Neurofibromatosis 1 and 2

Brain Pathology 7: 823-836 (1997)

Ian F. Pollack, M.D.1.3; John J. Mulvihill, M.D.2.3 based on the pattern of their manifestations, into distinct clinical groups (2). Improvements in imaging Department of Neurosurgery, Children's Hospital of techniques and advances in molecular genetics facili- Pittsburgh, University of Pittsburgh Brain Tumor Center, tated efforts to distinguish patients with NF1 (previ- Pittsburgh, PA ously known as peripheral neurofibromatosis) from * Department of Human Genetics, University of Pittsburgh those with NF2 (previously known as central neurofi- Graduate School of Public Health, Pittsburgh. PA bromatosis or bi:ateral acoustic neurofibromatosis). 3 University of Pittsburgh School of Medicine, Pittsburgh, PA NF1 is now recognized to be one of the most common genetic disorders, affecting one in 3000 to Neurofibromatosis (NF) 1 and 2 are multisystem 4000 people (3). The mode of inheritance is autoso- disorders associated with a variety of neoplastic ma1 dominant, although approximately 50% of cases and non-neoplastic manifestations that typically arise sporadically as new mutations. This syndrome progress in severity during the lifetime of the affect- results from mutations in a gene on chromosome ed patient. The importance of appropriately diag- 17q11.2 that encodes a large protein called neurofi- nosing these disorders stems from the fact that the bromin. A portion of this protein is a GTPase-activa- natural history of an associated neoplasm, such as a tor (4) that functions in signal transduction (5,6) by peripheral nerve tumor or an optic glioma, may be favoring the conversion of the active GTP-bound significantly different depending on whether or form of ms and related G-proteins to the inactive not the lesion arises in a person with NF. In addi- GDP-bound form. tion, the indications for therapeutic intervention, NF2 is one-tenth as common as NF1, affecting hierarchy of treatment options and long-term only 1 in 50,000 people (7). The chromosomal locus management goals may differ substantially for for the disorder was initially suggested by cytogenetic patients with NF-related versus sporadic tumors. studies of sporddic vestibular neurilemomas and Finally, recognition of the diagnosis comprises an meningiomas, :he characteristic tumors of NF2, essential step for providing appropriate multidisci- which frequently exhibited deletions of the long arm plinary evaluation and counseling to affected of chromosome 22. These observations provided a patients and their families. This article addresses basis for detailed mapping of this region in patients the principal manifestations of these disorders with NF2, which identified a common site of muta- and provides a contemporary review of the diagnos- tions at 22q12 (8). The gene product, referred to as tic and therapeutic issues that arise in children merlin (a moesin-, ezrin-, and Iadixin-like protein) or with NF1 and NF2. schwannomin, crncodes a polypeptide that may be involved in linking cytoskeletal elements with plas- Introduction ma membrane proteins (9). Neurofibromatosis (NF) is a descriptive term that Both the NFI and NF2 genes function as classical was coined by Frederick von Recklinghausen in 1882 tumor suppressors in that loss of both alleles is to characterize two patients with cutaneous tumors needed for tumorigenesis. Because affected patients that were thought to be composed of a combination are born with only one normal copy of the gene, a of neural and mixed cellular elements (1).This diag- single mutation or deletion that inactivates the sec- nostic category was later broadened to include ond allele would theoretically be sufficient to favor patients with an array of dermatological, ocular, and tumor formation. nervous system manifestations. Investigators later realized that patients with NF could be categorized, Diagnostic Criteria Diagnostic criteria that reflect the diverse mani- Corresponding author: Ian F. Pollack, M.D., Department of Neurosurgery, Children's festations of NFI have been proposed at a National Hospital of Pittsburgh, 3705 Fifth Avenue, Pi?tsburgh, PA Institutes of Health Consensus Development 15213; Tel.: 41 2-692-5881; Fax: 41 2-692-5921 ; E-mail: Conference (Table 1); they were devised, in part, for [email protected] high specificity in order to achieve a low rate of false- Consensus Criteria for the Diagnosis of NFI (14) The criteria for making a diagnosis of NF1 are met if a patient has two or more of the following: 1, Six or more cafe-au-lait macules that have a maximum diameter of >5 mm in prepubertal patients and >15 rnm in postpubertal patients 2. Two or more neurofibromas of any type or one plexiform neurofibrorna 3. Freckling in the axillary or inguinal regions 4. Optic gliorna 5. Two or more Lisch nodules (iris hamartomas) 6. A characteristic osseous lesion, such as sphenoid wing dysplasia or thinning of the long bone cortex with or without pseudoarthrosis 7. A first-degree relative (i.e., parent, sibling or child) with NF1 by the above criteria

Table 1. ly positive diagnoses. Affected patients exhibit a genetically transmissible. A segmental form of 32 combination of cafe-au-lait macules, Lisch nodules has also been suggested for patients who have multi- (iris hamartomas), axillary and inguinal freckling, ple peripheral neurilemomas in an extremity without skeletal lesions, such as sphenoid wing dysplasia and other features of NF2 (17). thinning of the long bone cortex, and optic gliomas, It has long been recognized that, even among as well as an increased incidence of other central ner- patients with typical (non-segmental) NF1 or "2, vous system and systemic tumors (10-1.2). there is significant variability in the severity of mani- The diagnostic criteria for NF2 are entirely differ- festations between members of different families. In ent than those for NF1 (Table 2), which helps to dis- view of this diversity, Parry et al. (15) favored sepa- tinguish these entities. Affected patients have a com- rating affected families with NF2 into two groups: a bination of eighth nerve as well as other cranial milder (Gardner) variant and a more severe (Wishart nerve neurilemomas, meningiomas, glial neoplasms, or Lee-Abbott) variant. The basis for this symptomat- neurofibromas, and juvenile posterior subcapsular ic heterogeneity is uncertain but may reflect differ- cataracts (14). Although caf6-au-lait macules and ences in the specific site of mutations in the SF1 cutaneous neurofibromas are sometimes seen, they or NF2 genes themselves (18). Information from are typically fewer in number than in patients with genetic testing of affected individuals (19,20), corre- NFl (15) and are not included among the consensus lated with clinical features, should help to clarify criteria for diagnosis. this issue. This strategy should also help to explain A distinct subgroup of patients with features the association of NF1 with other disorders, such of NFI exhibit signs, such as cafe-au-lait macules as Noonan syndrome (21), Watson syndrome, and and neurofibromas, that are restricted to certain juvenile xanthogranuloma (22). Genetic studies segments of the body. This so-called "segmental" should also help to resolve the diagnostic uncertain- form accounts for three to five percent of patients ty that often surrounds patients who meet only with NFI and appears to arise from mosaicism, in one criterion for these disorders, such as caf6-au-lait which a mutation of the NF1 gene occurs at some macules without any other manifestations of NFI or time after fertilization in the developing embryo multiple meningiomas without other features of (16). In cases in which the gonadal progenitors are NF2, because these findings may; reflect distinct spared (i,e., somatic mosaicism), the disorder is not syndromes (23,24).

Consensus Criteria for the Diagnosis of NF2 (14) The criteria for making a diagnosis of NF2 are met if a patient has either of the following: 1. Bilateral eighth nerve masses seen with appropriate imaging techniques, such as MRI or CT 2. A first-degree relative with NF2 and either unilateral eighth nerve mass or two of the following. A. Neurofibroma B. Meningioma C. Glioma D. Neurilernoma E. Juvenile posterior subcapsular cataract

Table 2 I.F. Pollack and J.J. Mulvihill: Neurofibromatosis 1 ana 2 825

An important caveat in interpreting any genetic studies for these disorders is that the exact features of NF1 and NF2 can vary widely within a single family (in which all affected individuals should have an identical NF mutation) (25). The explanation for such pleitropy may be the involvement of disease- modifying genes or interacting environmental factors. The practical implication is that contemporary genetic testing can accurately predict the occurrence of NF1 or NF2 but not its severity or specific features. A discussion of the major non-neurological and neurological manifestations of these disorders and their diagnosis and management is provided below.

Non-Neurological Manifestations NF7. Cafe-au-lait macules and axillary freckling result from abnormal collections of melanin pigment but without any neoplastic component. As such, they pose only a cosmetic concern. Similarly, Lisch Figure 1. This axial T2-weighted MRI demonstrates the charac- nodules simply represent melanocytic iris hamar- teristic areas of -r2 signal abnormality that are commonly detected in patients with NF1 within the basal ganglia and, tomas; although these lesions increase in frequency occasionally. within the cerebellum and other regions of :he during childhood and are present in more than 90 brain. Reproduced by permission of the publisher from: Pollack percent of affected patients by the completion of IF, Mulvihill JJ. 11996) Special issues in the management of puberty (26), they do not interfere with vision. gliomas in children with neurofibromatosis. In: Gliomas of Childhood: Curreni Perspectives, Pollack IF (ed), pp. 257-268, In contrast, skeletal manifestations can produce Kluwer Academic F’ub1ishers:Boston significant functional problems. Congenital bowing and/or dysplasia of the long bones, particularly the of chronic niyelomonocytic leukemia among tibia, may lead to pathological fractures that resist patients with KFl has been been noted to be more healing. The resulting pseudoarthrosis is extremely than 200 times ,greater than that of the general popu- difficult to correct, and some patients ultimately lation (30). Other neoplasms that occur with an require amputation (27). Osseous dysplasia can also increased frequency in patients with NF1 include involve the sphenoid bone as a congenital or neurofibrosarcoma, pheochromocytoma, rhab- acquired process (28), which leads to herniation of domyosarcoma, adenocarcinoma of the ampulla of temporal lobe contents into the orbit and, in some Vater, melanoma, non-Hodgkin’s lymphoma, and cases, produces pulsatile proptosis and seizures. lymphoblastic Icukemia (3,ll-13,31). Although some degree of scoliosis is present in NFZ. In patients with NF2, the major, serious many patients with NF1 (27),the curvature is usually non-neural manifestation is posterior subcapsular mild and does not require specific therapy. However, cataract, which is a progressive problem that affects in a small percentage of cases, the scoliosis becomes 85 percent of patients (32). Because these lesions can severe and requires treatment (29). Because many of threaten vision, conscientious ophthalmological fol- these patients have an associated intra- or extra-axial low-up is required, and surgical removal of the neurofibroma that may need to be addressed in con- cataract may be indicated. In patients with.unilatera1 junction with a spine-straightening procedure, mag- visual loss secondary .to one of these lesions, particu- netic resonance imaging (MRI) is an essential step in lar attention must be directed to monitoring and the preoperative evaluation. Other less serious spinal protecting vision in the contralateral eye, which manifestations of NF1 include vertebral scalloping includes preserving facial nerve function to maintain and non-neoplastic widening of the neural foramina eye closure and corneal protection. from dural ectasia and meningocele formation. An additional phenomenon that is occasionally Neurological Manifestations observed in patients with NFl is segmental hypertro- NF1. Focal Areas of lncreased T2 Signal. The most phy (3). Although there is often an associated neoplas- frequent abnormalities found on MRIs in patients tic component, the deformity is frequently out of pro- with NFl are foci of increased signal on T2-weighted portion to the size of the tumor. It remains uncertain images without either mass effect, changes on T1- whether this reflects generalized rnesenchymal dyspla- weighted image.;, or contrast enhancement (Figure l), sia in the involved area or a trophic effect of neuro- which are detec:ted in 60 to 80 percent of NF1 chil- genic and humoral factors released by the tumor. dren (33-35). These foci may be solitary, multiple or Patients with NFl are also at risk for a variety of confluent and 2re seen most commonly in the basal systemic malignancies. In particular, the relative risk ganglia, internal capsule, brain stem, and cerebellum. number of characteristic lesion types may bc swri either alone or in combination. The mildest abnormalities consist only of thickening of one or both optic nerves (33,39) (Figure 2A), which in some cases may represent hyperplasia of the optic nerve sheath rather than true neoplastic growth. Other patients exhibit a globular thickening of the optic nerves and chiasm (Figure 2B) that may occur in conjunction with T2 signaI abnormalities streaking backwards along the optic pathways and upwards into the hypothalamus. Biopsies of such lesions have generally confirmed the presence of low-grade gliomas (Figure 2C) (40-44). Finally, a small percentage of patients are diagnosed with a large mass arising from the optic chiasm and hypothalamus that may extend upward into the third ventricle, laterally into the temporal fossa, anteriorly beneath the frontal lobe and posteriorly into the perimesencephalic region. Optimal management of such lesions remains controversial because with the advent of sophisticat- ed imaging technology, most tumors are now detected in asymptomatic or minimally symptomatic individuals in whom the natural history is uncertain.

Figure 2. A. T-.c

Figure 5. This large exophytic midbrain mass was detected in a 16-year-old girl who suffered from headaches and confusion secondary to obstructive hydrocephalus. A. The lesion is hypointense to the brain on this unenhanced T1-weighted image. B. Central enhancement is seen on this gadolinium-enhanced image. C. Histopathological examination of the operative specimen demonstrated pilocytic astrocytoma. A final group of brain stem lesions in patients fuse involvement of a broad extent of one or more with NF1 are periaqueductal gliomas, which, unlike nerves (72). These lesions may arise subcutaneously, the above-mentioned lesions, are generally isointense within one or more peripheral nerves, on a major to the brain on T1-weighted images and non- nerve plexus or on an exiting spinal nerve root. enhancing. These lesions characteristically produce Subcutaneous neurofibromas usually begin as late-onset aqueductal stenosis and are presumed to raised subcutaneous masses that may enlarge and be low-grade gliomas or glial hamartomas, although biopsy confirmation has been reported in only a few cases (64,68). These indolent tumors generally remain quiescent for years without intervention, similar to the behavior of benign tectal tumors in patients without NF1 (68). We generally treat these patients symptomatically with third ventriculostomy or shunt insertions and obtain follow-up imaging on a yearly basis for five years and periodically there- after. Biopsy and adjuvant therapy are reserved for lesions that progress symptomatically. Neurofibromas. Paraspinal and peripheral neurofibromas are observed in the vast majority of patients with NFI. Although these tumors have been categorized in the past with neurilemomas, which are characteristic of NF2, these two groups of tumors are readily distinguished upon histological analysis (69,70). Neurilemomas characteristically exhibit alternating areas of cellular (Antoni A) architecture with palisading spindle cells that orient into'verocay bodies (71) and Antoni B architecture comprised of a loose array of spindle cells in a mucinous back- ground. Neurofibromas, however, are comprised of spindle cells in a myxomatous stroma incorporating myelinated and unmyelinated axons (Figure 6, A and B), which are rarely seen in neurilemomas (Figure 7, A and B). Neurofibromas are best demonstrated using MRI, which is useful for delineating the relationship between the tumor, surrounding nerve(s) and adja- Figure 6. A. H&E-stained paraffin section of neurofibroma. A peripheral nerve twig is disrupted by a chaotic proliferation of cent structures (72,73). Based on imaging appear- spindle-shaped tumor cells. Residual myelin fibers mark the ance, these lesions may be categorized as either remaining peripheral nerve. The cytoplasm of individual neo- fusiform or plexiform neurofibromas. The former plastic cells is difticult to resolve. Tumor nuclei are hyperchro- lesions are discrete neoplasms that involve a circum- matic and also sFindle in shape. B. Trichrome-stained paraffin section of neurofibrorna. Trichrome preparations permit easier scribed area of a nerve, whereas the latter exhibit dif- identification of residual myelinated fibers. the involved nerve (75,76) and others favoring intra- capsular enucleation. However, in many fusiform lesions, it is possible to resect multiple involved fascicles without sacrificing significant neural function (72). Intraoperative nerve stimulation techniques are useful to confirm that fascicles to be sectioned in order to remove the tumor are indeed nonfunctional. In some cases, complete resection is not feasible .. ,I, . without risking neurological impairment, and a subtotal resection may be advisable. For lesions that exhibit malignant features, operative and postoperative management involve a multidisciplinary approach incorporating neurosurgical, general surgical, orthopedic, medical oncology and radiation oncology input (77,78). For plexiform lesions, total resection is possible if only a single nerve is involved, in which case resection and reconstruction may be feasible (72,75,76,79). Complete resection is generally not practical for lesions of the brachial plexus or lum- bosacral plexus and, in such locations, is usually reserved for cases with malignancy (80). Similarly, for large plexiform lesions of the thoracic and abdominal cavities and the parapharyngeal region, complete resection is not a realistic goal. Subtotal resection is often indicated to relieve pain (for plesus lesions), pulmonary compromise (for large intrathoracic lesions), upper airway obstruction (for parapharvn- Figure 7. A. P&E-s:ained paraiiin seciion of neurilevoma geal neurofibromas), abdominal discomfort or Palisading of tlirror cell nuclei w:th interver,irg cytoplasm form spinal cord compression (from transforaminal cistinct Verocay bodies. B. H&E-s:ained paraffin section oi reurilemoma. At Great magnifica:ion. ;he spindle-shaped Tumor encroachment of a paravertebral tumor). Patients ce!!s are observed to grcw in a disorgarized mesh rese.r,bling with unresectable plexiform lesions are appropriate a neurofibrorm, except for the absence of entrapped r.erve candidates for NFl chemotherapy protocols. The f'bei twigs recent study of 13-cis retinoic acid and interferon-2u become pedunculated over time. Because these demonstrated efficacy of both regimens in stabilizing lesions arise from small cutaneous nerves, they may previously progressive disease, although objective be resected without neurological deficit, although disease regression was not observed (81). Future this is generally not practical because new lesions approaches will likely focus on inhibiting the ras continue to arise throughout the patient's life. pathways that are overactivated in patients with TFl However, resection is clearly indicated for lesions as a result of their impaired neurofibromin function. that are painful, enlarging rapidly, or arising in an Farnesyltrans-ferase inhibitors, which interfere with area prone to irritation, such as the belt-line. Because ras processing, are particularly promising in this a small percentage of these tumors will become regard and have shown efficacy against other ras- malignant (i.e., neurogenic sarcomas), patients are dependent neoplasms (82). encouraged to report lesions that enlarge rapidly, Par asp i n a 1 n eur o f i b r o m as are usu a 1lv fu s i f o r m become red or ulcerated or cause progressive discom- tumors that involve nerve roots at their entry into fort because excisional biopsy may be indicated. the spinal canal (Figure 8.4). Because most lesions Peripheral nerve neurofibromas, if symptomatic, enlarge slowly and patients commonly have multiple produce neurological dysfunction in the distribution lesions, intervention is reserved for tumors that pro- of a major nerve with pain and paresthesias, often gressively encroach into the spinal canal (Figure 8F). brought on by pressure upon the involved nerve These lesions are ty-pically approached using a (72). Unlike neurilemomas, which typically involve a laminectomy for the intraspinal component. The single fascicle of a major nerve, neurofibromas often extraspinal component may be removed transforami- involve many or all fascicles of a nerve, thereby lim- nally if the tumor is small and niedially located, but iting resectability (72). The management of these larger lesions require a separate, more laterally direct- lesions has been controversial, with some authors ed approach, which varies depending on the spinal recommending biopsy and observation (74), others level involved. Resection of the involved nerve root advocating en bloc resection with reconstruction of is often required to obtain cornplete tumor removal, I F Pollack and J J. Mulvlhill Neurofibromatosis 1 and 2 83 1 but this can often be accomplished without producing severe neurological impairment (83,84). NF2. Vestibular Neurilemomas. Tumors of the eighth cranial nerve occur in more than 90 percent of patients with NF2 and often become symptomatic in late adolescence or adulthood; however, with proactive screening of the young children of affected adults (85,86), an increasing number of lesions are detected during childhood (Figure 9). The finding in Figure 8. A. Mu1tisegmen;al involvement of the exiting spinal a child of a posterior cataract or multiple spinal cord nerve roots by neJrofibromas in a patient with NF1. These or peripheral nerve tumors without Lisch nodules, lesions caused no intraspinal compression and have remained caf6-au-lait macules or an alternative explanation, stable for more than four years without intervention. 6. should raise concern about a diagnosis of NF2, and lntraspinal growth 3f a paraspinal neurofibroma in a nine-year- such children should undergo an MRI examination old boy caused a mild, progressive Brown-Sequard syndrome; the intraspinal and extraspinal components of this lesion were for intracranial manifestations of the disorder. resected complete y three years ago, and the patient remains There is general agreement that MRI is the opti- free of disease progression. mal screening tool for vestibular neurilemomas in individuals at risk for NF2 and that periodic hearing any better than those with open resection, hearing tests are indicated for the functional evaluation of loss generally occurs in a delayed fashion, which affected patients. However, the indications and pre- provides the patient time to learn sign language and ferred approaches for the treatment of these lesions, lip reading. Another approach that has been advocat- once detected, remain controversial. In a patient ed in patients with bilateral tumors is subcapsular with a large lesion causing significant brain stem resection of the lesion, leaving a small amount of compression, the decision to proceed with surgical tumor adherent to the facial and acoustic nerves in resection is relatively clear-cut. However, for patients order to minimize the risk of irreversible nerve injury with small, asymptomatic lesions, the optimal (93). In the absence of objective data to support one approach for preserving function is less obvious. management approach vs. another, we believe that Some surgeons recommend early attempts at radical therapeutic decision-making should be individual- tumor resection because the chance for preserving ized, taking into account the risk tolerance of the hearing and avoiding facial nerve injury intraopera- patient, after the various management approaches tively is greatest when the lesion is small (87-89); in with their pros and cons have been thoroughly dis- skilled hands with lesions smaller than one centime- cussed with the patient and family. Because of the ter, the likelihood of preserving hearing exceeds 50% complexity of the management issues involved, a and that of maintaining facial nerve function supraregional approach to the care of affected exceeds 90%. However, the risks of iatrogenic hear- patients has been advocated in order to optimize ing loss are all “up-front” and pose a major concern functional outcome (94). in patients with functional hearing in whom tumor- or treatment-induced deafness in the contralateral ear is a significant long-term risk. Among those who favor early surgery in patients with bilateral tumors, some recommend first removing the larger lesion, which is most likely to pose an initial threat of ipsilateral hearing loss, whereas others advocate removing the smaller lesion, which theoretically affords the patient the best chance of achieving both tumor removal and ipsilateral hearing preservation. Tumor resection is often combined with placement of a cochlear or auditory brain stem implant, which may provide a way for ensuring at least some hearing preservation in patients with bilateral tumors who undergo surgical intervention (90,91). An equally convincing argument can be made for deferring surgery until there is objective evidence of tumor progression or hearing loss because of the vari- able natural history of these lesions. Stereotactic radiosurgery provides an alternative approach for the treatment of such lesions (92). Although it is uncertain whether the chances for hearing preservation are Figure 9. Bilatera vestibular neurilemomas in a 16-year-old child of a woman with known NF2. (e.g., cavernous sinus meningiomas), for Icsions that can only be partially removed and for those that recur after an extensive resection. lntraparenchyrnal Gliornas. Patient5 with NF2 may develop intrinsic glial neoplasms of the brain, but such lesions are less commonly seen than with SF1. In contrast, intraspinal intramedullary tumors are more common in NF2 (85,95,96). In such patients, ependymomas are more frequent than astrocytomas, whereas the converse is observed with NF1 (97). Because ependymomas are generally well circum- scribed, complete resection is often feasible and is indicated for lesions that are large and that show def- inite signs of progression (97). Extra cra n ia I Neurilern o mas and Me ii i rig ic ,mas. Intraspinal growth of a combination of nerve sheath tumors and meningiomas is seen in a significant percentage of patients with NF2 (Figure 10'4) (85,95), Because these tumors grow slowly and displace the surrounding neural structures, large lesions may be asymptomatic despite the severity of associated cord compression (Figure 106). However, such patients can exhibit rapid deterioration in neurological function with small amounts of subsequent tumor growth. Accordingly, even in the absence of symp- toms, we have generally advocated tumor resection for patients with radiographic evidence of pro- nounced cord compression. Not unexpectedly, we have observed that children who exhibit intact neu- Figure 10. A child with NF2 with multiple intraspinal tumors rological function preoperatively maintain this func- causing progressive myelopathy. A. Both a rneningioma and tion during the postoperative period, and many neurilemoma are apparent in this MRI. B. The severiry of the patients with significant deficits improve, whereas spinal cord corrpression by one of these lesiom is illus?rated. those with profound impairment fail to recover, The spirai cord, which IS apparent at the righ: and left of the f!gure. is flartened to a :hin ribbon tha: is draped around the which supports the concept of early surgery. Because large turror. The child recovered normal neurological function some patients exhibit severe multisegmental cord postopera:ively compression, we generally perform a screening evaluation of the entire spine in any newly diagnosed lntracranial Meningiomas and Non-Vestibular Cranial patient with NF2 who manifests myelopathy because Nerve Neurilemomas. Approximately half of patients several lesions at different levels may need to be with NF2 have intracranial meningiomas, and more removed (Figure 10A) (15,85,95). We do not, hocvev- than 30% have multiple non-vestibular neurilemo- er, routinely remove lesions that are producing little mas (15,85,86). From a therapeutic standpoint, many or no spinal cord compression and, instead, follow of the controversial issues regarding vestibular these tumors periodically with clinical evaluations neurilemomas also apply to other intracranial and MRI examinations of the spine. neurilemomas and meningiomas. These lesions Because most nerve sheath tumors in NF2 are exhibit unpredictable biological behavior, with some neurilemomas (70) rather than neurofibromas, these tumors remaining quiescent for extended intervals lesions generally arise from a single nerve fasciclr. and others enlarging rapidly. Because affected and are well encapsulated. Complete resection of patients often develop multiple inuacranial neurile- intraspinal lesions can often be achieved with mini- momas and meningiomas, we generally reserve oper- mal neurological morbidity (72) if injury to adjacent ative intervention for large lesions that are causing uninvolved fascicIes and to minimize cord manipula- obvious neural compression as well as those exhibit- tion is avoided. Similarly, extra-spinal neurilemomas ing progressive growth. However, vigilant imaging that arise on a peripheral nerve can usually be resect- and clinical follow-up are needed for lesions that are ed without significant loss of neural function. By managed conservatively. As noted above, radio- identifymg the involved fascicle entering and leaving surgery or focused radiotherapy techniques may pro- the tumor and dissecting off the surrounding unin- vide a useful therapeutic option for lesions that are volved fascicles, the surgeon can generally remove difficult to remove without significant morbidity the tumor arid leave the bulk of the nerve intact. I.F. Pollack and J.J. Mulvihill. Neurofibroma?osis 1 and 2 833

In general, meningiomas (Figure 11, A and B) can be removed without resecting any neural elements. However, because they often arise ventrolaterally within the spinal canal, great care must be taken to avoid excessive manipulation of the spinal cord during the course of tumor removal. We commonly use somatosensory evoked potential monitoring as a warning tool during the resection of meningiomas as well as large neurilemomas. The observation of laten- cy shifts or deterioration in the amplitude of the recordings in the absence of an alternative explanation guides us in altering our surgical plan to mini- .. mize inadvertent cord manipulation. 0 Counseling In addition to the acute evaluation and management of medical and surgical problems that arise in . .I. the context of NFl and NF2, affected patients and their families generally benefit from a comprehensive approach to their chronic multisystem genetic disorder, which is often best provided by a clinical geneticist or genetic counselor. A clinical geneticist or genetic counselor can clarify inheritance risks for the -.. 1 patient or parents; discuss reproductive options, including prenatal diagnosis, gene testing and assist- -4 ed reproductive procedures; offer anticipatory guid- ance; and conduct or expedite diagnostic examina- :i ' tions for other family members who may be at risk for having NF. As genetic testing becomes commer- Figure 11. A. H&E-stained paraffin section of meningiorna. cially available, the changing risks and benefits of Meningiomas have been subdivided into a variety of undergoing DNA analysis of the genes for NF1 and histopathological types of questionable prognostic significance. NF2 also need to be discussed with affected or poten- These figures demonstrate a meningotheliornatous subtype. tially affected families. Tumor cells have abundant eosinophilic cytoplasm and grow in a pavement with defined cell borders. B. H&E-stained paraffin Because patients and families affected by NF1 and section of rneningioma. NF2 are faced with a lifetime of uncertainty regarding potentially debilitating or life-threatening conse- Acknowledgment quences of the disorder, which may be superimposed This work was supported in part by National on chronic difficulties in learning and socialization Institutes of Health grant 1K08-NS01810 and by a (in NF1) and cosmetic concerns (both disorders), grant from the NF Clinic Association of Western social service or psychological support are often ben- Pennsylvania. eficial. Neuropsychological testing and early intervention services are particularly helpful in young References patients with NFl who are experiencing delays in 1. von Recklinghausen F 11882) Ueber die multiplen cognitive development in order to define specific fibrome der haut und ihre beziehung zu den multiplen areas of learning difficulty and facilitate proactive neurornen. Berlin. Hirschwald educational assistance. Also, local support groups, 2. 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