Overview
Definition:
Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disorder characterized by the development of tumors of the nervous system, primarily bilateral vestibular schwannomas, meningiomas, ependymomas, and gliomas
Vestibular schwannomas, arising from the Schwann cells of the vestibular nerve, are pathognomonic for NF2 and are a major cause of morbidity and mortality due to hearing loss and neurological deficits.
Epidemiology:
NF2 has an estimated incidence of 1 in 25,000 to 50,000 live births
It affects males and females equally
While adult onset is common, pediatric onset occurs in approximately 10-20% of cases, often with a more aggressive tumor burden and earlier onset of symptoms
The underlying cause is a mutation in the NF2 gene on chromosome 22q12, which encodes for the tumor suppressor protein merlin.
Clinical Significance:
Early detection and vigilant surveillance of vestibular schwannomas in pediatric patients with NF2 are crucial for preserving hearing, preventing cranial nerve palsies, and managing tumor growth effectively
Proactive management can significantly improve quality of life and long-term neurological outcomes, making this a high-yield topic for pediatric residents and those preparing for DNB and NEET SS examinations.
Clinical Presentation
Symptoms:
Progressive sensorineural hearing loss in one or both ears
Tinnitus, often unilateral
Vertigo or dysequilibrium leading to gait instability
Facial weakness or numbness due to compression of cranial nerves VII and V
Headaches and cranial nerve palsies beyond CN VIII
Ocular findings such as posterior subcapsular cataracts or epiretinal membranes are also common.
Signs:
Audiometry demonstrating asymmetric sensorineural hearing loss
Impaired vestibular function on caloric testing or videonystagmography
Cranial nerve deficits, particularly facial nerve weakness (CN VII) and sensory loss (CN V)
Signs of increased intracranial pressure if tumors are large or involve other cranial compartments
Ophthalmic examination revealing characteristic cataracts or other lesions.
Diagnostic Criteria:
The revised diagnostic criteria for NF2 often involve the presence of bilateral vestibular schwannomas or a unilateral vestibular schwannoma with onset before age 30 and at least one other NF2-associated tumor (meningioma, glioma, ependymoma, schwannoma of other cranial/spinal nerves)
Alternatively, a family history of NF2 and a unilateral vestibular schwannoma or any two of the other NF2-associated tumors suffice
Genetic testing for NF2 gene mutations can confirm the diagnosis.
Diagnostic Approach
History Taking:
Detailed family history for NF2 or related tumors
Inquire about progressive hearing loss, tinnitus, balance issues, headaches, and neurological symptoms
Age of onset of symptoms is critical
Document any prior neurosurgical procedures or radiation therapy
Screen for ocular symptoms like blurred vision or visual disturbances.
Physical Examination:
Comprehensive neurological examination focusing on cranial nerves, especially VIII, VII, and V
Assess hearing with gross tests (e.g., Weber, Rinne) and assess balance and gait
Thorough fundoscopy to detect optic nerve involvement and perform slit-lamp examination for cataracts and epiretinal membranes.
Investigations:
Auditory Brainstem Response (ABR) testing to objectively assess hearing pathways
Pure tone audiometry for detailed hearing assessment
Magnetic Resonance Imaging (MRI) of the brain and internal auditory canals with gadolinium contrast is the gold standard for detecting vestibular schwannomas and other intracranial tumors, with screening recommended annually or biennially in at-risk children
Genetic testing for NF2 mutations is highly recommended for definitive diagnosis
Annual ophthalmic examinations, including slit-lamp microscopy.
Differential Diagnosis:
Sporadic vestibular schwannomas
Other causes of hearing loss and vertigo (e.g., Meniere's disease, labyrinthitis)
Other genetic syndromes with predisposition to tumors (e.g., schwannomatosis, though NF2 is distinct)
Brain tumors unrelated to NF2.
Surveillance Protocol Pediatrics
Imaging Frequency:
Annual MRI of the brain and internal auditory canals with gadolinium contrast is recommended for all children diagnosed with NF2, starting from diagnosis or around age 10-12 if clinical suspicion is high but diagnosis is pending genetic confirmation
Frequency may increase to biannual if new lesions are detected or rapid growth is observed
MRI can detect tumors as small as 2-3 mm.
Audiological Monitoring:
Regular audiometric evaluations are critical, typically every 6-12 months, depending on the presence and size of vestibular schwannomas
This includes pure tone audiometry and speech discrimination testing
Auditory Brainstem Response (ABR) can provide objective measures of hearing function, especially in younger children who cannot reliably participate in behavioral audiometry.
Ophthalmic Monitoring:
Annual ophthalmological examinations, including slit-lamp biomicroscopy for posterior subcapsular cataracts and epiretinal membranes, and fundus examination
Early detection of ocular manifestations is important for management.
Neurological Assessment:
Periodic neurological examinations to assess for symptoms related to other cranial nerve involvement or spinal tumors
This should be integrated into routine follow-up visits, with more frequent assessments if symptoms arise.
Genetic Counseling:
Essential for affected individuals and their families to understand the inheritance pattern, risks, and implications of genetic testing and surveillance
Cascade screening of at-risk family members should be offered.
Management Of Vestibular Schwannomas
Observation And Timing Of Intervention:
Small, asymptomatic vestibular schwannomas may be managed with observation and continued surveillance
Intervention is typically considered when tumors cause significant hearing loss, vestibular symptoms, cranial nerve deficits, or show rapid growth
The decision involves balancing the risks of surgery with the risks of tumor progression.
Surgical Management:
Surgical resection is the primary treatment for symptomatic or growing vestibular schwannomas
Options include retrosigmoid approach, translabyrinthine approach, or middle fossa craniotomy, chosen based on tumor size, location, and the patient's hearing status
The goal is tumor debulking or complete removal while preserving neurological function, particularly hearing and facial nerve integrity.
Radiotherapy:
Stereotactic radiosurgery (e.g., gamma knife) or fractionated radiotherapy may be considered for carefully selected patients with residual tumors after surgery, unresectable tumors, or in cases where surgery is deemed too high-risk
It aims to control tumor growth rather than remove it.
Medical Management:
Currently, there is no specific medical therapy approved for shrinking vestibular schwannomas
However, bevacizumab, an anti-VEGF antibody, has shown promise in reducing tumor volume and improving neurological function in some NF2 patients, and is an area of ongoing research and potential off-label use, particularly for symptomatic meningiomas and ependymomas.
Complications
Hearing Loss:
Progressive and often irreversible sensorineural hearing loss is the most common complication
Bilateral involvement leads to profound deafness
Preservation of hearing is a major goal of early intervention.
Cranial Nerve Deficits:
Facial nerve paralysis or weakness (CN VII), trigeminal nerve dysfunction (CN V) causing facial numbness or pain, and dysphagia (CN IX, X) can occur due to tumor compression or surgical intervention.
Neurological Deficit:
Large tumors can lead to hydrocephalus, increased intracranial pressure, brainstem compression, and other neurological impairments
Spinal tumors can cause myelopathy and neurological deficits.
Postoperative Complications:
CSF leak, meningitis, cranial nerve injury, hemiparesis, and surgical site infection are potential risks associated with surgical intervention.
Prognosis
Factors Affecting Prognosis:
The prognosis in NF2 is variable and depends on the extent of tumor burden, rate of tumor growth, age of onset, and effectiveness of management
Early diagnosis and consistent surveillance are key to improving outcomes.
Outcomes:
With current management strategies, many individuals with NF2 can achieve long periods of stable disease, though hearing loss and neurological issues remain significant challenges
Life expectancy has improved with advances in imaging and surgical techniques.
Long Term Follow Up:
Lifelong, multidisciplinary follow-up is essential
This includes regular clinical examinations, audiological assessments, ophthalmic evaluations, and serial MRIs
Management requires a team approach involving neurologists, neurosurgeons, audiologists, ophthalmologists, geneticists, and oncologists.
Key Points
Exam Focus:
NF2 is characterized by bilateral vestibular schwannomas
Surveillance is critical in pediatrics
Annual MRI with contrast and regular audiometry are cornerstones of management
Differentiate NF2 from NF1
Consider bevacizumab for progressive disease.
Clinical Pearls:
Always suspect NF2 in a child with unilateral hearing loss or tinnitus that progresses
Early intervention can preserve hearing and facial nerve function
Genetic counseling and testing are paramount
Be aware of ocular manifestations like cataracts.
Common Mistakes:
Delaying MRI surveillance in symptomatic children
Underestimating the importance of audiometric monitoring
Not considering genetic testing for definitive diagnosis
Failing to involve a multidisciplinary team in management
Assuming all schwannomas are benign and non-progressive without close follow-up.