Neurofibromatosis 2

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Chapter 57 Neurofibromatosis 2

William H. Slattery, III

Neurofibromatosis 2 (NF2) is a rare syndrome characterized by bilateral vestibular schwannomas, multiple meningiomas, cranial nerve tumors, spinal tumors, and eye abnormalities. NF2 presents unique challenges to the otologist because hearing loss may be the presenting complaint leading to the diagnosis of the disorder. NF2 is quite invasive, requiring a multispecialist team approach for the evaluation and treatment of the disorder. The primary impairment is hearing loss resulting from bilateral vestibular schwannomas. NF2 must be characterized from neurofibromatosis 1 (NF1); although the names are linked, the disease entities are distinctly different. This chapter reviews the clinical characteristics of NF2, and current recommendations for evaluation and treatment.

NEUROFIBROMATOSIS 2 DIFFERENTIATED FROM NEUROFIBROMATOSIS 1

NF1 has distinctly different clinical characteristics from NF2. NF1 and NF2 have been differentiated as completely different genetic diseases based on the chromosome responsible for the disease. NF1 has been localized to chromosome 17, and NF2 has been localized to chromosome 22.

NF1 is a multisystem disorder in which some features may be present at birth and others are age-related manifestations. A National Institutes of Health (NIH) Consensus Development Conference identified the following seven features of the disease, of which two or more are required to establish the diagnosis of NF1:

1. Six café au lait spots equal to or greater than 5 mm in longest diameter in prepubertal patients and 15 mm in longest diameter in postpubertal patients
2. Two or more neurofibromas of any type or one plexiform neurofibroma
3. Freckling in the axilla or inguinal regions
4. Optic glioma (optic pathway glioma)
5. Two or more Lisch nodules (iris, hamartomas)
6. Distinct osseous lesion, such as sphenoid wing dysplasia or cortical thinning of the cortex of long bones with or without pseudarthrosis
7. First-degree relative (parent, sibling, or child) with NF1 according to the above-listed criteria

Some patients also manifest learning disabilities or language disorders. A careful examination and a detailed history of the patient’s symptoms help distinguish NF1 and NF2.

CLINICAL CHARACTERISTICS OF NEUROFIBROMATOSIS 2

Definition

The NIH Consensus Development Conference also developed guidelines for the diagnosis of NF2. NF2 is distinguished by bilateral vestibular schwannomas with multiple meningiomas, cranial tumors, optic gliomas, and spinal tumors. A definite diagnosis is made on the basis of the presence of bilateral vestibular schwannomas or developing a unilateral vestibular schwannoma by age 30 and a first-degree blood relative with NF2, or developing at least two of the following conditions known to be associated with NF2: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity/juvenile cortical cataract (Table 57-1).1

TABLE 57-1 Neurofibromatosis 2 (NF2) Diagnostic Criteria

INDIVIDUALS WITH THE FOLLOWING CLINICAL FEATURES HAVE CONFIRMED (DEFINITE) NF2
Bilateral VS or family history of NF2 (first-degree family relative) plus
Unilateral VS <30 years or
Any two of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
INDIVIDUALS WITH THE FOLLOWING CLINICAL FEATURES SHOULD BE EVALUATED FOR NF2 (PRESUMPTIVE OR PROBABLE NF2)
Unilateral VS <30 years plus at least one of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
Multiple meningiomas (≥2) plus unilateral VS <30 years or one of the following: glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract

VS, vestibular schwannomas.

There may be significant heterogeneity in the presentation of the disease from one individual to the next. Some individuals may have a very mild form of the disease with small vestibular schwannomas manifesting in an older individual. Meanwhile, some children present with multiple intracranial tumors at a very young age. Despite the heterogeneity of the disease within a family, the expression of NF2 tends to be very similar.2 There is a significant genetic component to the disease with much variability within the parameters of the observed phenotype. Studies have shown that a truncating mutation (nonsense and frame shift) may be linked with a more severe form of NF2.3–5 The more severe form of NF2 is termed Wishart form. Individuals with this severe form present with early onset of the disease with multiple intracranial schwannomas and meningiomas that result in blindness, deafness, paralysis, and death by age 40. Despite the strong genotype-phenotype correlation, individual differences in tumor growth occur within subjects, making it difficult to predict how an individual will change over time even when the genotype is known.

The milder form, or Gardner form, of NF2 is less debilitating. The schwannomas may remain stable for many years, few meningiomas develop, and patients may not develop symptoms until later in life and often have fewer disabilities. The genetic basis of the mild form has not been well characterized. Many of these may be mosaic forms of the disease, however.2-4,6-12

Prevalence and Incidence

The average age of diagnosis of NF2 is 25 years; however, many patients present with symptoms before the diagnosis. There is an average delay of diagnosis of approximately 7 years (Fig. 57-1). There is no difference in the proportion of men versus women who develop NF2, and no prevalence has been described based on ethnicity. Epidemiologic studies place the incidence of NF2 between 1 in 40,000 live births13 and 1 in 87,410 live births.14

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FIGURE 57-1 Time from first symptoms to first surgery.

Imaging Studies

All patients suspected to have NF2 should have a high-quality magnetic resonance imaging (MRI) scan performed with thin cuts through the internal auditory canal (IAC). All patients diagnosed with a unilateral vestibular schwannoma should have a dedicated IAC series to ensure there is not another tumor on the opposite side. Patients diagnosed with NF2 should have a complete spine series to evaluate the spine and stage the disease. Small spinal tumors commonly may be found in the cauda equina area, and occasionally a large asymptomatic schwannoma or meningioma may be found in the spine that could require treatment. Early treatment of spine tumors can significantly reduce the mortality associated with these tumors. Older patients who present with bilateral IAC tumors must be worked up for other carcinomas. It is unusual for patients older than 40 years to present with NF2, although with more sensitive MRI scanning techniques, more of these individuals are being diagnosed at an older age. Metastasis may rarely manifest with bilateral IAC lesions, and it is important that carcinoma be ruled out in any patient older than 40 years who presents with bilateral IAC lesions.

A patient identified with NF2 should have a complete cranial MRI scan with cervical thoracic and lumbar spinal imaging. This scan serves as a baseline. A 6-month follow-up MRI scan is recommended for the intracranial tumors. If the tumors exhibit stability, a yearly MRI scan is performed on the intracranial structures. Large tumors in the spine may be monitored with a similar frequency. If no spinal tumors are present, spinal imaging should be performed if the patient becomes symptomatic. Monitoring spinal tumors every 3 years is recommended when these are present. Intracranial imaging is performed on a yearly basis unless studies over several years indicate stability of the tumors.

Molecular Genetics

The NF2 gene was mapped to chromosome 22 q 12-2in 1993.15–17 The NF2 gene located at chromosome 22 codes for a tumor suppressive protein termed Merlin or Schwannomin. This protein negatively regulates Schwann cell production. The loss of this protein allows overproduction of Schwann cells. The mutation in the NF2 chain predisposes individuals to developing a schwannoma when the second hit occurs to the gene; control of Schwann cells is lost or mutated within the cell. Various types of mutations have been identified, including single base substitutions, insertions, and deletions.4,18–20 The mild, or Gardner, type of NF2 may be associated with missense mutations, whereas associations between the other mutations and phenotypes are not as clear.21 The occurrence of NF2 is not restricted to families known to carry the mutation. Frequently, genetic mosaicism occurs, which may not be detected by common mutation analysis techniques.22 Unilateral vestibular schwannomas may exhibit the same type of genetic markers as NF2.23 The mutations in unilateral vestibular schwannomas are confined to the affected tumor tissue. In patients with NF2, the mutation is present in all cell types.22

Family History

NF2 is an autosomal dominant disease, and 50% of children of affected individuals are at risk for developing the disease. Of patients in whom NF2 is diagnosed, 50% present with a family history of NF2. Half of all NF2-affected patients have no family history of NF2 and are considered founder cases. NF2 presentation and phenotype tend to be similar within families. The likelihood of NF2 occurring in related individuals who do not exhibit similar clinical symptoms to an affected family member is small. Consideration must still be given to screening these individuals for risks despite the lack of clinical symptoms. Individuals at risk for developing NF2 must be screened to provide an early diagnosis. Individuals at risk include children of NF2-affected patients and their siblings. Fifty percent of all children of NF2 patients are found to have the disease. Siblings of a diagnosed NF2 patient are at risk, especially if the parent also has NF2.

The type of screening and timing of screening depend on each NF2 center’s preference. Early screening is advocated so that tumors may be diagnosed presymptomatically. Screening may occur via MRI or genetic blood testing.

Screening

MRI screening of potentially affected individuals uses a postcontrast T1-weighted sequence of the full head with thin cuts through the IAC. A dedicated IAC MRI scan identifies most NF2 patients by showing any vestibular schwannomas. Screening of the spine and ophthalmologic examination should be considered if the cranial MRI scan is positive. An audiogram (pure tone thresholds) or current clinical standard auditory brainstem response (ABR) testing is likely to miss small vestibular schwannomas. MRI can diagnose presymptomatically.

MRI is recommended for at-risk children when this test can be performed without sedation; this usually can be done when the child is 7 to 9 years old. A recommended first step for children younger than 7 years is an audiogram. Any child with an NF2-associated symptom, such as hearing loss or facial weakness, should be screened without regard to the need for sedation or age; MRI should be performed as soon as possible after the symptoms become apparent.

Identification of the NF2 gene and chromosome 22 has made genetic testing possible. It is recommended that patients with NF2 see a genetic counselor to discuss the hereditary consequences of the disease. Blood testing for the mutation is able to identify the defect of the NF2 gene in approximately 70% to 75% of patients with a known diagnosis of NF2. If the defect is identified in the affected individual, potential family members may be screened. If the gene is not identified in the affected individuals, blood screening of family members cannot be performed. The use of blood screening for patients without a diagnosis of NF2 or with a suspected diagnosis of NF2 is not recommended. New mutations in patients with mild presentation are most likely to be missense mutations, and this is difficult to identify with genetic testing of NF2 patients.

Tumor Types

Bilateral vestibular schwannomas (acoustic neuromas) are benign neoplasms of the acoustic or eighth cranial nerve (Fig. 57-2).24 The tumors are thought to arise at the glioma–Schwann’s cell junction within the internal auditory meatus. The tumors most commonly arise from the superior vestibular nerve, although with NF2, tumors may be found on the cochlear and facial nerves within the internal auditory meatus. The consequences of a vestibular schwannoma are numerous, including hearing loss progressing to deafness, dizziness and balance problems, tinnitus, facial nerve paralysis, brainstem compression, and, if left untreated, death.

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FIGURE 57-2 Bilateral vestibular schwannomas are characteristics of NF2. A, Small bilateral vestibular schwannomas. B, Medium-size vestibular schwannomas that are compressing the brainstem. C, Giant bilateral vestibular schwannomas that are compressing the brainstem and causing hydrocephalus.

Despite the strong genetic effect in NF2, there is enormous variability in the number of tumor types, the rate of progression, and the disabilities experienced. This enormous variability is also found in patient presentation. Some patients may be asymptomatic. Patients who have no symptoms when diagnosed have generally been identified on the basis of genetic analysis conducted because a blood relative has NF2 or presymptomatic screening. Although the NIH criteria for NF2 require the presence of bilateral vestibular schwannomas for diagnosis, patients may first develop unilateral schwannomas as a young child with no other tumors, or adult patients may present with multiple meningiomas (cranial and spinal) and no vestibular schwannomas.9,25 Although the NIH criteria for NF2 imply that all NF2 patients develop bilateral vestibular schwannomas, some researchers are not convinced of this.36 Evans and colleagues26 based their conclusion on the observation of a possible variant form of NF2 manifesting with skin and spinal tumors in the absence of vestibular schwannomas. Nonetheless, the phenotype generally is reflective of the underlying disorder.

The natural history study of vestibular schwannomas in NF2 conducted at the House Ear Institute showed that 10 of 80 (12.5%) enrolled subjects had no symptoms at diagnosis, and 23 (28.8%) had cranial meningiomas and spinal meningiomas in addition to bilateral vestibular schwannomas. Nearly half (47.5%) had one vestibular schwannoma removed before enrollment. Generally, the tumor resected before enrollment was removed 1.5 years after discovery, and was an average of 2.1 cm at removal. Few patients in the natural history study had spinal tumors or meningiomas removed before enrollment. The preliminary data would indicate that, for this sample of NF2 subjects, the most salient medical issue is the growth of the vestibular schwannomas.

Intracranial Schwannomas

Vestibular schwannomas are the most common intracranial schwannoma associated with NF2. The most frequently identified nonvestibular schwannomas are schwannomas of CN III and V. Bilateral CN III or V schwannomas are the most common additional schwannomas seen. It is important to identify these lesions on MRI. Lower cranial nerve schwannomas may also be identified, but are much less frequently seen. A vestibular schwannoma rarely turns malignant, and sometimes the unilateral vestibular schwannoma may regress in size altogether. Growth of the tumors does not seem to be related either to loss of heterozygosity (genetic level of analysis) or to auditory functioning (phenotype level of analysis). For this reason, it is recommended that a patient have at least yearly MRI scans to track changes in size.33–40 All newly diagnosed patients should have a full head and spine study to stage their disease. After the disease is staged, a 6 month study is performed to determine if the tumor is fast-growing or slow-growing.41

CN V, or trigeminal nerve, schwannomas are the most common type seen after vestibular schwannomas. Oculomotor schwannomas are the third most common schwannomas seen intracranially. Occasionally, it is difficult to distinguish whether these schwannomas have arisen from the oculomotor, trochlear, or obducent nerve, especially when the tumor rises within the cavernous sinus. Trochlear and abducent schwannomas are extremely rare with only a handful of cases reported in the literature.

Facial nerve schwannomas may also be seen, although these are difficult to distinguish radiographically from vestibular schwannomas. Some patients may present with small facial schwannomas that are commonly encountered with large tumors where the distinction between the facial nerve and cochlear vestibular nerve cannot be found. CN III and V schwannomas are usually slow-growing and require treatment only when significant growth has occurred, or other intracranial complications are eminent.

Lower cranial nerve schwannomas can be quite significant in NF2 because these can lead to speech and swallowing disorders. When bilateral lower cranial nerve schwannomas or jugular foramen meningiomas are associated with these tumors, the patient may develop aspiration problems, which can cause significant morbidity. Glossopharyngeal, vagal, and hypoglossal neuropathies resulting from schwannomas on CN IX, X, and XII may lead to speech and swallowing disorders. Glossopharyngeal schwannomas are the most common schwannoma of the jugular foramen. These may manifest with swallowing difficulty, which may lead to the requirement of gastrostomy feeding tubes for nutritional status.

Vagal nerve defects may contribute to swallowing difficulties related to esophageal dysmotility. Vagal nerve deficits may manifest with voice hoarseness owing to vocal cord paralysis, but the most imminent issue is aspiration, which occurs because of loss of sensory innervation to the larynx and loss of the reflexive airway protective mechanisms. Aspiration is often silent in such cases and leads to life-threatening pulmonary complications including pneumonia. Tracheotomy may be required leading to other potential life-threatening complications, including pulmonary infection. It is believed that lower cranial nerve neuropathies may contribute to mortality associated with NF2.

Hearing Changes in Patients with Vestibular Schwannomas

Hearing loss is well documented as the most common presenting symptom in patients who have vestibular schwannomas.42–51 Auditory changes over time in vestibular schwannoma patients are less well known. Rosenberg52 studied the natural history of 80 patients with non-NF2 unilateral vestibular schwannomas for an average of 4.4 years. Rosenberg52 found a positive correlation between tumor growth and worsening pure tone average. There was no statistically significant correlation, however, between positive tumor growth and speech discrimination, change in ABR, and bithermal caloric electronystagmography test result over time.

Lalwani and colleagues53 reported that pure tone pattern speech receptive thresholds and word recognition scores were significantly worse in NF2 patients who had a mild form of NF2 and large tumors compared with patients with mild NF2 with small tumors. Loss of acoustic reflexes and prolonged wave III and V were also associated with larger tumors. In contrast, patients with severe NF2 showed no relationship among tumor size and pure tone levels, speech discrimination thresholds, or word recognition scores. The lack of association may have been due to complete loss of hearing in severe NF2 patients at the time of the assessment. The larger tumors were also associated with prolonged ABR waves III and V latencies. No data across time were reported. Generally, hearing is progressively impaired with increasing growth of vestibular schwannomas necessitating the need for surgical intervention or medical treatments in NF2 patients.

The natural history study evaluated hearing changes prospectively in 63 newly diagnosed NF patients, and found that hearing was stable after diagnosis. During the first 2 years after diagnosis, 27% of patients had a significant change in their hearing, and 73% had very stable hearing during the 2 year period. Patients with a family history of NF2 had more stable hearing after an initial diagnosis compared with patients without a family history. Patients with a family history are usually diagnosed at a younger age; the stability of hearing in this group may represent the younger age group. The better the hearing in the newly diagnosed patients, the more stable the hearing. Hearing changes did not vary between ears with each ear acting independently.54

Other Tumor Types in Neurofibromatosis 2

Meningiomas

NF2 has been associated with multiple central nervous system tumors, the most common of which are intracranial meningiomas (Fig. 57-3).55 Nearly all NF2 patients develop these tumors in time. Fifty percent of NF2 patients present with schwannomas and meningiomas; 90% present with spine tumors in addition to schwannomas. The presence of more than one type of tumor in a patient usually indicates a more aggressive disease course. The co-occurrence of vestibular schwannomas and meningiomas has been linked to a synergistic effect of increase in growth rate of the schwannoma and the meningioma beyond that expected of a sporadic schwannoma or meningioma.56,57 Despite the high number of patients with multiple tumors initially, most meningiomas and spinal tumors are asymptomatic and are first seen on MRI. In addition, multiple skin tumors may be found in patients with NF2 (Table 57-3).

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FIGURE 57-3 Multiple meningiomas can be seen in severe forms of NF2. Meningiomas may occur throughout the cranium and skull base area.

Meningiomas are monitored in NF2 unless they are quite large. Growing meningiomas may be surgically removed. Growing meningiomas may result in increased intracranial pressure, intractable headaches, hydrocephalus, and seizure disorders.

Spinal Tumors

Various spinal tumors may occur in NF2 patients, and can be found in the cervical, thoracic, and lumbar region. These tumors are categorized further as either extramedullary or intramedullary tumors depending on their presentation relative to the spinal cord. Extramedullary tumors are commonly schwannomas or meningiomas, whereas intramedullary tumors are often ependymomas, but these can be astrocytomas or schwannomas.58 Spinal tumors may often be numerous small tumors in the cauda equina. Tumors located in the cervical or thoracic region are usually solitary tumors, and these may grow to cause spinal cord compression. These tumors may have a solid or cystic component similar to schwannomas and meningiomas seen intracranially. These tumors may extend out the spinal foramen into the soft tissue causing spinal cord compression.59

As each NF2-related tumor grows and exerts pressure on surrounding structures, treatment encompasses surgical resection, radiation therapy, or both. Another treatment choice early on in the disease course is surgical decompression, in which space is created for the growing tumor, relieving the pressure of the tumor against the nerve. Continued growth of spinal tumors causes loss of motion, numbness, tingling, and, eventually, paralysis.

Eye Findings

NF2 subjects tend also to develop cortical and posterior subcapsular cataracts, which can lead to blindness (see Table 57-2).27 Retinal hamartomas have been observed in a few cases,2,28–30 but are not as frequent. Some subjects (2% to 3% of subjects)31,32 present with numbness or tingling in their arms or legs. Almost 30% of NF2 subjects may have surgery to remove spinal tumors, but the progression of spinal tumors associated with NF2 is not well described. At this time, the presence of vestibular schwannoma in NF2 and the consequences of not treating them are well known, and these tumors may be the most debilitating.

TABLE 57-2 First Symptoms of Neurofibromatosis 2

Symptoms Patients (%)
Neurologic 17.5
Skin tumor 11.7
Vision loss 10.7
Asymptomatic 10.7
Tinnitus 7.8
Weakness 2.9
Vertigo 1
Other/unspecified 4.9

TABLE 57-3 Tumor Type

Tumor Type Patients (%)
Bilateral vestibular schwannoma 99
Skin 50
Meningioma 46
Spinal 60

TREATMENT OPTIONS FOR VESTIBULAR SCHWANNOMAS IN NEUROFIBROMATOSIS 2

The treatment options for a patient with bilateral vestibular schwannomas vary considerably because of the wide variety of tumor sizes and clinical presentations. Associated symptoms (brainstem compression or hydrocephalus), loss of useful hearing, and the status of other intracranial tumors all must be considered when discussing treatment intervention.

Hearing Preservation

Patients who present with bilateral small tumors (<2 cm in greatest diameter) and good hearing may be candidates for hearing preservation procedures. In these patients, total tumor removal is attempted on the side of the larger tumor or on the side with worse hearing. If hearing is successfully preserved on the first side, contralateral tumor removal may be attempted 6 months later.

Hearing preservation rates for small unilateral tumors have approached 70%.51 The results in NF2 patients seem to be worse, however, than the results reported in patients with unilateral vestibular schwannomas.63 Doyle and Shelton64 found that 67% of NF2 patients underwent hearing presentation surgery using the middle fossa approach, and 38% of those had serviceable hearing postoperatively. Improvements in the middle fossa surgical approach were introduced in 1992 that led to a significant improvement in the outcomes of NF2 tumor removal. A more recent review of 18 NF2 patients who had middle fossa removal of their tumors reported that approximately 50% of patients had hearing preserved at the preoperative level; this compares with 25% in the previous study. The overall ability to preserve any hearing was still close to 68%.65 The results of this series have led to a more aggressive attempt to preserve hearing in NF2 patients. Patients who present with small tumors and good hearing are now routinely offered an attempt at hearing preservation. Long-term follow-up is still needed in NF2 patients because additional tumors may arise in the facial or cochlear nerves.

We have published our results treating children with NF2 with small tumors and good hearing. This retrospective chart review reported on 35 children with NF2 who had undergone middle fossa resection (47 surgeries) between 1992-2004. In 55% of surgeries, hearing of less than or equal to 70 dB pure tone average was maintained postoperatively. It is now our practice to perform middle fossa resection in children with NF2, and the sooner in the disease process, the better. Our results indicate that hearing and facial nerve function can be successfully preserved using this approach. Factors to consider include patient age, severity of additional NF2-related symptoms, and obtaining high-quality, thin-slice MR images before surgery. Bilateral middle fossa resection after hearing preservation on the first side is also successful and potentially preserves hearing in both ears.66

Observation without Surgical Intervention

Observation without surgical intervention is the most common treatment option used in patients with NF2 and is used when a small tumor is present in a patient with only one hearing ear or when bilateral tumors are too large for hearing preservation procedures. The patient is assessed routinely to ensure that brainstem compression or hydrocephalus does not result. Initially, MRI is performed 6 months after diagnosis, and then annual MRI scans are performed to document tumor size and determine if intervention is required. Surgical intervention is considered if life-threatening complications occur, the tumors become excessively large (increasing the perioperative morbidity), or the hearing becomes unserviceable.

Middle Fossa Craniotomy and Internal Auditory Canal Decompression without Tumor Removal

Middle fossa craniotomy and IAC decompression without tumor removal allows the tumor to grow without causing compression of CN VII and VIII. This procedure is recommended when progression of hearing loss occurs in a patient who is being observed. The bone surrounding the IAC is removed extensively, allowing the entire tumor and CN VII and VIII complex to be decompressed. The tumor itself is not removed because this may increase the risk of hearing loss. Stabilization and improvement of hearing may occur after this procedure.

Retrosigmoid Craniotomy with Partial Removal

Retrosigmoid craniotomy with partial removal in NF2 patients carries a significant risk because the cochlear fibers are dispersed throughout the tumor, in contrast to unilateral vestibular schwannomas (Fig. 57-4). The risk of hearing loss with partial removal is much higher, and this procedure is typically not recommended.

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FIGURE 57-4 Histology of a vestibular schwannoma. A, Unilateral non-NF2 vestibular schwannoma. Typical schwannoma stain with Bodian silver stain. It stains only the nerve fiber, so the schwannoma cells are not evident. The fibers on the surface of the tumor are visible, however. Nerve fibers of non-NF2 vestibular schwannomas are displaced by the schwannoma cells. B, Another Bodian silver stain with black strands embedded within the tumor, representing the nerve fibers invaded by the tumor. This invasion is different from that seen with non-NF2 solitary vestibular schwannomas. Non-NF2 solitary tumors invade the aggregates of cells and push the fibers aside, rather than invading between the fibers. NF2 vestibular schwannomas are histologically different from non-NF2 sporadic, unilateral tumors.

Non–Hearing Preservation, Translabyrinthine/Suboccipital Approach and Total Tumor Removal

The most common surgical procedure performed in patients with NF2 is non–hearing preservation, translabyrinthine/suboccipital approach and total tumor removal. Most patients present when either the tumor is too large for hearing preservation, or the hearing loss is already at a significant level and hearing preservation is not considered. This approach is used for patients with large tumors who have brainstem compression even if serviceable hearing exists. The translabyrinthine or suboccipital craniotomy approaches may be used for this procedure. The risk of a recurrent tumor is slightly higher with the suboccipital approach, however, and with inexperienced surgeons because residual tumor is often left in the lateral aspect of the IAC.

Auditory Brainstem Implant

The auditory brainstem implant was developed at the House Ear Institute to allow electric stimulation of the cochlear nucleus after bilateral vestibular schwannoma removal. The device is placed on the brainstem (Fig. 57-5) during translabyrinthine vestibular schwannoma removal. This device is indicated in individuals who have no serviceable hearing and are undergoing vestibular schwannoma removal. Most patients obtain enhanced communication skills with the device.

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FIGURE 57-5 CT scan showing placement of auditory brainstem implant within the lateral recess of the fourth ventricle.

Stereotactic Irradiation

Stereotactic irradiation has been recommended for some NF2 patients, but its use must be carefully considered because radiation exposure may induce or accelerate tumors in a patient with an inactivated tumor suppressor gene. It was reported more recently that two of four patients who had previously received radiation therapy developed a malignancy in the irradiated ear.67

Many algorithms have been proposed as treatment plans, but none are widely accepted among NF2 specialists. The range of treatment options is large—larger than for any other nervous system tumor. The potential benefits of treatment are great (hearing preservation), but the potential risks are also significant, and the riskiest procedures have the greatest potential benefit. Often patients have a window of opportunity when they can choose a risky but potentially beneficial procedure; once the window closes, they cannot go back. Patients, families, and care providers need to know the natural history of these tumors to make rational recommendations and decisions regarding these treatment options better. In addition, noninvasive and tumor-related markers of behavior need to be identified that can tailor further anticipatory guidance for any one patient.

MANAGEMENT OF NEUROFIBROMATOSIS 2

Initial evaluation of an NF2 patient can be very complex because this is a multisystem disease. An inadequate diagnosis may render a patient impaired because early diagnosis and treatment may have prevented further impairments. NF2 patients may typically see many different physicians, each with experience in a different field of expertise. NF2 patients require one physician to lead the treatment team—a case manager as it were—to ensure comprehensive care. A neurotologist, geneticist, neurosurgeon, or neurologist may function as the lead physician, depending on the NF2 center.

A comprehensive battery of tests is necessary for tumor detection and adequate staging. The initial MRI study showing the presence of bilateral vestibular schwannomas may be inadequate for tumor follow-up. A cranial MRI scan may not have included the IACs, or a spine series may have focused on only one segment of the spine. MRI with gadolinium and thin cuts through the IAC is necessary for the head. Particular attention is focused in the IACs, cavernous sinus, and jugular foramen areas. Any cranial nerve may have tumor formation and should have complete imaging.

Auditory assessment is necessary to determine the extent of hearing impairment. At a minimum, this assessment consists of a standard audiogram, with air and bone pure tone thresholds, and speech testing. Some centers prefer additional testing with ABR to assess cochlear nerve function. ABR testing is particularly helpful when considering a hearing preservation procedure. Electronystagmography testing has benefit in determining tumor location; however, its utility for clinical assessment is still under investigation.

A complete neurologic examination is required for individuals with suspected NF2. The standard neurologic assessment of dermatomes and muscle strength is required for assessment of potential spinal cord impairment. Cranial nerve testing may find subtle abnormalities for which the patient has slowly compensated. In addition, the patient may not even be aware of his or her own impairment. This is particularly true of the lower cranial nerves.

A complete MRI spinal cord survey is required to identify tumors within the spine. The use of spine screening is still under investigation for all NF2 patients. Patients with a significant tumor burden, a family history of spine tumors, or spinal tumor symptoms should definitely have a spine series. A spine series is required in all symptomatic patients.

A neuro-ophthalmologic examination is required for all patients with NF2. The potential for deafness in these individuals requires that everything be done to preserve vision. A slit-lamp examination is required. It is preferable that a patient be evaluated by an ophthalmologist familiar with NF2.

The initial comprehensive evaluation consists, at a minimum, of MRI of the IAC with gadolinium, auditory assessment, and physical examination. A comprehensive examination includes the previously mentioned MRI with the addition of a full spine series, an ABR test, and an ophthalmologic examination.

The timing of follow-up studies is currently inconsistent among NF2 specialty centers. We recommend repeat testing at 6 months and then yearly testing consisting of an MRI of the head and spine, neurology examination, and audiometric testing. When the growth rate from the tumors has been determined, some of these tests may be spread out over time. Spinal tumors tend to be very slow-growing, and after diagnosis may be imaged every 1 to 5 years. The potential for new tumor formation exists especially in patients with severe disease, and it is important that this information be conveyed to the NF2 patient so that comprehensive follow-up may occur.

GENETIC TESTING

Identification of the NF2 gene on chromosome 22 has made genetic testing possible. It is recommended that patients with NF2 see a genetic counselor to discuss the hereditary consequences of this disease. Genetic blood screening is able to identify the defect on the NF2 gene in approximately 70% to 75% of patients with a known diagnosis of NF2. If the defect is identified, potential family members may be screened. If the gene is not identified, blood screening of family members can be performed. The use of blood screening for patients without a diagnosis or with a suspected diagnosis of NF2 is not recommended. New mutations in patients with mild presentation are most likely missense mutations, which are difficult to identify by genetic testing.

SUMMARY

Care of patients with NF2 requires knowledge of all tumors and symptoms involved with the disorder. It is recommended that patients receive care in a center with expertise in NF2. The role of the neurotologist in this care is determined by the specialty center.

REFERENCES

1. Gutmann D.H., Aylsworth A., Carey J.C., et al. The diagnostic evaluation and multidisciplinary management of NF1 and NF2. JAMA. 1997;278:51-57.

2. Parry D.M., Eldridge R., Kaiser-Kupfer M.I., et al. Neurofibromatosis 2 (NF2): Clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet. 1994;52:450-461.

3. Evans D.G., Trueman L., Wallace A., et al. Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): Evidence for more severe disease associated with truncating mutations. J Med Genet. 1998;35:450-455. [published erratum appears in J Med Genet 361(1):87, 1999]

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