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Type 1 Neurofibromatosis Background Neurofibromatosis (NF) is a multisystem genetic disorder that commonly is associated with cutaneous, neurologic, and orthopedic manifestations. It is the most frequent of the so- called hamartoses. NF type 1 (NF1) is differentiated from central NF or NF type 2 in which patients demonstrate a relative paucity of cutaneous findings but have a high incidence of meningiomas and acoustic neuromas (which are frequently bilateral). NF1 has a better prognosis with a lower incidence of CNS tumors than NF2. However, morbidity and mortality rates in NF1 are not negligible. Some of the more severe complications are visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, vascular lesions, and long-bone abnormalities, which sometimes necessitate amputation. Pathophysiology The manifestations of NF1 result from a mutation in or deletion of the NF1 gene. The gene product neurofibromin serves as a tumor suppressor; decreased production of this protein results in the myriad of clinical features. Epidemiology Frequency International The estimated incidence of NF1 is 1 in 3000, but the actual frequency may be higher because of less than complete ascertainment of mildly affected individuals. Approximately half of affected individuals represent first cases in the family as a result of a new genetic event or mutation. Mortality/Morbidity Lifetime risks for both benign and malignant tumors are increased in NF1-affected individuals. Cutaneous or subcutaneous neurofibromas, optic nerve gliomas, dumbbell-shaped spinal cord tumors, and brain tumors represent some of the well-recognized nerve-related neoplasms. Adolescence for both genders may precipitate the development of subcutaneous and cutaneous neurofibromas. Increase in the size of existing neurofibromas and the appearance of new neurofibromas during pregnancy is a frequent observation in women with NF1. [1] Plexiform neurofibromas, generally larger, more diffuse, and locally invasive are seen in more than one fourth of patients with NF1 [2] and can present a surgical or medical management conundrum. The wisdom of watchful waiting versus intervention is often debated, with the recognition that complete resection of a plexiform neurofibroma without residual functional deficits is rarely possible. On the other hand, debulking or partial resection of plexiform neurofibromas may be undertaken for cosmetic purposes or if progressive functional consequences are anticipated. Gliomas in patients with NF1 tend to be lower grade and have a more favorable prognosis than in patients without NF1, with pilocytic astrocytomas and low-grade astrocytomas (subtype intermediate) being quite common. [3] However, diffusely infiltrating astrocytomas are also seen in a subset of patients and need to be managed accordingly. Malignant peripheral nerve sheath tumors (MPNSTs) and neurosarcomas are not uncommon in adolescents and adults with NF1, with an approximate lifetime risk of 10%. These malignancies frequently arise from large plexiform neurofibromas or extensive peripheral nerve lesions.

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Type 1 Neurofibromatosis BackgroundNeurofibromatosis (NF) is a multisystem genetic disorder that commonly is associated with cutaneous, neurologic, and orthopedic manifestations. It is the most frequent of the so-called hamartoses.

NF type 1 (NF1) is differentiated from central NF or NF type 2 in which patients demonstrate a relative paucity of cutaneous findings but have a high incidence of meningiomas and acoustic neuromas (which are frequently bilateral). NF1 has a better prognosis with a lower incidence of CNS tumors than NF2. However, morbidity and mortality rates in NF1 are not negligible. Some of the more severe complications are visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, vascular lesions, and long-bone abnormalities, which sometimes necessitate amputation.

PathophysiologyThe manifestations of NF1 result from a mutation in or deletion of the NF1 gene. The gene product neurofibromin serves as a tumor suppressor; decreased production of this protein results in the myriad of clinical features.

EpidemiologyFrequency

InternationalThe estimated incidence of NF1 is 1 in 3000, but the actual frequency may be higher because of less than complete ascertainment of mildly affected individuals. Approximately half of affected individuals represent first cases in the family as a result of a new genetic event or mutation.

Mortality/Morbidity

Lifetime risks for both benign and malignant tumors are increased in NF1-affected individuals. Cutaneous or subcutaneous neurofibromas, optic nerve gliomas, dumbbell-shaped spinal cord tumors, and brain tumors

represent some of the well-recognized nerve-related neoplasms. Adolescence for both genders may precipitate the development of subcutaneous and cutaneous neurofibromas. Increase in

the size of existing neurofibromas and the appearance of new neurofibromas during pregnancy is a frequent observation in women with NF1.[1]

Plexiform neurofibromas, generally larger, more diffuse, and locally invasive are seen in more than one fourth of patients with NF1[2] and can present a surgical or medical management conundrum. The wisdom of watchful waiting versus intervention is often debated, with the recognition that complete resection of a plexiform neurofibroma without residual functional deficits is rarely possible. On the other hand, debulking or partial resection of plexiform neurofibromas may be undertaken for cosmetic purposes or if progressive functional consequences are anticipated.

Gliomas in patients with NF1 tend to be lower grade and have a more favorable prognosis than in patients without NF1, with pilocytic astrocytomas and low-grade astrocytomas (subtype intermediate) being quite common.[3] However, diffusely infiltrating astrocytomas are also seen in a subset of patients and need to be managed accordingly.

Malignant peripheral nerve sheath tumors (MPNSTs) and neurosarcomas are not uncommon in adolescents and adults with NF1, with an approximate lifetime risk of 10%. These malignancies frequently arise from large plexiform neurofibromas or extensive peripheral nerve lesions. MPNSTs in patients with NF1 carry a poorer prognosis than in patients without this condition; tumor volume is an independent prognostic indicator.[4]

More than 1% of patients with NF1 develop an indolent symmetric sensory axonal neuropathy. However, some cases of polyneuropathy occur in association with diffuse nerve root lesions or MPNSTs.

Gastrointestinal stromal tumors (GIST), often multiple with a predilection for the proximal small bowel, may be seen in patients with NF1. Therefore, there should be a high index of suspicion for a GIST in a patient who presents with GI bleeding or intestinal obstruction.[5] Gene mutations typically seen in sporadic GISTs leading to malignant transformation are rarely identified in the GISTs removed from patients with NF1.[6] Instead, activation of the Ras-MAPK pathway and loss of heterozygosity of specific chromosomal regions may underlie the development of GISTs in patients with NF1.[7]

Learning disabilities with or without attention deficit hyperactivity disorder (ADHD) are seen in approximately 40% of NF1-affected individuals. A much smaller percentage experience more significant cognitive difficulties such as mild or moderate mental retardation.

Scoliosis in NF1 is often mild, but a subset of children younger than 10 years develop a more rapidly progressive form of scoliosis that requires aggressive intervention.

Bony abnormalities may be clinically silent, with radiographic evidence of long bone intramedullary fibrosis, cortical thinning, or vertebral dural ectasias often found incidentally.

Sphenoid bone dysplasia and long-bone bowing or pseudarthrosis are common features of NF1. In the past, congenital tibial pseudarthrosis led to below-the-knee amputation; however, recent advances in orthopedic

management with limb-sparing procedures have decreased the need for such drastic procedures.

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Osteoporosis  with statistically significant decreases in bone mineral density can be identified in individuals with NF1, perhaps even as early as childhood.[8]Whereas a number of metabolic pathways impacting bone metabolism have been implicated in the pathogenesis of bone abnormalities in people with NF, studies in children and teens with NF have provided evidence for increased rates of bone resorption as a likely cause for osteopenia.[9]

Emerging evidence shows that vitamin D deficiency combined with a higher than normal bone turnover contributes to decreased bone mineral density (BMD) in patients with NF1.[10] One study looking at adults with NF1 (mean age, early 40s), showed that 50% had osteopenia and 19% had frank osteoporosis. Males were more likely than females to have reduced BMD; 56% of patients had a low 25-hydroxy-vitamin D while 34% had elevated parathyroid hormone.[11] Judicious vitamin D supplementation may prove beneficial for patients with NF1 who have vitamin D deficiency or evidence of osteopenia.

Hypertension in NF1 can be seen at any age, with many adults with NF1 manifesting the usual essential form of hypertension. However, any person with NF1 and high blood pressure must be evaluated carefully for 2 alternative causes of hypertension (see Prognosis).

Pheochromocytomas are not rare in NF1 and can cause severe, fluctuating hypertension. Vascular stenosis (ie, renal artery stenosis secondary to fibromuscular dysplasia) also may result in hypertension that may

not respond well to standard pharmacologic management. Other vascular lesions, especially in the central nervous system, such as vascular ectasias, stenoses, moyamoya disease,

and aneurysms, occur more frequently in patients with NF1. Rarely, coronary artery aneurysms are identified in symptomatic or even asymptomatic individuals with NF1.[12]

Short stature is common in NF1; affected individuals are often shorter than their unaffected siblings. Macrocephaly is common in NF1 and should not cause undo alarm if present in affected infants or young children, unless

serial head circumference measurements confirm the rapid crossing of percentiles. Chiari type 1 malformations are seen with increased frequency in the NF1 population. Puberty usually occurs at a normal age, but precocious puberty with growth acceleration may occur in a small number of

individuals. When precocious puberty is present, the patient must be evaluated for a chiasmal lesion causing disruption of the hypothalamic-pituitary axis.Race

All races and ethnic backgrounds are affected equally. However, recent evidence indicates that the risk for optic nerve glioma is lower in African Americans than in Caucasians and Hispanics.

Sex

Males and females are affected equally with this autosomal dominant condition. Scoliosis may be especially severe in young girls compared to their male counterparts.

Age

Although the genetic change causing NF1 is present at conception, clinical manifestations may appear slowly over many years.

Diagnosis often is made earlier in children born to an NF1-affected parent; the clinical criteria for diagnosis are fulfilled more easily, and the clinician may be more attuned to this possible diagnostic concern.

If an at-risk individual reaches the age of 10 years without meeting the diagnostic criteria for NF1, he or she is unlikely to be affected.

History Clinical diagnosis requires the presence of at least 2 of 7 criteria to confirm the presence of neurofibromatosis, type 1. Many of

these signs do not appear until later childhood or adolescence, and thus confirming the diagnosis often is delayed despite a suspicion of NF1. The 7 clinical criteria used to diagnose NF1 are as follows:

Six or more café-au-lait spots or hyperpigmented macules greater than or equal to 5 mm in diameter in children younger than 10 years and to 15 mm in adults

Axillary or inguinal freckles Two or more typical neurofibromas or one plexiform neurofibroma Optic nerve glioma Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis First-degree relative (eg, mother, father, sister, brother) with NF1

Physical The earliest clinical finding usually seen in children with NF1 is multiple café-au-lait spots.

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These may be present at birth or may appear over time, frequently increasing in size and number throughout childhood. See

the image below. Café-au-lait spots in a 4-year-old boy. In adults, café-au-lait spots tend to fade and may be less obvious on clinical examination.

Axillary or inguinal freckles are rarely present at birth, but appear during childhood through adolescence. See the images

below. Axillary freckles. Inguinal freckles. Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children,

adolescents, and adults. See the image below. Multiple neurofibromas in a 28-year-old man. Deep lesions may be detected only through palpation, whereas cutaneous lesions may appear initially as small papules on

the trunk, extremities, scalp, or face. Puberty or pregnancy may be associated with an increased number of neurofibromas as well as more rapid growth of

preexisting lesions. Plexiform neurofibromas are more diffuse growths that can be locally invasive and quite deep; they may be associated with

bony erosion and pain. See the image below. Plexiform neurofibroma of the right thigh. Plexiform neurofibromas also may be accompanied by overlying hyperpigmentation or hypertrichosis. Rarely, rapid growth of a neurofibroma may occur and can be suggestive of malignant transformation.

Optic nerve tumors, which may be clinically silent, occur primarily in children younger than 5 years.

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Asymmetric, noncorrectable visual loss is the most common presenting symptom, but subtle peripheral field defects, color discrimination difficulties, optic nerve pallor, or proptosis may occur without visual acuity problems.

Some older children and adolescents may present with worsening vision secondary to a slow-growing optic nerve glioma (ONG) and, therefore, monitoring for visual difficulties should continue throughout childhood and adulthood. Adults may have a visually insignificant optic nerve glioma detected incidentally on a head imaging study.

Although Lisch nodules occasionally can be seen with a direct or indirect ophthalmoscope, especially in individuals with light-colored irides, they are usually not readily visible without using a slit lamp. See the image below.

Lisch nodules. Choroidal abnormalities with a patchy appearance may also be noted on funduscopic examination using infrared

monochromatic light. Retinal corkscrew vascular changes have also been described in some patients with NF1. Sphenoid bone dysplasia is usually asymptomatic, but occasionally can be associated with herniation through the bony defect.

In the occasional patient with a plexiform neurofibroma of the eyelid, ipsilateral sphenoid dysplasia is frequently present. Congenital pseudarthrosis may be evident at birth, with bowing of the tibia being the most typical presentation. See the image

below. Radial and ulnar bowing and obliteration of the intramedullary spaces. Thinning and angulation of long bones can occur throughout early childhood and adolescence, with prominence of the

anterior tibia and progressive deformity. Less commonly, bowing of the forearm can occur.

Scoliosis with or without kyphosis may become evident in childhood or adolescence. When found in a child younger than 10 years, it is associated with a much poorer prognosis and is likely to progress rapidly. Scoliosis detected during adolescence still should be monitored clinically, but is much less likely to require orthopedic

intervention. Blood pressure should be checked during every clinical visit because of the distinct possibility of alternative causes of

hypertension in NF1. Head circumference should be monitored throughout the first 3 years of life, as with any child. Relative macrocephaly should

not cause alarm, unless serial measurements suggest rapid growth with crossing of 2 or more percentile lines.

Causes NF1 is an autosomal dominant condition caused by decreased production of the protein neurofibromin, which has a putative

tumor suppressor function. Only oneNF1 gene need be deleted or mutated to produce the condition. The NF1 gene has been localized to the long arm of chromosome 17; more than 250 mutations leading to protein truncation

having been identified in affected individuals. A more severe phenotype has been observed in a subset of patients with a complete gene deletion.

The precise role of neurofibromin is not fully understood, but the multitude of clinical effects suggests that this gene product has diverse functions in various tissues.

Mutations in another gene (SPRED1) have been identified in a subset of patients described to have mild NF.[13] Individuals with a SPRED1 mutation may be incorrectly diagnosed with NF1 based on the presence of multiple café-au-lait spots and axillary or inguinal freckles, but these patients do not go on to develop the neurofibromas or Lisch nodules that are found in most adults with true NF1.

Differential Diagnoses Brainstem Gliomas Cauda Equina and Conus Medullaris Syndromes Low-Grade Astrocytoma

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Meningioma Neurofibromatosis, Type 2 Spinal Cord Hemorrhage Spinal Cord Infarction Spinal Epidural Abscess

Laboratory Studies Sequencing of the neurofibromin gene offers the highest detection rate and may approach 95% in clinically affected

individuals. Molecular testing may be extremely helpful for patients with a single clinical finding, such as multiple café-au-lait spots in the

absence of a positive family history. Neurofibromatosis type 1 (NF1) may be diagnosed by either of 2 methods during the prenatal period.

In a family with multiple affected members, linkage analysis can track theNF1 gene through the generations to determine which chromosome 17 region the fetus received. However, with advances in molecular diagnosis, family studies are rarely necessary.

For a parent with NF1 who is the only affected family member, gene sequencing can be used to identify a specific gene mutation. Identification of the mutation in the affected parent would permit prenatal diagnosis via amniocentesis or chorionic villus sample (CVS).

When a specific mutation is known, preimplantation genetic diagnosis can also be offered to couples using in vitro fertilization with selection of unaffected embryos for transfer.

Urinary free catecholamines (norepinephrine and epinephrine) as well as their metabolites (normetanephrine, metanephrine and vanillyl-mandelic acid) measured on a 24-hour urine collection are good biochemical screening tests for a suspected pheochromocytoma.[14]

Plasma catecholamines may also be measured using liquid chromatography. Measurement of free plasma metanephrine is more sensitive in detection of a pheochromocytoma than plasma catecholamines.[15]

Imaging Studies Radiography

Plain films may detect a variety of subtle and not so subtle bony abnormalities associated with NF1. See the image below.

Radial and ulnar bowing and obliteration of the intramedullary spaces. Radiographs should be obtained when clinical findings suggest possible modeling defects of the long bones or ribs, possible

bony erosion secondary to an adjacent plexiform neurofibroma, signs of scoliosis, or bone pain. MRI or CT scan

In the past, MRI or CT scans have been ordered routinely for patients with NF1. More recently, clinicians have moved away from standard screening and opted for head imaging in patients with specific indications.

Some clinicians prefer to perform a baseline CT scan or MRI in children or adults at the time of diagnosis, subsequently recommending another imaging study only if neurological problems arise. Other clinicians feel that baseline studies are of limited value, since detecting an asymptomatic optic nerve glioma would probably not prompt medical intervention.

MRI has become the preferred diagnostic head imaging study in NF1.

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MRI has been shown to frequently detect unidentified bright objects (UBOs) in the brain parenchyma of patients with NF1.

See the image below. Unidentified bright object (UBO) within the brain parenchyma. These bright spots seen on T2-weighted images generally do not enhance, cause no mass effect, and often resolve as the

individual gets older. They are believed to represent benign hamartomas in NF1 and are seen more often in children with NF1-related learning

disabilities. Brain CT scan or MRI should be considered to evaluate ventricular size when increasing head circumferences is noted in an

infant or young child. Rarely, hydrocephalus and/or a Chiari type 1 malformation are seen in children and even adults with NF1.

MRI is also a valuable tool in evaluating the optic nerves or optic chiasm. See the image below.

Left optic nerve glioma with thickening of the nerve and proptosis. It is indicated for patients with optic nerve pallor, visual changes, proptosis, or precocious puberty. Thin cuts through the orbits and optic nerves are an ideal way to identify subtle optic nerve pathology.

Head MRI should be considered in patients with headaches that are changing in quality or are increasing in frequency or intensity. Although brain tumors are less common in NF1 than in NF2, they can still occur in this clinical setting.

MRI has proven useful in evaluating internal lesions such as mediastinal masses, spinal cord tumors, deep plexiform neurofibromas, neurofibromas of the brachial or sacral plexus, and abdominopelvic lesions. Short T1-inversion recovery MR images can be used to accurately estimate the volume of a plexiform neurofibroma, which can be useful for both diagnosis and follow-up. In adults, unlike children where continued growth of plexiform lesions is quite common, rapid growth of a plexiform neurofibroma may portend malignant transformation.[16] Although MRI is not always helpful in differentiating benign peripheral nerve lesions from malignant lesions, central hypointense areas within a lesion noted on T2-weighted images (the so-called target sign) is more suggestive of a benign lesion.[17] On the other hand, MRI evidence of intratumoral lobulation or T1 high signal intensity are much more suggestive of malignancy.[18]

CT and MRI are first-line imaging studies when pheochromocytoma is suspected based on abnormal serum or urine screening tests.[14] If CT or MRI is unable to identify the suspected pheochromocytoma, then metaiodobenzylguanidine (MIBG) scintigraphy is indicated.[19]

Positron emission tomography: F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) may be used to stage and follow up MPNSTs before, during, and after therapy.[20]

Gallium-67 scintigraphy may be used as a screening tool for patients with NF, especially patients with a large plexiform neurofibroma when there is concern about 1 or more areas having undergone malignant transformation.[21]

Other Tests Electroencephalogram (EEG) is indicated in patients with symptoms suggestive of seizures. Seizures are reported more often

in patients with NF1 than in the general population, occurring in between 4 and 7%. MRI alone is generally sufficient for medical and/or surgical decision making. Occasionally, myelography is needed to clarify

the extent of a spinal cord tumor.

Procedures

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Slit-lamp examination by an experienced ophthalmologist can provide key diagnostic information in older children and adults who have only a single clinical criterion such as multiple café-au-lait spots.

The occurrence of Lisch nodules appears to be age dependent; more than 95% of NF1-affected individuals older than 10 years have this iris finding.

This examination is invaluable in determining if parents of an affected child carry the NF1 mutation, even when the parent has no other signs of the condition.

Histologic Findings Neurofibromas are generally well-differentiated tumors that contain elongated spindle-shaped cells as well as pleomorphic

fibroblast-like cells. Rarely, inflammatory cells may be seen in these otherwise benign-appearing lesions. Optic gliomas also are indolent, generally very low-grade lesions. In fact, optic nerve lesions associated with NF1 are less

aggressive and respond more favorably to current therapies than optic nerve tumors in the general population. Occasionally, a neurofibroma (typically large or deep plexiform neurofibroma or peripheral nerve sheath tumor residing within

the brachial or pelvic plexus) undergoes malignant transformation to a neurofibrosarcoma. Unlike benign neurofibromas, neurofibrosarcomas are characteristically hypercellular with giant cells, increased numbers of mitoses, and vascular proliferation.

Because collections of malignant cells may be present between larger masses of benign cells in a plexiform neurofibroma, examining a plexiform tumor carefully (ie, taking samples from multiple regions to confirm that it is indeed benign) is essential.

Medical Care For individuals diagnosed with neurofibromatosis type 1 (NF1), routine examinations should focus on the potential

complications. Annual examinations permit early detection of problems, decreasing morbidity and improving quality of life. Annual eye examinations are important in early detection of optic nerve lesions.

Cutaneous examination performed at each visit should look for new neurofibromas or progression of preexisting lesions. Plexiform neurofibromas may be locally invasive, therefore clinical evaluation should be directed at determining the extent of involvement and detecting evidence of bony erosion or nerve entrapment.

Skeletal involvement, including scoliosis, hemihypertrophy, or long-bone modeling defects, should be documented. Blood pressure should be checked at each visit and hypertension treated promptly if detected. Hypertension workup should

include evaluation for pheochromocytoma (ie, measurement of urinary catecholamines and metanephrines) and testing for renal artery stenosis. Percutaneous transluminal renal artery angioplasty may, in some cases, effectively treat renal artery stenosis secondary to fibromuscular dysplasia.

Interval history should focus on subtle sensory or motor symptoms such as paresthesia, radiculopathy, weakness, or muscle atrophy.

Patients should be asked about incontinence. At each visit, minor changes in the sensory or motor examination should be documented carefully.

Symptoms of spinal cord neurofibromas may be subtle and slowly progressive; prompt identification and early surgical intervention allow for optimal outcome.

Removal of neurofibromas for medical or cosmetic indications is one of the most common procedures on individuals with NF1. Recent advances in laser technology have permitted nonsurgical removal of small, cutaneous neurofibromas. However, careful surgical resection of small or large neurofibromas may leave an even smaller, less prominent scar.

Although laser treatment has been used for various cutaneous, hyperpigmented lesions (eg, port-wine stains, tattoos), it has not yet proven successful in permanent removal of café-au-lait spots.

Use of chemotherapy to treat malignant peripheral nerve sheath tumors (MPNSTs) that are unresectable or metastatic has been debated for a number of years, with less than optimal outcomes using a variety of combinations of agents. More recently, in vitro studies looking at a broader range of agents targeting the Ras and/or other relevant pathways have shown some promising results.

Farnesyl transferases used in combination with lovastatin have shown synergistic effects in growth inhibition of MPNST cell lines in vitro.[22]

Sorafenib also appears to inhibit MPNST cell growth in vitro.[23]

A rapamycin complex 1 inhibitor (RAD001) demonstrated decreased tumor cell growth when used alone, and, when used in combination with erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor), showed even further growth inhibition and tumor cell apoptosis.[24]

Hyaluronan oligomers, another promising agent, has shown efficacy in slowing growth of MPNSTs in animal models. These small molecules, when used in combination with a traditional chemotherapy agent (doxorubicin), substantially inhibit tumor growth.[25]

In the near future, studies such as these will likely lead to preclinical and then clinical trials for patients with unresectable MPNSTs.

Surgical Care

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Surgical resection of neurofibromas can be accomplished by any competent surgeon. Plastic surgery consultation is advisable for areas of great cosmetic concern such as the face. Resection is the treatment of choice for pheochromocytomas.[26]

Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention. Plexiform neurofibromas may be difficult to approach surgically, often recurring after resection because of residual tumor cell

collections deep in soft tissues. Surgeons must realize that removing some of these lesions can result in substantial blood loss and must plan accordingly.

Symptomatic peripheral nerve sheath tumors located along the nerves of the brachial or pelvic plexus sometimes require surgical intervention with the very real potential for postoperative nerve dysfunction. Added to this is the risk for malignant transformation that carries with it a very poor prognosis; the decision to operate requires much thought and careful consideration. One should always weigh the potential diagnostic benefits taking into account one's index of suspicion for malignancy, against the potential risks for long-term neurologic sequelae.

For many patients, neurofibromas on the scalp, along the hairline, or around the waist where clothes rub can cause great irritation and discomfort. Therefore, removing these should not be considered cosmetic but a necessary medical procedure.

Resection of spinal cord tumors is difficult but often necessary to prevent progressive paraplegia or quadriplegia.o Acting promptly when neurological symptoms appear is important to maximize operative success.o Surgical intervention may not guarantee a complete resection of the tumor, but it may serve a palliative function in some

cases.o Single fraction radiosurgery has been used in some centers to treat benign intradural extramedullary spinal cord tumors.

This technique may be used as a primary therapeutic approach or in cases of postsurgical progression or when residual tumor is a concern after a subtotal surgical resection.[27]

Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.o Following patients with NF1 when scoliosis is first detected is advisable, so that nonsurgical approaches may be used in an

attempt to obviate the need for a future spinal fusion procedure.o Limb-sparing procedures in addition to new bracing and casting technologies have decreased the need for amputation in

patients with a pseudarthrosis. See the image below. Below-the-knee amputation for tibial pseudarthrosis.o Patients with long-bone defects are best served by ongoing orthopedic care.

Some hypertensive patients with renal artery stenosis require surgical resection and repair instead of or following angioplasty.

Resection of a pheochromocytoma requires preoperative treatment with an alpha-blocker (preferably a selective postsynaptic alpha1-receptor antagonist) to offset the effects of catecholamine release during surgical manipulation of the tumor.[28]

Consultations The neurologist serves as a key consultant and provides valuable information concerning changes in neurological status by

performing a complete, focused examination. The neurosurgeon serves as an expert consultant when a spinal cord or brain tumor is identified and works closely with the

neurologist to determine the optimal timing and best surgical approach on an individual basis. The ophthalmologist serves as a valuable member of the NF1 consultation team, evaluating patients on an annual basis for

changes in visual acuity, field defects, or appearance of Lisch nodules. The geneticist provides information concerning diagnosis, diagnostic testing, inheritance, and risks for recurrence in future

children. Family planning options and prenatal diagnosis may be addressed in this clinical setting. The orthopedist is a key consultant for the many NF1-related bone abnormalities (eg, scoliosis, pseudarthrosis,

hemihypertrophy, bony erosion by plexiform neurofibromas). The developmental pediatrician may be an invaluable resource in evaluating a child with NF1 and learning disabilities. In addition to these most frequently used consultants, patients may need to see others for specific NF1 concerns. Examples

include the following: A nephrologist to help rule out renal vascular lesions A general or plastic surgeon to consider removal of neurofibromas An oncologist to manage and treat symptomatic optic nerve gliomas, brain tumors, neurosarcomas and MPNSTs An otolaryngologist for suspected hearing loss or an acoustic nerve lesion

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A dermatologist to assess cutaneous lesions An oculoplastic surgeon for an orbital plexiform neurofibroma

ActivityNo activity restrictions are necessary, except for an individual with specific orthopedic concerns (as recommended by the consulting surgeon).

Patients with spinal fusion procedures as well as individuals with significant long-bone weakness or pseudarthrosis may need to limit certain athletic activities.

Patients with neurological sequelae from spinal cord lesions may be restricted in their activities secondary to physical disabilities.

Medication SummaryNo known medical therapies are beneficial to patients with NF1. Several drug trials have been initiated, looking for medications that slow or halt the growth of neurofibromas. Thus far, none of these medications have demonstrated significant benefit, although various research trials involving chemotherapeutic and other agents are underway in an attempt to slow the growth of plexiform neurofibromas.

For a small subset of patients with pruritus due to cutaneous neurofibromas, diphenhydramine may provide some temporary relief. Such patients also are encouraged to avoid hot showers and baths, since hot temperatures may exacerbate itching.

Treatment with carboplatin shows efficacy in controlling the growth of visually significant optic gliomas.

AntihistaminesClass Summary

These agents may control itching by blocking effects of endogenously released histamine.

View full drug informationDiphenhydramine (Benadryl, Benylin, Diphen, AllerMax) 

First-generation antihistamine with anticholinergic effects that binds to H1 receptors in the CNS and the body.

Competitively blocks histamine from binding to H1 receptors. Has significant antimuscarinic activity and penetrates CNS, which causes pronounced tendency to induce sedation.

Approximately half of those treated with conventional doses experience some degree of somnolence. A small percentage of children paradoxically respond to diphenhydramine with agitation.

For symptomatic relief of pruritus caused by release of histamine in inflammatory reactions.

Alpha-adrenergic blocking agentsClass Summary

These agents cause vasodilation of veins and arterioles and decrease total peripheral resistance and blood pressure.

View full drug informationPrazosin (Minipress) 

Postsynaptic alpha1-antagonist, decrease blood pressure with minimal risk of reflex tachycardia.

View full drug informationDoxazosin (Cardura) 

Quinazoline compound selective alpha1-adrenergic antagonist. Inhibits postsynaptic alpha-adrenergic receptors, resulting in vasodilation of veins and arterioles and decrease in total peripheral resistance and blood pressure.

Antineoplastic agentsClass Summary

These agents inhibit cell growth and proliferation. The agent carboplatin has been used in the treatment of visually significant optic nerve gliomas.

View full drug informationErlotinib (Tarceva)

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Pharmacologically classified as a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells.

View full drug informationSorafenib (Nexavar) 

First oral multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for renal cell carcinoma.

View full drug informationCarboplatin (Paraplatin) 

Alkylating agent that has been used extensively in treatment of ovarian cancer, but with efficacy in treatment of optic nerve lesions in combination with vincristine sulfate.

Proceed to Follow-up 

Further Inpatient Care Hospitalization may be necessary for major surgical procedures and workup of uncontrolled hypertension. Many minor surgical procedures (eg, removal of cutaneous neurofibromas) may be done in an outpatient surgical setting.

Further Outpatient Care Although patients with neurofibromatosis type 1 (NF1) can be cared for in the primary care setting, additional medical

concerns need to be addressed on a routine basis. Some practitioners believe patients should be seen on an annual basis in a comprehensive NF center; others consider

themselves capable of providing the annual care and refer to consultants only for medical complications. An outline of reasonable guidelines in caring for patients with NF1 is as follows:

Annual examinations should focus on potential complications of NF. Each examination should include blood pressure measurement, assessment of the skin for typical lesions (including early

or growing neurofibromas), visual acuity check, evaluation of the eyes for evidence of proptosis or strabismus, and examination of the spine and extremities for any abnormalities.

Neurologic evaluation should include a careful history for headaches or motor or sensory symptoms as well as a comprehensive motor and sensory examination.

Annual ophthalmologic examinations should check for optic nerve pallor, visual acuity changes, visual field defects, and Lisch nodules. Patients should be referred to an ophthalmologist promptly if the treating physician has any concerns about visual acuity, evidence of proptosis, or a palpebral plexiform neurofibroma obstructing vision.

Complications Locally invasive plexiform neurofibromas Optic nerve gliomas, especially in children younger than 5 years Dumbbell-shaped spinal cord neurofibromas or neurofibromas of the brachial or sacral plexus Peripheral neuropathy Scoliosis Hypertension due to pheochromocytoma or renal vascular stenosis secondary to fibromuscular dysplasia Bony modeling defects that may lead to pseudarthrosis, thoracic cage asymmetry, or pathologic fractures Increased risk for brain tumors, leukemia, and other malignancies of neural crest origin (including neurofibrosarcomas and

MPNSTs) Learning disabilities, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), or rarely, mental

retardation

Prognosis Although most individuals with NF1 lead relatively long and healthy lives, the overall life expectancy may be reduced by as

much as 15 years. The major causes for this increased morbidity and subsequent mortality are hypertension, sequelae of spinal cord lesions, and malignancy.

Prompt attention to complications of NF1 and early detection of medical problems may significantly reduce the overall morbidity and mortality rates.

Patient Education Patients and their families may be referred to NF-specific national and regional support groups for continuous updates on

treatment advances and for emotional support. The previous National NF Foundation, Inc, now renamed The Children's Tumor Foundation, has a toll-free telephone number (1-800-323-7938). Parents and families can sign up to receive a newsletter. Neurofibromatosis, Inc is another support and resource group with a toll-free telephone number (1-800-942-6825).

Inform patients of symptoms that would require immediate medical attention, including headaches increasing in intensity or frequency or focal neurological deficits.

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Neurofibromatosis Type 2 

BackgroundCentral neurofibromatosis, or neurofibromatosis type 2 (NF2), is a multisystem genetic disorder associated with bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts, with a paucity of cutaneous features (which are seen more consistently in neurofibromatosis type 1[NF1]). (See the image below.)

Subcutaneous and cutaneous lesions in a young man with neurofibromatosis type 2; note paucity of cafe-au-lait spots.Although quite variable in its age of onset and severity of symptoms in affected individuals, NF2 is associated with significant morbidity and decreased life span. Furthermore, diagnosis in childhood is often difficult because of the absence of central nervous system (CNS) involvement at a young age. (See Prognosis, Clinical, and Workup.)

Complications of NF2 may include the following (See Clinical, Workup, and Treatment):

Unilateral or, frequently, bilateral vestibular schwannomas leading to tinnitus, hearing loss, and/or problems with balance Meningiomas, gliomas, ependymomas, and other cerebral, cerebellar, or spinal cord lesions that may result in neurologic

deficits, seizures, and/or hydrocephalus Peripheral nerve schwannomas, mixed tumors, and, occasionally, neurofibromas Peripheral neuropathies Visually significant juvenile cataracts

EtiologyNF2 is inherited as an autosomal dominant condition, although half of affected individuals have NF2 as a result of a new (de novo) gene mutation. The manifestations of NF2 result from mutations in (or, rarely, deletion of) the NF2gene, located on the long arm of chromosome 22. Affected individuals need only 1 mutated or deleted NF2 gene to exhibit signs of the condition.

The NF2 gene product known as merlin serves as a tumor suppressor; decreased function or production of this protein results in a predisposition to develop a variety of tumors of the central and peripheral nervous systems.

Increasing evidence indicates that merlin is involved in a number of cellular pathways and works in concert with other proteins to promote cellular adhesion and responses via the growth factor receptor.[1] Understanding these interactions may eventually lead to more effective targeted treatment strategies, since the benign nature of NF2 lesions makes tumors frequently less responsive to chemotherapy or radiation therapy.

Numerous mutations in the NF2 gene have been identified, most of which are predicted to result in production of a truncated protein with loss of its usual function.

EpidemiologyThe estimated incidence of neurofibromatosis type 2 (NF2) is 1 in 37,000 per year, with about half of affected individuals representing first cases in the family as a result of new, dominant mutations.

Although the genetic change causing NF2 is present at conception, the clinical manifestations occur over many years. The typical age of onset of symptoms is in the late teens to early 20s, but the age range covers the entire life span. Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmitted NF2. While NF2 is quite variable in severity from person to person, family studies have shown some intrafamilial consistency in age of onset. Somatic mosaicism for the NF2 mutation in sporadic cases may also complicate the clinical picture, resulting in underdiagnosis or late diagnosis.

PrognosisThe prognosis of neurofibromatosis type 2 (NF2) depends on a number of factors, including age of symptom onset, degree of hearing deficit, and number and location of various tumors. Although age of onset is relatively similar within families, the age range can vary from 2-70 years. While the tumors themselves are relatively indolent and do not undergo malignant

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transformation, studies performed in the late 1980s and early 1990s showed clearly that significant rates of mortality and morbidity are associated with the diagnosis of NF2.

One such study suggested that the survival from the time of actual diagnosis averages 15 years; however, this may be changing for the better with improved diagnosis, surgical techniques, surveillance, screening, and recognition of mild disease (due in part to increased physician awareness and availability of molecular diagnostic options).

Morbidity and mortality

Vestibular schwannomas are the most common and well-recognized feature of NF2 leading to significant morbidity. Symptoms of tinnitus, gradual hearing loss, and even vestibular dysfunction are frequently the initial signs of NF2. Although unilateral hearing loss is the number 1 presenting symptom, bilateral deafness would be expected to eventually occur in most affected individuals. Untreated vestibular schwannomas can extend locally and may result in brainstem compression, hydrocephalus, and, occasionally, facial nerve palsy.

Dumbbell-shaped spinal cord schwannomas are quite common in NF2 and result in significant morbidity; they present a great therapeutic challenge. Spinal cord ependymomas, astrocytomas, and meningiomas also occur, but less frequently. Intracranial meningiomas, on the other hand, are a frequent finding; they may be asymptomatic, or they may cause a variety of symptoms and CNS deficits.

Nonvestibular schwannomas occur in more than half of patients and are often diagnosed in patients with an earlier age at diagnosis of NF2. Cranial nerves III and V are most commonly involved, but the rare occurrence of jugular foramen schwannomas potentially impacting the glossopharyngeal, vagus, and/or spinal accessory nerves may lead to dysphagia, esophageal dysmotility, hoarseness, or aspiration.

On the other hand, nonvestibular schwannomas in patients with NF2 tend to be more indolent and to grow slowly over time. This can complicate treatment decision making, since options include surgery, radiation therapy, and watchful waiting.[2]

Posterior subcapsular, or juvenile, cataracts can predate CNS symptomatology. These cataracts may progress over time, leading to decreased visual acuity. A fair percentage of affected individuals are found to have retinal hamartomas or epiretinal membranes that may or may not be visually significant.

Sensory motor polyneuropathy is seen in some individuals with NF2 who may or may not have identifiable tumors along the length of the peripheral nerve(s) of interest.

Patient EducationPatients and at-risk family members should be made aware of specific symptoms, such as tinnitus, hearing deficits, focal weakness, sensory changes, or balance problems, that might suggest tumor growth and should prompt immediate medical attention.

Patients with vestibular schwannomas should be cautioned about diving and underwater activities, because of increased risks for disorientation and potential for drowning.

Patients and their families may be referred to neurofibromatosis (NF)-specific regional and national support groups for continuous updates on advances in treatment, as well as for emotional support. Neurofibromatosis, Inc., for example, can be reached at the toll-free number 1-800-942-6825.

The Children's Tumor Foundation has a toll-free number (1-800-323-7938) for information and to sign up for their newsletter.

The NF2 Review, located in Los Angeles, CA, can be reached at 1-213-483-4431 and not only has an NF2-specific newsletter, but also has a particular research interest in NF2, with a team of specialists working on auditory brainstem implants (ABIs) and the newest surgical approaches to vestibular schwannomas.

Online resources include the NIH Web site and an NF2 person-to-person support group known as the NF2 crew.

HistoryBecause approximately half of affected persons represent new gene changes, family history is often negative, making diagnosis all the more difficult. Clinical diagnosis of neurofibromatosis type 2 (NF2) requires that an individual present with at least 1 of the 3 following disease indications:

Bilateral eighth nerve masses visualized on magnetic resonance imaging (MRI) scan, using thin cuts, with and without gadolinium and on axial and coronal views

First-degree relative with documented NF2 for an individual with a unilateral eighth nerve mass, imaged as already described First-degree relative with documented NF2 for an individual with at least 2 of the following findings: meningioma, glioma,

schwannoma, juvenile cataract

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Physical ExaminationUnlike neurofibromatosis type 1 (NF1), which frequently is associated with a number of cutaneous diagnostic clues, NF2 is accompanied by few external signs.

Presenting symptoms include hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesions. Individuals at risk for NF2 should be screened carefully for early signs of hearing loss, motor or sensory changes, and visual deficits.

Optic nerve sheath meningiomas, while generally quite rare in children, may be a presenting sign of NF2.[3]

Cranial nerve palsies may stem from compression of adjacent nerves secondary to an expanding vestibular schwannoma or directly from nonvestibular cranial nerve schwannomas.

Differentiating clinically between the relatively common NF1 and the rare NF2 is occasionally problematic. Patients with NF2 almost never have a large number of cafe-au-lait spots (although in rare cases, 6 or more may be seen), whereas cafe-au-lait spots are numerous and ubiquitous in NF1. Neither axillary nor inguinal freckles are common occurrences in NF2.

Malignant transformation of benign growths is almost unheard of in NF2, unlike in NF1. However, individuals with either NF1 or NF2 can develop multiple subcutaneous lesions that may be clinically indistinguishable (see the images below). In NF2, these lesions most often are defined histologically as schwannomas or neurilemomas, while in NF1 these are defined histologically as neurofibromas. Subcutaneous neurofibromas are occasional findings in NF2.

Subcutaneous and cutaneous lesions in a young man with neurofibromatosis type 2; note paucity of cafe-au-

lait spots. Right neck mass in a patient with neurofibromatosis type 2. Facial asymmetry, OS proptosis, and exotropia, as well as several subcutaneous lesions on the forehead and face, in a 20-year-old man with

neurofibromatosis type 2. Posterior cervical scar from cord lesion resection, thoracic scoliosis, and subcutaneous masses in a young adult with neurofibromatosis type 2.Posterior subcapsular lenticular opacities, even in childhood, would be suggestive of NF2, whereas Lisch nodules would be diagnostic of NF1. Finally, although individuals with either NF1 or NF2 can develop dumbbell-shaped spinal cord tumors, schwannomas are common in NF2, whereas neurofibromas are seen primarily in NF1.

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Differential Diagnoses Brainstem Gliomas Ependymoma Meningioma Neurofibromatosis, Type 1

Approach Considerations Now that the gene for neurofibromatosis type 2 (NF2) has been identified, analysis for disease-causing mutations can

be offered in some clinical settings. Detection rates for molecular-based testing approaches 65%; therefore, such testing has some inherent limitations when trying to confirm a diagnosis of NF2. However, for a patient with suspected NF2 who is still young, has a negative family history, and may eventually develop additional criteria, the identification of a specific mutation may be very helpful.

In light of the high rate of somatic mosaicism in sporadic cases of NF2 (perhaps as many as 25%), molecular testing of tumor tissue may augment traditional molecular studies when analysis of deoxyribonucleic acid (DNA) obtained from blood lymphocytes is nondiagnostic.

Imaging studies and auditory, ophthalmic, and histologic examinations are also important in the diagnosis and management of NF2.

Genetic Studies Attempts to increase the detection rate of NF2 mutations have met with some success by using a variety of

technologies. Denaturing high-performance liquid chromatography has shown promise in identifying more point mutations in affected individuals, and, when used in conjunction with multiplex ligation-dependent probe amplification, may uncover NF2 gene rearrangements. The addition of a third technique, high-resolution melting analysis, rounds out the new molecular armamentarium, which enables exons to be more efficiently scanned, thereby further improving the detection rate by uncovering additional point mutations.[4]

For families with asymptomatic, at-risk members, the application of molecular testing is viewed from a slightly different perspective. Once the clinical diagnosis has been established unequivocally in a given individual, he or she could be offered direct molecular analysis to see if a mutation can be identified. If a mutation were found, then other asymptomatic family members might benefit from presymptomatic testing to see who would and who would not develop neurofibromatosis type 2 (NF2). Screening and surveillance recommendations would then be based on the results of this testing and, if a sibling or child of an affected person were found not to carry the mutation, he or she would need not be concerned about developing NF2 in the future.

For families in which no mutation can be identified in a known affected individual, linkage analysis or indirect genetic testing methods may be utilized. However, this requires cooperation on the part of the family, as well as DNA samples from multiple affected and unaffected individuals. Even utilizing the best technology available, diagnostic uncertainty may remain, depending on the geographical relationship between the genetic markers and the disease-causing gene. On the other hand, with advances that have taken place in genetic mapping and the likelihood of finding informative markers close to or within the gene itself, linkage analysis remains an excellent choice for determining risk from a molecular standpoint.

For a parent who has NF2, prenatal testing can be done on amniocytes or chorionic villi, either through direct gene mutation analysis when such a change has been identified or through linkage analysis. Prenatal testing may not be possible if the affected parent is the first affected person in the family and a mutation cannot be found. For an affected parent with a known mutation, preimplantation genetic diagnosis may be possible if the couple is willing to undergo in vitro fertilization with transfer of unaffected embryos.

One note of caution must be made in light of advances in molecular genetic technology. Presymptomatic testing of at-risk family members requires a vigorous informed consent process and might best be done during a genetic counseling session at a cancer, genetic, or neurofibromatosis center that specializes in such matters. This is of even greater concern when considering testing of minors, in whom the potential harm must be weighed against medical benefit.

Since aggressive medical surveillance can still be implemented in the absence of a definitive diagnosis and no preventive or curative measures are currently available, the decision to undergo presymptomatic testing for this adult-onset disease is a personal one that must be made after a frank and complete discussion with knowledgeable health professionals.

Imaging Studies Radiography Plain films of the spine may be helpful in evaluating scoliosis but are of limited value in looking for spinal cord tumors

that may occur in NF2. Magnetic resonance imaging Magnetic resonance imaging (MRI) remains the mainstay for diagnosis and screening of CNS, cranial nerve, and

spinal cord tumors (see the images below). At-risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRI scans of the head performed through their late 50s. Clear molecular diagnosis may help to

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modify risks for family members and prevent unnecessary testing for asymptomatic individuals who are found not to carry a gene mutation.

Meningioma to the left of midline in a patient with neurofibromatosis type 2.

Multiple meningiomas (on the left) on the surface of the brain in a patient with neurofibromatosis

type 2. Bilateral acoustic neuromas in a patient with neurofibromatosis type 2.

Bilateral acoustic neuromas and a left-sided meningioma in a patient with neurofibromatosis type 2.

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Small ependymoma in a patient with neurofibromatosis type 2.

Multiple meningiomas in a patient with neurofibromatosis type 2. MRI using 3-dimensional (3D) volumetrics is now the preferred method for following vestibular schwannoma growth

over time.[5]

MRI of the spine is indicated diagnostically when an individual presents with motor or sensory changes suggestive of a spinal cord lesion or lesions. The key point here is early detection, which may result in prompt action and provide a better outcome. However, routine MRI imaging of the spinal cord probably is not indicated for asymptomatic affected or at-risk individuals.

Auditory Evaluation Hearing evaluations, including brainstem auditory-evoked response (BAER), are important in the identification of early

hearing loss and may demonstrate latency abnormalities before a mass is detectable on MRI. In light of this, auditory screening on an annual basis may be quite useful in asymptomatic or presymptomatic individuals.

Once a vestibular schwannoma is identified, full audiometry testing, including acoustic reflex testing as well as BAER, is useful as a means of monitoring disease progression. Clinical experience clearly indicates that the size of the vestibular tumor often does not correlate with the degree of hearing loss.

Ophthalmic Examination Dilated eye examinations are an important part of the care of affected individuals because they are at a risk for

developing visually significant cataracts or retinal lesions. As a diagnostic test, an eye examination for lens opacities, retinal hamartomas, or epiretinal membranes may be quite useful even in a child at risk for neurofibromatosis type 2 (NF2). In fact, juvenile cataracts, as the name implies, frequently occur in children and may be seen long before there is any evidence of vestibular schwannomas.

For children and adults with NF2, annual eye examinations are recommended, since unrecognized visual impairment can further interfere with activities of daily living, especially in an individual with concomitant hearing loss.

Histologic Findings Unlike the tumors associated with neurofibromatosis type 1 (NF1), those found in NF2 are usually made up of 1 of 3

cell types—Schwann cells, glial cells, or meningeal cells. Although the tumors in NF2 can be locally invasive and cause significant morbidity as a result of their growth properties, they rarely, if ever, undergo malignant transformation. This is somewhat different than in NF1, in which plexiform neurofibromas occasionally develop into neurosarcomas.

However, vestibular schwannomas and meningiomas in NF2 tend to be more aggressive than they are in cases of sporadic tumors (ie, those not related to NF2), with a tendency for more extensive local invasion and with histologic evidence of increased mitoses.

 

Approach ConsiderationsFor individuals diagnosed with neurofibromatosis type 2 (NF2), medical care consists of routine examinations focusing on some of the potential complications related to CNS or spinal cord lesions. Interval history should focus on subtle motor or sensory symptoms, such as paresthesias, radiculopathies, weakness, or muscle atrophy. Unless clinical deterioration occurs, MRI of the head on an annual basis is reasonable, as is annual eye examinations and auditory screening using BAERs.

Annual neurologic assessment by a trained specialist is most useful in this clinical setting; the neurologist may detect subtle sensory or motor deficits even before the patient is aware of any difficulties.

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For patients with multiple medical problems associated with NF2, management by a team of specialists through a multidisciplinary clinic may provide the most comprehensive and cost-effective care over time. This is especially important with rapid advances in surgical management, including the use of such tools as stereotactic radiosurgery and auditory brainstem implants (ABIs).[6, 7, 8]

For at-risk individuals who do not carry a diagnosis of NF2, such as siblings and offspring of affected persons, optimal screening recommendations are more difficult to establish. However, since early detection of tumors may improve long-term outcome, many reasons exist to consider a program of surveillance and routine screening. For families in which a specific mutation or linkage has been established, at-risk individuals may choose to know for sure whether they are at risk.

Even when diagnostic certainty is not possible but an individual's chance of having NF2 is at least 50%, annual focused examination accompanied by annual head MRI scans and hearing evaluations with BAERs seems to be a reasonable screening option.

Treatment setting

Although care of the patient with neurofibromatosis type 2 theoretically can be done in the primary care setting, the complexity, rarity, and multisystem involvement encountered in this condition suggest that medical care in a disease-specific, multidisciplinary clinic may permit optimal management.

Radiation Treatment and ChemotherapyAlthough surgical resection of symptomatic tumors represents the most common approach to clinically significant lesions, in some rare instances, radiation and/or chemotherapy may be recommended to treat disabling ependymomas. However, concerns remain regarding additional risks of radiation therapy in a patient with a germline tumor suppressor gene mutation (ie, someone with NF2), as opposed to an individual with an isolated, non–NF2-related tumor.

Therapeutic use of erlotinib has shown promise in the treatment of unresectable, progressive vestibular schwannomas, resulting not only in a decrease in tumor size but also in improvement in auditory function. Further clinical trials are in order before use of this oral chemotherapeutic agent can be recommended on a routine basis.[9] A trial of bevacizumab, an antivascular endothelial growth factor monoclonal antibody, also showed some efficacy in the shrinkage of vestibular schwannomas; the drug improved hearing in some patients with unresectable tumors.[10]

Early in vitro studies have suggested that Gleevec, a tyrosine kinase inhibitor, may be useful in the treatment of vestibular and spinal cord schwannomas in patients with NF2.[11]

Tumor Resection and RadiosurgerySurgical resection of tumors remains the mainstay of treatment in neurofibromatosis type 2 (NF2), with recent advances in surgery permitting preservation of hearing for some affected individuals. For small vestibular schwannomas, surgical resection and stereotactic radiosurgery have been used and may preserve hearing and facial nerve function in selected patients.[6]

Larger tumors may require surgical resection despite irreversible hearing loss, especially when there is evidence of brainstem compression, facial nerve palsy, or, in extreme cases, early hydrocephalus. Larger tumors may be approached surgically if a patient has a significant decline in hearing, since a debulking procedure may result in preservation of hearing or, at the minimum, prolongation of auditory decompensation. Interestingly, one report indicates that spontaneous regression of one vestibular schwannoma has been seen in several patients following resection of another, contralateral vestibular schwannoma.[12]

Studies have shown efficacy in the surgical treatment of nonvestibular cranial nerve schwannomas using a combination of microsurgery and radiosurgery.[13]

Unlike the vestibular lesions, intracranial meningiomas, may be quite slow growing; surgical resection should be considered only when such lesions are causing serious, disabling symptoms.

Resection of spinal cord tumors is often quite difficult and the risks and benefits of surgery must be considered on an individual basis. To maximize operative success, acting promptly is important when neurologic symptoms appear, yet complete resection of a spinal cord tumor may not always be possible and in some cases serves a primarily palliative function. Single fraction radiosurgery may also be used to treat spinal cord schwannomas, either serving as primary therapy or, following surgery, being used if residual tumor or tumor progression occurs.[14]

Surgical resection of cutaneous or subcutaneous growths can be accomplished by any competent surgeon, although plastic surgical consultation is advisable for areas of great cosmetic concern, such as the face.

Auditory Brainstem Implants

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ABIs have been used successfully in some patients with hearing loss secondary to vestibular schwannomas. In many cases, an ABI does not restore hearing but instead improves the patient's ability to appreciate environmental sounds and facilitates communication.[15] ABIs in patients with neurofibromatosis type 2 (NF2), while providing some auditory input, do not enable high levels of speech recognition, presumably because of cochlear nerve damage in these patients.[16]Prior to surgery, ABI candidates should be engaged in a frank discussion about their expectations regarding this procedure, and a careful evaluation should be made of their family support system.[7, 8]

ActivityActivity restriction is not necessary except as recommended by the neurologist or neurosurgeon on the basis of neurologic deficits. However, patients with vestibular schwannomas need to be warned about potential balance problems, which may worsen in an underwater situation. Therefore, these individuals should be advised to never swim alone and to have someone with them at all times if they are diving or snorkeling. If disorientation occurs underwater as a result of acoustic nerve involvement, such activities may need to be curtailed.

ConsultationsThe neurologist and neurosurgeon work closely together in the management of central and spinal cord lesions in neurofibromatosis type 2 (NF2). The neurologist provides valuable information regarding any changes in neurologic status over time, whereas the neurosurgeon provides insight into selecting the optimal procedure and makes decisions regarding timing for surgical intervention.

The otolaryngologist or otologist is an important consultant in the surgical management of vestibular schwannomas, especially if ABIs are being considered. (Cochlear implants have not been as effective in the treatment of NF2 as originally hoped and generally are reserved for a small subset of patients with vascular compromise of the cochlea without substantial nerve involvement.)

The audiologist serves as an essential member of the management team for individuals with acoustic nerve lesions. After performing annual hearing evaluations by BAER to document disease progression, he or she can provide advice regarding usefulness of amplification. For many patients, augmentation may permit good sound discrimination well into the course of the disease. The audiologist also may make suggestions regarding any additional services, such as speech therapy or classes for lip reading or sign language, that may be helpful as hearing deficits grow.

The ophthalmologist is an important team member and can assist in the diagnosis and care of the patient with NF2. Early detection of juvenile cataracts is quite helpful in making a diagnosis in an at-risk child with minimal symptomatology. Furthermore, annual follow-up for affected individuals permits early detection and possible intervention for visual loss secondary to lenticular lesions.

Finally, the geneticist may provide diagnostic and genetic information to affected and at-risk individuals. For family members who are considering molecular testing, an explanation of risks, benefits, and test reliability to all individuals is essential as part of the informed consent process. Issues of potential insurance discrimination, confidentiality, and privacy need to be discussed, as do personal perspectives on such testing, before an individual can provide consent. For couples considering prenatal diagnosis for NF2, genetic consultation is recommended.

Long-Term MonitoringThe following is an outline of reasonable guidelines in the care of the patient with NF2:

Annual neurologic examination looking for subtle deficits or changes in neurologic status that might suggest disease progression

Annual hearing screening with BAER, with referral to an audiologist for amplification, augmentation, or speech therapy recommendations

Annual MRI to monitor existing lesions or look for presymptomatic lesions Annual ophthalmologic evaluations to monitor visual acuity

Medication SummaryNo effective medical therapies are known for neurofibromatosis type 2 (NF2). However, in rare instances in which surgical resection of symptomatic ependymomas is not possible, chemotherapy with lomustine, vincristine, and prednisone, or carboplatin and vincristine, following radiation therapy, may serve a palliative function.

As previously mentioned, therapeutic use of erlotinib has shown promise in the treatment of unresectable, progressive vestibular schwannomas, resulting not only in a decrease in tumor size but also in improvement in auditory function. Further clinical trials are in order before use of this oral chemotherapeutic agent can be recommended on a routine basis.[9] A trial of

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bevacizumab, an antivascular endothelial growth factor monoclonal antibody, also showed some efficacy in the shrinkage of vestibular schwannomas; the drug improved hearing in some patients with unresectable tumors.[10]

Early in vitro studies have suggested that Gleevec, a tyrosine kinase inhibitor, may be useful in the treatment of vestibular and spinal cord schwannomas in patients with NF2.[11]

Antineoplastic AgentsClass Summary

Antineoplastic agents act by inhibiting the key factors responsible for neoplastic transformation of cells.

View full drug informationVincristine ( Vincasar PFS) 

Vincristine inhibits tubulin polymerization; therefore, it targets dividing cells.

View full drug informationCarboplatin 

This analog of cisplatin is used in treatment regimens for relapse.

View full drug informationLomustine (CeeNU) 

Lomustine inhibits RNA and DNA synthesis through alkylation of DNA and carbamylation of DNA polymerase, and alteration of RNA, enzymes, and proteins.

CorticosteroidsClass Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

View full drug informationPrednisone 

Prednisone, a synthetic glucocorticoid analog, acts as a potent immunosuppressant. It may inhibit cyclooxygenase, which, in turn, inhibits prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.