Surgical Management of Neurofibromatosis Type 1 and 2

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Chapter 48 Surgical Management of Neurofibromatosis Types 1 and 2

James H. Tonsgard, Bakhtiar Yamini, David M. Frim

Neurofibromatosis types 1 and 2 (NF1 and NF2) are genetic diseases that commonly affect the brain, peripheral nerves, spinal roots, spinal cord, and dura. While the type of neurologic complications in NF1 and NF2 are also found in patients without NF, management frequently is different. It is important for the neurosurgeon to be aware of not only the range of neurologic complications that occur in NF but also their clinical course in NF patients. This chapter covers the neurologic complications, the indications for surgery, and the surgical approach to the tumor types found in NF1 and NF2. The details of the techniques of tumor removal are similar to those used for removal of the same tumors in patients without NF. Because NF1 and NF2 have very different complications, the two diseases are presented separately.

Neurofibromatosis Type 1

NF1 is an autosomal dominant genetic disorder caused by a mutation or deletion of the neurofibromin gene on the long arm of chromosome 17.1 The diagnosis of NF1 requires the presence of two or more major criteria: six or more café-au-lait spots, two cutaneous neurofibromas, one plexiform neurofibroma, certain bony abnormalities, an optic glioma, iris Lisch nodules, or a first-degree relative with NF1.2 Diagnosis has primarily been clinical, but genetic testing identifies at least 95% of patients who meet the clinical criteria. While there are no silent carriers of NF, clinical manifestations are variable, even within the same family.3 Because NF1 may affect virtually any organ system and some complications such as plexiform neurofibromas commonly involve adjacent organs, a multidisciplinary team is essential for management. Such a team should include a pediatrician, neurologist, geneticist, ophthalmologist, neurosurgeon, orthopedist, plastic surgeon, and oncologist. NF1 is a progressive disorder. Some complications worsen with age. Moreover, complications of NF1 are usually age specific. Plexiform neurofibromas can be considered congenital, although they may not require surgical intervention until later in life. Optic gliomas usually present between 18 months and 7 years of age.4 Iris Lisch nodules usually appear between 10 and 21 years of age. Cutaneous neurofibromas commonly occur in teenagers or young adults, and malignant peripheral nerve sheath tumors (MPNSTs) are a complication of young adults.5

Neurologic Complications of NF1 and Indications for Neurosurgical Intervention

The neurologic complications of NF1 include headaches, learning disabilities, seizures, peripheral nerve tumors, spinal nerve root tumors, dural ectasias, deafness, optic gliomas, areas of high-intensity signal on magnetic resonance imaging (MRI), tumors of the brain parenchyma, and aqueductal stenosis.6 Migraine headaches are a common feature.7 Learning disabilities and hyperactivity occur in at least 50% of patients.8 Deafness occurs in 10% of NF1 patients and is not caused by tumors.9 Brain tumors and optic gliomas occur in a small percentage of patients. The incidence is increased compared with the normal population.10 All patients with NF1 develop peripheral nerve tumors.

Peripheral Nerve Tumors

Five types of peripheral nerve tumors occur in NF1: schwannomas, discrete neurofibromas (sometimes called cutaneous or dermal neurofibromas), diffuse neurofibromas, plexiform neurofibromas, and MPNSTs. Schwannomas are infrequently found in patients with NF1. This tumor is more typical of NF2 and is discussed in the section on NF2. Diffuse neurofibromas most commonly present as boggy caplike lesions of the scalp that involve the subcutaneous tissue, stopping at the fascia.11 Diffuse neurofibromas of the scalp do not progress beyond the hairline and are best left alone unless there is evidence of rapid growth.

Discrete neurofibromas and plexiform neurofibromas involve a proliferation of fibroblasts, Schwann cells, perineural cells, mast cells, extracellular matrix, axons, and blood vessels.12 These two tumors differ histologically, primarily in the extent of extracellular matrix. Plexiform neurofibromas have more extracellular matrix. Both tumors cause expansion of the nerve. Nerve fibers run through the tumor. Plexiform neurofibromas may involve small peripheral nerves, large peripheral nerves, nerve trunks, plexus, or spinal roots. Motor nerves, sensory nerves, or both are affected. Plexiform neurofibromas may be associated with markedly dilated veins. Plexiform neurofibromas involve the skin with or without involvement of underlying muscle, or they may be confined to deeper tissues. Plexiform tumors are felt to be congenital or to appear within the first year of life. Growth is highly variable. Some tumors remain static, others relentlessly increase, and still others undergo spurts of growth and periods of quiescence. Plexiform neurofibromas may appear discrete and isolated, diffuse and infiltrative, or nodular with multiple grapelike clusters.13 Plexiform neurofibromas commonly infiltrate adjacent muscle and sometimes infiltrate adjacent organs, such as the bladder or esophagus. Plexiform neurofibromas occur in at least 50% of all patients.14 Large areas of hyperpigmentation with fine hair may overlie plexiform neurofibromas.

Discrete or cutaneous neurofibromas occur in all patients with NF1. These tumors usually appear in teenagers or adults.15 Early appearance of large numbers of neurofibromas is associated with complete deletion of the NF1 gene.16 Isolated neurofibromas may involve both motor and sensory nerves in the epidermis and/or dermis.

MPNSTs occur in 4% to 10% of all patients with NF1. These tumors arise within plexiform neurofibromas usually between 15 and 50 years of age.5 Earlier onset is uncommon but occurs. MPNSTs may be multifocal in some patients. MPNSTs are highly malignant, with rapid hematogenous dissemination. Outcome for patients with MPNSTs is poor. The best outcome is associated with radical resection.17

Indications for Removal of Peripheral Nerve Tumors

Neurofibromas, either discrete or plexiform, should be removed or resected only if they are symptomatic. Discrete neurofibromas may be associated with some discomfort and/or itching as they grow. Rarely, isolated neurofibromas cause compression of a motor nerve with distal weakness. Discrete neurofibromas should be removed if they produce significant discomfort or are located in exposed areas that are stigmatizing. Discrete neurofibromas may recur near the site of removal but usually not for several years if removal is complete. Resection of plexiform neurofibromas is more difficult. Plexiform neurofibromas frequently have diffuse projections that make complete removal impossible. Moreover, plexiform neurofibromas sometimes involve large nerves or nerve roots, so complete resection results in disability. Nevertheless, resection of plexiform neurofibromas should be considered if they cause cosmetic disfigurement, pain, or compromise of function. No successful chemotherapy has been identified for plexiform neurofibromas, although there are ongoing experimental trials of medication. Growth of plexiform neurofibromas is sometimes stimulated by radiation therapy. Histologic identification is not an indication for surgery unless the tumor is suspected to be malignant.

MPNSTs are commonly associated with pain. There are no reliable radiologic characteristics to distinguish MPNSTs from plexiform neurofibromas.12 While MPNSTs commonly enhance with contrast and lack a homogeneous appearance, the same is true of some benign plexiform tumors. A helpful distinguishing feature is that MPNSTs commonly take up gallium in radioisotope scans.18,19 Positron-emission tomography scans may also be useful in diagnosis.20 Because MPNSTs arise within plexiform neurofibromas, in which only a small portion of the tumor is malignant, biopsies can be negative. Computed tomography (CT)–directed needle biopsy is preferred when an MPNST is suspected. MPNSTs do not respond well to chemotherapy or radiation therapy.20

Spinal Nerve Root Tumors and Dural Ectasias

Tumors of spinal roots are plexiform neurofibromas. One nerve root or multiple roots may be affected. Nerve root involvement is associated with enlargement of the neural foramen on MRI or scalloping of vertebral bodies on radiography. Virtually any nerve root may be affected, but the high cervical and lower lumbar spine are the most common sites. There is a subset of patients who show involvement of virtually all spinal roots. Nerve root tumors may extend through the neural foramen and expand and compress the cord, or they may remain static. Surgery is indicated if there is pain or compression of the spinal cord.

Dural ectasias are a weakening or expansion of the dural covering of a spinal root that is independent of a nerve root tumor. Dural ectasias commonly erode the vertebral body and may produce large dilated pockets anterior to the vertebral body (so-called anterior meningoceles). This is associated with pain, scoliosis, and sometimes vertebral instability.21 Dural ectasias increase in size or remain static. They can be seen in early childhood, suggesting that they may be congenital defects. Surgery is indicated if there is intractable pain or vertebral instability.

Brain Tumors, MRI Abnormalities, and Hydrocephalus

High-intensity signals are present on T2 images in MRI of the brain in roughly 50% of all patients with NF1. Common locations are the basal ganglia, cerebellum, midbrain, and pons. The lesions do not enhance and are less easily visible on T1 images. They are not visible on CT scans. These areas of increased signal are sometimes referred to as unidentified bright objects, heterotopias, or hamartomas. The latter terms are misleading, because the etiology of the lesions is unclear.22 They may be more common in children with learning disabilities but also occur in children without any cognitive difficulties. Areas of hyperintensity depend on age. They are less common after age 20.23 In younger patients, the hyperintense signals may increase or decrease over time. They are not tumors and do not require radiologic follow-up or biopsy.

Optic gliomas or visual pathway tumors occur in 15% of patients with NF1.24 Optic gliomas are pilocytic astrocytomas (World Health Organization grade I).25 They commonly affect the chiasm, as well as one or both optic nerves. The tumors may extend into the hypothalamus or along the optic radiations.4 Impairment of vision occurs in only 20% to 30% of patients with optic gliomas.26 If treatment is required, chemotherapy is preferred.27 The tumors do not require biopsy. The age of onset is between 16 months and 8 years of age. Screening is done with regular eye exams rather than imaging. Optic gliomas are almost never symptomatic after age 8,4 but progression of tumors after treatment may occur. Not all optic gliomas respond to current chemotherapy regimes.

Tumors of the brain parenchyma (not including optic pathway tumors) occur in 2% to 3% of patients with NF1.28 The cerebellum and brain stem are the most common locations.29 Brain stem tumors involve the midbrain, pons, or medulla. They commonly have an exophytic component. Some enhancement with contrast may be seen. The natural history of brain stem tumors is usually benign.30 Almost all are grade I astrocytomas. They may be associated with recurrent coughing, intermittent difficulty swallowing, or choking, but they are not associated with any weakness or persistent cranial nerve palsies. Rarely, they produce obstructive hydrocephalus. Once a brain stem tumor has been identified, it is prudent to obtain imaging at intervals for a few years to prove that the lesion is stable.31 Brain tumors in other locations can vary from grade I to grade IV astrocytomas. In general, brain tumors in patients with NF1 are more indolent than in normal individuals. Some tumors even regress over time. Highly malignant gliomas also occur in patients with NF1. Tumors should not be biopsied unless they are clearly symptomatic or show progression over time.

Aqueductal stenosis is a rare complication of NF1. Symptoms include headache, vomiting, progressive gait disturbance, incontinence, and cognitive difficulties.32 The onset may be insidious and recognition delayed. Surgical intervention usually results in significant improvement, even when the symptoms appear to be long-standing.

Surgical Approach to the Lesions of Neurofibromatosis Type 1

Peripheral Nerve Lesions

Tumors of small peripheral nerves are usually discrete neurofibromas. The surgical approach is a direct linear incision along the length of the nerve. Care must be taken to dissect down to the expanded nerve sheath, incise it, and deliver the lesion through the incision. Electric nerve stimulation is useful to ensure that motor function is identified and preserved. In the absence of any motor function, nerve sectioning above and below the lesion with complete removal is appropriate. The cut nerve endings should be sewn into a nearby muscle to reduce the likelihood of painful postresection neuroma. When motor function is identified in the nerve entering the neurofibroma, we advocate intracapsular removal, incising the tumor sheath to deliver the intracapsular portion and remove it in its entirety but leaving the residual nerve in continuity. Often the bulk of the functional nerve is expanded and external to the tumor capsule. Function can be preserved by leaving the capsule in continuity with the nerve. After resection, the wound is closed in layers.

Large Nerves and Plexus

Neurofibromas of large peripheral nerves, such as the sciatic, common peroneal, or divisions of the brachial and lumbosacral plexus, are more complicated to approach than tumors of small cutaneous nerves. Tumors of large nerves are invariably plexiform tumors. The anatomic structures entering and leaving the area of the tumor must be carefully identified and dissected before tumor resection is attempted. The approach to the brachial plexus and lumbosacral plexus is similar to that of any lesion in those areas. However, plexiform neurofibromas often adhere to and follow the nerve trunks as an axis of growth. The tumors often envelop the entire plexus and adjacent tissue. Maximal debulking should be attempted while preserving function. The dissection must proceed along the anatomic plane of the nerve, and electric stimulation and monitoring of all involved nerves in the plexus is mandatory. Some success has been reported with a more radical approach to plexiform neurofibromas of the plexus with postresection nerve grafting. We do not advocate that approach because of the potential for disability, the long recovery period, and the likelihood of recurrence.

Spinal Nerve Root Tumors

Spinal nerve root tumors are plexiform neurofibromas that grow from the nerve root into the intraspinal space either intradurally or epidurally and exit through the neural foramen, producing a dumbbell appearance. The tumors may occur at any level of the spine. Because some patients have enlargement of multiple nerve roots, care must be taken to identify tumors that are symptomatic. Only those lesions that are symptomatic or threaten to become symptomatic should be approached. Spinal cord compression or canal compromise is the most reliable indication for surgery.

In the cervical spine, spinal root tumors are usually approached posteriorly to relieve spinal cord compression. A laminectomy is performed through a midline incision. In young adults and children, an osteoplastic laminoplasty provides stability to the spine. In addition, the presence of bony lamina provides a landmark for dissection if patients require reoperation for recurrent tumor.

Intradural tumors without any extradural component are approached similarly to any nerve sheath tumor in the intradural space. They are usually dorsal or dorsolateral to the spinal cord but occasionally occur more ventrally. A midline or paramedian durotomy is performed once adequate exposure has been achieved by bony decompression. The nerve root involved is identified and stimulated. If it is a sensory root, which is usually the case, the root is sectioned proximal to the tumor. The tumor bulk is removed as the tumor is followed into the neural foramen. When there is minimal extension of the tumor beyond the neural foramen, the bulk of the tumor is removed from the intraspinal space. Residual tumor in the foramen is left to ensure adequate cerebrospinal fluid (CSF) closure. The dura is closed either primarily or with an expansile duraplasty patch graft, and the lamina is replaced where appropriate. This approach presumes that tumor regrowth, though likely, will be slow and easily monitored. We do not resect a small residual epidural tumor. Radical excision does not enhance symptomatic relief. An epidural tumor is highly vascular, and radical resection may cause significant bleeding. Radical resection entails removal of the lateral or ventral dura, resulting in CSF leakage. Moreover, recurrence from small amounts of a residual tumor is rare.

When the plexiform neurofibroma is primarily extradural, the approach is posterior with wide unilateral or bilateral bony decompression. The tumor is dissected in the epidural space. The epidural venous structures above and below are cauterized and divided. The tumor capsule is entered sharply and removed intracapsularly. We recommend the intracapsular approach to epidural tumors to preserve nerve root function. Removal of the tumor with its capsule and dural sheath interrupt both sensory and motor nerve function. In the thoracic region, radical removal can be performed, but radical removal in the cervical and lumbar region would cause significant morbidity.

Spinal Nerve Root Tumors with Large Extra-axial Components

Spinal nerve root tumors with significant extra-axial extension are particularly challenging. In the cervical spine, extension of the tumor may compress the trachea or invade the esophagus. In the lumbosacral region, extra-axial tumor commonly compresses the rectum or invades the bladder.14 An interdisciplinary surgical team is essential for resection of these tumors. The intraspinal portion of the procedure is performed identically to the procedure for purely spinal tumors, whether they be intradural or epidural. However, patient position and the incisions are dictated by the extra-axial portion of the tumor.

In the cervical spine, where all nerve roots carry significant function, the tumor is removed intracapsularly. Upon decompression of the intraspinal space, the posterior incision is closed and a separate incision is made for resection of the extra-axial extension into the neck. The diffuse nature of plexiform neurofibromas frequently results in poorly defined margins of adjacent organs. Care must be taken to avoid entry into the trachea, esophagus, and great vessels. The goal of tumor resection in the neck is usually decompression of the airway. Plexiform neurofibromas almost never compromise the great vessels. Preservation of function of adjacent structures limits the extent of removal of the tumor.

In the thoracic region, when the extra-axial extent of the tumor is large, tumor removal is accomplished in the lateral position using either a single or two adjacent incisions—one for thoracotomy and a second (or an extension of the first) for laminectomy. The patient is positioned for a thoracotomy, and the approach to the intrapleural space is performed by a thoracic surgeon. The neural foramina are identified in the pleural space. The extra-axial portion of the tumor is removed, along with its pleural investment, with dissection along major vascular structures. The enlarged spinal foramina can be approached from the front by the neurosurgeon. When the foramina are wide and the intraspinal tumor is small, the resection can be completed from the anterolateral approach by foraminotomy and partial vertebrectomy. When the intraspinal extent is large or difficult to reach through the neural foramina from the front, we enlarge the incision or make a separate midline posterior incision. The lateral position for laminectomy (or osteoplastic laminoplasty) permits a standard approach to the epidural or intradural components of the tumor. In general, plexiform neurofibromas in the thoracic space requiring a transthoracic approach can be resected in their entirety, if there is no intradural extension, by sectioning the nerve root as it exits the dural sac. An intraspinal tumor can be delivered through the widened foramen, along with a portion of the extraspinal intraforaminal tumor, achieving a near-complete resection. This is one of the few situations in which removal of the involved neural structure causes minimal residual functional loss.

Tumors in the lumbosacral region with large extra-axial extensions are best approached in the lateral position through a large flank incision. The tumor is dissected through the retroperitoneum, and the lumbosacral plexus is identified. The extra-axial portion of the tumor is followed to the neural foramen and removed. If the tumor cannot be adequately removed from the lateral approach, the intraspinal portion of the tumor is approached posteriorly. This can be accomplished during the same procedure through a laminectomy, either by lengthening the flank incision or by creating a separate midline lumbar incision. Occasionally, the flank incision is closed and the patient is repositioned for a posterior approach. If the retroperitoneal surgery is extensive, the spinal portion of the tumor can be removed at a later date in the prone position. Because the lumbar and sacral nerves are functionally important, tumors of these nerves must be approached intracapsularly. Resection should be limited to decompression and debulking. Recurrence is unusual.

Lesions of the Cranial Vault and Brain

Patients with NF1 may have a variety of parenchymal abnormalities on MRI. Of the parenchymal brain lesions in NF1, only symptomatic tumors with radiologic characteristics of malignancy or progression require surgical intervention. Treatment of these lesions entails biopsy and aggressive resection, where possible, followed by adjunctive chemotherapy and radiotherapy. The treatment protocols are identical to high-grade astrocytomas in normal individuals. Treatment of the optic pathway tumors is not surgical. Diagnostic biopsy is not required. When optic pathway tumors progress, chemotherapy may be indicated.27

The aqueductal stenosis that is associated with NF1 is treated as any congenital aqueductal stenosis lesion. Endoscopic third ventriculocisternostomy is the approach of choice. If that procedure is not available or a large optic glioma limits access to the floor of the third ventricle, standard lateral ventricular shunting adequately treats this problem.

Neurofibromatosis Type 2

NF2 is an autosomal dominantly inherited disease due to a mutation or deletion in the long arm of chromosome 22 of the merlin gene.33 The diagnosis depends on the presence of bilateral eighth-nerve tumors or the presence of a unilateral eighth-nerve tumor before 30 years of age in an individual with a first-degree relative with NF2 or two of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior cataract.9 Genetic testing is also available and may identify as many as 95% of patients with germline mutations. NF2 is characterized by the presence of multiple central nervous system (CNS) tumors. The clinical hallmark is bilateral vestibular nerve schwannomas. Patients may have multiple supratentorial meningiomas and schwannomas of the cranial nerves, in addition to vestibular tumors. Meningiomas occur along the spine, and schwannomas may develop along spinal nerve roots.34 Roughly 33% of NF2 patients have intramedullary tumors of the spinal cord or brain stem that are either ependymomas or astrocytomas.35 Juvenile posterior subcapsular cataracts and retinal hamartomas occur in 80% of patients.36 Skin tumors occur in patients with NF2 but are not particularly prominent.

The clinical presentation of NF2 in adults is usually unilateral deafness. Facial weakness, visual impairment, dizziness, or painful peripheral nerve lesions may also be presenting complaints.37 Spinal cord compression or seizures are late symptoms. Children with NF2 more commonly present because of a cataract or signs and symptoms related to cranial meningiomas, brain stem tumors, or spinal cord tumors.38 The spectrum of severity of NF2 is variable. Early studies suggested two clinical phenotypes: the Gardner phenotype with milder disease, fewer tumors, and later onset and the Wishart phenotype with more tumors, earlier onset, and rapid progression.37 Molecular studies demonstrate that more severe disease is seen in patients with frameshift or nonsense mutations. These patients are also more likely to have intramedullary spinal tumors. A milder phenotype is seen in patients with missense mutations, in-frame deletions, or large deletions.38 A mild phenotype, particularly in patients with a unilateral vestibular schwannoma with no family history of NF2, may also be due to somatic mosaicism of the NF2 gene. Somatic mosaicism is found in one third of patients with no family history of NF2 and has a lower rate of transmission of the disease than germline mutations.39

NF2 is completely distinct from NF1, although rare patients may have features of both diseases. Two additional disorders must be distinguished from NF2: Schwannomatosis is characterized by multiple schwannomas of the peripheral, spinal, or cranial nerves without evidence of a vestibular schwannoma.40 Schwannomatosis can be familial, although most cases are sporadic.41 Meningiomatosis is an autosomal dominant disorder characterized by multiple meningiomas along the spinal cord, as well as supratentorially.42

Tumors Associated with NF2

Schwannomas

Schwannomas are typically nodular masses surrounded by a fibrous capsule consisting of epineurium and some nerve fibers. The tumors consist predominantly of Schwann cells with alternating patterns of cellularity.43 Glandular or cystic areas sometimes occur. Schwannomas are virtually never malignant. Unlike neurofibromas, in which axons run through the tumor, schwannomas are usually extrinsic to the nerve and separate from the majority of the axons. However, when schwannomas involve small nerves, the tumor frequently engulfs the nerve, making separation from the nerve difficult. Schwannomas of the vestibular nerves are histologically similar to schwannomas of other nerves. Frequently, vestibular schwannomas in NF2 are multinodular and less vascular than sporadic tumors.44 Although these tumors were originally called acoustic neuromas, they arise from the vestibular nerve. They usually impair hearing, but vestibular symptoms may also be prominent at the time of presentation. Schwannomas of the other cranial nerves are found in at least 25% of patients, particularly the third and fifth cranial nerves.9 Schwannomas of the spinal nerves are present in the majority of patients.35,37

Meningiomas

Meningiomas arise from arachnoid cells of the leptomeninges. Meningiomas in patients with NF2 are predominantly fibrous, but meningothelial tumors also occur.45 Meningiomas infrequently show evidence of pleomorphism or malignancy and act more aggressively, invading bone. Orbital meningiomas may occur in childhood and must be distinguished from optic gliomas. Meningiomas of the cerebellar pontine angle are occasionally confused with vestibular schwannomas. Meningiomas of the skull base produce brain stem compression and are an important cause of mortality in NF2. An en plaque meningioma occurs in some patients with NF2 late in their disease.

Astrocytomas, Ependymomas, and Hamartomas

Astrocytomas and ependymomas occur in as many as a third of NF2 patients.35 The most common site is the brain stem or cervical cord.46,47 Syrinx formation is not uncommon. These tumors are typically indolent in NF2. A more malignant profile in spinal cord tumors is rare and usually related to prior radiation therapy. Evidence of rapid growth or symptoms related to the tumors is an indication for surgery, but radiation and chemotherapy are usually not indicated. Hamartomas of the brain are frequently found in patients with NF2. They are a mixture of Schwann cells, glia, and meningeal cells.47

Indications for Neurosurgery

NF2 is not a surgically curable disease. Lesions recur and progress. The entire CNS can be involved. The tumors of NF2 do not respond to conventional chemotherapy. However, molecular studies are beginning to suggest alternative chemotherapeutic approaches.48 Radiation therapy can be considered for lesions that are not surgically accessible. Lesions are usually addressed surgically when they are symptomatic. Special considerations involved in the surgery of the vestibular schwannomas are discussed later. In patients with the more benign phenotype, with few and slow-growing tumors, surgical intervention is reserved for prevention of impending symptoms or for symptomatic tumors. In its most aggressive form, however, the disease can progress rapidly and cause severe disability that leads to death. In that situation, surgical intervention is palliative to improve quality of life.

A variety of approaches with different goals and complications are available for vestibular schwannomas. Single or multiple fraction stereotactic radiosurgery (i.e., gamma knife, as well as other types) is advocated in some centers.49,50 Studies of NF2 patients with vestibular schwannomas treated with these techniques suggest good local disease control and a relatively low incidence of side effects that is at least comparable to results with microsurgery techniques.51,53 However, both single dose and multiple fraction radiotherapy are not without potential complications for NF2 patients.38,49,50,54 Radiotherapy may have limited usefulness and limit the options for recurrent or new vestibular tumors. We prefer a microsurgery approach to vestibular schwannomas. Regardless of the approach, all centers agree that intervention should only occur when there is documentation of tumor growth or progressive hearing loss. Because of the variety of approaches available, it is important to discuss the risks and benefits of each with the patient. For those opting for a microsurgery approach, it is important to discuss goals for surgery and define the degree of aggressiveness of the surgical approach with the patient before surgery. Aggressive removal of vestibular schwannomas may cause facial nerve injury. Facial nerve injury may be extremely distressing to patients and predisposes them to ocular injury. These complications should be discussed with patients. Consideration of cochlear implantation may also influence surgical decisions.55 Surgical removal of intramedullary spinal cord tumors is indicated only when there are signs of spinal cord compression. Because multiple tumors may develop over time along the length of the spine, the number of surgical interventions is limited. Schwannomas of the spinal nerves rarely cause problems. Surgery on these tumors should be avoided.

Surgical Approach to the Lesions of NF2

Vestibular Schwannoma (Acoustic Neuroma)

The technical approach to a vestibular schwannoma in an NF2 patient is identical to sporadic tumors. However, surgical decisions in NF2 patients are affected by the presence of bilateral disease and the knowledge that the disease is not surgically curable. Surgical approaches include radical resection, partial removal, and decompression. Suboccipital retrosigmoid, translabyrinthine, or middle cranial fossa approaches can all be appropriately used for tumor removal. The arguments for these various approaches are outlined elsewhere in this text. The translabyrinthine approach permits greater exposure of the tumor but results in deafness. The middle cranial fossa approach is used primarily for decompression. We prefer the suboccipital retrosigmoid approach, with the goal of sparing hearing.52 This operation entails drilling open the posterior aspect of the internal auditory meatus, followed by subtotal resection of the tumor, preserving facial nerve function at all costs. Electrophysiologic monitoring of the eighth cranial nerve helps to preserve hearing.

We advocate early surgery on one side if one of the vestibular tumors is less than 1.5 cm in diameter. When the tumor is small, early surgery reduces the size of the tumor and preserves hearing and facial nerve function. If the tumors are greater than 1.5 cm, we prefer to wait until there is significant motor dysfunction due to brain stem compression. When motor dysfunction is present in patients with large bilateral tumors, we recommend subtotal resection of one of the tumors. If brain stem compression is predominantly unilateral, subtotal resection of the larger tumor relieves brain stem compression and preserves facial nerve function and hearing. However, when patients have very large bilateral tumors and bilateral brain stem compression, the appropriate operation may be a radical subtotal resection on one side, sacrificing hearing and preserving facial nerve function. In the latter situation, aggressive tumor removal may compromise facial nerve function. Chemotherapy with bevacizumab may also be an option.48

In patients with large vestibular tumors, the presence of additional CNS tumors may affect the surgical approach to a vestibular tumor. If there are multiple large CNS tumors and the vestibular schwannoma is causing brain stem compression, subtotal resection of the vestibular tumor for brain stem decompression alone may be more appropriate than radical resection. Because vestibular schwannomas may remain stable for prolonged periods, simple decompressive subtotal resection can provide symptomatic relief for several years.

In children and young adults, the vestibular tumors may be small. If one of the tumors is less than 1.5 cm in size, we recommend operating on the smaller tumor. Resection is performed with the goal of preserving hearing on that side. Successful resection of the smaller tumor, with preservation of hearing on that side, permits radical resection of the contralateral tumor at a later time, when hearing loss on that side will not affect quality of life.

Other Intracranial Tumors

The technical surgical approach to the removal of brain tumors in patients with NF2 is identical to the same tumor in normal individuals. However, the potential for multiple recurrent CNS tumors and multiple surgeries must be considered before deciding on surgery. Tumors are only removed when they are symptomatic. Meningiomas in NF2 are removed for cortical compression causing neurologic deficit or for seizure generation. En plaque meningiomas, even when very large and diffusely compressive, should be watched in patients with NF2, especially if there is a large additional tumor burden. Meningiomas invading the bone require an aggressive surgical approach with wide margins and demand the participation of a cranial facial surgeon.

Spinal Cord Lesions

The surgical approach to intramedullary spinal tumors of NF2 is identical to intramedullary spinal tumor in normal individuals. The levels of interest are exposed by generous bony removal, the dura is opened and retracted, a midline myelotomy is performed, and pial retraction stitches are placed after the tumor has been reached by gentle dissection under the microscope. Ependymomas in NF2 are usually well circumscribed. They can be debulked and dissected from normal spinal cord tissue with care. Although the spinal cord may appear thinned and compressed, recovery from a first surgery is generally good.

Hydrocephalus

Hydrocephalus can occur either from tumor obstruction of CSF pathways or from tumor protein production within the CSF, causing reduced CSF absorption. Hydrocephalus is treated with tumor removal or ventriculoperitoneal shunting. Frequently, hydrocephalus is observed postoperatively after removal of an intraventricular or subarachnoid tumor (e.g., vestibular schwannoma). Despite treatment with anti-inflammatory glucocorticoids, the malabsorption of CSF, presumed to be from inflammatory insult at the villus absorptive surface, rarely resolves. Knowledge of the type of hydrocephalus, obstructive versus absorptive, as well as consideration of the presumed elevated CSF protein in the presence of multiple CNS tumors, may affect the choice of shunting valve system.

Conclusions

The NFs are not surgically curable diseases. Unfortunately, the limited usefulness of adjuvant therapy leaves surgery as the primary treatment to alleviate symptoms. While surgery provides symptomatic relief, it may not alter the course of disease. Surgery should be limited to the removal of tumors that are symptomatic or that threaten to cause symptoms. The technical surgical approach to the tumors of NF1 and NF2 is generally similar to the approach of the same tumor in patients without NF. However, the decision of when to operate and to what level of aggressiveness is often affected by the disease and is of critical importance in NF. Even though the relentless progression of disease may at times be discouraging, the ability of neurosurgery to alleviate symptoms and improve longevity and quality of life is significant.

Key References

Aoki S., Barkovich A.J., Nishimura K., et al. Neurofibromatosis types 1 and 2: cranial MR findings. Radiology. 1989;172:527-534.

Balasubramniam A., Shannon P., Hodaie M., et al. Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: case report and review of the literature. Neuro Oncol. 2007;9:447-453.

Chan A.W., Black P., Ojemann R.G., et al. Stereotactic radiotherapy for vestibular schwannomas: favorable outcome with minimal toxicity. Neurosurgery. 2005;57:60-70.

Cohen B.H., Rothner A.D. Incidence, types, and management of cancer in patients with neurofibromatosis. Oncology. 1989;3:23-38.

Duffner P.K., Cohen M.E., Seidel F.G., et al. The significance of MRI abnormalities in children with neurofibromatosis. Neurology. 1989;39:373-378.

Evans D.G.R., Baser M.E., O’Reilly B., et al. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg. 2005;19:5-12.

Friedrich R.E., Korf B., Funsturer C., et al. Growth type of plexiform neurofibromas in NF1 determined on magnetic resonance images. Anticancer Res. 2003;23:949-952.

Huson S.M., Harper P.S., Compston D.A.S. Von Recklingausen neurofibromatosis: a clinical and population study in southeast Wales. Brain. 1988;111:1355-1381.

Ilgren E.B., Kinnier-Wilson L.M., Stiller C.A. Gliomas in neurofibromatosis: a series of 89 cases with evidence for enhanced malignancy in associated cerebellar astrocytomas. Pathol Ann. 1985;20:331-358.

Listernick R., Charrow J., Greenwald M.J., et al. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr. 1994;125:63-66.

Louis D.N., Ramesh V., Gusella J. Neuropathology and molecular genetics of neurofibromatosis 2 and related tumors. Brain Pathol. 1995;5:163-172.

Mathieu D., Kondziolka D., Flickinger J.C., et al. Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates. Neurosurgery. 2007;60:460-470.

Mautner V.F., Tatagiba M., Lindenau M., et al. Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. Am J Roentgenol. 1995;165:951-955.

McCormick P., Torres R., Post K., et al. Intramedullary ependymoma of the spinal cord. J Neurosurg. 1990;72:523-532.

McKenna M., Halpin C., Ojemann R., et al. Long-term hearing results in patients after surgical removal of acoustic tumors with hearing preservation. Am J Otolaryngol. 1992;13:134-136.

Mulvihill J.J., Parry D.M., Sherman J.L. NIH Conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis): an update. Ann Intern Med. 1990;113:39-52.

Neff B., Wiet R.M., Lasak J.M., et al. Cochlear implantation in the neurofibromatosis type 2 patient: long-term follow-up. Laryngoscope. 2009;117:1069-1072.

Packer R.J., Ater J., Allen J., et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86:747-754.

Plotkin S.R., Stemmer-Rachamimov A.O., Barker F.G.2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Eng J Med. 2009;361:358-367.

Pollack I.F., Shultz B., Mulvihill J.J. The management of brainstem gliomas in patients with neurofibromatosis 1. Neurology. 1996;46:1652-1660.

Samii M., Gerganov V., Samii A. Microsurgery management of vestibular schwannomas in neurofibromatosis type 2: indications and results. Prog Neurol Surg. 2008;21:169-175.

Sordillo P.P., Helson L., Hajdu S.I. Malignant schwannoma: clinical characteristics, survival, and response to therapy. Cancer. 1981;47:2503-2509.

Sorensen S.A., Mulvihill J.J., Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis: survival and malignant neoplasms. N Engl J Med. 1986;314:1010-1015.

Tonsgard J.H., Kwak S.M., Short M.P., et al. CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions. Neurology. 1998;50:1755-1760.

Warbey V.S., Ferner R.E., Dunn J.T., et al. [18F]FDG PET/CT in the diagnosis of malignant peripheral nerve sheath tumors in neurofibromatosis type-1. Eur J Nucl Med Mol Imaging. 2009;36:751-757.

Numbered references appear on Expert Consult.

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