General Child Neurology
May. 31, 2021
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This article includes discussion of neurofibromatosis type 2, acoustic neurofibromatosis, central neurofibromatosis, and NF2. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Neurofibromatosis 2 (NF2) is a tumor predisposition syndrome most commonly associated with the development of multiple schwannomas (classically bilateral vestibular schwannomas), meningiomas, and ependymomas. This disorder is caused by mutations in the neurofibromatosis 2 gene, a tumor suppressor gene that encodes for merlin/schwannomin and is located on chromosome 22.
• Neurofibromatosis type 2 is an autosomal dominant disorder caused by mutations of the neurofibromatosis type 2 gene, a tumor suppressor gene located on chromosome 22, whose normal protein product is Merlin/Schwannomin.
• The average age of onset for neurofibromatosis type 2 is 22 years old, but patients may also present in childhood. The majority of affected children do not present with the vestibular or auditory complaints typical of adult patients.
• Classically, patients have bilateral vestibular schwannomas (CN 8), which are frequently responsible for the initial presenting complaints (ie, hearing loss and tinnitus) in adult patients. Other associated sequelae include nervous system tumors (ie, meningiomas, schwannomas affecting other cranial nerves or spinal nerve roots, and gliomas), lens abnormalities, and peripheral neuropathy, among others.
• Although neurofibromatosis type 2 patients sometimes display cutaneous features (eg, pigmented skin lesions called “cafe au lait” spots) typical of neurofibromatosis type 1, these skin findings are typically less common and less numerous than in neurofibromatosis type 1 patients.
• Treatments currently target specific disease manifestations (ie, tumors, cataracts, neuropathy) rather than the underlying disease process. Genetic counseling is recommended to first-degree relatives of affected individuals.
Neurofibromatosis type 2 has also been called central or acoustic neurofibromatosis because of its characteristic involvement of the central nervous system with tumors, especially meningiomas and acoustic neuromas that are now termed vestibular schwannomas (24). It is much less common than neurofibromatosis type 1, with which, historically, it was often confused (93). It accounts for 5% to 10% of all cases of neurofibromatosis (24). Neurofibromatosis type 2 is now well characterized clinically as an autosomal dominant disorder with genetic origins on the long arm of chromosome 22, distinct from neurofibromatosis type 1 (84; 103).
Wishart reported the first patient with probable neurofibromatosis type 2 who had multiple intracranial tumors and no recorded cutaneous features (104). Harvey Cushing reported a case of acoustic neuromas in 1917 and considered it to be a form of neurofibromatosis because the pathological changes were so similar to those seen in von Recklinghausen cases (20). However, from the time of von Recklinghausen's report in 1865 until recently, neurofibromatosis type 1 and neurofibromatosis type 2 were frequently classified as the same disease and referred to as von Recklinghausen disease or multiple neurofibromatosis (93). The perception that neurofibromatosis type 1 and neurofibromatosis type 2 were 1 disease arose because café au lait spots and peripheral nerve tumors can occur in either condition (93). Following the recognition of the autosomal dominant inheritance pattern of acoustic neuromas, these tumors were considered 1 of the complications of neurofibromatosis type 1 (45).
Gardiner and Frazier reported a large family from Pennsylvania with neurofibromatosis type 2 and suggested that the bilateral acoustic neuromas represented a separate form of neurofibromatosis (38). The subclassification was not adopted at that time, however. A large study of neurofibromatosis in 1956 reported 5% of patients with what was called multiple neurofibromatosis, who had bilateral acoustic neuromas and, in retrospect, probably had neurofibromatosis type 2 (93).
A follow-up study of the Gardiner and Frazier family in 1970 again concluded that the condition was different from von Recklinghausen disease and suggested that it be called central neurofibromatosis (106). This subclassification was more widely accepted by the 1980s (49; 80), and the natural history of neurofibromatosis type 2, with its greater morbidity and mortality in the majority of affected individuals, was recognized (46; 58). Moreover, the absence of acoustic neuromas in neurofibromatosis type 1 was also appreciated (81). The NIH Consensus Panel agreed in 1987 on clinical guidelines for diagnosis and nomenclature, recommending the name neurofibromatosis type 2 rather than central or acoustic neurofibromatosis (70). The mapping of the neurofibromatosis type 2 gene to chromosome 22 confirmed the impression of neurofibromatosis type 2 as a distinct entity (84). Research surrounding neurofibromatosis type 2 has been dominated by gene studies and the process in which these gene abnormalities impact disease course. This translational research has guided current research efforts in neurofibromatosis type 2 and has subsequent powerful clinical impact in future potential therapeutic options.
Adults. Most adult patients present with symptoms of hearing loss, tinnitus, and impaired balance related to vestibular schwannomas. The average age of symptom onset is 18 to 24 years, and most patients will present by age of 30 years. Approximately 20% to 30% of patients present with symptoms related to cranial and spinal meningiomas with headaches, seizures, weakness, and paresthesias (30; 26). Peripheral neuropathies, mostly axonal in nature, are also common in neurofibromatosis 2 (96). Ocular findings can affect a majority of neurofibromatosis 2 patients and include cataracts, epiretinal membranes, hamartomas, and optic nerve sheath meningiomas (13). Dermatologic manifestations in neurofibromatosis 2 are less common compared to neurofibromatosis type 1 but can affect nearly 70% of patients, including cutaneous and subcutaneous nodules, which are usually schwannomas (60) or tumors of mixed type (neurofibroma/schwannoma). The tumors can be subtle and easily overlooked.
Children. Although neurofibromatosis 2 most commonly presents in adulthood, approximately 20% of patients will present before the age of 15. Symptoms referable to vestibular schwannomas are uncommon in children at presentation and account for only 15% to 30% of patients. Visual symptoms are common presenting complaints for children, such as strabismus because of a cranial nerve schwannoma, cataract, visual loss due to a retinal lesion, or proptosis due to an orbital ridge meningioma. Unilateral facial nerve paralysis due to a seventh nerve schwannoma or seizures due to a meningioma are also presenting complaints in some children (27; 26).
A diagnosis of neurofibromatosis 2 is made based on fulfilling a set of clinical criteria, otherwise known as the Manchester criteria (Table 1) (26). Baser and colleagues proposed updated criteria to improve diagnostic accuracy by assigning different points for presence of spinal tumors, cutaneous schwannomas, cranial nerve schwannomas, mononeuropathy, cataracts, or peripheral neuropathies before or after the age of 30 (06).
Bilateral vestibular schwannomas or
Unilateral vestibular schwannoma plus any two of the following: meningioma, schwannoma, or juvenile posterior lenticular opacities or
First-degree relative with neurofibromatosis type 2 plus:
1. Unilateral vestibular schwannomas or
2. Any 2 of the following: meningioma, glioma, schwannoma, or juvenile posterior lenticular opacities
At least 2 meningiomas plus
1. Unilateral vestibular schwannoma
2. Any 2 of the following: glioma, neurofibroma, schwannoma, and cataract
The diagnosis of neurofibromatosis 2 can also be made using genetic testing. However, one third to one half of all nonfamilial cases are mosaics and may be falsely negative. Rigorous genetic testing often involves the genetic blood test plus testing of tumor sample.
Vestibular schwannomas. Vestibular schwannomas arise from the vestibular portion of the eighth cranial nerve. They occur in up to 95% of patients with neurofibromatosis 2 (26). The most common symptom associated with vestibular schwannomas is sensorineural hearing loss, which ultimately leads to deafness. Tinnitus and imbalance are also commonly seen. As the vestibular schwannomas grow they can impact adjacent nervous tissue, producing facial weakness or incoordination (30). Vestibular schwannomas are multifocal, and pathologic studies reveal multiple tumors along the eighth nerve in the majority of patients. It is also important to recognize that new tumors occur over time (68; 98).
Growth rate for vestibular schwannomas is variable and difficult to predict (08; 74). The median time to 20% growth in vestibular schwannomas was 21 months, with nearly 50% of vestibular schwannomas showing a saltatory growth pattern. Vestibular schwannomas showed more rapid growth compared to other cranial nerve schwannomas (55). In 1 study evaluating conservative management for vestibular schwannoma, a median growth rate of 1.4 mm per year with patients younger than 20 having a faster growth rate was demonstrated (2.6 mm per year compared to 0.9 mm per year) (74).
The clinical course for hearing loss is progressive but unpredictable and can occur in a gradual, stepwise, or sudden fashion. There is limited understanding of the mechanism for hearing loss. Tumor size or growth rate does not correlate with hearing loss (37). Other postulated mechanisms include intralabyrinthine hemorrhage, intraneural edema, and intralabyrinthine inflammation (77). One study suggests that hearing loss may be related to accumulation of intralabyrintine protein in some patients due to an inflammatory response that may cause cochlear aperture obstruction (04). Vestibular schwannomas also secrete cytokines such as tumor necrosis factor alpha, which can lead to cochlear damage (22).
Cranial nerve schwannomas. Schwannomas can grow along any of the cranial nerves, with the exception of cranial nerve I and II. These other schwannomas may or may not be symptomatic and are commonly detected incidentally on screening MRIs. Based on a study by the Neurofibromatosis 2 Natural History Consortium, about 50% of patients had nonvestibular cranial nerve schwannomas, with the oculomotor (CNIII) and trigeminal nerve (CN V) most commonly affected. Neuropathies of these cranial nerves are rare; however, schwannomas of the lower cranial nerves can cause dysphagia and aspiration (36).
Cranial meningiomas. Meningiomas are the second most common tumor type in neurofibromatosis 2 and occur in 45% to 58% of patients (03). Symptoms are related to compression of adjacent neural tissue and include headaches, weakness, seizures, and visual disturbance. Neurofibromatosis 2 patients with meningiomas have a 2.5-fold higher relative risk of mortality compared to those without (05). Patients with neurofibromatosis 2 are likely to have multiple meningiomas. In a long-term natural history study of meningiomas in neurofibromatosis 2 patients, 52% of patients had 3 or fewer meningiomas, whereas almost 30% had 7 or more. The most common location for meningiomas are along the falx (72%) and skull base (25%); the orbital ridge is another common location, whereas only 3% were intraventricular. Although meningiomas in neurofibromatosis 2 are more aggressive compared to sporadic meningiomas, the vast majority are grade I. Grade II and grade III tumors are reported to represent 24% and 5% of meningiomas requiring resection, respectively. There can be multiple histological subtypes within the same specimen. Among the grade I meningiomas, 55% are reported to be transitional, 35% fibroblastic, and 10% meningotheial. In Goutagny’s study, 66% of meningiomas showed no growth over 110 months of observation (39).
A genotype-phenotype analysis of patients showed that patients with truncation mutations in neurofibromatosis 2 and mutations at the 5’ end of the gene were more likely to develop cranial meningiomas. Mutations in exons 1 to 13 carried a higher risk of cranial meningioma formation compared to exons 14 to 15. Men under the age of 20 have a higher risk of meningioma formation (95). Dewan and colleagues performed whole exosome sequencing on grade I and grade II meningiomas from a single neurofibromatosis 2 patient that demonstrated increased chromosomal translocations as well as mutations in ADAMTSL3 and CAPN (21). Chromosomal loss and homozygous deletions are also commonly observed and may explain a more aggressive growth rate.
Spinal tumors. Spinal tumors, both intramedullary and extramedullary tumors, are common in neurofibromatosis 2. The incidence is as high as 90% of patients (61). They can occur along any portion of the spine, although the cervical and lumbosacral spine are the more common locations. Extramedullary tumors include schwannomas and meningiomas, whereas intramedullary tumors are ependymomas. It is important to understand that all 3 types are commonly present in the same patient. Differentiation can be challenging based solely on radiographic appearance, but careful MR imaging is an essential step in characterizing the spinal tumors.
Schwannoma. Spinal schwannomas are the most common spinal tumors (72). These are intradural, extramedullary tumors that grow from dorsal nerve roots. They are commonly multiple and can grow in a multicentric pattern (43). In a retrospective analysis by Malis of nearly 100 extramedullary spinal tumors, 58 of them were schwannomas, whereas the rest were meningiomas (57). It is also important to recognize that although 90% of patients have extramedullary spinal tumors, only 33% of them presented with localizable symptoms. The most frequent symptoms are motor and sensory deficits followed by sensory only deficits (71).
Meningioma. The incidence of spinal meningiomas is estimated to be similar to schwannomas (61; 57). In the retrospective analysis by Malis, spinal meningiomas were associated with morbidity and mortality, with death attributed to growth of multiple meningiomas (57). This is presumably due to high cervical spine tumors.
Ependymoma. Ependymomas are intramedullary spinal tumors in neurofibromatosis 2 and can be seen in approximately 20% to 50% of patients (61; 72). Some intramedullary tumors in neurofibromatosis 2 were incorrectly described as astrocytomas in the older literature. Ependymomas are the only intramedullary tumor in neurofibromatosis 2. Ependymomas occur most frequently in the cervical spine and cervicomedullary junction (86%), followed by thoracic (62%) and lumbar spine (8%) (30; 76). In a retrospective analysis of 55 neurofibromatosis 2 patients with spinal ependymomas, almost 60% had multiple ependymomas, and nearly 76% were asymptomatic. In that study, only 20% of patients underwent surgery for symptomatic progression (76). Ependymomas commonly have a cystic component. Most patients with multiple ependymomas had a unique MRI appearance described as a “string of pearls” (71). The presence of spinal ependymomas are highly associated with other extramedullary spinal tumors and intracranial meningiomas (71). Although ependymomas usually are asymptomatic, they can grow and produce symptoms based on their location, and those symptoms can be life threatening for tumors involving the medulla. In a series by Plotkin and colleagues, all the ependymomas were low grade (WHO grade I or II) (76).
Peripheral schwannoma. Nearly 70% of neurofibromatosis 2 patients have peripheral schwannomas affecting the paraspinal and cutaneous nerves as well as the nerve trunks and plexi. Symptoms include sensory loss, pain, and weakness (42). Plexiform schwannomas occur in the cutaneous and subcutaneous tissue and are most commonly located in the head and neck region. Patients with plexiform schwannomas are more likely to have neurofibromatosis 2 but can occur in the absence of neurofibromatosis (10; 09). Small schwann cell neoplasms, otherwise referred to as tumorlets, have been seen within the paraspinal nerve roots in neurofibromatosis 2 patients and may be precursors to schwannomas (97).
Peripheral neuropathy is a potential complication in neurofibromatosis 2 and can occur in the absence of visible tumor cells. A potential mechanism for neurofibromatosis 2-related peripheral neuropathy is deficiency in merlin isoform 2, which is implicated in maintaining axonal integrity (87). Peripheral neuropathy can be asymptomatic. Careful evaluations including EMG of patients with neurofibromatosis 2 indicate that as many as 67% of patients can have peripheral neuropathies. Patients with absent reflexes, unexplained muscle weakness, or atrophy should be evaluated for peripheral neuropathy (88).
Cataracts. The most common ophthalmic complication of neurofibromatosis 2 is cataracts, which occur in 60% to 80% of patients, often at an early age (including infancy or childhood) (26). Cataracts in patients under 50 years of age are specific to neurofibromatosis 2 and are most commonly located in the posterior subcapsular lenticular space, but they can also occur in the capsular and peripheral regions (15). Most patients are asymptomatic; however, up to 25% have visual difficulty due to cataracts requiring removal (17).
Epiretinal membranes, retinal hamartomas, optic disc tumors. Epiretinal membranes are developmental abnormalities that are reported in neurofibromatosis 2 with a frequency of 20% to 80% and are often detectable at an early age. Epiretinal membranes are translucent-semitranslucent membranes with white borders but are usually not a cause of vision loss (63). In a long-term retrospective study of ophthalmologic findings in neurofibromatosis 2 patients, 44% of patients had epiretinal membranes (13). Ocular findings can precede the discovery of other neurologic issues by an average of 5 years (94).
Retinal hamartomas are raised masses along the macula which appear as areas of thickened increased pigmentation (78). They occur in 6% to 22% of neurofibromatosis 2 patients and are associated with visual acuity loss (16). Optic disc tumors have been reported in as many as 13% of patients with neurofibromatosis 2. Early onset manifestations of neurofibromatosis 2 and increased severity are found in patients with early onset visual problems.
Optic nerve sheath, cavernous sinus, orbital ridge meningiomas. Optic nerve sheath meningiomas are strongly associated with neurofibromatosis 2 and may be seen in up to 30% to 40% of patients (13a; 13b). They are usually unilateral though 5% may be bilateral (23). Symptoms include loss of visual acuity and color perception from optic nerve compression. The triad of optic atrophy, optociliary vein shunting, and vision loss are pathognomonic for optic nerve sheath meningiomas, with proptosis and strabismus arising later in disease course (Frisen et al 1973; 13).
Cavernous sinus meningiomas in children are rare and if present should prompt an evaluation for neurofibromatosis 2. Presenting symptoms include strabismus, visual dysfunction, and oculomotor nerve dysfunction (34).
Skin tumors. Skin tumors are estimated to occur in up to 70% of neurofibromatosis 2 patients, although only a minority of patients have greater than 10 skin tumors (26). There are 3 main types: plaque-like intracutaneous lesion, which are hyperpigmented with excess hair; subcutaneous nodules formed by thickened nerves; and intracutaneous tumors, which are usually schwannomas (60). Café au lait spots, a frequently found abnormality in neurofibromatosis 1, sometimes occur in neurofibromatosis 2 but are usually not multiple. They occur in approximately 30% to 50% of patients and are fewer in number compared to neurofibromatosis 1 patients (30; 60).
Neuropsychology and quality of life. Although patients with neurofibromatosis 2 typically have slow growing tumors, the tumors can cause significant neurologic morbidity, which compromises patients’ quality of life. There is increasing interest in the impact on quality of life in patients in neuro-oncology (59). Accordingly, similar assessments are being performed in neurofibromatosis 2 patients (19; 62). Patients with neurofibromatosis 2 are more likely than the general population to report lower quality of life with an incidence similar to cancer patients. Patients with hearing impairment, facial weakness, and gait instability reported lower quality of life, with greater vestibular schwannoma tumor volume correlating with greater impact on quality of life (19; 62). The primary concern of patients with neurofibromatosis 2 is deafness, which affects communication and socialization. Patients with neurofibromatosis 2 also demonstrated greater psychosocial stress given uncertainty of their disease course as well as pain (19).
A 21-year-old, previously healthy man presented with a complaint of tinnitus and decreased hearing in his right ear. On neurologic examination he was found to have sensorineural hearing loss in the right ear that was confirmed to be of a moderate degree in audiometric testing. The only other finding was that of a 2 by 2.5 cm café au lait spot on his left shoulder. There was no family history of hearing loss, other neurologic problems, or skin lesions. He was found to have bilateral eighth nerve masses, small in size on the left and moderate on the right. These appeared to be vestibular schwannomas and confirmed a diagnosis of neurofibromatosis type 2. He was thought to have the disease by occurrence of a spontaneous mutation because there was an absence of family history of neurofibromatosis type 2.
He was referred to a center with a dedicated neurofibromatosis type 2 program and underwent surgery for resection of each of the tumors sequentially. The left-side, small tumor was gross totally resected without postoperative hearing or facial nerve deficit. The right-side, larger tumor could be radically but not totally resected with a residual postoperative mild facial nerve palsy and slightly greater hearing deficit in the right ear. He had had stable hearing and surveillance MR imaging for 8 years when the hearing in his right ear significantly decreased further. The right side tumor had markedly increased in size with no evidence of growth of the left tumor, whereas audiometric testing of hearing was decreased (though not absent) on the right and still normal on the left. He underwent a total resection of the right-side tumor at that time with postoperative total deafness in the right ear, but no worsening of the facial nerve deficit. He did well following the surgery, with no further hearing loss or other neurologic problems until the age of 36 years, when he had a focal motor seizure that secondarily generalized. MRI showed an enhancing mass at the surface of the posterior right frontal lobe that was a benign meningioma that was gross totally resected. At the age of 42 years, he had remained without progression of any neurologic symptoms or further seizures since the last surgery.
Chromosomal localization and merlin. Neurofibromatosis 2 is caused by a mutation in a gene located at chromosome 22q12. Neurofibromatosis 2 is due to inactivation of the neurofibromatosis 2 gene (18). Loss of the second allele is thought to occur in the majority of patients.
The protein product is merlin, which is a member of the FERM gene family (ezrin, radixin, moesin). Merlin shares 64% sequence similarity to the other members of the family of proteins. FERM proteins link plasma membrane receptors to the cortical actin cytoskeleton. Thus, merlin can be regarded as a scaffold protein indirectly linking F-actin, transmembrane receptors, and intracellular effectors to modulate receptor-mediated signaling pathways controlling cell growth, proliferation, and survival. The receptors linked to Merlin include tyrosine kinase, cell adhesion, small GTPases, mTOR, PI3K/Akt, and the Hippo pathways. Merlin does not stay at the cell membrane but also migrates to the nucleus and induces growth suppression through inhibition of CRL4 E3 ubiquitin ligase and increases YAP by inhibiting Lats 1 and Lats2 in the nucleus. YAP and TAZ are major effectors of the tumor suppressor Hippo pathway. Abnormalities in the Hippo pathway are linked to a number of cancers as well as disorders of Schwann cell proliferation and myelination (18; 73; 79).
Neurofibromatosis 2 is a relatively rare condition with an estimated incidence of 1 out of 25,000 to 33,000 births (31; 29). There is a high rate of somatic mosaicism, which is estimated to occur in approximately 25% of cases and results in missed diagnoses (52).
Neurofibromatosis 2 is inherited in an autosomal dominant disorder with an estimated risk of transmission of 50% to offspring with nearly 100% penetration. A significant portion of cases, about 50% to 60%, have no prior family history and represent de novo mutations (83). Patients with somatic mosaicism can also transmit the mutation but at a lower rate, which is estimated at 8% to 12% (33).
Currently, there are no truly preventive measures for any of the clinical manifestations of neurofibromatosis 2. Diagnosis and detection of vestibular schwannomas as early as possible in at-risk family members should help in the management of these tumors and prevent or minimize some of the consequences (93). First-degree relatives of patients already diagnosed with neurofibromatosis 2 are at increased risk for having the disease. The child of a parent with neurofibromatosis 2 has a 50% risk of having the disease (30).
Neurofibromatosis 2 appears to be most frequently misdiagnosed as neurofibromatosis 1, especially when the cutaneous manifestations of the disease are prominent. The features most useful in distinguishing neurofibromatosis 2 from neurofibromatosis 1 are usually lower number of café au lait spots, the absence of axillary freckling, and the different appearance of the skin and peripheral nerve tumors, which are also less numerous than they may be in neurofibromatosis type 1 (93). Moreover, vestibular schwannomas are extremely rare if they occur at all in neurofibromatosis 1 (24).
Patients with neurofibromatosis 2 have also been diagnosed as having isolated vestibular or spinal schwannomas or meningiomas when other signs of neurofibromatosis 2 were not sought. Isolated vestibular schwannomas generally occur in older individuals (4th or 5th decade) with no other family members affected and with no other manifestations of neurofibromatosis 2 (100). This is an important distinction because management implications are different.
A separate clinical entity, known as schwannomatosis, is characterized by the presence of multiple schwannomas sparing the vestibular nerves. A case report identified 2 patients with multiple schwannomas with development of cutaneous neurofibromas who did not have neurofibromatosis 2 mutations, therefore illustrating that development of schwannomas with neurofibromas is not solely related to neurofibromatosis 1 or 2 (82).
The diagnostic assessment of patients suspected of having neurofibromatosis 2 should include a detailed clinical and family history. The physical examination should focus on the skin for detection of characteristic cutaneous lesions, and the neurologic examination should focus on cranial nerve function. Ophthalmologic examination is helpful to confirm the typical posterior lens abnormalities of neurofibromatosis 2 when they are present (24).
Cranial MRI may give other clues to diagnosis, such as the presence of tumors on other cranial nerves or meningiomas (93). All patients with a new diagnosis are recommended to undergo full spinal MR imaging with and without gadolinium enhancement to aid in prognostication. Patients with intramedullary spinal tumors (primarily ependymomas, but also astrocytomas) should have annual follow-up imaging. Those with dumbbell neural foraminal tumors, spinal meningiomas, and cauda equina tumors probably can be followed with repeat imaging if symptoms change or appear (41). Whole body MRI use is being investigated as a way to better measure tumor burden (75).
Standard audiometric testing, including vestibular testing, is an important perioperative measure of eighth nerve function for decisions about best operative management but is not particularly useful for early detection of vestibular schwannomas in neurofibromatosis 2 because hearing loss frequently is a later finding than imaging abnormalities or brainstem auditory-evoked responses (11).
Genetic testing. Genetic testing of blood samples in second-generation members of neurofibromatosis 2 families is at least 93%. However, diagnosis is more difficult in the first generation where as many as 30% of patients are mosaics. Mosaics can carry the mutation in too small a proportion (or even none) of their lymphocytes to make the diagnosis via blood tests. Testing of tumor samples is often required in first-generation individuals (01; 91). A variety of mutations have been demonstrated including missense mutations, nonsense, large deletions, splice-site mutations, point mutations, and small deletions. Missense mutations (which result in a complete protein product) and large deletions (which result in no protein product) are both associated with milder phenotype. Milder disease is also seen in patients with mutations in exons 9 to 15. Missense mutations are associated with longer survival than patients with nonsense and frameshift mutations. Extensive lists of neurofibromatosis 2 mutations are available. It is important to recognize that some patients who were thought to have schwannomatosis actually have neurofibromatosis 2. Careful assessment of patients with multiple schwannomas, particularly where there is a family history, should include genetic testing for neurofibromatosis 2 as well as MRIs of the brain and IACs. Genetic testing provides important information for patient management and should be done in all patients (26).
Vestibular schwannoma. Vestibular schwannomas present the most frequent challenge in patient management. Although most vestibular schwannomas are benign tumors, they cause significant morbidity primarily due to hearing loss, which has a major impact on quality of life. Patients with neurofibromatosis 2 consistently indicate that hearing loss is their major concern. However, removal of vestibular schwannomas is difficult. Pathologic studies demonstrate that vestibular schwannomas are multifocal. Removal of vestibular schwannoma is associated with significant potential complications including hearing loss and facial nerve injury. The main indications for intervention are brainstem compression, progressive hearing loss, and other cranial nerve (most commonly facial) dysfunction (25). Treatment options include conservative management (observation), surgery, radiosurgery, and chemotherapy.
Surgery. Due to increase rate of recurrence, more aggressive growth pattern compared to sporadic vestibular schwannoma and younger age of presentation surgery is favored over radiosurgery (85; 101). In a retrospective review, 20% of patients initially treated with radiotherapy required surgery, whereas another 13% were managed conservatively despite growth (101). It is important to recognize that small tumors may remain stable for years and that surgery for all small tumors would result in overtreatment of some tumors that may never grow or produce hearing loss. Surgery should be considered when there is evidence of growth on serial MRI or when significant brainstem compression is present. In patients with bilateral vestibular schwannoma where 1 tumor is growing, management decisions become more complicated.
Surgical approach for vestibular schwannoma is commonly retrosigmoid or translabyrinthine. A translabyrinthine approach is commonly performed due to lack of useful hearing at time of surgery as well as low likelihood of hearing preservation. This approach also allows for excision of an adjacent facial nerve tumor with reinnervation anastomosis (101). However, the translabyrinthine approach can be done with good hearing preservation. The middle fossa approach to vestibular schwannoma should be considered only in small tumors. Injury of the adjacent facial nerve is a possible complication with all surgical approaches and can lead to inability to close the ipsilateral eye, causing corneal ulcerations and potentially blindness (25; 26; 101). Thus, surgery for neurofibromatosis 2-related vestibular schwannomas are ideally referred to centers with experience and expertise. Considerations for operating must take into account hearing dysfunction, tumor size and growth rate, extent of brainstem compression, facial nerve function (07), and the presence of a contralateral vestibular schwannoma.
Radiotherapy. Stereotactic radiosurgery (SRS) has been used frequently in neurofibromatosis 2-related vestibular schwannomas, especially small to medium-sized tumors (less than 3 cm). The advantage of stereotactic radiosurgery compared to surgery is its minimally invasive nature and its potential for reasonable hearing and facial nerve function preservation (53). Tumor control rates with stereotactic radiosurgery for sporadic versus neurofibromatosis 2-related vestibular schwannomas were similar at 87% at 5 years (54). In a series by Kruyt and colleagues, a lower marginal dose of radiation was used (11 Gy compared to greater than 12 Gy), with good hearing preservation at 1 to 6 years as well as lower reported complications, namely facial neuropathy (92; 54). However, although short-term hearing preservation is good with stereotactic radiosurgery, long-term hearing loss is a significant risk due to cochlear radiation. Stereotactic radiosurgery may also make subsequent surgery more difficult. There is the additional risk of malignant transformation from radiation in a tumor predisposition syndrome. Malignant peripheral nerve sheath tumors have been reported in patients with neurofibromatosis 2 who have had stereotactic radiosurgery. Although the numbers are small, this is a uniformly fatal complication rarely seen in neurofibromatosis 2 patients without stereotactic radiosurgery. In an extensive review of the literature, the estimated overall risk for malignant transformation in vestibular schwannoma in neurofibromatosis patients is 25 per 100,000 compared to 1 to 2 per 100,000 without radiation (28; 90).
Conservative management. Neurofibromatosis 2-related vestibular schwannomas have a variable growth rate and may even slow down with age (07; 08). Given potential risks of surgery and radiotherapy, a conservative management approach is advisable in asymptomatic patients with serviceable hearing and stable imaging (74). Patients should undergo annual MRIs of the brainstem as well as audiological assessments for close follow up (69; 32). In a study of patients with bilateral vestibular schwannomas and serviceable hearing, 66% of patients maintained serviceable hearing after 6 years of follow up, and there was no correlation between growth rate and hearing preservation (74). In a careful review of the literature, Sughrue and colleagues concluded that patients with tumor growth greater than 2.5 mm/year had a nearly doubled rate of hearing loss at 7 years compared to almost 15 years for the other patients (99). Patients with less than 2.5 mm/year of growth and stable hearing may be ideal candidates for conservative management.
Chemotherapy. In a landmark publication by Plotkin and colleagues, vestibular schwannomas were shown to be enriched in vestibular endothelial growth factor receptors, and at least 40% of patients responded to bevacizumab with either tumor shrinkage or improvement in hearing. Bevacizumab is an antiangiogenic agent inhibiting vascular endothelial growth factor. Vestibular schwannomas have been shown to express vestibular endothelial growth factor within tumor cells as well as have increased vessel density attributed with excessive vestibular endothelial growth factor (77; 105). These findings led to a compassionate use study of bevacizumab (5 mg/kg given every 2 weeks) in patients with high risk of hearing loss from progressive vestibular schwannomas, showing a reduction of tumor size in 60% of patients and improvement in word recognition in 4 of 7 patients (77). In a retrospective analysis of bevacizumab use in neurofibromatosis 2 vestibular schwannomas, 90% of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years. Radiographic response, defined as stable or decreased tumor size, was seen in 88% at 1 year and 54% at 3 years (75). In a prospective study performed in the United Kingdom, use of bevacizumab (7.5 mg/kg every 3 weeks) lead to hearing stability or improvement in 86% of patients and partial radiographic response in almost 40% of patients (66). In general, treatment with bevacizumab is well tolerated, with the most common toxicities being fatigue, myalgias, proteinuria, amenorrhea, and hypertension (67). Relapse after cessation of therapy as well as possible kidney injury are concerns. However, these studies demonstrated that a chemotherapeutic approach is possible for vestibular schwannoma. Additionally, pathologic studies indicate that vestibular schwannoma is associated with a significant inflammatory response. A retrospective study of vestibular schwannoma suggested that patients who took aspirin regularly had reduced growth of vestibular schwannoma (48). A subsequent retrospective analysis of 564 vestibular schwannoma patients using aspirin or other nonsteroidal anti-inflammatory drugs disputes this finding (44). Nevertheless, the findings indicate that the inflammatory response in vestibular schwannoma could be a potential therapeutic target. Both the bevacizumab trial and the aspirin study have at least partially shifted the focus for management of vestibular schwannoma in neurofibromatosis 2. Clinical trials of different agents for vestibular schwannoma are now a potential option for patients and provide hope of future management (51).
Hearing preservation. Despite conservative and aggressive management with surgery and radiation, hearing loss remains a persistent problem in neurofibromatosis 2. Because hearing loss is much a major contributor to morbidity in neurofibromatosis 2, hearing preservation is a critical focus of management. Hearing preservation dictates choices in terms of surgical management of vestibular schwannomas. Consideration of hearing preservation plays a role in when and how to do surgery in patients with bilateral disease where 1 tumor is growing. In patients with unilateral hearing loss and a growing contralateral tumor, bevacizumab may be considered. Alternatively, surgery with implantation of an augmented hearing device should be considered.
Hearing implants are auditory brainstem implants (ABI) and cochlear implants (CI). The choice of implant depends upon the extent of hearing preoperatively as well as intraoperative assessment of cochlear nerve response through electrophysiological testing. If patients have cochlear nerve action potential then a cochlear implant may be placed; however, neuropraxia from surgical manipulation can cause absent responses; thus, repeat testing 6 to 8 weeks after surgery is recommended. If no response is noted after 6 to 8 weeks, then auditory brainstem implant is indicated (102).
Auditory brainstem implants are electrodes that are placed on the brainstem over the cochlear nuclear complex during vestibular schwannoma surgery (89). Outcomes from auditory brainstem implants are variable, with only a small amount of patients recovering function to understand conversational speech (89). Much of the benefit with understanding speech with auditory brainstem implants has been seen in combination with lip reading (86). Thus, if cochlear nerve function is intact, cochlear implants should be considered the first choice for hearing rehabilitation.
Cranial meningioma. Approaches to managing cranial meningiomas in neurofibromatosis 2 are similar to patients with sporadic meningiomas, with standard of care consisting of conservative management for asymptomatic and slowly growing tumors and surgical resection for those that are symptomatic or show rapid growth. In a longitudinal study by Goutagny and colleagues, 66% of meningiomas in 74 patients showed minimal to no growth in over 9 years of follow up. Thus, conservative management is a safe management strategy (40). The multiplicity of meningiomas and their location in higher-risk anatomical areas, such as optic nerve sheath and skull base, in neurofibromatosis 2 may present a surgical challenge. Radiosurgery has been suggested as a potential treatment alternative (56; 12). In a 22-year patient series of stereotactic radiosurgery, 15 patients were treated for numerous meningiomas with single fraction stereotactic radiosurgery (median dose 16 Gy) with a 5- and 10-year local control rate of 96%; no cases of malignant transformation and only 1 case of radiation necrosis were seen during the follow-up period (12). However, this is a small series, and concerns about radiation induced malignant transformation or change in tumor to a more aggressive meningioma type remains a significant concern.
Ependymoma. The optimal management of neurofibromatosis 2-related ependymomas is usually conservative. A significant number of patients are asymptomatic despite potentially having multiple ependymomas (76). Surgery can be considered for symptomatic patients. A retrospective study compared outcomes of conservative management versus surgical intervention of spinal ependymoma based on differing practice patterns in neurofibromatosis 2 centers in the United Kingdom and France. In the conservatively managed group from the United Kingdom, 27% experienced neurologic deterioration on follow up, whereas 11% of those patients operated in a neurofibromatosis 2 specialty center experienced postoperative decline. Based on these findings, patients with growing symptomatic ependymomas may be considered for surgery; however, surgery should be done in a center with significant expertise with this problem (47). In our experience, a very limited resection with puncture of the cystic component can provide relief for years. In patients who remain symptomatic, bevacizumab should be considered. Bevacizumab can decrease the cystic component of the tumor but does not necessarily shrink the solid component of the tumor (35; 65).
Eye lesions. Neurofibromatosis 2 patients require annual dilated funduscopic examination to monitor for potential ocular complications, which as previously discussed include cataracts, epiretinal membranes, and hamartomas. Approximately 10% to 25% of patients with cataracts experience vision degradation for which extraction can be performed (15; 13). Hamartomas remain a significant problem that can progress over time and cause visual loss.
Patients with neurofibromatosis 2 have a decreased life expectancy. For patients diagnosed in the 1970s and 80s, the life expectancy after diagnosis was a dismal 15 years with an average age of death of 36 years (30). A retrospective study of neurofibromatosis 2 patients in the United Kingdom to evaluate predictors of risk of mortality found that earlier age of diagnosis, presence of meningiomas, and treatment at a non-specialty center were associated with poorer outcome (05). Although it is clear that life expectancy has improved over the last 10 years, early death is still a reality for the most severely affected patients. Genetic analysis demonstrates that patients who are mosaics or patients with missense mutations have a better outcome compared to those with nonsense, frameshift, splice-site mutations and deletions (05).
A deleterious effect of pregnancy on the natural history of neurofibromatosis type 2 has been suggested by a few studies (02; Kanter et al 1978). This, taken together with a report that vestibular schwannomas were more common and larger in women than men with neurofibromatosis type 2, and the finding of estradiol receptors on schwannomas and meningiomas, led to the suggestion that there may be a hormonal effect on the course of the disease. Other reports have not confirmed either pregnancy or gender effect (30).
With regard to potential anesthetic complications for which a patient undergoing vestibular schwannoma surgery might be at increased risk, the use of nitrous oxide as an anesthetic agent during surgery has been implicated in the development of tension pneumocephalus (64). The exact pathophysiology associated with the use of nitrous oxide in this setting is debated but may be related to its greater solubility than nitrogen in blood, which results in changes in middle ear pressure leading to the pneumocephalus.
Karen S Dixit MD
Dr. Dixit of Northwestern University Feinberg School of Medicine has no relevant financial relationships to disclose.See Profile
James H Tonsgard MD
Dr. Tonsgard, Director of the University of Chicago Ambulatory Program for Neurofibromatosis, has no relevant financial relationships to disclose.See Profile
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Novocure for advisory board membership, and research support from BMS.See Profile
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