Neurofibromatosis Type 2 Treatment & Management

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). ^{[5, 30, 31]}

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 can be coordinated 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.

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.

Bevacizumab is an antivascular endothelial growth factor monoclonal antibody that shows some efficacy in decreasing the size of vestibular schwannomas. Bevacizumab may be recommended to radiographically reduce the size or prolong tumor stability in patients without surgical options, and can improve hearing or prolong time to hearing loss. ^{[32, 33, 4]}

Lapatinib is a kinase inhibitor (epidermal growth factor (EGF)-receptor human epidermal growth factor 2 (HER2) kinase) that may also be considered for use in reducing the size of vestibular schwannomas and to improve hearing. ^{[34, 4]} Additionally, there is some evidence that lapatinib may inhibit the growth of meningiomas in NF2. ^[35]

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. ^[5]

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. In addition, bevacizumab can be used in cases of residual tumor in patients in which complete resection is not possible. ^[33] Interestingly, one report indicates that spontaneous regression of one vestibular schwannoma has been seen in several patients following resection of another, contralateral vestibular schwannoma. ^[36]

Studies have shown efficacy in the surgical treatment of nonvestibular cranial nerve schwannomas using a combination of microsurgery and radiosurgery. ^[6]

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. ^[37]

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.

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. ^[7] 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. ^[38] 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. ^{[30, 31]}

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.

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.

The following is an outline of reasonable guidelines in the care of the patient with neurofibromatosis type 2 (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