Neurofibromatosis Type 2 Imaging 

Updated: Jun 07, 2022
Author: Andrew L Wagner, MD; Chief Editor: James G Smirniotopoulos, MD 

Practice Essentials

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are 3 clinically distinct tumor predisposition syndromes with a shared tendency toward development of peripheral and central nervous system neoplasms. Disease expression and complications of NF1, NF2, and SWN are highly variable, necessitating a multidisciplinary approach to care to optimize outcomes. Imaging plays an important role in informing management decisions for people with tumors associated with these syndromes.[1]

NF2 is a rare autosomal dominant disorder characterized by development of multiple nervous system tumors due to a mutation in the NF2 tumor suppressor gene.[2]  The tumor most commonly associated with this syndrome is the vestibulocochlear (cranial nerve [CN] VIII) schwannoma (VS); as many as 10% of patients with this tumor have NF2. Although NF2 shares a name with neurofibromatosis type 1 (NF1; von Recklinghausen disease), the 2 diseases are separate entities.

Although penetrance is nearly 100% by 60 years of age, some patients suffer from a severe form of the disease and develop multiple tumors at an early age; others are asymptomatic until later in life. Management options for VS include surgery, stereotactic radiation, and observation with serial imaging. Advancements in research into the molecular biology underlying NF2 have led to a better understanding of the etiology and pathogenesis of VS. These novel signaling pathways may be used to identify targeted therapies for these tumors.[2]

Contrast-enhanced magnetic resonance imaging (MRI) is used to screen for NF2 of the brain and spine.[3, 4, 5] Contrast is important for detecting small schwannomas, particularly of spinal nerve roots, as well as small intraparenchymal ependymomas.[6] Newer sequences, such as high-resolution fast spin-echo (FSE) T2 cisternography and true inversion recovery, can aid evaluation of CNs.[7, 8, 9]

Contrast-enhanced computed tomography (CT) scans and gas CT cisternography, as well as myelography, have had a limited role in diagnosis since the emergence of MRI, but occasionally, they must be used in patients in whom MRI is contraindicated.[10]

(See the images of NF2 below.)

Axial T1-weighted postcontrast image demonstrates Axial T1-weighted postcontrast image demonstrates bilateral internal auditory canal-enhancing masses that are diagnostic for neurofibromatosis type 2 (NF2). No biopsy is necessary for the diagnosis. Notice the en plaque meningioma anterior to the brainstem.
Sagittal T1-weighted postcontrast image of the tho Sagittal T1-weighted postcontrast image of the thoracic spine reveals an enhancing extra-axial meningioma (arrow) anterior to the cord with a complex enhancing mass (arrowheads) that represents a conus ependymoma filling the spinal canal in the lower thoracic spine.

Neurofibromas are rarely found in NF2, which has led some to propose that this disease should be termed schwannomatosis, or MISME syndrome, with the acronym reflecting the following terms[11] :

  • Multiple inherited schwannomas

  • Meningiomas

  • Ependymomas

The term MISME has been used widely as a mnemonic for remembering the disease.

Although a presumed case of NF2 was first described in 1882 by Wishart, this 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.[12, 13, 14, 15]

In 1988, the National Institutes of Health released a conference statement regarding neurofibromatosis that addressed the diagnosis of NF2.[16] Criteria chosen for the diagnosis of NF2 included the following (only 1 criterion was needed to make the diagnosis):

  • Bilateral CN VIII masses seen with appropriate imaging techniques (eg, CT, MRI)

  • 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

A revision to the diagnostic criteria of NF2 was proposed that involves the addition of a section for a presumptive or probable diagnosis of NF2.[17]

Modified criteria for a definitive diagnosis of NF2 include the following:

  • 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 yr) or any 2 of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity (juvenile cortical cataract)

Modified criteria for a presumptive diagnosis of NF2 are as follows:

  • Early onset of unilateral CN VIII schwannomas on MRI or CT scan in patients younger than 30 years with 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 for diagnosis of NF2 in patients who do not have bilateral acoustic neuromas at initial workup. These 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.[18]

Although CN schwannomas, except for CN VIII schwannomas, may 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, this diagnosis should be considered in the workup of patients with multiple extra-axial brain or spinal tumors, regardless of whether they are meningiomas or schwannomas.

Limitations of techniques

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

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 invasive and is less sensitive than MRI.

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

Interventions

Radiologic intervention plays a limited role in patients with NF2. With large meningiomas, intravascular embolization can be performed to shrink the tumor before further treatment is provided, although this has not been described specifically in patients with NF2.[19, 20, 21]

The antiangiogenic agent bevacizumab is currently the only drug used clinically for NF2-related vestibular schwannoma (NF2-VS). In a meta-analysis conducted to systematically and comprehensively investigate the reliability and toxicity of bevacizumab for treatment of NF2-VS, Shi and colleagues found that nearly one third of NF2-VS patients may benefit significantly from bevacizumab by hearing improvement and tumor reduction. Menstrual disorders were the most common adverse events. The high-dose regimen did not show better efficacy, but results varied considerably according to patient age. Although benefits have been seen in several cases, the standardized dosage remains unclear.[22]

Meningiomas and schwannomas grow slowly in most patients with NF2, but these multiple craniospinal tumors can show sudden rapid growth and can manifest as neurologic symptoms. In a case report of a pediatric NF2 patient with multiple craniospinal tumors, Kim and colleagues explained that NF2 is linked with abnormalities in the NF2 gene, which is located on chromosome 22 and is involved in merlin production. They found that in a 12-year-old male presenting with headache and hearing impairment in the right ear, MRI revealed a right frontal meningioma, bilateral vestibular and trigeminal schwannomas, and a brainstem tumor. NF2 was diagnosed, and the patient underwent brain surgery and radiotherapy followed by brain MRI revealing progression of VS, trigeminal schwannoma, and brainstem tumor. He was treated with bevacizumab (5 mg/kg) every 2 weeks for 6 months, and study authors reported that all craniospinal tumors were stable without signs of neurologic deterioration after completion of chemotherapy. Thus, researchers found that these tumors could be controlled with local symptomatic and systemic bevacizumab treatments.[23]

A cranial nerve (CN) schwannoma, including a unilateral CN VIII schwannoma or a meningioma in a younger patient, suggests the possibility of NF2, which should result in genetic testing and a full MRI of the brain and spine. Older patients with meningiomas or a unilateral CN VIII schwannoma should not undergo an expensive workup for NF2 because the disease usually presents before the age of 40 years. Patients older than 60 years with bilateral internal auditory canal (IAC) masses are unlikely to have NF2 if it has not been diagnosed previously. A few cases of bilateral IAC metastases have been reported.

NF2 is a rare, progressive, and incurable genetic disorder associated with progressive hearing loss and eventual deafness. As a group, patients with NF report high levels of stress and depressive symptoms. In a live-video randomized controlled trial, Carter and associates reported the first evidence of improvement in symptoms of depression and perceived stress among deaf patients living with NF2 who participated in a virtual mind-body program tailored to adults with NF2 who are deaf (the Relaxation Response and Resiliency Program for Deaf NF2 [d3RP-NF2]). Measures of depression at baseline, post intervention, and at 6-month follow-up revealed improved quality of life and resiliency among these patients.[24]

NF2 is an autosomal dominant condition. Because NF2 is almost always diagnosed during the reproductive years, patients and their families should receive extensive genetic counseling following diagnosis, and their children should be screened early in life.

 

Radiography

Intracranial abnormalities found in NF2 are not visible on plain radiographs, except in cases of hyperostosis from a meningioma. Widening of the neural foramina and scalloping of the posterior aspect of vertebral bodies can be seen on plain radiographs of the spine; these result from pressure erosion caused by schwannomas rather than from dural ectasia, which causes bony malformations in NF1.

Scoliosis is associated with NF2 and can be measured most accurately on plain radiographs, although CT scanning or MRI may be necessary for evaluation of some of the more subtle spinal deformities. NF2 has been associated with scoliosis; however, it is an uncommon cause of scoliosis, and no study has described scoliosis as a presenting sign of NF2.

Foraminal widening and posterior vertebral scalloping are not specific for NF2. Dural ectasia of NF1, as well as some bone dysplasias, can cause scalloping of posterior vertebral bodies similar to that seen in NF2; however, scalloping in NF2 is a result of associated tumors. Although scalloping from NF1 and scalloping from NF2 are occasionally indistinguishable on plain radiographs, either MRI or CT scanning can easily distinguish between the two.

 

Computed Tomography

CN VIII schwannomas

CN VIII schwannomas are visualized on CT scans as strongly but heterogeneously enhancing cerebellopontine angle masses that extend from the internal auditory canal (IAC). On precontrast imaging, these schwannomas are isodense to hypodense with respect to brain tissue and may have associated cysts or hemorrhage.

Tumor pressure often results in widening of the IAC and is best visualized via bone windows. Gas CT cisternography, with 0.5- to 1-mm slices, can show small tumors within the IAC that typically are missed on routine CT scanning. Small schwannomas of other CNs are easily overlooked or are not visualized because of their proximity to osseous structures and the relatively poor contrast resolution of CT scanning.

Intracranial meningiomas

Intracranial meningiomas present as enhancing extra-axial masses, often with internal calcifications and adjacent hyperostosis best visualized via bone windows. Adjacent white matter with decreased attenuation is commonly seen when tumors are large, likely representing edema. Persistence of this abnormality for years after the tumor has been resected suggests the likely existence of a demyelinating factor as well.

When large enough, meningiomas may exhibit mass effect on brain parenchyma and can be aggressive at times, invading adjacent bone. Without contrast, meningiomas may have the same attenuation as the brain, but they typically have higher attenuation values resulting from the presence of calcium and a high nuclear-to-cytoplasmic ratio. Small tumors can be missed, particularly over the calvarium and in the posterior fossa, where beam-hardening artifact is the worst.

Spinal schwannomas

Spinal schwannomas appear either as dumbbell-shaped enhancing masses extending out of the neural foramina or as intradural extramedullary masses within the spinal canal. CT scans show widening of the foramina or pressure erosion on the adjacent vertebral body; sagittal reformatted images are useful.

Spinal meningiomas

Spinal meningiomas are found as intradural extramedullary masses, usually in the thoracic spine. They are best imaged on CT myelography, although they usually show enhancement on contrast CT scans. Occasionally, meningiomas extend into the neural foramina and appear as dumbbell-shaped masses with widening of the neural foramina. In these cases, distinguishing them from schwannomas or from neurofibromas is difficult.

Spinal ependymomas

Spinal ependymomas are intra-axial enhancing masses seen most frequently in the cervical cord and conus. When the conus or filum is involved, an ependymoma may be pedunculated and appear as an extra-axial mass. Cervical cord ependymomas are well-marginated enhancing tumors that may exhibit associated cyst formation.

Degree of confidence

CT scanning should be performed only in patients with NF2 for whom MRI is contraindicated, because MRI provides superior tumor imaging and characterization. When CT scanning must be used, high-resolution techniques must be performed in the axial and coronal planes, and CT cisternography should be considered for detecting small tumors.

Even when tumor is visualized, tumor type is often difficult to identify on CT scans because of extensive overlap in tumor appearance. CT myelography is adequate for depicting extra-axial lesions of NF2, but it is relatively insufficient for detecting ependymomas. CT scanning with 3-dimensional (3-D) volumetric rendering can be useful in preoperative planning for patients with NF2 and associated scoliosis or spinal dystrophy.

 

Magnetic Resonance Imaging

CN VIII schwannomas

Cranial nerve VIII (CN VIII) schwannomas are well-defined masses that arise from the internal auditory canal (IAC) and frequently extend into the cerebellopontine angle, demonstrating an ice cream cone or mushroom shape.[25, 26, 27, 28, 29, 30]

(See the image below.)

Magnetic resonance image (MRI) in a 62-year-old ma Magnetic resonance image (MRI) in a 62-year-old man who presented with unilateral hearing loss. This MRI shows an enhancing mass in the right internal auditory canal (IAC) that was interpreted as a probable cranial nerve VIII (CN VIII) schwannoma. Although no other abnormalities were detected, the examination was performed as a limited MRI and revealed only the internal IACs. Further screening was not indicated because the chance that this patient had NF2 was exceedingly low.

CN VIII schwannomas often have heterogeneous signals, but they are typically isointense to hypointense on T1-weighted images and hyperintense on T2-weighted images.

High-resolution, heavily T2-weighted sequences have been used to detect small CN VIII schwannomas and appear to be approximately as sensitive as contrast MRI. With this technique, bright CSF around CN VII and CN VIII is used as a contrast agent, and schwannomas appear as small, rounded masses that efface CSF within the canal. This technique is also useful in detecting cochlear involvement by the tumor because cochlear turns are normally easily identified as curvilinear areas of increased signal.

Following contrast administration, CN VIII schwannomas enhance avidly but often heterogeneously, particularly in larger tumors.

Nonenhancing areas of necrosis are often present as schwannomas enlarge, and associated cysts or blood products from internal hemorrhage may be present.

Other CN schwannomas have a similar MRI appearance and differ only in location, occurring along the paths of other CNs. The multiplanar capability of MRI is particularly useful in distinguishing a CN schwannoma from a meningioma adjacent to a nerve.

Meningiomas

Meningiomas in NF2 have the same distribution and signal characteristics as spontaneous meningiomas, occurring most frequently along the falx and over the convexities.[31]

(See the images below.)

Sagittal T1-weighted postcontrast image in a patie Sagittal T1-weighted postcontrast image in a patient with known neurofibromatosis type 2 that demonstrates 2 midline meningiomas (arrowheads), one over the convexity and one along the vein of Galen. The enhancing mass in the medulla (arrow) most likely is an ependymoma.
Axial postcontrast T1-weighted image shows a large Axial postcontrast T1-weighted image shows a large enhancing sellar meningioma surrounding both internal carotid arteries in this case of neurofibromatosis type 2 (NF2) (black arrows). Enhancing tissue in the ethmoid air cells also represents a meningioma extending through the cribriform plate. Meningiomas in patients with NF2 can be more aggressive and invasive than spontaneous meningiomas. Note the small, round, enhancing extra-axial mass posterior to the tectum (white arrow). Although this could represent another meningioma, the shape and location suggest it is a trochlear (CN IV) schwannoma instead.

Meningiomas are extra-axial tumors that demonstrate cortical buckling and a CSF cleft. A confluent area of white matter with increased T1 signal and decreased T2 signal may be seen in the adjacent brain parenchyma and is likely the result of a combination of vasogenic edema and demyelination.

Meningiomas typically are isointense with gray matter on all sequences and, when small, can be difficult to detect without contrast. Signal intensity can vary, and almost any combination of T1 and T2 signals may be seen.

Cyst formation is uncommon, but calcification occurs frequently and can cause the tumor to appear heterogeneous.

Following gadolinium administration, intense and generally homogeneous enhancement is seen; a dural tail of enhancing dural tissue is often found extending from the dural attachment of the tumor, although this finding is not specific for meningioma.[32, 33]

Meningiomas in patients with NF2 may be more aggressive than spontaneously occurring ones; these tumors may invade adjacent calvarium and may extend into the paranasal sinuses.

Spinal meningiomas

Spinal meningiomas are associated with NF2 and are often multiple in number. Unlike intracranial meningiomas, the spinal type calcifies in less than 10% of patients.[34]

(See the image below.)

Sagittal T1-weighted postcontrast image of the tho Sagittal T1-weighted postcontrast image of the thoracic spine reveals an enhancing extra-axial meningioma (arrow) anterior to the cord with a complex enhancing mass (arrowheads) that represents a conus ependymoma filling the spinal canal in the lower thoracic spine.

Spinal meningiomas are typically intradural and extra-axial but can present as dumbbell-shaped masses extending through the neural foramina. In this situation, distinction from a neurofibroma or a schwannoma is difficult, although the schwannoma should be brighter on T2-weighted images.

Meningiomas are usually isointense relative to the spinal cord on all image sequences and enhance strongly following gadolinium administration. Although most spinal meningiomas have a broad dural attachment similar to that of their intracranial counterparts, dural tail signs are found less frequently in spinal meningiomas.

Spinal ependymomas

Spinal ependymomas found in NF2 are divided into 2 groups: those that occur in the upper cord and those that occur in the conus.

Cord tumors are well-marginated, intensely enhancing lesions, frequently associated with cyst formation and hemorrhage. Ependymomas may be isointense or hypointense relative to the spinal cord on T1-weighted images and are always bright on T2-weighted images, although a peripheral rim of decreased T2 signal has been proposed to be suggestive of ependymoma.

Conus ependymomas are often large tumors that can fill the entire spinal canal with heterogeneous signal and enhancement. When small, the tumors may be well-marginated intra-axial lesions, but when larger, they may appear to arise from the extra-axial space.

Extradural masses

Multiple extradural masses extending through the neural foramina are found in both NF1 and NF2, although in NF2 (unlike in NF1), these tumors are usually schwannomas. Tumors often have both an intraspinal and an extraspinal component, demonstrate a classic dumbbell shape, and typically are multilevel and bilateral. Signal intensities for spinal schwannomas are the same as for intracranial schwannomas, and strong contrast enhancement is seen. Because of the multifocality of spinal schwannomas and their association with scoliosis, coronal MRI is often helpful.

Gadolinium-based contrast agents have been linked to development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). This disease has occurred in patients with moderate to end-stage renal disease after they were given a gadolinium-based contrast agent to enhance magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Degree of confidence

MRI is the imaging modality of choice in NF2 and is accurate in detecting even small tumors. Separation of intracranial schwannomas from meningiomas may be difficult at times but usually is of little clinical value. Evaluation of extent, size, and number of intracranial tumors in NF2 is accomplished best by MRI because of its multiplanar capability, its contrast resolution, and the spectrum of pulse sequences, each of which adds different information.

Spinal schwannomas, meningiomas, and ependymomas are also visualized best on MRI. Usually, no other imaging modality is necessary either at the time of diagnosis or as part of a follow-up regimen. Although MRI can be used to image osseous vertebral abnormalities associated with NF2, CT scanning shows them better.

Imaging plays an important role in informing management decisions for people with tumors associated with these syndromes. Technological advances, including whole-body and localized imaging strategies, routine anatomic and advanced MRI sequences such as diffusion-weighted imaging (DWI) with quantitative apparent diffusion coefficient (ADC) mapping, and metabolic imaging techniques (MR spectroscopy and positron emission testing), are among the most up-to-date clinical imaging techniques for people with NF1, NF2, and SWN.[1]

 

Angiography

Angiography is of limited use in NF2 because most tumors are not visualized. An exception is the "mother-in-law sign" ("arrives early and stays late") of meningioma contrast enhancement. This sign comes from recognition of meningiomas during angiography by their early contrast enhancement and delayed washout. Early contrast enhancement is caused by enlarged feeding vessels, usually pial or meningeal arteries, and delayed tumor staining results from lack of capillary blood-brain barriers within the tumor. Unfortunately, as with many signs in radiology, this finding is not specific and may be seen with other hypervascular tumors as well.

Because ependymomas and schwannomas are not particularly vascular, they often are not visible on angiography; however, when large enough, secondary mass effect on adjacent brain can be recognized.