Neurofibromatosis 2 (bilateral acoustic schwannomas). What is it? A review of literature and an update.
CE Desouza, RD Nagpal
International Hearing Foundation, Bombay, Maharashtra.
C E Desouza
International Hearing Foundation, Bombay, Maharashtra.
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Desouza C E, Nagpal R D. Neurofibromatosis 2 (bilateral acoustic schwannomas). What is it? A review of literature and an update. J Postgrad Med 1992;38:27-31
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Desouza C E, Nagpal R D. Neurofibromatosis 2 (bilateral acoustic schwannomas). What is it? A review of literature and an update. J Postgrad Med [serial online] 1992 [cited 2019 Jun 18 ];38:27-31
Available from: http://www.jpgmonline.com/text.asp?1992/38/1/27/735
Radiological imaging in NF2
Robert Smith is credited with first describing a patient with what he called “multiple skin neurogenic tumours”. However, it was Friedrich von Recklinghausen's description in 1882, which made the disease a recognised entity. Von Recklinghausen's disease was initially thought to present in three patterns.
1. a predominantly peripheral type;
2. a predominantly central type in which the occurrence of bilateral acoustic schwannoma was a characteristic feature; and
3. a mixture of peripheral and central types.
Improved understanding of this condition led to the formulation of a new classification, based primarily on Genetic, and somatic, differences, at the National Institutes for Health Consensus Development Conference in 1988. This classifies the conditions as Neurofibromatosis 1 (NF1, previously known as peripheral von Recklinghausen's disease) and Neurofibromatosis 2 (NF2, previously known as central von Recklinghausen's disease or bilateral acoustic neurofibromatosis).
The neurofibromatoses belong to the group of neurocutaneous syndromes, the other common ones being the Sturgeweber syndrome, Von Hippel-Linday syndrome and the tuberous sclerosis complex. The neurofibromatoses have been considered to be “neurocristopathies", a term used to describe syndromes thought to arise from dysontogenesis of neural crest tissue. Kanter et al find this concept useful to explain otherwise perplexing associations such as pigmentary skin changes, peripheral nerve tumors and endocrine abnormalities occurring simultaneously. This concept can explain the common manifestations seen in NF1 and NF2 despite the fact that they arise from disorders associated with different chromosomes. The characteristics of NIF11 and NF2 are listed in [Table:1].
The two neurofibromatoses, NFl and NF2, despite their common names and superficial similarities are indeed different disorders. Patients with neurofibromatosis tend to develop cranial & tumours and dyspiasias of astrocytic and neuronal origin (e.g. astrocytoma, glioma, neurofibroma, hamartoma) while patients with NF 2 develop tumours of the lining of the brain (schwannomas, meningiomas and ependymomas).
Neurofibromatosis 1 and 2 are hereditary autosomal disorders presenting without skip generations. However, the family history is positive in only about 50% of cases,. In the others, spontaneous mutation is believed to have occurred.
Rouleau et al, established that the defective gene causing neurofibromatosis 2 is located on chromosome 22 and is therefore, distinct from NFl which is caused by a defective gene located near the centromere of chromosome 17 . In an earlier report, Seizinger et al linked the loss of chromosome 22 to the tumorigenesis of acoustic neuromas. An inherited mutation of chromosome 22 may be recessive at cellular level but becomes expressed when a second event occurs.
One mutation (inherited) is on one copy of chromosome 22 but is small and cannot be detected by standard karyotyping techniques. The second event affects the other (previously normal) copy of chromosome 22. This can take place through processes like point mutation, transolocation or chromosome loss. The exact process and the various mechanisms involved are not clear. One of the substances thought to be involved is glial growth factor. Increased glial growth factor like activity is found in acoustic schwannomas, with a subsequent increase in cell growth. It is thought that tumour cells secrete this substance in an autocrine fashion, leading to further growth.
The clinical features of NF2 presumably arise from mutations in DNA and are manifested through general biologic mechanisms. These mechanisms include those of derivatives of the embryonic neural crest, schwann cell neuron interactions bone formation, melanin regulation, oncogenes and antioncogenes, nerve growth factor and its receptor and mast cell biology.
Two animal models are emerging for the evaluation of the neurofibromatoses. Marine biologists have identified schools of damsel fish with pigmented skin tumours resembling neurofibromas. The fish with these tumours swim along corals making researchers think that the disease is a horizontally transmitted disease. Researchers at the National Cancer Institute tried replicating the paresis associated with human T- lymphocyte virus 1 in Caribbean populations by transgenically inserting its tat protein gene into mice. The mice developed neurofibromas instead of paralysis. The neurofibromas were situated in the skin. They also developed nerve tumours of the brain. This disease was then transmitted to next generations in an autosomal dominant manner. It is hoped that the isolation of human genes responsible for causing the neurofibromatoses will result in improved animal model systems.
Sadeh et al reported a patient who presented with both NFl and NF2 simultaneously, with a rapidly progressive course. The father was a documented case of NF1 and the mother had NF2, indicating that both NFl and NF2 can be transmitted together and manifest equally in the same person without exclusion of the other. The neurofibromatoses "breed true"; for example a patient with a family history of NF2 has a risk of developing only NF2. It is extremely unlikely that such a patient will develop NF1. The same holds true for NF1.
Costantino et a1 state that the symptoms in NF2 usually first manifest in the 2nd decade, with the earliest complaint being a hearing loss. Martuza and Ojeman report a more fulminant course in young patients of NF2 and a higher incidence of multiple central nervous system tumours in these patients.
Nager's  report showed a female preponderance. However, Martins and Benitez found no evidence of sex preponderance. Kasantikul et al  noted that acoustic schwannomas were larger in females than in males. Miller and Hall  noted that neurofibromatoses inherited from the mother were more severe than those inherited from the father. Reports in literature ,, have described cytaneous neurofibromas and central neurofibromas as first appearing or enlarging during pregnancy. Regression of both following delivery has also been documented,. Counselling women afflicted with this disease is important as the risk of pregnancy causing an exacerbation of theses lesions is real; this is also accompanied by the risk of genetic transmission of NF2 to the child.
Most authors, agree that acoustic schwannomas in patients of documented NF2 grow slowly. Malis describes unequal and disproportionally rapid rates of growth of different tumours in the same patient. He also describes detecting bilateral acoustic schwannomas in a symptomatic patients.
The possibility of NF2 should be entertained in any patient who presents with multiple neurogenic tumours in the absence of any other etiology, or with either a meningioma of the posterior fossa or an acoustic schwannoma before 30 years of age. There should be a high index of suspicion when there is involvement of separate and distinct compartments of the central nervous system, spinal column and cranial nerves. Patients presenting with bilateral acoustic schwannomas may or may not present with the peripheral stigmata associated with the neurofibromatoses. However, the peripheral stigmata in NF2 are much more mild as compared to those in NF1.
Pure tone audiometry must be part of any evaluation for NF2. When patients with NF2 present early, pure tone audiogram will usually demonstrate as asymmetrical sensorineural hearing loss. In the late stages patients may present with profound sensorineural hearing loss bilaterally. Brainstem evoked response audiometry (BERA) has been proved to have great predictive powers for acoustic schwannomas,. Results have been found to be abnormal in 95% to 100% of patients with tumours confirmed by radiographic imaging, surgery or both. Patients with neurofibromatosis 2 were found to have reversed amplitude ratios of waves I and V, prolonged interpeak latencies from wave I to wave V, and absent wave forms beyond waves I or II or BERA testing.
Advances in imaging procedures have made the early detection of these lesions easier. CT scanning as compared to conventional radiology has the advantage of being less invasive, while demonstrating the vascularity and nature of the lesion, determining the presence and degree of hydrocephalus, and identifying satellite pathologies intractanially as well as extracraniaily. Recently, magnetic resonance imaging (MRI) has been described,, as a better tool since it has all the advantages of CT scanning without the patient being subjected to ionizing radiation. In addition, the introduction of gadolinium DTPA as a paramagnetic substance has made gadolinium enhanced MR1 the imaging method of choice in bilateral acoustic schwannomas.
Despite the recent advances in imaging and detection techniques, these lesions continue to pose a formidable challenge in management.
The management of these lesions is complex and multifaceted because of the high morbidity and mortality following surgery.
In recent times emphasis has been laid on the preservation of hearing in individuals affected with these lesions,,.
Total removal of the tumour is the aim, whilst making a concerted effort to preserve the 7th cranial nerve. Ojemann and Martuza have noted that in unilateral acoustic schwannomas the 7th cranial nerve lies on the periphery of the tumour and can be preserved, whereas in bilateral acoustic schwannomas the 7th and 8th cranial nerves are surrounded by multilobulated tumor masses between the multiple lobules. They have reported an instance where a meningioma was discovered within the multiple lobules of the acoustic schwannoma. They believe that schwannomas in patients with unilateral acoustic schwannomas occur from a single (clonal) cell. Thus, such a schwannoma would displace the 7th cranial nerve to the periphery. In NF2 the schwannomas are of multicellular origin and would thus surround and engulf the 7th cranial nerve.
The second (contralateral) tumour, if large and causing pressure on the pons and/or cerebellum, also needs to be excised as soon as the patient is fit for surgery following surgery on the first side. Efforts should be redoubled to preserve the 7th cranial nerve on the contralateral side, especially if this was not possible on the first side. Bilateral 7th cranial nerve palsies can be very debilitating notwithstanding the availability of reinnervation procedures. Preservation of the cochlear division of the 8th cranial nerve becomes crucial in the presence of useful hearing. On the contralateral side, one may go as far as leaving behind a small part of the tumour to spare the 7th and 8th cranial nerves and follow the patient's progress by serial CT scanning. Very small tumours with useful facial and audiological function may be closely followed by without surgical intervention. This permits the patient to enjoy a period of hearing as some of these lesions grow very slowly and many years may elapse before surgical intervention becomes essential. Other intracranial lesions like meningiomas can co-exist simultaneously. The lesion, which is considered more life threatening, should be removed. The decision to remove them should be based on which tumour needs to be excised first. However, this philosophy serves only as a guideline and it is difficult to adopt a set pattern for the treatment of all cases. Treatment is individualised and is based on factors such as the patient's age and occupation, tumour size, satellite pathologies, current neurologic status, the growth rate of the tumours and the patient's compliance.
The use of stereotactic cobalt 60 gamma radiotherapy in patients with bilateral acoustic schwannomas has been reported,. Stereotactic cobalt 60 gamma (gamma knife) radiotherapy is synonymous with the delivery in a single session of a high dose of ionising radiation to a pre-selected and stereotactically localized intracranial volume of tissue. The dose is delivered by means of numerous and very precisely collimated narrow beams of ionizing radiation. There is a rapid reduction of the dose of radiation at the periphery of the pre-selected volume of tissue to be irradiated. This is so that only one specific volume of tissue is irradiated. The advantages described are that it can be performed on an outpatient basis and is associated with low morbidity and no mortality. Following stereotactic cobalt 60 gamma irradiation, necrosis of the tumour with an arrest in growth is noticed. However, the patient may still develop a facial paralysis and decrease in hearing.
There have been recent reports, in literature debating the use of radiation therapy for patients suffering with bilateral acoustic schwannomas. These controversies have arisen because of the lack of accepted parameters for the selection of patients to undergo radiation. However, it is generally agreed that the use of radiation therapy can remain an option for those individuals who decline surgery, for patients who have had unsuccessful tumour removal one or more times, and for elderly medically unfit patients. Radiation for these lesions is reported to act by two mechanisms: 1) a direct cytotoxic effect on the tumour cells and 2) an intraturnoral delayed vascular obliterative response leading to death of the tumour. Other reported benefits of stereotactic radiotheraphy include reduction in cost and a return to full employment status within a matter of 3-5 days. Stereotactic surgery using the “gamma knife" has been advocated by several workers, as a safe and effective alternative to miscrosurgical removal of these lesions. Radiotherapy can be used in small schwannomas as large schwannomas are likely to be life threatening and will require surgical intervention.
Chemotherapy as another alternative modality in the treatment of NF2 was described by Jahrsoerfer and Benjamin. They reported the use of doxourbicin hydrochloride, cyclophposhamide and dacarbazine in two cases. Following treatment, further growth of the tumour was arrested. Chemotherapy, however, is still an experimental modality as compared to radiotherapy.
The survival of patients declining any treatment is variable. Young et al found that survival without intervention ranged from 2 to 42 years.
Other areas of treatment encompassing the care of these patients include rehabilitation, genetic counselling, alternative methods of communication, vocational counselling, screening of first degree relatives, as well as psychiatric guidance. In the US, the Acoustic Neuroma Association and the National Neurofibromatosis Foundation have proved to be useful organization in the rehabilitation of afflicted patients.
NF2 characteristically affects young patients in the second decade. The presence of bilateral acoustic schwannomas may or may not be accompanied by peripheral stigmata. Though NF2 is caused by a defect on chromosome 22, at times it becomes difficult to explain how the first generation of patients are afflicted. Treatment of these patients is complex. At present, only surgery and radiation therapy are available. A controversy exists on the application of the "gamma knife" in radiation therapy. However, as more data become available, this issue will hopefully be resolved. While surgery and radiation therapy are available for the treatment of the schwannomas, other aspects of treatment such as vocational rehabilitation, alternative methods of communication, screening of first degree relatives and genetic counselling are as important and should not be forgotten.
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