Neurofibromatosis Type 2 

Updated: Sep 19, 2018
Author: David T Hsieh, MD, FAAP; Chief Editor: Amy Kao, MD 

Overview

Practice Essentials

Central neurofibromatosis, or neurofibromatosis type 2 (NF2), is a genetic disorder marked by the predisposition to develop a variety of tumors of the central and peripheral nervous systems. In contrast to neurofibromatosis type 1 (NF1), NF2 produces less frequent and usually less prominent  cutaneous manifestations. (See the image below.)

Subcutaneous and cutaneous lesions in a young man Subcutaneous and cutaneous lesions in a young man with neurofibromatosis type 2; note paucity of cafe-au-lait spots.

Signs and symptoms

Clinical diagnosis of NF2 requires that an individual present with at least 1 of the following clinical scenarios[1] :

  • Bilateral vestibular schwannomas

  • A first degree relative with NF2 AND

    • Unilateral vestibular schwannoma OR

    • Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

  • Unilateral vestibular schwannoma AND

    • Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

  • Multiple meningiomas AND

    • Unilateral vestibular schwannoma OR

    • Any two of: schwannoma, glioma, neurofibroma, cataract

However, because approximately half of cases result from new mutations, family history is often negative.

Unlike NF1, which frequently is associated with a number of cutaneous diagnostic clues, NF2 is accompanied by fewer and less prominent external cutaneous signs. Presenting symptoms include the following:

  • Hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesions

  • Visual deficits

  • Cranial nerve palsies

See Clinical Presentation for more detail.

Diagnosis

Diagnosis of NF2 involves the following:

  • Genetic testing

  • Imaging studies

  • Auditory, ophthalmic, and histologic examinations

Genetic testing

  • Once the clinical diagnosis has been established unequivocally in a given individual, direct molecular analysis can be offered

  • Detection rates for molecular-based testing approaches approaches 72% in simplex cases and 93% in familial cases[1]

  • If a mutation is found, other asymptomatic family members might benefit from presymptomatic testing

  • Molecular testing of tumor tissue may augment traditional molecular studies when analysis of DNA obtained from blood lymphocytes is nondiagnostic

  • For families in which no mutation can be identified in a known affected individual, linkage analysis or indirect genetic testing methods may be utilized

  • Presymptomatic testing of at-risk family members requires a vigorous informed consent process and might best be done during a genetic counseling session at a cancer, genetic, or neurofibromatosis center that specializes in such matters

Prenatal testing for NF2 is as follows:

  • When a parent has NF2, prenatal testing can be done on amniocytes or chorionic villi, either through direct gene mutation analysis when such a change has been identified or through linkage analysis

  • Prenatal testing may not be possible if the affected parent is the first affected person in the family and a mutation cannot be found

  • If a prospective parent has a known NF2 mutation, preimplantation genetic diagnosis may be possible if the couple is willing to undergo in vitro fertilization with transfer of unaffected embryos

Magnetic resonance imaging

  • MRI remains the mainstay for diagnosis and screening of CNS, cranial nerve, and spinal cord tumors

  • At-risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRI scans of the head performed through their late 50s

  • MRI using 3-dimensional (3D) volumetrics is now the preferred method for following vestibular schwannoma growth over time[2]

  • Routine MRI imaging of the spinal cord probably is not indicated for asymptomatic affected or at-risk individuals

  • MRI of the spine is indicated diagnostically when an individual presents with motor or sensory changes suggestive of a spinal cord lesion or lesions

Auditory Evaluation

  • Hearing evaluations, including brainstem auditory-evoked response (BAER) may demonstrate latency abnormalities before a mass is detectable on MRI

  • Auditory screening on an annual basis may be quite useful in asymptomatic or presymptomatic individuals

  • Once a vestibular schwannoma is identified, full audiometry testing, including acoustic reflex testing as well as BAER, is useful as a means of monitoring disease progression

  • The size of the vestibular tumor often does not correlate with the degree of hearing loss

Ophthalmic Examination

  • Annual eye examinations are recommended for children and adults with NF2

  • Dilated eye examinations for lens opacities, retinal hamartomas, or epiretinal membranes may be quite useful even in a child at risk for NF2

  • Juvenile cataracts may be seen long before a child shows any evidence of vestibular schwannomas

See Workup for more detail.

Management

Medical care for patients with NF2 consists of routine examinations focusing on early detection of some of the potential complications related to CNS or spinal cord lesions.[3] Management by a team of specialists through a multidisciplinary clinic may provide the most comprehensive and cost-effective care over time. The following is an outline of reasonable guidelines in the care of the patient with NF2:

  • Annual neurologic examination looking for subtle deficits or changes in neurologic status that might suggest disease progression

  • Annual hearing screening with BAER, with referral to an audiologist for amplification, augmentation, or speech therapy recommendations

  • Annual MRI to monitor existing lesions or look for presymptomatic lesions

  • Annual ophthalmologic evaluations to monitor visual acuity

Treatment of symptomatic tumors is as follows:

  • Surgical resection represents the most common approach to clinically significant lesions

  • Rarely, radiation and/or chemotherapy may be recommended to treat disabling ependymomas

  • Palliative chemotherapy for surgically unresectable ependymomas may be attempted with lomustine, vincristine, and prednisone, or carboplatin and vincristine, following radiation therapy

  • Erlotinib has shown promise in the treatment of unresectable, progressive vestibular schwannomas

Tumor resection and radiotherapy

  • For small vestibular schwannomas, surgical resection and stereotactic radiosurgery may preserve hearing and facial nerve function in selected patients[4]

  • Larger tumors may require surgical resection despite irreversible hearing loss

  • A debulking procedure may result in preservation of hearing or, at the minimum, prolongation of auditory decompensation

  • Nonvestibular cranial nerve schwannomas may be treated effectively with a combination of microsurgery and radiosurgery[5]

  • Unlike vestibular lesions, intracranial meningiomas may be quite slow growing; surgical resection should be considered only when such lesions are causing serious, disabling symptoms

  • Resection of spinal cord tumors is often quite difficult, and the risks and benefits of surgery must be considered on an individual basis

  • Resection of cutaneous or subcutaneous growths can be accomplished by any competent surgeon

Auditory Brainstem Implants

  • Auditory brainstem implants (ABIs) have been used successfully in some patients with hearing loss secondary to vestibular schwannomas

  • ABIs often improve the patient's ability to appreciate environmental sounds and facilitate communication[6]

  • ABIs in patients with NF2 do not enable high levels of speech recognition

See Treatment and Medication for more detail.

Background

Central neurofibromatosis, or neurofibromatosis type 2 (NF2), is a multisystem genetic disorder associated with bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts, with a paucity of cutaneous features (which are seen more consistently in neurofibromatosis type 1 [NF1]). (See the image below.)

Subcutaneous and cutaneous lesions in a young man Subcutaneous and cutaneous lesions in a young man with neurofibromatosis type 2; note paucity of cafe-au-lait spots.

Although quite variable in its age of onset and severity of symptoms in affected individuals, NF2 is associated with significant morbidity and decreased life span. Furthermore, diagnosis in childhood is often difficult because of the absence of central nervous system (CNS) involvement at a young age.[7] (See Prognosis, Clinical, and Workup.)

Complications of NF2 may include the following (See Clinical, Workup, and Treatment):

  • Unilateral or, frequently, bilateral vestibular schwannomas leading to tinnitus, hearing loss, and/or problems with balance

  • Meningiomas, gliomas, ependymomas, and other cerebral, cerebellar, or spinal cord lesions that may result in neurologic deficits, seizures, and/or hydrocephalus

  • Peripheral nerve schwannomas, mixed tumors, and, occasionally, neurofibromas

  • Peripheral neuropathies

  • Visually significant juvenile cataracts

Etiology

NF2 is inherited as an autosomal dominant condition, although half of affected individuals have NF2 as a result of a new (de novo) gene mutation. The manifestations of NF2 result from mutations in (or, rarely, deletion of) the NF2 gene, located on the long arm of chromosome 22. Affected individuals need only 1 mutated or deleted NF2 gene to exhibit signs of the condition.

The NF2 gene product known as merlin serves as a tumor suppressor; decreased function or production of this protein results in a predisposition to develop a variety of tumors of the central and peripheral nervous systems.[8]

Increasing evidence indicates that merlin is involved in a number of cellular pathways and works in concert with other proteins to promote cellular adhesion and responses via the growth factor receptor.[9] Understanding these interactions may eventually lead to more effective targeted treatment strategies, since the benign nature of NF2 lesions makes tumors frequently less responsive to chemotherapy or radiation therapy.

Numerous mutations in the NF2 gene have been identified, most of which are predicted to result in production of a truncated protein with loss of its usual function.

Epidemiology

The estimated incidence of neurofibromatosis type 2 (NF2) is 1 in 37,000 per year, with about half of affected individuals representing first cases in the family as a result of new, dominant mutations.

Although the genetic change causing NF2 is present at conception, the clinical manifestations occur over many years. The typical age of onset of symptoms is in the late teens to early 20s, but the age range covers the entire life span, to include congenital forms in infancy through the elderly.[10, 11, 12] Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmitted NF2. While NF2 is quite variable in severity from person to person, family studies have shown some intrafamilial consistency in age of onset. Somatic mosaicism for the NF2 mutation in sporadic cases may also complicate the clinical picture, resulting in underdiagnosis or late diagnosis.

Prognosis

The prognosis of neurofibromatosis type 2 (NF2) depends on a number of factors, including age of symptom onset, degree of hearing deficit, and number and location of various tumors. Although age of onset is relatively similar within families, the age range can vary from 2-70 years. While the tumors themselves are relatively indolent and do not undergo malignant transformation, studies performed in the late 1980s and early 1990s showed clearly that significant rates of mortality and morbidity are associated with the diagnosis of NF2.

One such study suggested that the survival from the time of actual diagnosis averages 15 years[13] ; however, this may be evolving with improved diagnosis, surgical techniques, surveillance, screening, and recognition of mild disease (due in part to increased physician awareness and availability of molecular diagnostic options).[14]  In a more recent study of 1,192 patients with NF2, increased mortality is associated with early age at diagnosis (< 20 years old) and with the presence of intracranial meningiomas.[14]  Genetically, reduced mortality is associated with slice-site or missense mutations compared to patients with truncating mutations, and also reduced in mosaic patients compared to non-mosaic patients with NF2.[14]

Morbidity and mortality

Vestibular schwannomas are the most common and well-recognized feature of NF2 leading to significant morbidity. Symptoms of tinnitus, gradual hearing loss, and even vestibular dysfunction are frequently the initial signs of NF2. Although unilateral hearing loss is the most frequently presenting symptom, bilateral deafness would be expected to eventually occur in most affected individuals. Untreated vestibular schwannomas can extend locally and may result in brainstem compression, hydrocephalus, and, occasionally, facial nerve palsy.

Dumbbell-shaped spinal cord schwannomas are quite common in NF2 and result in significant morbidity; they present a great therapeutic challenge. Spinal cord ependymomas, astrocytomas, and meningiomas also occur, but less frequently. Intracranial meningiomas, on the other hand, are a frequent finding; they may be asymptomatic, or they may cause a variety of symptoms and CNS deficits.[15]

Nonvestibular schwannomas occur in more than half of patients and are often diagnosed in patients with an earlier age at diagnosis of NF2. Cranial nerves III and V are most commonly involved, but the rare occurrence of jugular foramen schwannomas potentially impacting the glossopharyngeal, vagus, and/or spinal accessory nerves may lead to dysphagia, esophageal dysmotility, hoarseness, or aspiration.

On the other hand, nonvestibular schwannomas in patients with NF2 tend to be more indolent and to grow slowly over time. This can complicate treatment decision making, since options include surgery, radiation therapy, and watchful waiting.[16]

Posterior subcapsular, or juvenile, cataracts can predate CNS symptomatology. These cataracts may progress over time, leading to decreased visual acuity. A fair percentage of affected individuals are found to have retinal hamartomas or epiretinal membranes that may or may not be visually significant.

Sensory motor polyneuropathy is seen in some individuals with NF2 who may or may not have identifiable tumors along the length of the peripheral nerve(s) of interest.

Patient Education

Patients and at-risk family members should be made aware of specific symptoms, such as tinnitus, hearing deficits, focal weakness, sensory changes, or balance problems, that might suggest tumor growth and should prompt immediate medical attention.

Patients with vestibular schwannomas should be cautioned about diving and underwater activities, because of increased risks for disorientation and potential for drowning.

Patients and their families may be referred to neurofibromatosis (NF)-specific regional and national support groups for continuous updates on advances in treatment, as well as for emotional support. Neurofibromatosis, Inc., for example, can be reached at the toll-free number 1-800-942-6825.

The Children's Tumor Foundation has a toll-free number (1-800-323-7938) for information and to sign up for their newsletter.

The NF2 Review, located in Los Angeles, CA, can be reached at 1-213-483-4431 and not only has an NF2-specific newsletter, but also has a particular research interest in NF2, with a team of specialists working on auditory brainstem implants (ABIs) and the newest surgical approaches to vestibular schwannomas.

Online resources include the NIH Web site and an NF2 person-to-person support group known as the NF2 crew.

 

Presentation

History

As approximately half of affected persons represent new gene changes, family history is often negative, making diagnosis often times challenging. Clinical diagnosis of neurofibromatosis type 2 (NF2) requires that an individual present with at least 1 of the following clinical scenarios:[1]

  • Bilateral vestibular schwannomas

  • A first degree relative with NF2 AND

    • Unilateral vestibular schwannoma OR

    • Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

  • Unilateral vestibular schwannoma AND

    • Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

  • Multiple meningiomas AND

    • Unilateral vestibular schwannoma OR

    • Any two of: schwannoma, glioma, neurofibroma, cataract

There are rare cases, however, in which the clinical diagnosis of NF2 should be reconsidered. This can include the presence of unilateral vestibular schwannoma in the absence of a germline NF2 mutation in which LZTR1-related schwannomatosis should be considered.[17] In addition, bilateral vestibular schwannomas occuring later in life has been reported to occur sponatneously.[18]

Physical Examination

Unlike neurofibromatosis type 1 (NF1), which frequently is associated with a number of cutaneous diagnostic clues, NF2 is accompanied by few external signs.

Presenting symptoms include hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesions. Individuals at risk for NF2 should be screened carefully for early signs of hearing loss, motor or sensory changes, and visual deficits.

Optic nerve sheath meningiomas, while generally quite rare in children, may be a presenting sign of NF2.[19]

Cranial nerve palsies may stem from compression of adjacent nerves secondary to an expanding vestibular schwannoma or directly from nonvestibular cranial nerve schwannomas.

Differentiating clinically between the relatively common NF1 and the rare NF2 is occasionally problematic. Patients with NF2 almost never have a large number of cafe-au-lait spots (although in rare cases, 6 or more may be seen), whereas cafe-au-lait spots are numerous and ubiquitous in NF1. Neither axillary nor inguinal freckles are common occurrences in NF2.

Malignant transformation of benign growths is almost unheard of in NF2, unlike in NF1. However, individuals with either NF1 or NF2 can develop multiple subcutaneous lesions that may be clinically indistinguishable (see the images below). In NF2, these lesions most often are defined histologically as schwannomas or neurilemomas, while in NF1 these are defined histologically as neurofibromas. Subcutaneous neurofibromas are occasional findings in NF2.

Subcutaneous and cutaneous lesions in a young man Subcutaneous and cutaneous lesions in a young man with neurofibromatosis type 2; note paucity of cafe-au-lait spots.
Right neck mass in a patient with neurofibromatosi Right neck mass in a patient with neurofibromatosis type 2.
Facial asymmetry, OS proptosis, and exotropia, as Facial asymmetry, OS proptosis, and exotropia, as well as several subcutaneous lesions on the forehead and face, in a 20-year-old man with neurofibromatosis type 2.
Posterior cervical scar from cord lesion resection Posterior cervical scar from cord lesion resection, thoracic scoliosis, and subcutaneous masses in a young adult with neurofibromatosis type 2.

Posterior subcapsular lenticular opacities, even in childhood, would be suggestive of NF2, whereas Lisch nodules would be diagnostic of NF1. Finally, although individuals with either NF1 or NF2 can develop dumbbell-shaped spinal cord tumors, schwannomas are common in NF2, whereas neurofibromas are seen primarily in NF1.

 

DDx

 

Workup

Approach Considerations

Now that the gene for neurofibromatosis type 2 (NF2) has been identified, analysis for disease-causing mutations can be offered in some clinical settings. Detection rates for molecular-based testing approaches 72% in simplex cases; therefore, such testing has some inherent limitations when trying to confirm a diagnosis of NF2. However, for a patient with suspected NF2 who is still young, has a negative family history, and may eventually develop additional criteria, the identification of a specific mutation may be very helpful.

In light of the high rate of somatic mosaicism in sporadic cases of NF2 (perhaps as many as 25%), molecular testing of tumor tissue may augment traditional molecular studies when analysis of deoxyribonucleic acid (DNA) obtained from blood lymphocytes is nondiagnostic.

Imaging studies and auditory, ophthalmic, and histologic examinations are also important in the diagnosis and management of NF2.

Genetic Studies

Attempts to increase the detection rate of NF2 mutations have met with some success by using a variety of technologies. Denaturing high-performance liquid chromatography has shown promise in identifying more point mutations in affected individuals, and, when used in conjunction with multiplex ligation-dependent probe amplification, may uncover NF2 gene rearrangements. The addition of a third technique, high-resolution melting analysis, rounds out the new molecular armamentarium, which enables exons to be more efficiently scanned, thereby further improving the detection rate by uncovering additional point mutations.[20]

For families with asymptomatic, at-risk members, the application of molecular testing is viewed from a slightly different perspective. Once the clinical diagnosis has been established unequivocally in a given individual, he or she could be offered direct molecular analysis to see if a mutation can be identified. If a mutation were found, then other asymptomatic family members might benefit from presymptomatic testing to see who would and who would not develop neurofibromatosis type 2 (NF2). Screening and surveillance recommendations would then be based on the results of this testing and, if a sibling or child of an affected person were found not to carry the mutation, he or she would need not be concerned about developing NF2 in the future.

For families in which no mutation can be identified in a known affected individual, linkage analysis or indirect genetic testing methods may be utilized. However, this requires cooperation on the part of the family, as well as DNA samples from multiple affected and unaffected individuals. Even utilizing the best technology available, diagnostic uncertainty may remain, depending on the geographical relationship between the genetic markers and the disease-causing gene. On the other hand, with advances that have taken place in genetic mapping and the likelihood of finding informative markers close to or within the gene itself, linkage analysis remains an excellent choice for determining risk from a molecular standpoint.

For a parent who has NF2, prenatal testing can be done on amniocytes or chorionic villi, either through direct gene mutation analysis when such a change has been identified or through linkage analysis. Prenatal testing may not be possible if the affected parent is the first affected person in the family and a mutation cannot be found. For an affected parent with a known mutation, preimplantation genetic diagnosis may be possible if the couple is willing to undergo in vitro fertilization with transfer of unaffected embryos.

One note of caution must be made in light of advances in molecular genetic technology. Presymptomatic testing of at-risk family members requires a vigorous informed consent process and might best be done during a genetic counseling session at a cancer, genetic, or neurofibromatosis center that specializes in such matters. This is of even greater concern when considering testing of minors, in whom the potential harm must be weighed against medical benefit.

Since aggressive medical surveillance can still be implemented in the absence of a definitive diagnosis and no preventive or curative measures are currently available, the decision to undergo presymptomatic testing for this adult-onset disease is a personal one that must be made after a frank and complete discussion with health professionals.

Imaging Studies

Radiography

Plain films of the spine may be helpful in evaluating scoliosis but are of limited value in looking for spinal cord tumors that may occur in NF2.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) remains the mainstay for diagnosis and screening of CNS, cranial nerve, and spinal cord tumors (see the images below). At-risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRI scans of the head performed through their late 50s. Clear molecular diagnosis may help to modify risks for family members and prevent unnecessary testing for asymptomatic individuals who are found not to carry a gene mutation.

Meningioma to the left of midline in a patient wit Meningioma to the left of midline in a patient with neurofibromatosis type 2.
Multiple meningiomas (on the left) on the surface Multiple meningiomas (on the left) on the surface of the brain in a patient with neurofibromatosis type 2.
Bilateral acoustic neuromas in a patient with neur Bilateral acoustic neuromas in a patient with neurofibromatosis type 2.
Bilateral acoustic neuromas and a left-sided menin Bilateral acoustic neuromas and a left-sided meningioma in a patient with neurofibromatosis type 2.
Small ependymoma in a patient with neurofibromatos Small ependymoma in a patient with neurofibromatosis type 2.
Multiple meningiomas in a patient with neurofibrom Multiple meningiomas in a patient with neurofibromatosis type 2.

MRI using 3-dimensional (3D) volumetrics is now the preferred method for following vestibular schwannoma growth over time.[2]

MRI of the spine is indicated diagnostically when an individual presents with motor or sensory changes suggestive of a spinal cord lesion or lesions. The key point here is early detection, which may result in prompt action and provide a better outcome. However, routine MRI imaging of the spinal cord probably is not indicated for asymptomatic affected or at-risk individuals.

Although whole body MRI is often utilized within clinical trials, its use within clinical practice is still being defined. Short-tau inversion recovery (STIR) sequences have been particularly useful for the detection of whole body tumor burden.[21]

Auditory Evaluation

Hearing evaluations, including brainstem auditory-evoked response (BAER), are important in the identification of early hearing loss and may demonstrate latency abnormalities before a mass is detectable on MRI. In light of this, auditory screening on an annual basis may be quite useful in asymptomatic or presymptomatic individuals.

Once a vestibular schwannoma is identified, full audiometry testing, including acoustic reflex testing as well as BAER, is useful as a means of monitoring disease progression. Clinical experience clearly indicates that the size of the vestibular tumor often does not correlate with the degree of hearing loss.

Ophthalmic Examination

Dilated eye examinations are an important part of the care of affected individuals because they are at a risk for developing visually significant cataracts or retinal lesions. As a diagnostic test, an eye examination for lens opacities, retinal hamartomas, or epiretinal membranes may be quite useful even in a child at risk for neurofibromatosis type 2 (NF2). In fact, juvenile cataracts, as the name implies, frequently occur in children and may be seen long before there is any evidence of vestibular schwannomas.

For children and adults with NF2, annual eye examinations are recommended, since unrecognized visual impairment can further interfere with activities of daily living, especially in an individual with concomitant hearing loss.

Histologic Findings

Unlike the tumors associated with neurofibromatosis type 1 (NF1), those found in NF2 are usually made up of 1 of 3 cell types—Schwann cells, glial cells, or meningeal cells. Although the tumors in NF2 can be locally invasive and cause significant morbidity as a result of their growth properties, they rarely, if ever, undergo malignant transformation. This is somewhat different than in NF1, in which plexiform neurofibromas occasionally develop into neurosarcomas.

However, vestibular schwannomas and meningiomas in NF2 tend to be more aggressive than they are in cases of sporadic tumors (ie, those not related to NF2), with a tendency for more extensive local invasion and with histologic evidence of increased mitoses.

 

Treatment

Approach Considerations

For individuals diagnosed with neurofibromatosis type 2 (NF2), medical care consists of routine examinations focusing on some of the potential complications related to CNS or spinal cord lesions.[3] Interval history should focus on subtle motor or sensory symptoms, such as paresthesias, radiculopathies, weakness, or muscle atrophy. Unless clinical deterioration occurs, MRI of the head on an annual basis is reasonable, as is annual eye examinations and auditory screening using BAERs.

Annual neurologic assessment by a trained specialist is most useful in this clinical setting; the neurologist may detect subtle sensory or motor deficits even before the patient is aware of any difficulties.

For patients with multiple medical problems associated with NF2, management by a team of specialists through a multidisciplinary clinic may provide the most comprehensive and cost-effective care over time. This is especially important with rapid advances in surgical management, including the use of such tools as stereotactic radiosurgery and auditory brainstem implants (ABIs).[4, 22, 23]

For at-risk individuals who do not carry a diagnosis of NF2, such as siblings and offspring of affected persons, optimal screening recommendations are more difficult to establish. However, since early detection of tumors may improve long-term outcome, many reasons exist to consider a program of surveillance and routine screening. For families in which a specific mutation or linkage has been established, at-risk individuals may choose to know for sure whether they are at risk.

Even when diagnostic certainty is not possible but an individual's chance of having NF2 is at least 50%, annual focused examination accompanied by annual head MRI scans and hearing evaluations with BAERs seems to be a reasonable screening option.

Treatment setting

Although care of the patient with neurofibromatosis type 2 theoretically can be done in the primary care setting, the complexity, rarity, and multisystem involvement encountered in this condition suggest that medical care in a disease-specific, multidisciplinary clinic may permit optimal management.

Radiation Treatment and Chemotherapy

Although surgical resection of symptomatic tumors represents the most common approach to clinically significant lesions, in some rare instances, radiation and/or chemotherapy may be recommended to treat disabling ependymomas. However, concerns remain regarding additional risks of radiation therapy in a patient with a germline tumor suppressor gene mutation (ie, someone with NF2), as opposed to an individual with an isolated, non–NF2-related tumor.

Therapeutic use of erlotinib has shown promise in the treatment of unresectable, progressive vestibular schwannomas, resulting not only in a decrease in tumor size but also in improvement in auditory function. Further clinical trials are in order before use of this oral chemotherapeutic agent can be recommended on a routine basis.[24] A trial of bevacizumab, an antivascular endothelial growth factor monoclonal antibody, also showed some efficacy in the shrinkage of vestibular schwannomas; the drug improved hearing in some patients with unresectable tumors.[25]

Early in vitro studies have suggested that Gleevec, a tyrosine kinase inhibitor, may be useful in the treatment of vestibular and spinal cord schwannomas in patients with NF2.[26]

Tumor Resection and Radiosurgery

Surgical resection of tumors remains the mainstay of treatment in neurofibromatosis type 2 (NF2), with recent advances in surgery permitting preservation of hearing for some affected individuals. For small vestibular schwannomas, surgical resection and stereotactic radiosurgery have been used and may preserve hearing and facial nerve function in selected patients.[4]

Larger tumors may require surgical resection despite irreversible hearing loss, especially when there is evidence of brainstem compression, facial nerve palsy, or, in extreme cases, early hydrocephalus. Larger tumors may be approached surgically if a patient has a significant decline in hearing, since a debulking procedure may result in preservation of hearing or, at the minimum, prolongation of auditory decompensation. Interestingly, one report indicates that spontaneous regression of one vestibular schwannoma has been seen in several patients following resection of another, contralateral vestibular schwannoma.[27]

Studies have shown efficacy in the surgical treatment of nonvestibular cranial nerve schwannomas using a combination of microsurgery and radiosurgery.[5]

Unlike the vestibular lesions, intracranial meningiomas, may be quite slow growing; surgical resection should be considered only when such lesions are causing serious, disabling symptoms.

Resection of spinal cord tumors is often quite difficult and the risks and benefits of surgery must be considered on an individual basis. To maximize operative success, acting promptly is important when neurologic symptoms appear, yet complete resection of a spinal cord tumor may not always be possible and in some cases serves a primarily palliative function. Single fraction radiosurgery may also be used to treat spinal cord schwannomas, either serving as primary therapy or, following surgery, being used if residual tumor or tumor progression occurs.[28]

Surgical resection of cutaneous or subcutaneous growths can be accomplished, although plastic surgical consultation is advisable for areas of great cosmetic concern, such as the face.

Auditory Brainstem Implants

ABIs have been used successfully in some patients with hearing loss secondary to vestibular schwannomas. In many cases, an ABI does not restore hearing but instead improves the patient's ability to appreciate environmental sounds and facilitates communication.[6] ABIs in patients with neurofibromatosis type 2 (NF2), while providing some auditory input, do not enable high levels of speech recognition, presumably because of cochlear nerve damage in these patients.[29] Prior to surgery, ABI candidates should be engaged in a frank discussion about their expectations regarding this procedure, and a careful evaluation should be made of their family support system.[22, 23]

Activity

Activity restriction is not necessary except as recommended by the neurologist or neurosurgeon on the basis of neurologic deficits. However, patients with vestibular schwannomas need to be warned about potential balance problems, which may worsen in an underwater situation. Therefore, these individuals should be advised to never swim alone and to have someone with them at all times if they are diving or snorkeling. If disorientation occurs underwater as a result of acoustic nerve involvement, such activities may need to be curtailed.

Consultations

The neurologist and neurosurgeon work closely together in the management of central and spinal cord lesions in neurofibromatosis type 2 (NF2). The neurologist provides valuable information regarding any changes in neurologic status over time, whereas the neurosurgeon provides insight into selecting the optimal procedure and makes decisions regarding timing for surgical intervention.

The otolaryngologist or otologist is an important consultant in the surgical management of vestibular schwannomas, especially if ABIs are being considered. (Cochlear implants have not been as effective in the treatment of NF2 as originally hoped and generally are reserved for a small subset of patients with vascular compromise of the cochlea without substantial nerve involvement.)

The audiologist serves as an essential member of the management team for individuals with acoustic nerve lesions. After performing annual hearing evaluations by BAER to document disease progression, he or she can provide advice regarding usefulness of amplification. For many patients, augmentation may permit good sound discrimination well into the course of the disease. The audiologist also may make suggestions regarding any additional services, such as speech therapy or classes for lip reading or sign language, that may be helpful as hearing deficits grow.

The ophthalmologist is an important team member and can assist in the diagnosis and care of the patient with NF2. Early detection of juvenile cataracts is quite helpful in making a diagnosis in an at-risk child with minimal symptomatology. Furthermore, annual follow-up for affected individuals permits early detection and possible intervention for visual loss secondary to lenticular lesions.

Finally, the geneticist may provide diagnostic and genetic information to affected and at-risk individuals. For family members who are considering molecular testing, an explanation of risks, benefits, and test reliability to all individuals is essential as part of the informed consent process. Issues of potential insurance discrimination, confidentiality, and privacy need to be discussed, as do personal perspectives on such testing, before an individual can provide consent. For couples considering prenatal diagnosis for NF2, genetic consultation is recommended.

Long-Term Monitoring

The following is an outline of reasonable guidelines in the care of the patient with NF2:

  • Annual neurologic examination looking for subtle deficits or changes in neurologic status that might suggest disease progression

  • Annual hearing screening with BAER, with referral to an audiologist for amplification, augmentation, or speech therapy recommendations

  • Annual MRI to monitor existing lesions or look for presymptomatic lesions

  • Annual ophthalmologic evaluations to monitor visual acuity

 

Medication

Medication Summary

No effective medical therapies are known for neurofibromatosis type 2 (NF2). However, in rare instances in which surgical resection of symptomatic ependymomas is not possible, chemotherapy with lomustine, vincristine, and prednisone, or carboplatin and vincristine, following radiation therapy, may serve a palliative function.

As previously mentioned, therapeutic use of erlotinib has shown promise in the treatment of unresectable, progressive vestibular schwannomas, resulting not only in a decrease in tumor size but also in improvement in auditory function. Further clinical trials are in order before use of this oral chemotherapeutic agent can be recommended on a routine basis.[24] A trial of bevacizumab, an antivascular endothelial growth factor monoclonal antibody, also showed some efficacy in the shrinkage of vestibular schwannomas; the drug improved hearing in some patients with unresectable tumors.[25]

Early in vitro studies have suggested that Gleevec, a tyrosine kinase inhibitor, may be useful in the treatment of vestibular and spinal cord schwannomas in patients with NF2.[26]

Antineoplastic Agents

Class Summary

Antineoplastic agents act by inhibiting the key factors responsible for neoplastic transformation of cells.

Vincristine ( Vincasar PFS)

Vincristine is a vinca alkaloid that is cell cycle–specific (M phase). The mitotic apparatus is arrested in metaphase via disruption of the microtubules. Absorption of vincristine through the GI tract is variable; therefore, administer the drug intravenously. It is metabolized extensively in the liver and excreted primarily via bile. Neurotoxicity is the limiting factor during therapy. Peripheral neuropathy is vincristine's most common adverse effect at usual doses.

Carboplatin

Analog of cisplatin used in treatment regimens for relapse. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase.

Lomustine

Lomustine inhibits RNA and DNA synthesis through alkylation of DNA and carbamylation of DNA polymerase, and alteration of RNA, enzymes, and proteins.

Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Prednisone (Rayos)

Prednisone, a synthetic glucocorticoid analog, acts as a potent immunosuppressant. It may inhibit cyclooxygenase, which, in turn, inhibits prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.