79.1 Introduction

Neurofibromatosis type 2 (NF2) is a rare neurogenetic syndrome inherited in an autosomal dominant pattern, with an estimated incidence of roughly 1:30,000.s. Literatur Although heritable, approximately 50% of people with NF2 have a de novo mutation. The causative mutation on chromosome 22q11.2 leads to inactivation of the tumor suppressor protein Merlin. The lack of functional Merlin has been shown to decrease apoptosis and increase proliferation indexes in Schwann cells. Loss of both copies of normal NF2 results in tumor formation in multiple different cell types (Schwann, arachnoidal, and ependymal cells) leading to nervous system tumors including schwannomas of the cranial and peripheral nerves, meningiomas, and ependymomas (Fig. 79‑1 ). A more detailed discussion regarding the molecular biology and genetics of NF2 can be found in Chapters 5 and 78.

Neurofibromatosis was first described by the German pathologist Friedrich Daniel von Recklinghausen in 1882, and was subsequently stratified into types 1 and 2 when the associated genes for the two conditions were identified on separate chromosomes. Neurofibromatosis type 1 (NF1) and NF2 are now known to be distinct clinical entities. NF1 is far more common (estimated 1:3,000) and often diagnosed at an earlier age based on the high frequency of dermatologic findings such as café au lait spots and cutaneous neurofibromas. In contrast, NF2 is often diagnosed in the teenage years or later when the initial signs and symptoms related to intracranial or spinal tumors begin to manifest. The most common presenting symptoms of NF2 include hearing loss, tinnitus, balance dysfunction, cranial neuropathy, and/or focal weakness suggestive of expanding intracranial or spinal lesions.s. Literatur ^,​ s. Literatur

The diagnosis of NF2 can be made on the basis of either clinical or molecular evidence. Patients with an established family history of NF2 are often identified early in the course of disease from screening protocols or heightened suspicion. This is particularly true in cases where a causative mutation for a specific individual is known, as family members can be screened for the same mutation in order to confirm the diagnosis, even before clinical symptoms develop. In contrast, an early clinical diagnosis of NF2 in patients without a family history of the disease can be challenging, as the presenting signs and symptoms are frequently nonspecific.s. Literatur ^,​ s. Literatur Furthermore, even with radiographic evidence of a tumor, the diagnosis of NF2 can be initially missed or overlooked, as tumors occurring in NF2 are common tumors in the general population and can occur metachronously or in a nonconventional pattern. Although the constellation of multiple schwannomas and meningiomas is a hallmark of NF2, some patients may initially present with only one or two tumors—findings that may not directly suggest NF2 or reach diagnostic criteria at initial presentation.s. Literatur ^,​ s. Literatur ^,​ s. Literatur ^,​ s. Literatur ^,​ s. Literatur Furthermore, nodular enhancement of cranial nerves from leptomeningeal disease related to malignant or inflammatory conditions, or multiple meningiomas as seen in meningiomatosis not associated with NF2, can mimic NF2 (Fig. 79‑2 ). Importantly, it is now known that intracranial schwannomas and meningiomas can occur in some patients with schwannomatosis, a distinct syndrome that has many overlapping features with NF2, making the accurate diagnosis of NF2 even more challenging.s. Literatur ^,​ s. Literatur ^,​ s. Literatur Given that NF2 is rare and that the presenting symptoms and imaging findings can occur coincidentally or in the setting of other disease processes, clinicians need to be knowledgeable about the spectrum of NF2 and have a high index of suspicion to make the correct diagnosis in a timely manner.

79.2 Diagnostic Criteria for Neurofibromatosis Type 2

Clinical diagnostic criteria for NF2 were originally proposed by the National Institutes of Health (NIH) in 1987 to distinguish NF2 from NF1, and were subsequently revised in 1991.s. Literatur Additional groups such as the Manchester group in 1992s. Literatur and a panel of experts convened by the National Neurofibromatosis Foundation (NNFF) in 1997 developed independent guidelines.s. Literatur In all proposed criteria, the presence of bilateral vestibular schwannomas (VSs) is pathognomonic for NF2 because of the rarity of such an event occurring spontaneously. Since NF2 is autosomal dominant, all guidelines also allow a first-degree relative with NF2 paired with either a unilateral VS or the presence of two other features that are part of the NF2 spectrum (i.e., meningioma, schwannoma, ependymoma, or juvenile cataract) as diagnostic criteria. While the presence of bilateral VS is a clear criterion for the diagnosis of NF2, some clinicians were concerned that the initial diagnostic criteria were overly restrictive, missing younger patients who would later develop full features of NF2. To address this, the NNFF recommended differentiating between “confirmed NF2” and “presumed NF2” in order to encourage regular clinical evaluation in those suspected of having NF2.s. Literatur The finding of a VS or meningioma in a young person less than 30 years of age, for instance, raises suspicion for NF2s. Literatur and although not all cases of VS in a young patient lead to later development of NF2,s. Literatur several patients will eventually develop NF2 based on clinical criteria.s. Literatur

In 2002, Baser et al reviewed the sensitivity and specificity of the four previously proposed clinical diagnostic criteria against a large series of patients in the United Kingdom NF2 registry that presented without bilateral VSs, but later met criteria for NF2. While the specificity was 100% with each of the existing criteria, the sensitivity of any one of the criteria was ≤ 70%.s. Literatur Baser et al then offered revised criteria to increase the diagnostic sensitivity by developing a scoring system that ascribed points to family history, presence of unilateral or bilateral schwannoma, one or more meningiomas, cutaneous schwannoma, other cranial nerve tumors, mononeuropathy, or cataract with more points ascribed when any of the aforementioned occurred in people younger than 30 years. With these criteria, the sensitivity increased to 80% while maintaining 100% specificity. The Baser revised system also allows for additional genetic testing for indeterminate cases.s. Literatur As mentioned earlier, there are recent calls to further revise the criteria to clarify between NF2 and schwannomatosis based on LZTR1 testing.s. Literatur The clinical diagnostic criteria currently in use are shown in Table 79‑1 .

79.3 Other Conditions with Overlapping Clinical Features

The complexity of appropriately applying even the most exacting diagnostic criteria still leaves uncertainty in diagnosis and difficulty in discerning NF2 from overlapping conditions. For example, another neurogenetic condition, schwannomatosis, is clinically and genetically distinct from NF2, but the syndromes share several clinical and molecular features. Like NF2, schwannomatosis is characterized by multiple schwannomas of the spine and peripheral nerves but without bilateral VS (Table 79‑2 ).s. Literatur As mentioned earlier, it is now recognized that patients with schwannomatosis may have unilateral VS or meningioma.s. Literatur ^,​ s. Literatur Some families have been described with multiple meningiomas without VS or with unilateral VS.

There is also mosaicism of NF2 that complicates the ability to clinically diagnose NF2. In these cases, the mutation affects only a portion of the individual’s cells and therefore only a segment of the body develops tumors. This localized effect makes the distinction between sporadic tumors, segmental NF2, and schwannomatosis challenging. Genetic mosaicism can also lead to difficulties in acquiring a molecular diagnosis, as lymphocyte blood testing is often negative. In such cases, the diagnosis can only be confirmed via molecular testing of several individual tumors and serum. However, access to multiple tissue samples is rarely feasible and tumor biopsy is not advised if performed only for the purpose of establishing a genetic diagnosis.s. Literatur

Finally, when assessing a patient with apparent bilateral VS, with or without additional cranial nerve schwannomas or meningiomas, it is important to take a detailed history to ensure that there has not been prior radiation involving the affected area resulting in radiation-induced neoplasia rather than NF2-driven neoplasms. It is also important to ensure that there are no other signs of a systemic process that can lead to leptomeningeal thickening, or multiple cranial neuropathies such as Lyme’s disease, neurosarcoidosis, or cancer with leptomeningeal involvement.

79.4 Vestibular Schwannomas

In NF2, schwannomas can occur along any cranial nerve, either in isolation or with multiple contiguous or clusters of tumors. Compared to other cranial nerves, schwannomas develop on the vestibular nerves with much greater frequency—approximately 60% of patients with NF2 have bilateral VS on their initial assessment, and over 95% will have bilateral VS by the age of 30 years.s. Literatur ^,​ s. Literatur As discussed elsewhere in this text, the consequences of VS growth are numerous but can include hearing and vestibular loss, trigeminal neuropathy or neuralgia, facial nerve paralysis, and eventually brainstem compression, hydrocephalus, and death.

The behavior of VS in people with NF2 is highly variable with individual tumors following linear, sigmoid, logarithmic, and overall irregular growth curves based on traditional linear measurements on MRI.s. Literatur Despite this variability, there is consensus that these tumors grow over time with the majority of NF2-associated VS doubling their volume within 5 years.s. Literatur Further, left and right VSs often grow at similar rates in people with NF2, but the onset of growth is variable resulting in different tumor volumes on either side.s. Literatur Overall, VSs tend to slow in growth as patients age, with being more rapid growth in children and young adults, but growth can occur life-long.s. Literatur ^,​ s. Literatur ^,​ s. Literatur A recent natural history study assessing volumetric growth of 39 VSs in 52 patients with NF2 over a median of 36 months showed that with volumetric measures, growth patterns are most commonly saltatory, followed with equal frequency by exponential or linear growth but intermixed with long periods of stability.s. Literatur Given this variability, patients with NF2 are recommended to undergo MRI brain with thin cuts through the internal auditory canals at least annually and more frequently if there is evidence of active growth or if receiving treatment.s. Literatur

Several studies have demonstrated that there is not a strong association between absolute tumor size (as assessed with MRI volumetrics) and hearing function based on both retrospective and prospective evaluations.s. Literatur ^,​ s. Literatur ^,​ s. Literatur ^,​ s. Literatur ^,​ s. Literatur ^,​ s. Literatur Given the weak association between these two parameters, it is important to pair MRI and audiometric testing together during clinical surveillance. Hearing loss in the absence of tumor growth commonly occurs, suggesting that other tumor, paracrine, or systemic factors play a role in hearing deterioration. The converse is also true, which a tumor may increase in size without clear progression of sensorineural hearing loss. Hence, both evaluations are needed and audiometry should be performed at least annually, but for young patients, people with recent changes in hearing, or those in active treatment, audiometry should be done more frequently as clinically indicated.