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.

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