2 variant in blood or in two anatomically distinct tumours (for mosaic disease)
• MRI with gadolinium thin section sequences of the internal auditory canals and brain: bilateral enhancing masses in the cerebellopontine angles and internal acoustic canals; whole spine MRI for spinal tumours; MRI surveillance of other cranial nerve lesions.
• Audiometry, speech discrimination and auditory brainstem response; vestibular function tests.
• Ophthalmological examination (cataracts, retinal lesions), and skin examination.
• Genetic testing: NF2 sequencing and deletion or duplication analysis in blood (with tumour testing if negative, for mosaicism), and LZTR1 and SMARCB1 testing in schwannomatosis cases without NF2 variants.

Management is complex and in a multidisciplinary specialist centre, aimed at preserving function (hearing, facial nerve, brainstem) and quality of life.

• Surveillance: MRI of the brain and internal auditory canals every 6 to 12 months (yearly if stable), whole spine MRI every 2 years, ophthalmological assessment annually, and audiometry yearly; more frequent in children and in rapidly growing tumours.
• Vestibular schwannoma treatment:
  • Observation for small, asymptomatic tumours with serviceable hearing (Class A or B), since growth is variable.
  • Bevacizumab 5 to 7.5 mg/kg intravenously every 2 to 3 weeks (up to 10 mg/kg every 2 weeks) for rapidly growing tumours or threatened hearing. It causes tumour shrinkage in about 40 percent and hearing improvement in about 30 to 50 percent. Give for 6 months at least, then continuation, with a possible drug holiday.
  • Bevacizumab adverse effects: hypertension, proteinuria, bleeding, impaired wound healing, thromboembolism, and amenorrhoea. Monitor blood pressure and urine protein. Low dose regimens are used.
  • Microsurgical resection (translabyrinthine, retrosigmoid or middle fossa approaches) for tumours causing brainstem compression or large size (above 2.5 to 3 cm), aiming for facial nerve preservation, and hearing preservation in smaller tumours.
  • Timing is planned to preserve hearing in the better ear, with the larger tumour removed first or the side with worse hearing.
  • Stereotactic radiosurgery (gamma knife, 12 to 13 Gy to the margin) for tumours below 3 cm, with growth control in 70 to 90 percent; risk of hearing loss and facial neuropathy; the potential for malignant transformation is considered in NF2.
  • Partial resection with decompression for large tumours, with sequential treatment.
• Hearing rehabilitation: hearing aids, cochlear implantation (when the cochlear nerve is preserved), and auditory brainstem implant. The auditory brainstem implant is placed at the time of tumour removal or later, for bilateral deafness, with environmental sound awareness and speech aid in about 20 to 40 percent.
• Sign language and lip reading training should begin early. Offer vestibular rehabilitation.
• Other tumours: meningiomas (observation, surgery or radiosurgery if symptomatic), spinal ependymomas and schwannomas (surgical resection for neurological deficit, with bevacizumab as a medical option), and peripheral nerve tumours (resection if painful). Brigatinib and other targeted agents are under investigation.
• Ophthalmological care: cataract extraction, amblyopia treatment, and treatment of retinal conditions.
• Genetic counselling: autosomal dominant inheritance (50 percent risk to offspring, with penetrance of nearly 100 percent by age 60), reproductive options, and screening of at risk relatives by genetic testing or MRI from age 10 to 12 years.
• Psychosocial support, pain management, and multidisciplinary planning.