Open access peer-reviewed chapter

Neurofibromatosis Type 2: Case Presentation and Review of the Literature

Written By

Tayler D. Payton and Marcus L. Ware

Submitted: 17 January 2023 Reviewed: 17 January 2023 Published: 21 February 2023

DOI: 10.5772/intechopen.1001100

From the Edited Volume

Neurofibromatosis - Diagnosis and Treatments

Lee Roy Morgan

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Abstract

Patients diagnosed with neurofibromatosis type 2 (NF2) are likely to develop vestibular schwannomas, meningiomas, and other tumors that may be difficult to treat. These tumors and their locations can pose unique challenges for patients, caregivers, and medical providers. We describe a case of a patient with NF2 who presented with multiple tumors including bilateral vestibular schwannomas and multiple meningiomas. This case highlights the medical and surgical complexity of care of patients with NF2 and the need for ongoing surveillance by a multidisciplinary medical team. We also provide a brief review of literature focusing on NF2 and its treatment.

Keywords

  • neurofibromatosis type 2
  • case studies
  • NF2
  • vestibular schwannomas
  • meningiomas

1. Introduction

Our patient is a 63-year-old gentleman with several weeks’ history of drooling, dysarthria, and altered mental status. His relevant past medical history included a brain tumor that had been removed 10 years earlier at a local hospital (no records available). According to his family, the patient had a single follow-up visit after surgery and had done well since. On examination, the patient was confused; he was oriented to people, but not place or time. Cranial nerve examination was unremarkable except for dysarthria and slight tongue deviation to the left. He had severe ataxia with a positive Romberg sign. His neurological exam was otherwise normal. He had an MRI that showed small bilateral vestibular schwannomas and multiple meningiomas including a large tumor attached to the falx on the right, a large tumor in the occipital region, and a cerebellar tumor causing compression of the fourth ventricle (Figure 1). Given these findings, the patient was diagnosed with neurofibromatosis Type 2 (Table 1).

Figure 1.

Post-contrast T1-weighted MRI images in the axial orientation. Panel A shows a large meningioma that is attached to the posterior falx. Panel B shows a large meningioma attached to the dura of the posterior fossa. The arrows in this panel point to his vestibular schwannomas. Panels A and B show brain compression and narrowing of the right lateral ventricle in Panel A and 4th ventricle in Panel B. Panel C shows that the compression has been alleviated in the occipital area, and Panel D shows decompression in the posterior fossa. Panels A and B were performed before surgery. Panels C and D were performed 3 months after surgery.

1.Bilateral vestibular schwannomas <70 years of age
2.Unilateral vestibular schwannoma <70 years and a first-degree relative with NF2
3.Any two of the following: meningioma, schwannoma (non-vestibular), ependymoma, cerebral calcification, cataract, and first-degree relative to NF2 or unilateral vestibular schwannoma and negative LZTR1 testing.
4.Multiple meningiomas and unilateral vestibular schwannoma or any two of the following: schwannoma (non-vestibular), neurofibroma, glioma, cerebral calcification, and cataract
5.Constitutional or mosaic pathogenic NF2 gene mutation from the blood or by the identification of an identical mutation from two separate tumors in the same individual.

Table 1.

Clinical criteria for NF2 [1, 2].

The patient’s symptoms were clinically related to cerebral compression and hydrocephalus caused by his right occipital and large cerebellar tumor. He was offered surgical intervention. The patient underwent a combined right occipital and posterior fossa craniotomy for tumor removal. Pathological evaluation of both tumors showed WHO Grade I meningioma. His postoperative images showed excellent resection with good decompression (Figure 1). The patient did well postoperatively, and he returned to his normal level of function over the next 3 months. The patient was followed in our multidisciplinary CNS clinic every 4 months thereafter with an MRI of the brain with and without contrast.

One year after surgery, the patient began having difficulty with his balance and developed bilateral hand weakness. He had an MRI that showed compression of the foramen magnum with development of a cervical syrinx (Figure 2). The patient was offered and underwent a suboccipital craniectomy with C1 and C2 laminectomies and duroplasty to decompress his cerebellum and brainstem. The patient did well after surgery and returned to his normal function after 6 weeks. Eight months after surgery, he had a routine MRI with and without contrast that showed growth of three of his tumors. The patient was not symptomatic at the time. Given his history, the patient and his family elected to have these tumors treated with stereotactic radiosurgery. These tumors were treated with 12 Gy to a 50% isodose line (a relatively low dose of radiosurgery). Three months after this treatment, he developed gait instability, and MRI showed extensive edema associated with treated tumors. He was treated with dexamethasone (steroids) for 6 months. His symptoms resolved after several weeks of treatment. Unfortunately, we attempted to wean his steroids on three occasions with return of his symptoms. At this point, the patient was treated with bevacizumab infusion every 2 weeks. His swelling resolved after 4 cycles, and bevacizumab was discontinued. The patient is currently at his baseline and has continued follow-up in our multidisciplinary CNS clinic.

Figure 2.

A T2-weighted sagittal view of the cerebellum and cervical spine of our patient. In Panel A, we can see the compression of the cerebellum with a syrinx in the cervical spinal cord. Panel B shows decompression of the cerebellum with reduction in size of the syrinx in the spinal cord. The arrows point to the syrinx in these two images.

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2. Literature review

Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones [3]. Neurofibromatosis has three types: NF1, which is the most prevalent in 96% of the cases, NF2 in 3% of the cases, and schwannomatosis (SWN) in less than 1% of cases. NF1, or Von Recklinghausen’s disease, causes a variety of clinical manifestations such as multiple flat, light-brown patches of skin pigment (café-au-lait spots), skin fold freckling, visible neurofibromas under the skin, and small nodules of the iris (Lisch nodules) [3]. NF1 gene located on 17q encodes a tumor suppressor protein called neurofibromin, a tumor suppressor protein that is produced in nerve cells, oligodendrocytes, and Schwann cells. A mutation in neurofibromin that renders it nonfunctional promotes the growth of neurofibromas throughout nerves in the entire body.

NF2 is an autosomal dominant multiple neoplasia syndrome that is a result of mutations in the NF2 suppressor gene, which is located on chromosome 22q [4]. The clinical diagnostic criteria have changed over time [5]. The current diagnostic criteria are described in Table 1 [1, 2]. This gene encodes for the protein Merlin (moesin-ezrin-radixin-like protein) also known as Schwannomin [6]. Merlin is involved in the anchorage of the cytoskeleton to the cell membrane and is important for cell growth, protein translation, and cellular proliferation. Merlin blocks signaling caused by integrins and tyrosine receptor kinases at the membrane [7]. The absence of a normally functioning Merlin protein has been found to be associated with a predisposition to tumor formation [8]. This protein also negatively regulates Schwann cell production, and loss of this protein’s functionality allows for Schwann cells to overproduce [7]. Various types of mutations, such as protein-truncating alterations (frameshift deletions/insertion and nonsense mutations), splice-site mutations, and missense mutations have been identified [9]. The milder type of NF2, Gardner type, has been found to be associated with missense mutations [10]. Nonsense/frameshift mutations produce a truncated protein and tend to be associated with a more severe phenotype, earlier onset, more rapid disease progression, and higher tumor burden with more spinal and intracranial tumors in addition to vestibular schwannomas [11].

Although many patients have symptoms before coming to medical attention, the average age of diagnosis of NF2 is 25 years [10]. Epidemiological studies place the incidence of NF2 between 1 in 33,000–40,000 live births, and there is no apparent difference in the proportion of men versus women who develop NF2 [10]. No prevalence has been described based on ethnicity. The actuarial survival after diagnosis is 15 years, and the average age of death is 36 years.

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3. Tumors associated with NF2

Schwannomas are proliferations of neoplastic cells which show histologic, ultrastructural, and molecular similarities to the Schwann cells of the peripheral nervous system. They often arise at the glioma–Schwann cell junction within the internal auditory meatus and commonly arise from the superior vestibular nerve [10]. Vestibular schwannomas are the most common tumor in NF2 and are usually present bilaterally. Bilateral vestibular schwannomas are the distinctive feature of neurofibromatosis type 2 and are identified in 90–95% of patients [12]. This was the finding that established the diagnosis in our patient presented here (Table 1). Vestibular schwannomas clinically present as hearing loss progressing to deafness, dizziness and balance problems, tinnitus, facial nerve paralysis, and brainstem compression. Although more than 99% of vestibular schwannomas in NF2 are benign, they remain a substantial cause of morbidity because of their location [13]. Vestibular schwannomas rarely progress to malignancy, and sometimes unilateral vestibular schwannomas completely regress in size [14]. In the case presented here, the patient has partial hearing loss and functions well with hearing aids. His hearing is monitored annually, and he continues to do well. Trigeminal nerve schwannomas are the most commonly seen after vestibular, with oculomotor schwannomas following as the third most common schwannoma seen intracranially [10].

Meningiomas are the second most common tumor type in NF2, and the most common central nervous system tumor occurring throughout the central nervous system in 50–75% of individuals, often with multiple tumors [15]. Meningiomas are proliferations of neoplastic cells with histologic, ultrastructural, and immunophenotypic evidence of meningothelial cell differentiation. These proliferations can vary in histological appearances and genetic aberrations. Intracranial meningiomas are diagnosed in 45–58% of patients with NF2, and spinal meningiomas are diagnosed in approximately 20%. NF2-associated meningiomas occur most frequently in the supratentorial region in the frontal, parietal, and temporal regions as well as along the falx cerebri [16]. Although some meningiomas remain static and do not require active treatment, meningiomas associated with NF2 tend to be higher grade than sporadic tumors [5]. In the case discussed here, our patient has a predominance of meningiomas. Meningioma growth and associated swelling were the major cause of morbidity in this patient. Nearly all patients with NF2 develop meningiomas at some time throughout the progression of the syndrome. 50% of patients with NF2 present with schwannomas and meningiomas; 90% present with spine tumors in addition to schwannomas [10].

Ependymomas are proliferations of neoplastic cells with histologic, molecular, and ultrastructural similarities to the ependymal cells of the ventricles and spinal canal [16]. These tumors are diagnosed in approximately 33–53% of individuals with NF2, most commonly involving the posterior fossa and cervicomedullary region of the spine. Ependymomas associated with NF2 more often arise in patients who possess a truncating NF2 mutation, indicating that this tumor type is more associated with aggressive variants of NF2. Various spinal tumors may occur in patients with NF2 and can be found in the cervical, thoracic, and lumbar regions. Continued growth of spinal tumors causes loss of motion, numbness, tingling, and eventually paralysis [10].

Studies show that NF2 patients are frequently diagnosed with peripheral neuropathies [16]. Peripheral neuropathy in NF2 patients often presents as a mononeuropathy in children and as a polyneuropathy in adults. Nerve biopsies from patients with NF2 suggest that peripheral neuropathy results from local compression of nerves by Schwann cells tumors or non-mass-forming Schwann cell proliferations. Peripheral neuropathy can be difficult to treat and involves symptomatic control like neuropathic medication.

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4. Patient presentation

Patients with NF2 can present with a variety of clinical manifestations. Ophthalmologic abnormalities are present in most patients, including cataracts (70–80%), retinal changes (20–44%), strabismus (12–50%), amblyopia (12%), optic nerve sheath meningiomas and other optic pathway tumors (10–27%), and extra-ocular movement abnormalities (10%). NF2 patients may also develop retinal hamartomas [16]. Cutaneous lesions are a frequent manifestation that patients present with NF2; however, cutaneous lesions are far more common with the NF1 subtype [16]. The cutaneous nodules associated with NF2 tend to present in a paler form and have more irregular margins in comparison to the lesions seen in NF1. There are three types of skin tumors that occur in NF2: NF2 plaques, nodular schwannomas, and neurofibromas. Approximately 70% of NF2 patients exhibit cutaneous lesions, and the most frequent type are “plaque-like” dermal plexiform schwannomas associated with slight pigmentation and increased hair growth. Subcutaneous nodular schwannomas that are associate with peripheral nerves are also present [16].

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5. Patient management and treatment

The central goal of management of NF2 should be to maintain patient function and quality of life while managing tumor load. This can be extremely challenging. The literature shows strong evidence that these patients are best managed by a multidisciplinary team involving genetics, neurosurgery, otolaryngology, ophthalmology, neurology, radiology, pathology, and audiology [17]. Patients with NF2 at centers with this approach have better outcomes overall. We have embraced this multidisciplinary approach, and NF2 patients are followed in our Multidisciplinary CNS Tumor Clinic with these services available. In general, treatments for patients with NF2 can be divided into 4 major categories: conservative therapy, surgery, radiosurgery, and chemotherapy.

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6. Conservative therapy

Despite the high prevalence of patients with multiple tumors, most meningiomas and spinal tumors are asymptomatic and are first discovered on MRI [10]. We recommend routine surveillance in all patients with NF2 whether or not they are symptomatic from their tumors. Patient visits should always include a complete physical examination and the appropriate imaging which usually includes a high-quality MRI of the brain and/or spine with and without contrast. MRIs are always compared to the previous MRIs for any detrimental changes. This comparison may be challenging in patients with multiple tumors in multiple locations (such as the patient presented here). A dedicated neuroradiologist is essential in these cases. The frequency of visits and imaging may vary from 4 months to annually based on clinical parameters. Patients with vestibular schwannomas require regular audiology evaluations, and patients with tumors affecting the optic pathway require regular vision evaluations. At our center, this is performed by a neuro-ophthalmologist. The patient discussed here was found to have asymptotic tumor growth during a routine surveillance visit. Such care allows tumors to be treated before they can grow to larger sizes.

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7. Surgery

Surgery is often the treatment of choice when an NF2 patient has a tumor that is actively growing. Growing meningiomas may result in increased intracranial pressure, intractable headaches, hydrocephalus, and seizure disorders [10]. The patient presented here had symptoms from direct cerebral and cerebellar compression as well as hydrocephalus. In the case of this patient, surgery was necessary, and the patient derived great benefit from this intervention. Meningiomas involving the skull base may be much more difficult to remove and have a higher risk of postoperative neurological morbidity. Spinal meningiomas and schwannomas can cause symptomatic compression and often require surgery. The difficulty of removing these tumors depends on tumor size and location. Ependymomas rarely require removal. However, when spinal ependymomas are removed, they may also be challenging and require an experienced team. Vestibular schwannomas should be surgically addressed when they are growing because they can cause brainstem compression, hearing loss, and facial paralysis. We firmly believe that these tumors should be operated at centers that have multidisciplinary teams that manage a high volume of patients.

The patient presented here also had an additional surgery for decompression of an acquired Chiari malformation with associated syrinx, or expanded space within the spinal cord. A Chiari malformation is defined as the caudal displacement of the cerebellar tonsils below the level of the foramen magnum [18]. Syringomyelia, or the presence of a syrinx, can present in 30–70% of cases and can cause neurological deficits [19]. The cause of this problem is the lack of flow across the foramen magnum, and first-line treatment involves restoring this flow surgically. Adequate decompression with restoration of flow leads to resolution of the syrinx with abatement of symptoms. In this case, our patient presented with difficulty with balance and developed bilateral hand weakness; both are classical symptoms of cervical syrinx. In this case, the patient had known posterior fossa crowding that improved after decompression. We attribute his development of a syrinx to both scarring after surgery, which can decrease the flow of CSF across the foramen magnum, and residual compression caused by other tumors in his posterior fossa that were not addressed by his previous surgery. As expected, surgical decompression of the posterior fossa, cervical laminectomies, and duroplasty restored the flow of CSF from his posterior fossa to the spinal canal and resulted in deflation of his syrinx and complete resolution of his symptoms. Although this is not a problem that is unique to patients with NF2 or meningiomas, this case is instructive in the management of acquired Chiari malformation and the management of associated syrinx.

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8. Radiosurgery

Stereotactic radiosurgery (SRS), or radiosurgery, is a treatment of tumors and other lesions using well-collimated, multiple small beams of ionizing radiation to treat a target, while reducing toxic exposure to surrounding tissues. SRS has been shown to be a safe and effective treatment for vestibular schwannomas and meningiomas in patients who do not have NF2 [20, 21, 22]. A recent study has shown that this is also the case in patients with NF2 [23]. These authors showed that in 18 patients with 120 convexity meningiomas, radiosurgery achieved a 99.1% tumor control rate with only a 0.8% risk of radiation-induced adverse events. The tumor volume ranged from 0.10 to 21.3 cm3 (median 0.66 cm3), with a median marginal dose range of 12–25 Gy (median 12 Gy) in this study. These results show that radiosurgery was safe and effective overall. Our patient experienced radiation-induced edema that had a protracted course after treatment with radiosurgery. The tumors treated in our patient were 5.9, 11.5, and 26.1 cm3 and were all treated with 12 Gy to the 50% isodose line. The radiation doses between tumors were negligible. Given that our patient had swelling associated with even the smallest tumor treated, we suspect that this is an idiosyncratic outcome that we cannot attribute to radiation dose or tumor size.

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9. Chemotherapy

There are established chemotherapy treatments for NF2. Vascular endothelial growth factor (VEGF)-A is important in the growth of schwannomas [24, 25]. Studies have shown tumor shrinkage and hearing improvement after patients begin treatment with bevacizumab (a monoclonal antibody against VEGF-A) [25, 26, 27, 28, 29]. There are a number of ongoing phase II clinical trials looking at this drug as a possible treatment. There are ongoing phase II clinical trials evaluating other agents including Icotinib, Axitinib, everolimus, Crizotinib, Brigatinib, and Selumetinib [3]. There is no current chemotherapy for meningiomas. The current data for the treatment of meningiomas with bevacizumab are mixed at best [30, 31, 32, 33, 34]. Our patient was placed on bevacizumab to treat his cerebral edema. Although this was quite effective in reducing the swelling associated with his tumor, there was no notable changes in the size of either of his vestibular schwannomas or meningiomas secondary to bevacizumab.

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10. Conclusion

In our case report, we detail the care of one of our patients with NF2. We have used this case to emphasize the challenges involved in the care of these patients. This patient has done well overall secondary to the care provided to him by all of his providers. We have also reviewed the literature of NF2 and other conditions affecting his care. Our goal with this description and review of the literature is to better elucidate the needs of these patients and the issues involved in providing care for patients with NF2.

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Written By

Tayler D. Payton and Marcus L. Ware

Submitted: 17 January 2023 Reviewed: 17 January 2023 Published: 21 February 2023