eMedicine Specialties > Radiology > Brain/Spine

Neurofibromatosis Type 2

Author: Andrew L Wagner, MD, Assistant Professor of Radiology, Instructional Faculty, University of Virginia School of Medicine; Director of Neuroradiology, Department of Radiology, Rockingham Memorial Hospital
Contributor Information and Disclosures

Updated: Mar 17, 2008

Introduction

Background

Neurofibromatosis 2 (NF2) is an inherited autosomal dominant syndrome characterized by multiple schwannomas, meningiomas, and ependymomas.^1,2 The most common tumor associated with the syndrome is the vestibulocochlear (cranial nerve [CN] VIII) schwannoma, and as many as 10% of patients with this tumor have NF2. Although it shares a name with neurofibromatosis type 1 (NF1; von Recklinghausen disease), the 2 diseases are separate entities. Neurofibromas are rarely found in NF2, which has led some to propose that the disease be termed schwannomatosis or MISME syndrome, the acronym for the following terms:

• Multiple inherited schwannomas
• Meningiomas
• Ependymomas

The term MISME has become used widely as a mnemonic to remember the disease.

Although a presumed case of NF2 was first described in 1882 by Wishart, the disease was not separated from von Recklinghausen disease until 1987, when it was demonstrated that the 2 disorders arose from different chromosomes. The genetic defect responsible for NF2 is a deletion of a portion of chromosome 22, the same chromosomal abnormality found in spontaneous spinal schwannomas, indicating that a single location causes Schwann cell tumor growth.^3,4,5,6

In 1988, the National Institutes of Health released a conference statement regarding neurofibromatosis that addressed the diagnosis of NF2.⁷ The criteria that were chosen for the diagnosis of NF2 were the following, of which only 1 criterion was needed to make the diagnosis:

• Bilateral CN VIII masses seen with appropriate imaging techniques (eg, computed tomography [CT] scanning or magnetic resonance imaging [MRI])
• A first-degree relative with NF2 and either a unilateral CN VIII mass or 2 of the following:
  • Neurofibroma
  • Meningioma
  • Glioma
  • Schwannoma
  • Juvenile posterior subcapsular lenticular opacity

In the past 2 decades, a revision to these diagnostic criteria of NF2 was proposed that concerns the addition of a section for presumptive or probable diagnosis of NF2. These modified criteria are listed as follows⁸ :

• Definite diagnosis of NF2
  • Bilateral CN VIII schwannomas on MRI or CT scan (no biopsy necessary)
  • First-degree relative with NF2 and either unilateral early-onset CN VIII schwannoma (age <30 y) or any 2 of the following:
    • Meningioma
    • Glioma
    • Schwannoma
    • Juvenile posterior subcapsular lenticular opacity (juvenile cortical cataract)
• Presumptive diagnosis of NF2
  • Early onset of unilateral CN VIII schwannomas on MRI or CT scan detected in patients younger than 30 years and 1 of the following:
    • Meningioma
    • Glioma
    • Schwannoma
    • Juvenile posterior subcapsular lenticular opacity
  • Multiple meningiomas (>2) and unilateral CN VIII schwannoma or 1 of the following:
    • Glioma
    • Schwannoma
    • Juvenile posterior subcapsular lenticular opacity

Baser et al studied 4 different sets of diagnostic criteria and concluded that none of them is adequate in diagnosing patients who do not have bilateral acoustic neuromas at the initial workup. The authors proposed that a single set of diagnostic criteria should be devised to supplant the 4 existing sets, although when or if this will occur is not certain.

Although CN schwannomas, except for CN VIII schwannomas, also occur spontaneously, they are relatively rare. Thus, the presentation of any patient with multiple CN schwannomas, an unusual intracranial schwannoma, or a single CN III (oculomotor), CN IV (trochlear), or CN VI (abducens) schwannoma should prompt screening for NF2. In addition, consider the diagnosis in the workup of patients with multiple extra-axial brain or spine tumors, regardless of whether they are meningiomas or schwannomas.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Understanding Lung Cancer Medications.

Related eMedicine topic:
Neurofibromatosis Type 1

Related Medscape topics:
Resource Center Genomic Medicine
Resource Center Head and Neck Cancer

Pathophysiology

Lesions of the brain and spine eventually occur in almost all patients with NF2. CN VIII schwannomas are the hallmark of the disease, but schwannomas can be found involving any CN from CN III to CN XII, with CN V (trigeminal) as the next most frequently involved. Spontaneously occurring CN VIII schwannomas have a similar appearance but typically occur later in life. Dural-based meningiomas are commonly seen in NF2 and are often multiple in number, occasionally seeding the meninges with tiny tumor foci.

Meningiomas found in NF2 resemble spontaneously occurring meningiomas in location and appearance, and although NF2 meningiomas are similar to vestibular schwannomas, they occur at an earlier age. Consider the diagnosis of NF2 in any patient younger than 30 years with meningioma or CN schwannoma.

Ependymomas are the most common intraparenchymal tumor in NF2, although gliomas are rarely associated with the syndrome and schwannomas rarely present as a solely intraparenchymal lesion. Multiple studies have described benign intracranial calcifications, particularly of the choroid plexus, cerebellar hemispheres, and cerebral cortex, in association with NF2.

Spinal tumors seen in NF2 include schwannomas, meningiomas, and ependymomas. Schwannomas may present as intradural extramedullary masses or may involve the exiting nerve roots. Nerve root tumors in NF2 may present as dumbbell-shaped lesions extending through the neural foramina, similar to the neurofibromas of NF1, but histology reveals that most of these are schwannomas.

Meningiomas present as intradural extramedullary masses that are similar to spontaneous meningiomas and typically involve the thoracic spine; they are often multiple in number. Most intramedullary spine tumors in NF2 are ependymomas and arise in either the upper cervical cord or the conus. Different genotypes in NF2 have been correlated with differing incidences of various spinal neoplasms: patients with frameshift and nonsense mutations have higher incidences of all spinal tumors but especially intramedullary tumors.

A few ocular abnormalities occur in NF2, including a form of early-onset cataract termed juvenile posterior subcapsular lenticular (or lens) opacity.^{9,10,11,12,13} Hamartomas of the retina and choroids are common in NF2, and a patient's vision may be affected by optic nerve (CN II) sheath meningiomas.

Although patients with NF2 may have cutaneous schwannomas that resemble skin tags, they rarely have caf é -au-lait spots and do not demonstrate the cutaneous neurofibromas that typically result in the early diagnosis of NF1. Because symptoms from CN VIII schwannomas usually begin in the third decade, patients with NF2 are typically diagnosed later in life than patients who have NF1.

Frequency

United States

The incidence of NF2 is approximately 1 per 30,000-40,000 persons.

International

The incidence of NF2 is approximately 1 per 30,000-40,000 persons.^14,15

Mortality/Morbidity

Hearing loss resulting from CN VIII schwannomas constitutes the most common morbidity associated with NF2. When the vestibular tumors are small, they can be resected completely with preservation of hearing; however, if the tumors are large, debulking is often all that is possible without damaging the facial nerve (CN VII) and CN VIII. Other tumors, such as meningiomas and ependymomas, cause symptoms from mass effect on the adjacent structures and are occasionally debulked or removed, although usually, serial MRIs are done for follow-up of these tumors.

Despite the large number of tumor types found in NF2, malignant transformation is rare and may be iatrogenic in many patients. In an international study by Baser et al, 5% of patients who received external-beam radiation developed malignant tumors at previously irradiated sites, whereas fewer than 1% of patients who did not receive radiation therapy developed malignancies.¹⁶ This suggests that the number of malignancies in the first group were radiation associated, similar to data regarding hereditary retinoblastoma. Fortunately, radiation therapy has a limited role in NF2 and is reserved for aggressive tumors and for patients who refuse surgical intervention.

• Mortality age is variable in patients with NF2, and many patients have relatively normal life spans. Age at diagnosis, the presence of intracranial meningiomas, and whether the patient was treated at a specialty center or not have been cited as the strongest predictors of mortality risk.¹⁷

Race

A racial predilection exists for NF2, although because the disease is autosomal dominant with a high penetrance, many patients have a strong family history.^1,14,18

Sex

Male and female patients are approximately equally affected because the disease is autosomal dominant.¹⁹

Age

Typically, the diagnosis of NF2 is made in the second or third decade of life, with a peak in the 20s. The diagnosis usually is made as a result of symptoms associated with CN VIII schwannomas. NF2 may be diagnosed earlier in children with a family history of the disease, as a result of early screening, or in those who initially present with diplopia or vision loss.

As a result of the high penetrance of NF2, patients with NF2 almost always present with this condition before age 60 years. Most are diagnosed before age 40 years.

Anatomy

CN VIII leaves the brainstem at the level of the mid pons and runs through the ambient cistern toward the internal auditory canal (IAC), adjacent to CN VII. Within the canal, CN VIII runs in the inferior portion, underneath the crista falciformis. Bill's bar, a thin layer of arachnoid tissue that can have a small osseous component, divides the upper portion of the canal into anterior and posterior segments, separating the upper portion of CN VIII (posterior) from CN VII (anterior). Whereas in sporadic cases a CN VIII schwannoma involves only CN VIII, in NF2, CN VII and the entire CN VIII are often encased by the tumor, making resection much more problematic.

Presentation

The clinical presentation of NF2 varies, but approximately 45% of patients are first diagnosed because of symptoms resulting from CN VIII schwannomas, such as hearing loss, tinnitus, balance impairment, and weakness in CN VII distribution. This is because CN VIII schwannomas are symptomatic at a relatively small size.

Meningiomas and other schwannomas are the next most common tumors to cause initial symptoms as a result of mass effect on the adjacent structures. Less frequently, skin tumors and visual loss are the initial findings, except when NF2 is diagnosed in the pediatric population.

In pediatric patients, ocular abnormalities are the most common reason to consider the diagnosis of NF2, although some children are diagnosed through screening when a family history is present. MacCollin and Mautner found that in 18 patients younger than 16 years, ocular abnormalities were the presenting symptom in 8 (44%), and only 1 patient (5.6%) presented with hearing loss.²⁰ Symptoms related to spinal tumors (eg, paraplegia, pain) and skin tumors each occurred in 4 patients (22%). Bosch et al found that although 78% of patients with adult-onset NF2 kept a visual acuity of 1 in both eyes, only 14% of patients with childhood onset did.⁹

Although children with CN VIII schwannomas may become symptomatic in their teens, most patients are not diagnosed until their third decade, with a mean age at diagnosis of 20 years. A proposed mild form of NF2, the Gardner form, has been described as occurring later in life as a result of a smaller tumor burden. The disease may also be exacerbated during pregnancy.

Preferred Examination

Screen for NF2 using contrast-enhanced MRI of the brain and entire spine.^21,22,23 Contrast is important for detecting small schwannomas, particularly of the spinal nerve roots, as well as small intraparenchymal ependymomas.²⁴ Newer sequences, such as high-resolution fast spin-echo (FSE) T2 cisternography and true inversion recovery, can aid evaluation of the CNs.²⁵

Contrast-enhanced CT scan studies or gas CT cisternography, as well as myelography, have had limited roles since the emergence of MRI, but occasionally, they must be used in patients in whom MRI is contraindicated.²⁶

Limitations of Techniques

As a result of its excellent contrast and multiplanar capabilities, MRI optimally depicts the number, size, location, and extent of the central nervous system (CNS) neoplasms found in NF2. However, MRI does not detect most of the ocular abnormalities associated with the disease; these are evaluated best using funduscopy. In addition, cortical and choroid plexus calcifications may be missed on MRI, particularly when using FSE techniques. These are visualized better on CT scan studies.

Gas CT cisternography, in which injected intrathecal gas is maneuvered to outline CN VIII, is more sensitive than routine CT scan studies, but it is also invasive and less sensitive than MRI.

Myelography and CT myelography can depict spinal schwannomas well, but because they cannot be used to visualize intra-axial tumors, they are only indicated when patients cannot undergo MRI.

Differential Diagnoses

Meningioma, Brain
Meningioma, Spine
Schwannoma, Cranial Nerve
Tuberous Sclerosis

Other Problems to Be Considered

• Other phakomatoses
• Cowden disease: Associated with multiple meningiomas, neurofibromas, and hamartomas, including Lhermitte-Duclos disease (cerebellar gangliocytoma), but not associated with CN VIII schwannomas
• Multiple meningiomatosis and meningioangiomatosis: Considered by some to be formes frustes of NF2; others consider them separate diseases
• Basal cell nevus syndrome (Gorlin syndrome): Associated with meningiomas, astrocytomas, and medulloblastomas but not associated with schwannomas

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