Neurofibromatosis Type

NF2 is a much less common disorder, with an incidence of approximately 1 in 40,000 live births (one tenth that of NF1). This disorder shows no regard for race or sex. Previously, NF2 has been referred to as bilateral acoustic or central neurofibro-matosis because of the presence of its hallmark lesion: bilateral acoustic neuromas (vestibular schwannomas). In addition to this hallmark lesion, NF2 is characterized by multiple intracra-nial and intraspinal tumors. Cutaneous stigmata do not figure prominently in this disease.

NF2 is an autosomal dominantly inherited disorder with the causative gene located at the 22q11 locus on the long arm of chromosome 22. This tumor-suppressor gene was first identified and cloned in 1993, and since then much work has gone into characterizing the nature of its protein product: merlin, or schwannomin. This protein is believed to function as a cytoskeletal protein. Loss of heterozygosity for the NF2 gene has been demonstrated in tumors such as vestibular schwannomas, meningiomas, and neurofibromas in NF2 patients. In general, those mutations leading to premature termination of protein translation result in a more severe phenotype. By using linkage analysis, with markers flanking the NF2 gene, a presumptive diagnosis of this disorder can be made in families with two or more affected individuals. This is relatively time consuming and expensive, however, and therefore the diagnosis of NF2 still remains largely a clinical one.

Diagnostic criteria for NF2 devised at the 1987 NIH Consensus Development Conference on Neurofibromatosis37 were subsequently revised by the National Neurofibromatosis Foundation (NNFF) Clinical Care Advisory Board (Table 108-3). Patients with NF2 clinically may report a variety of difficulties. The majority of these are neurologic, including hearing impairment, tinnitus, imbalance, weakness, seizures, numbness or paresthesias, or impaired vision. Approximately 11% are identified while asymptomatic as a result of screening within affected families. Only 10% of patients become symptomatic before age 10.15 In addition, new signs and symptoms may develop with increasing age, and therefore the evaluation of an NF2 patient must involve long-term, continued serial assessments.

As in NF1, patients with NF2 may suffer from a variety of ophthalmologic conditions. Juvenile posterior subcapsular lenticular opacities are the most common ocular findings in NF2, present in approximately 50% of patients. These lesions have the potential to cause visual impairment, and consideration of their surgical removal may be indicated. This is of par-

FIGURE 108-5 Gadolinium-enhanced coronal mag

Table 1 08-3

Diagnostic Criteria for Neurofibromatosis 2

Definite NF2

Bilateral vestibular schwannomas, or

Positive family history plus unilateral vestibular schwannoma before age 30 or two of: meningioma, schwannoma, glioma, juvenile posterior subcapsular lenticular opacity

Probable NF2

Unilateral vestibular schwannoma before age 30, plus one or more of: meningioma, schwannoma, glioma, juvenile posterior subcapsular lenticular opacity, or

Two or more meningiomas plus unilateral vestibular schwannoma before age 30 or one of: glioma, schwannoma, juvenile posterior subcapsular lenticular opacity

NF2, Neurofibromatosis 2.

Source: Modified from criteria for NF2 from the National Neurofibromatosis Foundation (NNFF) Clinical Care Advisory Board (www.nf.org).

ticular importance, given the fact that this group of patients is also at risk for bilateral hearing loss. Additional ocular manifestations of NF2 include retinal hamartomas, epiretinal membranes, and rarely Lisch nodules. Combined, these findings hold diagnostic significance, because they may be detectable at an early age, assisting in the diagnosis of NF2 before the development of central nervous system tumors.

Aside from these ocular findings, the majority of features of NF2 involve the nervous system. As mentioned earlier, the hallmark of this disorder is bilateral vestibular schwannomas (Figure 108-5). Patients with NF2 often become symptomatic from these tumors decades earlier than those with spontaneous tumors. Sensorineural hearing loss is commonly the first complaint, although patients may also suffer from tinnitus, ataxia, headache, or facial nerve dysfunction. Diagnostic adjuvants include the use of MRI, audiometry, and brainstem auditory evoked responses (BAERs).

The standard of care for neuroimaging to detect vestibular schwannomas in NF2 patients involves thin-slice MRI of the head, with and without a contrast agent centered on the internal auditory canal. Both axial and coronal views and fat-saturation sequences should be performed. BAERs have a high positive predictive value for these tumors, showing an abnormal result in more than 95% of patients with tumors confirmed by imaging or at surgery. In contrast to the normal population, patients with vestibular schwannomas show a reversed amplitude ratio of waves I and V, as well as prolonged interpeak latencies between waves I and V. Other abnormalities include absent waveforms beyond waves I or II, and interaural differences. Pure tone audiometry provides evidence for hearing loss of a sensorineural nature.

As with spontaneous vestibular schwannomas, the growth rate of these lesions in NF2 patients is variable, with rates between 1 and 10 mm per year. Considering the often slow growth rate, following these patients conservatively, with sequential MRI to rule out continued growth, is warranted in the neurologically stable patient. Further treatment may be con-

FIGURE 108-5 Gadolinium-enhanced coronal mag netic resonance imaging through the posterior fossa depicting bilateral vestibular schwannomas, the right tumor larger than the left one, in a 15-year-old boy with neurofibromatosis 2.

sidered when there is evidence of symptomatic or radiologic progression. Treatment decisions must, however, weigh factors such as the patient's age and social, psychologic, and occupational circumstances against the rate of tumor progression. In addition, special consideration must be given to the possible treatment-related morbidities because these patients are at risk of possible bilateral hearing loss.

Surgery has long been considered the gold standard treatment for vestibular schwannomas. The timing and methods for surgical intervention have been well described elsewhere.55 In general, earlier surgery on smaller lesions provides the best hope for a complete resection with maximal hearing preservation and facial nerve function. As with surgery for spontaneous vestibular schwannomas, surgery for the patient with NF2 should be limited to tertiary or quaternary care centers with neurosurgeons and otolaryngologists familiar with this disease.

Recently, the options of stereotactic fractionated radiation therapy and stereotactic radiosurgery have become available for the treatment of vestibular schwannomas in the patient with NF2. Good rates of hearing preservation and tumor control rates equal to those with surgery have been reported.2 Tumor control rates of up to 98% have been reported in patients with NF2.54 Long-term follow-up for these patients is still lacking, however. In addition, one must consider carefully the use of radiation as treatment in a patient population with abnormal tumor-suppressor genes because of the theoretic risk of inducing malignant tumor transformation or induction of secondary malignancies in the irradiated field.

In addition to bilateral vestibular schwannomas, patients with NF2 are susceptible to a variety of other tumors of the

FIGURE 108-6 Right cavernous sinus, medial sphe

noid wing meningioma depicted in this gadolinium-enhanced axial magnetic resonance image in a patient with neurofibromatosis 2.

neuraxis. Among these are meningiomas, ependymomas, schwannomas of other cranial or peripheral nerves, and rarely low-grade spinal cord astrocytomas. Of these, meningiomas are the next most common intracranial pathology after bilateral vestibular schwannomas (Figure 108-6). They may be single or multiple and may occur in either a synchronous or metachro-nous fashion. Their behavior resembles that of spontaneous intracranial meningiomas, as should their treatment. The nature and treatment of intracranial and intraspinal ependymomas in the context of NF2 also resemble those of their spontaneous counterparts (Figure 108-7). Schwannomas may affect nerves other than the vestibulocochlear nerve. The next most common cranial nerve affected by schwannomas is the trigeminal nerve. In addition, schwannomas can arise from sensory roots in the cervicothoracic region, occasionally forming "dumbbell" tumors as they extend through and expand the intervertebral foramen. Peripherally, lesions arising from cutaneous nerves in NF2 patients are often schwannomas as well, in contrast to the neurofibromas seen in NF1 patients.

The care of patients with NF2 and their families should involve the coordinated efforts of the neurosurgeon, otolaryn-gologist, and geneticist. At the initial diagnosis, the patient should undergo a complete neurologic and otologic assessment, followed by imaging of the entire craniospinal neuraxis, audiometry, and BAERs. Subsequently, annual or biannual evaluations are recommended between the ages of 15 and 45 years.15 Ophthalmologic assessment should be undertaken when the patient becomes symptomatic from ocular abnormalities. For family members of a patient with NF2, either clinical, radiologic, or molecular testing may be performed. If molecular testing is positive, baseline clinical and imaging studies should follow. If no tumors are identified, serial exam

FIGURE 108-7 Gadolinium-enhanced sagittal mag-

netic resonance image of upper cervical spine, slightly off the midline, depicting multiple small enhancing tumors in the intraspinal space. These most likely represent intradural schwannomas, which must be followed with serial imaging studies.

FIGURE 108-7 Gadolinium-enhanced sagittal mag-

netic resonance image of upper cervical spine, slightly off the midline, depicting multiple small enhancing tumors in the intraspinal space. These most likely represent intradural schwannomas, which must be followed with serial imaging studies.

inations and imaging studies are recommended every 3 years. Individuals with negative molecular testing or normal MRI scans at age 30 are unlikely to have inherited the disorder, and further screening in these individuals may not be justified.

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