Chapter 63. Neurofibromatosis Type 2

• Bilateral vestibular schwannomas
• Posterior subcapsular lenticular opacities
• Spinal tumors
• Skin tumors or lesions

Neurofibromatosis type 2 (NF2) is the official name for the syndrome whose hallmark is bilateral vestibular schwannomas (VS) (Figure 63–1). NF2 replaces a variety of synonyms that have been associated with this entity: central neurofibromatosis, bilateral acoustic neurofibromatosis, cranial neuromatosis, central schwannomatosis, neurofibromatosis universalis, familial bilateral acoustic neuroma syndrome, familial bilateral acoustic neurofibromas, Wishart–Gardner–Eldridge syndrome, neurinomatosis, and neurofibrosarcomatosis. The first known description of the clinical course and postmortem findings of NF2, almost two centuries ago, was of a patient who developed bilateral deafness, had intractable headaches and vomiting, and died at age 21.

NF2 has long been confused with classic von Recklinghausen syndrome and has only recently been recognized as a distinct diagnostic entity. In 1987, a consensus panel of the National Institutes of Health officially differentiated the clinical manifestations associated with classic von Recklinghausen syndrome or peripheral neurofibromatosis from those of a predominantly intracranial subtype or central neurofibromatosis. The two syndromes were designated NF1 and NF2, respectively. Molecular genetic investigations confirmed this clinical differentiation: the gene responsible for NF1 was located near the proximal long arm of chromosome 17, whereas the gene responsible for NF2 was located on chromosome 22.

NF2 is much rarer than NF1, with an incidence estimated between 1:33,000 and 1:50,000. Inheritance of NF2 is autosomal dominant and gene penetrance is above 95%. NF2 most frequently presents in the second and third decades of life. VS represent approximately 8% of intracranial tumors and account for approximately 80% of the tumors found in the cerebellopontine angle. Most cases of VS occur sporadically, are unilateral, and present in the fifth decade. Patients with NF2 have bilateral VS and represent 2–4% of patients with VS.

The recent identification of the gene responsible for NF2 has significantly advanced our understanding of the molecular pathology, as well as the factors responsible for the clinical heterogeneity among patients with NF2. The NF2 gene encodes for the protein merlin or schwannomin, has been shown to have homology to the ezrin–radixin–moesin family of genes, which functions as membrane-organizing proteins. These proteins have a basic function indigent to all cells, which are postulated to link cytoskeletal proteins to the plasma membrane. It has been proposed to represent a recessive tumor suppressor, whose deletion or inactivation alters the abundance, localization, and turnover of cell-surface receptors, thus initiating tumorigenesis. Understanding the function of merlin in tumor formation will lead to the development of novel therapies that may eventually alleviate the suffering associated with NF2.

NF2 results from the inheritance of a mutation in merlin (or schwannomin) protein on chromosome 22. The NF2 gene is spread over approximately 100 kb on chromosome 22q12.2 and contains 17 exons. The coding sequence of the messenger RNA is 1785 bp in length and encodes a protein of 595 amino acids. The gene product is similar in sequence to a family of proteins the include moesin, ezrin, radixin, talin, and members of the protein 4.1 superfamily. These proteins are involved in linking cytoskeletal components with the plasma membrane and are located in actin-rich surface projections such as microvilli. The N-terminal region of the merlin protein is thought to interact with components of the plasma membrane and the C-terminal with the cytoskeleton. Although the exact function of the NF2 protein is as yet unknown, the evidence available so far suggests that it is involved in cell–cell or cell–matrix interactions and that it is important for cell movement, cell shape, and communication. The loss of function of the merlin protein therefore could result in a loss of contact inhibition and consequently lead to tumorigenesis. NF2 gene defects have been detected in other malignant disorders including meningiomas, malignant mesotheliomas, melanomas, and breast carcinomas.

Approximately 50% of affected patients have no family history of NF2. Therefore, these patients represent new germ line mutations in the NF2 gene. To date, more than 200 mutations of the NF2 gene have been identified, including single-base substitutions, insertions, and deletions. Genotype–phenotype correlation studies suggest that mutations in the NF2 gene, which result in protein truncation, are associated with a more severe clinical presentation of NF2 (Wishart type), whereas missense and splice site mutations are associated with a milder (Gardner type) form of the disease. Retinal abnormalities were associated with the more disruptive protein truncation mutations of the NF2 gene. Although mutations in the NF2 gene play a dominant role in the biology of VS, it is also possible that other genetic loci contribute to the development of VS.

Symptoms and Signs

Patients with NF2 usually present in the second and third decades of life, rarely after age 60. Patients' symptoms are attributable to VS, cranial meningiomas, and spinal tumors. The presentation of NF2 can vary considerably, but has been broadly divided into two subtypes based on the severity of disease: Gardner and Wishart NF2 subtypes (Table 63–1). The more severe Wishart type of NF2 is characterized by an early onset of tumors, a more rapid course of disease progression, and the presence of multiple other tumors in addition to bilateral VS. In contrast, the milder Gardner subtype is characterized by a later onset of symptoms, a more benign course of disease, and a tumor burden usually limited to bilateral VS. Many patients with NF2, however, cannot easily be categorized into these subtypes and have many overlapping features.

Hearing impairment is the presenting symptom in nearly 50% of patients. The hearing loss is usually progressive and is associated with poor speech discrimination. Auditory dysfunction is accompanied with tinnitus in 10% of patients. Although the tumors arise from the vestibular nerve, acute vertigo is uncommon since the slow-growth pattern of the tumors allows the central nervous system to compensate. The tumor size at presentation is variable. Generally, younger patients have smaller tumors and older patients harbor larger tumors. VS are larger in patients with the more severe type of NF2 associated with spinal tumors or meningiomas.

Skin tumors are present in nearly two-thirds of patients with NF2. Café-au-lait spots, which are the hallmark of NF1, are also frequently found in patients with NF2. In contrast to patients with NF1, patients with NF2 invariably have fewer than six of these hyperpigmented lesions. Juvenile posterior subcapsular lenticular opacities are common and have been reported in up to 51% of patients with NF2. A proportion of these opacities are thought to be congenital and can be useful in the early diagnosis of NF2 in related family members. Retinal abnormalities are usually associated with the more disruptive protein truncation mutations of the NF2 gene. Muscular weakness or wasting is the initial presenting feature in up to 12% of patients with NF2. Distal, symmetric, sensorimotor neuropathy, though uncommon, may complicate NF2. Because of the heightened awareness of familial risks in individuals diagnosed with NF2, nearly 10–15% of patients diagnosed with NF2 are asymptomatic and are diagnosed as a result of screening.

Imaging Studies

Magnetic resonance imaging (MRI) with gadolinium-diethylenetriamine pentaacetic acid enhancement is the current gold standard for the radiological investigation of VS and spinal tumors. VS are typically isointense or mildly hypointense to brain on T1-weighted images, but they enhance markedly with gadolinium. As a group, VS enhance far more than any other intracranial tumors, but there is sufficient overlap among tumors of different types that the degree of enhancement alone is not pathognomonic. The enhancement may or may not be homogeneous owing to cystic components in the schwannomas. Intratumoral hemorrhage may cause focal areas of hypointensity or hyperintensity, largely dependent on the age of the hemorrhage. With T2-weighted images, VS have an intensity between that of brain and cerebrospinal fluid.

The resolution of thin-sectioned gadolinium-enhanced MRI scans centered on the internal auditory meatus is such that lesions as small as 1 mm can be picked up. False-negative images are thought to be very rare, but the exact incidence is hard to establish because more sensitive study techniques are currently unavailable. Occasional false-positive gadolinium-enhanced MRI scans have been reported, most commonly as a result of viral mononeuronitis of the seventh or eighth cranial nerves. MRI imaging has an important role in the postoperative evaluation of patients with NF2. It also plays an important role in monitoring tumor growth rates when a nonsurgical approach is undertaken and in screening family members at risk of having NF2. MRI of the cervical spine should be performed on every patient with NF2 to exclude asymptomatic spinal cord lesions, assess therapeutic options in symptomatic patients, and assist in surgical planning.

Special Tests

Audiological Testing

Patients with NF2, as well as their family members, should undergo complete audiological testing to assess the level of hearing. Although audiological evaluation alone is not sufficient to screen patients or family members for NF2, it can play a valuable role in management. Pure-tone audiometry is useful as a means of monitoring the function in patients diagnosed with NF2, in deciding when function is deteriorating significantly, and in determining the better hearing ear.

It is a commonly held belief that sporadic VS have a more predictable audiological profile when compared with that of NF2-associated vestibular tumors. This is incorrect. The auditory phenotype of a large number of patients with NF2 who were enrolled in an ongoing clinical and genetic study at the National Institutes of Health demonstrated that patients with NF2 had a more predictable audiological profile for a given size tumor than had been previously described with sporadic VS. However, this association between tumor size and auditory findings did not hold true for the subgroup of patients with spinal tumors, meningiomas, or both.

Auditory brainstem response testing has limited usefulness in reliably diagnosing VS in NF2. Interaural latency measurements are not useful in this population because of their bilateral tumors. Auditory brainstem response also is not reliable in detecting small tumors. The bilateral presentation of VS in NF2 means that there is potential for symmetric abnormalities in audiological investigations; therefore, audiometry alone cannot be used to exclude NF2. Pure-tone audiometry, speech audiometry, acoustic reflexes, and brainstem-evoked response audiometry are poor screening modalities for patients with NF2.

Genetic Testing

Genetic testing for the detection of mutations in the NF2 gene is available at some medical centers and private genetic testing centers. However, it is expensive and its exact role in the management of a patient with NF2 and the identification of family members at risk has not been clearly delineated.

The criteria for confirmed or definite NF2 are listed in Table 63–2. Some patients who do not meet the diagnostic criteria for NF2 should still be considered at risk for this disorder. These include people with a family history of NF2, those younger than 30 y of age with unilateral VS or meningioma, and those with multiple spinal tumors (Figure 63–2). In addition, it would be prudent to evaluate the following people for NF2: (1) patients with a unilateral VS plus any one of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity; (2) patients with two or more meningiomas and unilateral VS; and (3) patients with two or more meningiomas and one or more of the following: glioma, schwannoma, or a juvenile posterior subcapsular lenticular opacity.

NF2 should be differentiated from NF1. The diagnostic criteria for NF1 are met by an individual if two or more of the following are found: (1) six or more café-au-lait macules >5 mm in greatest diameter in prepubertal individuals, and café-au-lait macules >15 mm in diameter in postpubertal individuals, (2) two or more neurofibromas of any type or one plexiform neurofibroma, (3) freckling in the axillary or inguinal regions, (4) optic glioma, (5) two or more Lisch nodules (iris hamartomas), (6) a distinct osseous lesion (eg, sphenoid dysplasia or thinning of the long bone cortex) with or without pseudoarthrosis, or (7) a first-degree relative with NF1 by the above criteria.

The differential diagnosis of cerebellopontine angle lesions includes meningiomas, epidermoid tumors, lipomas, and arachnoid cysts. In cases of unilateral VS, consideration of NF2 should clearly arise when unilateral VS is encountered in a patient under the age of 30. NF2 is implicated in half of all cases of VS presenting before the age of 20. In these young patients with unilateral VS, it behooves the clinician to obtain ophthalmological consultation to look for posterior subcapsular cataracts associated with NF2. A spinal MRI scan should also be performed to detect spinal tumors.

The management of VS in patients with NF2 is a clinically challenging problem in contemporary neurotology. The bilaterality of vestibular tumors makes the common complications associated with surgical intervention more significant. Hearing loss following surgical removal in a patient with NF2 with a large contralateral VS or in what may be an only-hearing ear represents a significant morbidity. In patients with NF2 who are followed up medically, the complications associated with natural growth, including eventual hearing loss, cranial nerve palsies, and brainstem compression, are also important management considerations. The population of patients with NF2 often presents a difficult therapeutic dilemma because neither operative nor nonoperative management offers an acceptable risk–benefit ratio. Characteristics identifying the more aggressive or faster-growing tumors would be useful in planning treatment such as choosing between expectant observation and the surgical extirpation of disease. Recently, great deal of excitement has been generated by clinical trials with bevacizumab, an antibody against vascular endothelial growth factor. This treatment rationale is based on the presence of VEGF and its receptors in VS. Early results are promising and have demonstrated reduction in tumor volume and preservation of hearing.

Surgical Management

The decisions concerning the management of patients with NF2 are significantly different from those of sporadic unilateral VS, and are guided by the fact that patients with NF2 eventually develop bilateral profound deafness. It is advisable for these patients to learn lip reading at an early stage after the initial diagnosis. Patients with NF2 have a lifelong tendency to form intracranial tumors and are never cured of their underlying disease. The management priority should therefore be to maintain function even at the expense of incomplete tumor removal, if that is required. Once an ear has become deaf, total tumor resection should be performed. However, when both ears hear well, some divergence in opinion exists. Some surgeons advocate a resection of the larger tumor via a hearing-sparing approach, whereas others favor removal of the smaller tumor with the rationale that this provides a better chance of hearing preservation. The tumor associated with brainstem compression or central nervous system dysfunction should always be resected first, regardless of the hearing status. If the initial operation is successful in preserving hearing, the surgical excision of the second tumor could be undertaken. If the hearing is not preserved, the second tumor is followed expectantly until the hearing is lost, brainstem encroachment requires removal, or the tumor appears to be enlarging rapidly. Incomplete removal in an only-hearing ear has been recommended to preserve hearing. Unfortunately, even incomplete removal may impair or eliminate residual hearing.

The surgical treatment of spinal tumors, meningiomas, as well as VS requires a team approach with a neurotologist, a neurosurgeon, a neuroanesthesiologist, and a neurophysiologist for cranial nerve monitoring. Spinal tumors and meningiomas are generally observed; signs of growth, neurological compromise, or clinical deterioration usually lead to surgical intervention. Occasionally, a meningioma can be resected at the same time as another intracranial tumor, such as a VS, is being addressed.

Stereotactic Radiation Therapy

Stereotactic radiosurgery is a method of using ionizing radiation to destroy a precisely defined area of intracranial tissue. The technique combines a stereotactic delivery device with ionizing radiation. The radiation dose in stereotactic radiosurgery is delivered by several precisely collimated beams of ionizing radiation. The radiation dose gradient is extremely sharp at the target tissue, resulting in a sharply circumscribed area of high-dose radiation. As a result, the delivery of radiation to adjacent tissues and, hence, associated adjacent tissue damage is minimized. Stereotactic radiosurgery as a treatment option is usually not recommended in patients with NF2.

Hearing Restoration

The preservation of hearing, if technically possible, is far preferable to hearing restoration. Because of the short-life expectancy of patients with NF2, partial tumor removal in an attempt to preserve hearing is more acceptable as a strategy in these patients. An increased awareness of NF2 and an earlier presentation and diagnosis mean that the likelihood that hearing will be preserved is increased. However, sooner or later, in all cases, hearing is lost owing to either tumor progression or the surgical intervention designed to remove the tumor.

Cochlear Implants

A cochlear implant may be an option in patients in whom the cochlear nerve has been preserved. Of concern, however, is the impact of a cochlear implant on the ability of the patient to obtain MRI scans for diagnostic or follow-up purposes. This problem may be overcome by either removing the magnet from the receiver or developing newer-generation implants without magnets.

Auditory Brainstem Implant

An auditory brainstem implant is a method of restoring hearing when hearing loss is due to the destruction of the auditory nerve. It is an alternate treatment option for the profoundly deaf because cochlear implants cannot be used in this patient population. The Nucleus 22-channel auditory brainstem implant design was first presented at the Second International Symposium on Cochlear Implants in Iowa in 1989. This is a multichannel brainstem prosthesis with transcutaneous signal transmission. The original design was slightly modified in 1993 and is now approved by the Food and Drug Administration. The implantation of an auditory brainstem implant can be carried out at the same time as tumor removal. During surgery, the visualization of the cochlear nucleus complex is necessary, with a recommendation for intraoperative monitoring of the facial and glossopharyngeal nerves. The measurement of electrically evoked auditory brainstem potentials is important in determining the optimum placement of the auditory brainstem implant on the cochlear nucleus complex.

The severity of the clinical phenotype determines the prognosis for patients with NF2. In turn, the severity of the clinical phenotype is determined by the underlying genotype or the type of genetic mutation. Patients with nonsense and frameshift mutations in the NF2 gene have a clinically more severe disease with an earlier onset than those with missense mutations. The onset of hearing loss was earlier (20.2 vs 28.4 y) and more prevalent (85% vs 81.3%) in patients with the more significant mutations. Therefore, the type of mutation of the NF2 gene is likely to have a large effect on the severity of the disease and the aggressiveness of the VS. Furthermore, because some sporadic VS are also associated with mutations in the NF2 gene, the variety of clinical presentations in these tumors could be related to the location and type of the mutation.