Neurofibromatosis: Type 2

Author(s): An Ngo-Huang, DO and Nikola Dragojlovic, DO

Originally published:08/01/2017

Last updated:

1. Disease/Disorder:

Definition

Neurofibromatosis type 2 (NF2) is a hereditary syndrome characterized by non-malignant nervous system tumors involving the nerve sheath and meninges. Associated conditions include ocular impairments, cutaneous lesions, and neuropathies. It is a related but distinct disorder from neurofibromatosis type 1 (NF1).

Etiology

 NF2 is caused by mutations of the NF2 gene on chromosome 22q12.2 encoding the protein merlin (also known as schwannomin), a cytoskeletal protein that regulates cell growth and proliferation; thus, the absence of merlin may predispose to tumor formation.1

Epidemiology including risk factors and primary prevention

Incidence is 1 in 25,000 live births, with onset of symptoms in the late teens to early 20s. NF2 is an autosomal dominant condition, with a positive family history. However, 50% of the cases may be due to de novo mutations.1,2 There is phenotypic variability because of sporadic mutations, even within families. Given the high rate of transmission from an affected parent, genetic testing and counseling is paramount. Prenatal testing via amniocentesis or chorionic villus sampling is also available. Risk factors for more severe presentation include frame shift and nonsense mutations identified on genetic testing, and younger age at diagnosis.1

Patho-anatomy/physiology

The hallmark of NF2 is bilateral vestibular schwannomas, occurring in up to 95% of patients. Paraspinal schwannomas involve the dorsal nerve root and have a classic “dumb bell” radiographic appearance.

Over half of patients also have at least one intracranial meningioma in their lifetime; spinal meningiomas are less common. NF2-associated meningiomas tend to be higher grade and may grow more rapidly. Gliomas (i.e. ependymomas and astrocytomas) may be seen on imaging, but tend to be less symptomatic.1

There is risk for malignant transformation of tumors; however, the rate of radiation-associated malignant transformation is higher.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The course of disease in NF2 is variable but progressive. All tumors in this disorder have a high rate of recurrence, and the morbidity associated with multiple tumors across the neuraxis and need for multiple surgical resections is high.

Vestibular schwannomas are typically slow-growing, but cause vestibular impairment, vertigo, hearing loss, and tinnitus. Meningiomas result in headaches, seizures, and weakness. Visual impairment from ocular conditions is common, as are early impairments in mobility. In contrast to NF1, osseous lesions are not typically seen.

Specific secondary or associated conditions and complications

Facial nerve mononeuropathy is common given its close proximity to vestibular schwannomas and risk of perioperative injury. Sensorimotor, axonal peripheral polyneuropathy is seen in up to 5% of patients.

Ocular manifestations include cataracts, optic meningiomas, and retinal hamartomas. Plaque-like cutaneous lesions are common, but have low rate of tumor occurrence.

2. Essentials of Assessment

History

Those affected present with hearing loss and vestibular dysfunction from vestibular schwannomas. There is cognitive impairment with intelligence quotient (IQ) in low-average range. Pain and gait abnormalities occur due to polyneuropathy. Paraplegia or tetraplegia, with neurogenic bowel and bladder, occurs due to meningiomas, ependymomas, and both central and peripheral neurofibromas.

Physical examination

Patients suspected of having NF2 should undergo:

  • Thorough skin evaluation for cutaneous or subcutaneous neurofibromas.
  • Ophthalmoscopic or slit-lamp examination for ocular abnormalities.
  • Complete neurologic examination including cranial nerve, reflexes, sensory testing, assessments of coordination and balance.
  • Musculoskeletal evaluation to assess for atrophy, changes in tone, strength testing, joint range of motion and alignment, and gait.

Diagnosis of NF2 is made by Baser criteria:3

  • Bilateral vestibular schwannomas, or
  • First-degree relative with NF2 plus
    • Unilateral vestibular schwannoma or

Any two of: meningioma, gliomas, schwannoma, or juvenile posterior lenticular opacities.

Functional assessment

Useful clinical functional assessments include:

  • Functional Independence Measure (FIM), Activity Measure for Post-Acute Care (AM-PAC)
  • Mobility: Timed Up and Go (TUG), Six Minute Walk test (6MWT)
  • Vestibular function: Berg Balance Scale (BSS)
  • Cognition: Mini Mental Status Exam (MMSE), neuropsychological testing

Quality of life: Short Form-36 (SF-36), Patient Health Questionaire-9 (PHQ-9)

Laboratory studies

Genetic testing identifies abnormalities of the NF2 gene on chromosome 22, altering expression of the tumor suppressor merlin. Frame shift and missense mutations are most common in familial cases.

Hypothalamic-pituitary-adrenal axis disorders are possible in those with optic chiasm gliomas. Otherwise, there are no known lab abnormalities specific to NF2.

Imaging

Contrast-enhanced magnetic resonance imaging (MRI) of the brain or spinal cord is often required to appropriately characterize tumors prior to resection. Additional neuroimaging may be necessary if other focal neurologic signs or symptoms are observed.

Supplemental assessment tools

Audiologic testing is common to assess hearing and identify those in needs of hearing aids. Vestibular testing is used to identify and treat balance impairments and vertigo associated with vestibular schwannomas.

Early predictions of outcomes

In a study of 268 NF2 patients by Selvanathan et al,4 those with frame shift and nonsense mutations on genetic testing were diagnosed at younger age and with higher tumor burden. Younger age at diagnosis is a poor prognostic risk factor, as tumor burden is higher in affected children than adults.

Environmental

The functional assessment includes knowledge of living situation, housing, access to transportation, and interests. Home or vehicle modifications may be required. A home safety evaluation can help limit falls and improve safety. Individualized school or occupational accommodations help improve community reintegration.

Social role and social support system

Family and peer support is critical for those with NF2, who will inevitably suffer prolonged hospital courses and functional declines. The Neurofibromatosis Network and Children’s Tumor Foundation offer online content, as well as local, state, and regional resources for counseling and support.

Professional issues

Quality of life is often impacted by a range of symptoms including hearing loss, difficulty with communicating or expressing emotions due to facial weakness, and self-consciousness. Thus, social support and support from a multidisciplinary care team are vital.

3. Pain Management Approach

Available or current treatment guidelines

Unfortunately, there is no cure for NF2. Treatment guidelines focus on early detection of tumors and appropriate treatment including surgical resection, chemotherapy, radiation therapy, and multidisciplinary rehabilitation.

Patients will require annual hearing evaluation, which may include brainstem auditory evoked responses to detect for clinical signs of schwannoma recurrence before additional symptoms develop. Annual ophthalmologic and cutaneous evaluations are required to monitor for disease progression. Craniospinal MRI, beginning at age 10-12 years, should be repeated every 2 years for those under 20 years old, and every 3-5 years thereafter. If tumors are detected, imaging should be performed annually.1

At different disease stages

Functional deficits are commonplace for patients with NF2. As hearing deteriorates, hearing aids and compensatory strategies are necessary. The course of vestibular impairment mimics hearing loss. After vestibular schwannoma resection, facial weakness, dysgeusia, hearing loss, vestibular dysfunction, and headaches are common.

Intellectual disability, though not an intrinsic part of the disease, is under recognized in those with a history of intracranial intervention. Weakness, paresis, and spasticity also follow intracranial involvement. Damage to the cranial nerves and brain stem is not only disabling, but can be life-threatening.

Neurogenic bowel and bladder due to intracranial or spinal tumor involvement predispose to infections, constipation, and impair community integration.

Impairments after spinal tumor resection include spinal cord injury, neurogenic bowel and bladder, neuropathic and spinal pain syndromes.

Post-radiation sequelae include myelopathy, plexopathy, lymphedema, encephalopathy, and pain syndromes. Progression of chemotherapy-induced peripheral neuropathy adds to weakness, atrophy, and pain.

Disuse osteoporosis, due to poor mobility, portends a high fracture risk. Fall risk is heightened by vestibular, sensory, and proprioceptive deficits. Many patients will require wheelchairs for mobility by early adulthood.

Coordination of care

Appropriate multi-disciplinary care may include neurology, neurosurgery, orthopedic surgery, otolaryngology, ophthalmology, endocrinology, and radiation oncology. Patients with NF2 frequently require inpatient rehabilitation after surgical interventions and all disciplines of outpatient therapies. Needs for durable medical equipment fluctuate. Multi-disciplinary clinics can enhance coordination by temporally and spatially uniting providers.

Patient & family education

Genetic counseling is crucial in familial cases of NF2. Given the phenotypic variance within families, education from physicians and therapists is vital to address new impairments that have not been previously seen, or to provide prognostic information and enhance delivery of care upon hospital discharge.

Measurement of Treatment Outcomes

Serial monitoring of functional status, including mobility, self-care, and performance of activities of daily living is key to optimizing quality of life. In addition, community integration and participation in enjoyed activities outside the home should be discussed during follow up visits.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

NF2 patients with recurrent or multiple new tumors have complicated medical courses, requiring multiple surgeries for decompression and resection, radiation and/or chemotherapy, and may benefit from multiple inpatient rehabilitation stays to address their progressive functional deficits.

The physiatrist has a prominent role in coordination of care with other physicians, providing access to appropriate therapies and screening tests, monitoring for and treating sequelae including pain, bowel and bladder impairments, and procuring needed adaptive equipment.

4. Cutting edge/emerging and unique concepts and practice

Cutting edge concepts and practice

Targeted therapy agents have been on the horizon for NF2; however, chemotherapy with a vascular endothelial growth factor inhibitor, bevacizumab, has shown response in hearing improvement and tumor reduction.2,5

Genetic testing in patients with NF2 continues to advance and reveal new implications for tumorigenesis and prognosis. In the future, this data may be used to individualize surgical and medical treatments, and better plan for future health care and equipment needs.

5. Gaps in the evidence-based knowledge

Gaps in the evidence-based knowledge

The appropriate timing of surgical interventions, and efficacy of radiation therapies and chemotherapeutic agents continues to be studied. The incidence of functional impairment following tumor development and treatment is not well characterized. Furthermore, impact of rehabilitation efforts on functional outcomes, prognosis, and quality of life still need exploration.

References

  1. Ardern-Holmes S, Fisher G, North K. Neurofibromatosis type 2. J Child Neurol. 2017;32(1):9-22.
  2. Kresak JL, Walsh M. Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis. J Pediatr Genet. 2016;5(2):98-104.
  3. Baser ME, Friedman JM, Joe H, et al. Empirical development of improved diagnostic criteria for neurofibromatosis 2. Genet Med. 2011;13(6):576-81.
  4. Selvanathan SK, Shenton A, Ferner R, et al. Further genotype–phenotype correlations in neurofibromatosis 2. Clin Genet. 2010;77(2):163-70.
  5. Blakeley JO, Ye X, Duda DG, et al. Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol. 2016;34(14):1669-75.  

Bibliography

Boone N-X, Aboukais R, Baroncini M, et al. Pediatric neurofibromatosis type 2: clinical and molecular presentation, management of vestibular schwannomas, and hearing rehabilitation. Child’s Nervous System 2016;32(12):2403-2413.

Lloyd SKW and Evans GR. Neurofibromatosis type 2 (NF2): diagnosis and management. In: Said G and Krarup C, eds. Handbook of Clinical Neurology. Amsterdam (Netherlands): Elsevier B.V.; 2013. Chapter 54.

Maniakas A, Saliba I. Neurofibromatosis 2 vestibular schwannoma treatment: a review of the literature, trends, and outcomes. Otol Neurotol 2014;35(5):889-894.

Ngo A. Neurofibromatosis Type 1 and Type 2. In: Shin KY and Buschbacher R, eds. Cancer Rehabilitation (Rehabilitation Medicine Quick Reference Series). New York (NY): Demos Medical Publishing; 2013. Chapter 14.

Patel CM, Ferner R, Grunfeld EA. A qualitative study of the impact of living with neurofibromatosis type 2. Psychol Health Med. 2011;16(1):19-28.

Plotkin SR, Ardern-Holmes SL, Barker FG 2nd, et al. Hearing and facial function outcomes for neurofibromatosis 2 clinical trials. Neurology 2013;81(21):S25-S32.

Yohay K. Neurofibromatosis types 1 and 2. Neurologist. 2006;12(2):86-93.

Author Disclosures

An Ngo-Huang, DO
Nothing to Disclose

Nikola Dragojlovic, DO
Nothing to Disclose

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