d Neurosurg 74:910-915, 1991
Bilateral cerebellopontine angle tumors in neurofibromatosis type 2 D. BaLowmN, F.R.C.S., T. T. K1NG, F.R.C.S., E. CHEVRETTON, F.R.C.S., AND A. W. MORRISON, D.L.O., F.R.C.S.
Departments 01 Otolaryngology and Neurosurgery, The Royal London Hospital, Whiteehapel, London, England In a series of over 500 cases of cerebellopontine angle tumors, 19 patients had bilateral neurinomas. Four of these tumors arose from the facial rather than the acoustic nerve. A conservative policy regarding surgery has been adopted in an effort to prevent hearing loss for as long as possible. Nevertheless, all patients operated on in this series are now totally deaf. The results of managing these patients surgically and conservatively are discussed. KEY W O R D S
9
nenrofihromatosis
9
acoustic nerve tumor
facial nerve tumor
9
hearing loss
N 1822, Wishart > described a case of what seems to have been a bilateral acoustic nerve tumor. The condition was, until recently, regarded as a central form ofvon Recklinghausen's neurofibromatosis. However, in 1980, Kanter and his colleagues m reviewed recent evidence and concluded that the two conditions were distinct. In support of their conclusion, later reports have demonstrated that the genetic abnormality in von Rccklinghausen's disease (peripheral neurofibromatosis or neurofibromatosis type 1) is found on chromosome 17 ~ and loss of genetic material on chromosome 22 is present in patients with unilateral tumors 24 and in those with bilateral tumors. 15'23 These changes were also seen in meningiomas and spinal tumors occurring in patients with central neurofibromatosis, or neurofibromatosis type 2. 25 Although familial association has been widely investigated, 4'6''7'2sonly a minority of cases encountered clinically give a family history, as most cases are the result of a spontaneous mutation. Despite important advances in understanding the genetics of this disease and improvements in diagnostic imaging techniques, the management of patients with bilateral acoustic nerve tumors remains difficult. There are only a few accounts of patient outcome, and the earlier literature is gloomy in this regard. Frykholm 5 presented six patients operated on by Olivecrona and reviewed 13 others from the literature. Of the former six patients, four died shortly after operation and Olivecrona :~ himself thought that little good came from operating on such patients. Pool and Pava 2~ had equally
I
910
poor results in their six patients. These early reports were mainly concerned with whether surgery could offer any useful survival, bilateral facial nerve palsies and total deafness being considered relatively unimportant consequences. In recent years, some larger series of bilateral cases have been reported with better operative results due to the introduction of microsurgical methods, an improved ability of otologists to make a relatively early diagnosis, and the concentration of cases of acoustic nerve tumors in special units. 7'9"~7Because of the paucity of reports on patient management and the relatively small numbers contained in each series, it seems worthwhile to present a series of 19 patients encountered over a period of 21 years and to examine their outcome. Particular interest is attached to the speed of disease progression, the need for an operation, and the timing, extent, and outcome of surgery. The outlook for useful survival and for hearing preservation is also examined.
Clinical Material and M e t h o d s
Criteria for Patient Selection The criteria for the diagnosis of bilateral cerebeUopontine angle tumors included either bilateral operations in the same patient, the demonstration of bilateral tumors by scanning, or a combination of both. This study was retrospective, with all patients followed either until death or to the time of writing.
J. Neurosurg. / Volume 74/June, 1991
Bilateral tumors in neurofibromatosis type 2
FIG, 1. Diagram presenting the clinical course of five patients with neurofibromatosis type 2 who did not undergo operation. The length of symptomatic period prior to diagnosis, size of tumor at diagnosis, and length of follow-up period for each patient is shown. See key for definitions of symbols.
Patient Presentation
There were 11 males and eight females with an average age at presentation of just under 30 years; the average age for our 444 patients with unilateral tumor was 47 years. Five patients were under 20 years of age at diagnosis and 10 were under 30 years. Family history, based solely on what the patients knew about cutaneous lumps, deafness, and acoustic nerve tumors in close relatives, was available in 17 cases; a positive history was found in only three of those cases. Twenty-two children have been born to these patients but, at the time of writing, a detailed survey of the offspring had not been carried out, although three children are known to be affected. Peripheral manifestations were evident in seven of our patients but they were florid in only two (Cases 5 and 14). All 19 patients had deafness of some degree when diagnosed. In 13 patients, deafness was the principal reason for seeking medical advice. Features found at presentation and during clinical evaluation are summarized in Figs. 1 and 2. Presenting characteristics were categorized according to the presence of unilateral or bilateral deafness and the existence of a contributory family history. Four patients (Cases 7, 9, 10, and 15) presented with deafness in one ear only and were treated initially as having a unilateral tumor. Family history was noncontributory in each of these four cases. Computerized tomography (CT) scans J. Nem'osurg. / Volume 74 / June, 1991
FIG. 2. Diagram showing the clinical course of 14 patients who had one or two operations. See key for definitions of symbols. were not available in two patients and failed to show a second lesion in the other two. Eight patients (Cases 1, 2, 3, 4, 12, 13, 16, and 18) complained of bilateral deafness when first examined. Family history was noncontributory in each case, and only one patient (Case 18) had peripheral manifestations which were minor. Four of the five patients who did not undergo surgery fell into this category; the other four patients (Cases 12, 13, 16, and 18) had large bilateral tumors, more than 2 cm in diameter, and all of these were operated on for both tumors. A positive family history and/or obvious peripheral manifestations were found in six patients (Cases 5, 6, 8, 14, 17, and 19) in whom one or both of these features rendered the diagnosis fairly evident. All six were bilaterally deaf to some degree. One patient without these manifestations (Case 11) presented elsewhere with difficulty in walking, believed to be caused by an intramedullary cervical tumor. This led to surgical exploration but no biopsy. Postoperatively, increased deafness was followed by a CT scan and a correct diagnosis. Clinical Evaluation Neurological signs and symptoms, as well as raised intracranial pressure, were evident in 13 cases and con-
911
D. Baldwin, et al. sisted of ataxia, trigeminal symptoms, and nystagmus, singly or in combination. Papilledema was present in eight patients and developed in a ninth (Case 17) a few months after the first of his large bilateral tumors was removed. The size of the tumors at diagnosis is presented in Figs. 1 and 2; 14 of the 19 patients had at least one large tumor when first diagnosed. Nine patients had other tumors of the central nervous system (meningiomas, nerve tumors, or intramedullary spinal tumors) and one had a large intrathoracic neurofibroma. Diagnoses were made by pneumoencephalography or positive-contrast cisternography in earlier cases. More recent cases have been diagnosed by either CT scanning, with or without air, or magnetic resonance (MR) imaging. Patient Management The patients fell into three groups regarding their surgical management: no operation (Fig. 1), or one or two operations (Fig. 2). The translabyrinthine approach was used in surgical cases, except in Cases 6 and 7 or when subtotal removal was attempted to preserve hearing. No Operation. The first five patients did not undergo surgery and were kept under observation for periods of between 4 and 6 years; four remain well (Fig. 1). In Case 5, there was a history of florid peripheral manifestations of neurofibromatosis dating from childhood. Following an exploratory operation for intramedullary cervical cord tumor, this patient became progressively disabled and eventually died. Autopsy findings suggested that the eighth nerve tumors had enlarged considerably since the original diagnosis and may have contributed to her death. All five conservatively treated patients were diagnosed at relatively late ages (average age 44 years, range 31 to 50 years). One Operation. Cases 6 and 7 (Fig. 2) underwent unilateral operations. In each case, the first tumor was removed in the era before CT scanning was available. One patient (Case 6) survived for 20 years, dying at 79 years of age, although it is probable that the second tumor was ultimately the cause of death. The other patient (Case 7) remains generally well 25 years after operation while still suffering from some trigeminal neuralgia. As this patient is now only 50 years of age and her remaining tumor is large, it seems likely that a second operation will become necessary. Two Operations. The remaining 12 patients (Fig. 2) had both of their tumors removed, although not all of them at this institution. Patient age at diagnosis ranged from 11 to 40 years (average 23 years). In cases managed at this hospital, a conservative approach to surgery was followed and intervention undertaken on one side only when progressive neurological deficit or raised intracranial pressure was apparent. In no case was an attempt made to preserve hearing by early operation on a small tumor, as recommended by the National Institutes of 912
Health consensus document. "~The operative results are shown in Fig. 2, where the interval between operations is represented graphically. Intervention was necessary, at the time of diagnosis in eight patients and was delayed for between 1 and 5 years (average 388 years) in four others. In two patients (Cases 8 and 19), each of whom was operated on elsewhere, both tumors were removed at the time of hospital admission. In one patient (Case 19), operation on the second side was confined to a subtotal removal; the patient underwent total tumor removal on the same side 10 years later at our institution. In the remaining patients, an interval of between 3 months (Case 17) and 9 years (Case 15) elapsed between the first and second operation, the latter of which entailed total removal in all patients except Case 16 (see below). A problem arises when surgery becomes necessary, and the larger or only remaining tumor is on the side of residual hearing which, even at very low levels, may assist the patient with lip reading. Subtotal removal with opening of the internal auditory meatus to decompress the cochlear nerve, as suggested by Martuza and Ojemann, J6 was attempted under these circumstances in two patients (Cases 10 and 17) but failed, the patients being rendered completely deaf by this conservative operation. In each case, conservative management was followed shortly after by total removal. In Case 16, subtotal removal relieved severe trigeminal neuralgia and resulted in preservation of poor hearing in the ear for another 12 years. Although now totally deaf, this patient has not required further surgery and his facial function on the side of the residual tumour remains normal. Radiosurgery was employed in one patient (Case 15), but failed to prevent progressive loss of hearing on the side of the second tumor which, after 2 years, had enlarged and was excised. This technique is an attractive solution in such difficult cases but its efficacy in preventing progressive hearing loss is not impressive, as reported by Nor6n, et al. ~
Results
Role of Tumor Growth Evidence of tumor growth was available in 15 cases: from serial CT scanning in 13 patients, from repeated vertebral arteriography in one (Case 14), and at autopsy in one (Case 5). Four patients have shown no discernible increase in size of their small or medium-sized bilateral tumors over periods of 4 to 5 years; in one patient (Case 16), the remaining large tumor remained static following a subtotal removal carried out 12 years previously. In nine patients there was a demonstrable increase in size which occurred at a variable rate. In a patient (Case 8) with a history of maternal inheritance, and who presented at the age of 11 years, enormous tumor growth occurred over 4 years (Fig. 3). In two patients (Cases 10 and 15), a contralateral tumor grew J. Neurosurg. / Volume 74~June, 1991
Bilateral t u m o r s in n e u r o f i b r o m a t o s i s
type 2
Fl(;. 3. Computerized tomography (CT) suans in Case 8. I+(!fi and U('lller. Air-CT scans showing bilateral acoustic nerve tumors at age of It ~cars, Ri~,kt 1.eft-sided enhanced ( T scan showing enormous t u m o r growth 4 ,,'cats later,
from being initially invisible on a first-generation CT scanner image to being large (> 2 cm in diameter) 9 and 8 years later, respectively. As with unilateral tumorsY =27 rates of growth are variable.
Patient Morla/it), Three patients in this series died. One patient (Case 5) did not undergo operation and lived for 6 years after diagnosis. Another patient (Case 6) died in old age having survived her first operation for 20 years. The third patient (Case 14) died at 26 years of age as a consequence of paraplegia, 10 years after diagnosis and after total resection of both tumors and a laminectomy for multiple spinal neurofibromas. No deaths were attributable to surgery. It is probable that the acoustic nerve tumor(s) contributed to the death of the first two patients, although one (Case 5) also had an intramedullary cervical cord glioma.
Hearing Loss Of the four survivors in the group without surgery, one has good hearing unilaterally, two have some residual hearing, and one is totally deaf. The two patients (Cases 6 and 7) undergoing unilateral resection became completely deaf in the unoperated ear within a few years of surgery. The 12 survivors of bilateral operations were followed for periods ranging from 1 to 12 years (average 4.5 years). All are now completely deaf, either through natural progression or due to surgery; however, one patient (Case 16) retained some hearing for 12 years after subtotal removal of a tumor. All tumors in this patient group were large. The outlook for hearing in these patients has, therefore, been dismal.
Facial Nerve D~:/icil The facial nerve, which was at risk 26 times in this series, fared somewhat better. Both patients with unilateral tumors removed prior to microsurgical techJ. ,,\r~,ttrostlr~./ Vohtme 74/June. 1991
niques had facial paralyses treated by faciohypoglossal anastomosis. Of the 12 patients with bilateral operalions, two underwent both operations and four underwent one operation elsewhere. Three of these eight facial nerves have maintained fair function. In operations carried out by us, 16 nerves were at risk. Seven nerves were preserved with the following results: normal function in one patient (Case 16) undergoing subtotal removal, minimal recovery in one patient, and fair function (considerable weakness and synkinesis) in five patients. Five other facial nerves were repaired with a sural nerve graft which failed in one patient, and provided minimal recovery, in one and fair recovery in another. In Case 18, bilateral facial nerve tumors and grafts resulted in fair function on one side and minimal recovery on the other. Altogether, therefore, nine of these 20 facial nerves were preserved and maintained some function. Adding to these the four nerves which recovered in part after nerve grafting, 13 of the 20 nerves functioned and two of the 12 patients who had bilateral operations either here or elsewhere have some bilateral facial movement. Five faciohypoglossal anastomoses were performed; however, it would seem wise to avoid this procedure in neurofibromatosis type 2 because a further cranial nerve has to be sacrificed.
General Resull,~ Aside from total deafness and facial palsies, the clinical results of treatment in the survivors were better than one might have expected. Four of the unoperated patients are alive and leading normal lives. One patient who underwent unilateral resection leads a restricted but independent life. Of the l 1 survivors of bilateral operations, five are independent although restricted and six are leading satisfactory lives; one (Case 19) is a practicing radiologist, one (Case 15) runs a building company, and a third (Case 10) now works for a real 913
D. Baldwin, et al. estate agency, being no longer able to practice as a barrister. Another patient, a young girl (Case 18), is taking a college course, and two others (Cases 12 and 16) have returned to their former occupations. Additional Operations
Six additional operations of the central nervous system were required in five patients and are indicated by closed triangles in Fig. i. Two cervical laminectomies were carried out for the diagnosis of intramedullary glioma, one cervical laminectomy for the removal of a large foramen magnum neurinoma arising on the C-2 nerve root, one lumbar laminectomy for multiple neurofibromas, one posterior fossa exploration for a cystic astrocytoma of the medulla, and one shunt placement for hydrocephalus. Discussion
Central neurofibromatosis, or neurofibromatosis type 2, affects about one in 50,000 individuals, compared to one in 4000 for yon Recklinghausen's disease, or neurofibromatosis type l.lS The frequency with which patients with bilateral tumors are encountered, compared to those with unilateral tumors, varies in different r e p o r t s , 3"9"14'22 with ratios ranging from 1:108 to 1:50. 26 Our 19 cases occurred among a group of 444 acoustic nerve tumors, comprising 4% of the total, or at a ratio of 1:23. It is clear that the condition is rare and no surgeon, even one in a unit specializing in the treatment of unilateral tumors, is likely to see many cases, which aggravates the difficulty of deciding on treatment. In recent years, the earlier gloom surrounding these cases has somewhat lifted but the problems remain clear. Patients face the possibility of total hearing loss; surgery is likely to hasten this possibility and there is a higher than average chance of producing facial paralysis. It has been observed by Martuza and Ojemann ~6that the facial nerve may be engulfed by the lesion in cases of bilateral acoustic nerve tumors, making nerve preservation impossible. In our series, four tumors (one each in Cases 9 and 19, and both in Case 18) demonstrably arose from the facial nerve, a circumstance to which neurofibromatosis type 2 is probably disposed. ,2 Therefore, at least four tumors arose from the facial nerve, a rate of 15% of all bilateral tumors operated upon. This rate is much higher than that observed in unilateral acoustic nerve tumors (between 1% and 2%'J), or even lower if cases of neurofibromatosis type 2 are excluded. The observation of Martuza and Ojemann could be explained by the nerve of origin of the neurinoma rather than the biological behavior of a tumor that is not histologically different from a unilateral acoustic nerve tumor. A similar explanation may account for the contention that it is impossible to preserve the cochlear nerve at surgery for bilateral tumors. ,3 However, this is not always the case as hearing has been successfully preserved in previously reported 914
cases of bilateral acoustic nerve tumors. 7~1~ Other tumors, both intrinsic, especially in the cervical cord, and extrinsic, may require treatment, thereby adding to the morbidity. Diagnosis has been made much easier with CT and MR imaging, which may reveal an unsuspected tumor on the other side in an apparently unilateral problem. In five of our cases, most of them presenting before the availability of CT and MR imaging, the bilateral nature of the disease was not recognized; however, such a possibility should always be considered in patients presenting under the age of 25 years. The majority of our cases had large tumors at the time of diagnosis. This may not be the case in the future, since fairly small tumors can be detected by MR imaging (Fig. 4), and if careful follow-up examinations and screening of the offspring of known cases are performed, diagnosis may be apparent before the patient's hearing is seriously affected. In the present state of our ability to preserve hearing in patients with unilateral acoustic nerve tumors, early detection may present a dilemma, the resolution of which has already been suggested: ~ namely, an attempt may be made to remove one tumor while hearing is normal on both sides. If successful, removal of the opposite tumor could follow. This approach requires a good deal of courage on the part of both surgeon and patient; indeed, one may doubt whether it is justified by the present results. In cases of large bilateral tumors, a more conservative approach, such as that practiced here, may be considered since symptoms progress at a variable rate. Our findings suggest that delaying surgery, even if the tu-
FIG. 4. Magnetic resonance image with gadolinium administration in Case 2 revealing an intracanalicular tumor and a left-sided medium-sized tumor (arrowheads). Hearing was poor on the right side but normal on the left. J. Neurosurg. / Volume 74/June, 1991
Bilateral tumors in neurofibromatosis
type 2
mors are of considerable size and especially if hearing is good in at least one ear, is reasonable and allows some patients the benefit of residual auditor}, function for a number of years. The problem associated with early diagnosis of bilateral tumors is that of heating preservation, and the techniques needed to accomplish this can only be developed by operating on the more common unilateral lesions. Careful follow-up examinations of patients' offspring, probably requiring MR imaging rather than repeated audiometry only, may allow early surgery, and hearing preservation. 2 However, cranial nerve function may be threatened even then as, in our experience, some o f these tumors arise on the facial nerve and others may possibly be of cochlear nerve origin.
Acknowledgments The authors are indebted to Dr. T. H. Koeze for Figs. 1 and 2, and to Mr. John Firth who generously provided followup information regarding Case 8. References 1. Barker D, Wright E, Nguyen K, et al: Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science 236:1100-1102, 1987 2. Dutcher PO Jr, House WF, Hitselberger WE: Early detection of small bilateral acoustic tumors. Am J Otol 8: 35-38, 1987 3. Edwards CH, Paterson JH: A review of the symptoms and signs of acoustic neurofibromata. Brain 74:144-190, 1951 4. Eldridge R: Central neurofibromatosis with bilateral acoustic neuroma, in Riccardi VM, Mulvihill JJ (eds): Advances in Neurology, Volume 29: Neurofibromatosis. New York: Raven Press, 1981, pp 57-65 5. Frykholm R: Treatment of bilateral acoustic tumors. Report of six cases operated on, with a review of thirteen cases from the literature. Acta Chir Scand 92:451-469, 1945 6. Gardner WJ, Frazier CH: Bilateral acoustic neurofibroma. A clinical study and field survey of a family of five generations with bilateral deafness in thirty eight members. Arch Neurol Psychiatry 23:266-302, 1930 7. Glasscock ME III, Woods CI, Jackson CG, et ai: Management of bilateral acoustic tumors. Laryngoscope 99: 475-484, 1989 8. Henschen F: Zur Histologie und Pathogenese der KleinhirnbNckenwinkeltumoren. Arch Psychiatry Nervenkn 56:21-[22, 1915 9. Hitselberger WE, Hughes RL: Bilateral acoustic tumors and neurofibromatosis. Arch Otolaryngol 88:700-711, 1968 10. Kanter WR, Eldridge R, Fabricant R, et al: Central neurofibromatosis with bilateral acoustic neuroma. Genetic, clinical and biochemical distinctions from peripheral neurofibromatosis. Neurology 30:851-859, 1980
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11. King TT, Morfison AW: Primary facial nerve tumors within the skull. J Nenrosurg 72:1-8, 1990 12. Laasonen EM, Troupp H: Volume growth rate of acoustic neurinomas. Neuroradiology 28:203-207, 1986 13. Linthicum FH Jr, Brackmann DE: Bilateral acoustic tumors. A diagnostic and surgical challenge. Arch Otolaryngol 106:729-733, 1980 14, Malis LI: Acoustic Neuroma Surgery. Randolph, Mass: Codman & Shurtlett, 1987 15, Martuza RL, Eldridge R: Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318: 684-688, 1988 16. Martuza RL, Ojemann RG: Bilateral acoustic neuromas: clinical aspects, pathogenesis, and treatment. Neurosurgery 10:1-12, 1982 17. Moyes PD: Familial bilateral acoustic neuroma affecting 14 members from four generations. J Neurosurg 29: 78-89, 1968 18. National Institutes of Health Consensus Development Conference: Neurofibromatosis. Conference statement. Arch Neurol 45:575-578, 1988 19. Nor6n G, Arndt J, Hindmarsh T, et al: Stereotactic radiosurgical treatment of acoustic neurinomas, in Lunsford LD (ed): Modern Stereotactic Neurosurgery. Boston: Martinus Nijhoff, 1988, pp 481-489 20. Olivecrona H: The neurinomas, in Olivecrona H, T6nnis W (eds): Hundbueh der Neurochirurgie, Vol IV. Berlin: Springer-Verlag, Teil IV, 1960, pp 221-223 21. Pool JL, Pava AA: Acoustic Nerve Tumours, ed 2. Springfield, Ilk Charles C Thomas, 1970, p 84 22. Revilla AG: Neurinomas of the cerebellopontine recess. A clinical study of one hundred and sixty cases including operative mortality end results. Bull Johns Hopkins Hosp 80:254-296, 1947 23. Rouleau GA, Wertelecki W, Haines JL, et at: Genetic linkage of bilateral neurofibromatosis to a DNA marker on chromosome 22. Nature 329:246-248, 1987 24. Seizinger BR, Martuza RL, Gusella JF: Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma. Nature 322:644-677, 1986 25. Seizinger BR, Rouleau G, Ozelius LJ, et al: Common pathogenetic mechanism for three tumor types in bilateral acoustic neurofibromatosis. Science 236:317-319, 1987 26. Tos M, Thomsen J, Harmsen A: Acoustic neuroma surgery: results of translabyrinthine tumour removal in 300 patients. Discussion of choice of approach in relation to overall results and possibility of preserving hearing. Br J Neurosurg 3:349-360, 1989 27. Valvassori GE, Guzman M: Growth rate of acoustic neuromas. Am J Otol 10:174-176, 1989 28. Wertelecki W, Rouleau GA, Duane W, et al: Neurofibromatosis 2: clinical and DNA linkage studies of a large kindred. N Engl J Med 319:278-283, 1988 29. Wishart JL: Case of turnouts in the skull, dura mater and brain. Edinburgh Med Surg J 18:393-397, 1822 Manuscript received August 8, 1990. Accepted in final form December 19, 1990. Address reprint requests to: T. T. King, F.R.C.S., Department of Neurosurgery, The Royal London Hospital, Whitechapel, London E1 1BB, England.
915
Bilateral cerebellopontine angle tumors in neurofibromatosis type 2 D. BaLowmN, F.R.C.S., T. T. K1NG, F.R.C.S., E. CHEVRETTON, F.R.C.S., AND A. W. MORRISON, D.L.O., F.R.C.S.
Departments 01 Otolaryngology and Neurosurgery, The Royal London Hospital, Whiteehapel, London, England In a series of over 500 cases of cerebellopontine angle tumors, 19 patients had bilateral neurinomas. Four of these tumors arose from the facial rather than the acoustic nerve. A conservative policy regarding surgery has been adopted in an effort to prevent hearing loss for as long as possible. Nevertheless, all patients operated on in this series are now totally deaf. The results of managing these patients surgically and conservatively are discussed. KEY W O R D S
9
nenrofihromatosis
9
acoustic nerve tumor
facial nerve tumor
9
hearing loss
N 1822, Wishart > described a case of what seems to have been a bilateral acoustic nerve tumor. The condition was, until recently, regarded as a central form ofvon Recklinghausen's neurofibromatosis. However, in 1980, Kanter and his colleagues m reviewed recent evidence and concluded that the two conditions were distinct. In support of their conclusion, later reports have demonstrated that the genetic abnormality in von Rccklinghausen's disease (peripheral neurofibromatosis or neurofibromatosis type 1) is found on chromosome 17 ~ and loss of genetic material on chromosome 22 is present in patients with unilateral tumors 24 and in those with bilateral tumors. 15'23 These changes were also seen in meningiomas and spinal tumors occurring in patients with central neurofibromatosis, or neurofibromatosis type 2. 25 Although familial association has been widely investigated, 4'6''7'2sonly a minority of cases encountered clinically give a family history, as most cases are the result of a spontaneous mutation. Despite important advances in understanding the genetics of this disease and improvements in diagnostic imaging techniques, the management of patients with bilateral acoustic nerve tumors remains difficult. There are only a few accounts of patient outcome, and the earlier literature is gloomy in this regard. Frykholm 5 presented six patients operated on by Olivecrona and reviewed 13 others from the literature. Of the former six patients, four died shortly after operation and Olivecrona :~ himself thought that little good came from operating on such patients. Pool and Pava 2~ had equally
I
910
poor results in their six patients. These early reports were mainly concerned with whether surgery could offer any useful survival, bilateral facial nerve palsies and total deafness being considered relatively unimportant consequences. In recent years, some larger series of bilateral cases have been reported with better operative results due to the introduction of microsurgical methods, an improved ability of otologists to make a relatively early diagnosis, and the concentration of cases of acoustic nerve tumors in special units. 7'9"~7Because of the paucity of reports on patient management and the relatively small numbers contained in each series, it seems worthwhile to present a series of 19 patients encountered over a period of 21 years and to examine their outcome. Particular interest is attached to the speed of disease progression, the need for an operation, and the timing, extent, and outcome of surgery. The outlook for useful survival and for hearing preservation is also examined.
Clinical Material and M e t h o d s
Criteria for Patient Selection The criteria for the diagnosis of bilateral cerebeUopontine angle tumors included either bilateral operations in the same patient, the demonstration of bilateral tumors by scanning, or a combination of both. This study was retrospective, with all patients followed either until death or to the time of writing.
J. Neurosurg. / Volume 74/June, 1991
Bilateral tumors in neurofibromatosis type 2
FIG, 1. Diagram presenting the clinical course of five patients with neurofibromatosis type 2 who did not undergo operation. The length of symptomatic period prior to diagnosis, size of tumor at diagnosis, and length of follow-up period for each patient is shown. See key for definitions of symbols.
Patient Presentation
There were 11 males and eight females with an average age at presentation of just under 30 years; the average age for our 444 patients with unilateral tumor was 47 years. Five patients were under 20 years of age at diagnosis and 10 were under 30 years. Family history, based solely on what the patients knew about cutaneous lumps, deafness, and acoustic nerve tumors in close relatives, was available in 17 cases; a positive history was found in only three of those cases. Twenty-two children have been born to these patients but, at the time of writing, a detailed survey of the offspring had not been carried out, although three children are known to be affected. Peripheral manifestations were evident in seven of our patients but they were florid in only two (Cases 5 and 14). All 19 patients had deafness of some degree when diagnosed. In 13 patients, deafness was the principal reason for seeking medical advice. Features found at presentation and during clinical evaluation are summarized in Figs. 1 and 2. Presenting characteristics were categorized according to the presence of unilateral or bilateral deafness and the existence of a contributory family history. Four patients (Cases 7, 9, 10, and 15) presented with deafness in one ear only and were treated initially as having a unilateral tumor. Family history was noncontributory in each of these four cases. Computerized tomography (CT) scans J. Nem'osurg. / Volume 74 / June, 1991
FIG. 2. Diagram showing the clinical course of 14 patients who had one or two operations. See key for definitions of symbols. were not available in two patients and failed to show a second lesion in the other two. Eight patients (Cases 1, 2, 3, 4, 12, 13, 16, and 18) complained of bilateral deafness when first examined. Family history was noncontributory in each case, and only one patient (Case 18) had peripheral manifestations which were minor. Four of the five patients who did not undergo surgery fell into this category; the other four patients (Cases 12, 13, 16, and 18) had large bilateral tumors, more than 2 cm in diameter, and all of these were operated on for both tumors. A positive family history and/or obvious peripheral manifestations were found in six patients (Cases 5, 6, 8, 14, 17, and 19) in whom one or both of these features rendered the diagnosis fairly evident. All six were bilaterally deaf to some degree. One patient without these manifestations (Case 11) presented elsewhere with difficulty in walking, believed to be caused by an intramedullary cervical tumor. This led to surgical exploration but no biopsy. Postoperatively, increased deafness was followed by a CT scan and a correct diagnosis. Clinical Evaluation Neurological signs and symptoms, as well as raised intracranial pressure, were evident in 13 cases and con-
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D. Baldwin, et al. sisted of ataxia, trigeminal symptoms, and nystagmus, singly or in combination. Papilledema was present in eight patients and developed in a ninth (Case 17) a few months after the first of his large bilateral tumors was removed. The size of the tumors at diagnosis is presented in Figs. 1 and 2; 14 of the 19 patients had at least one large tumor when first diagnosed. Nine patients had other tumors of the central nervous system (meningiomas, nerve tumors, or intramedullary spinal tumors) and one had a large intrathoracic neurofibroma. Diagnoses were made by pneumoencephalography or positive-contrast cisternography in earlier cases. More recent cases have been diagnosed by either CT scanning, with or without air, or magnetic resonance (MR) imaging. Patient Management The patients fell into three groups regarding their surgical management: no operation (Fig. 1), or one or two operations (Fig. 2). The translabyrinthine approach was used in surgical cases, except in Cases 6 and 7 or when subtotal removal was attempted to preserve hearing. No Operation. The first five patients did not undergo surgery and were kept under observation for periods of between 4 and 6 years; four remain well (Fig. 1). In Case 5, there was a history of florid peripheral manifestations of neurofibromatosis dating from childhood. Following an exploratory operation for intramedullary cervical cord tumor, this patient became progressively disabled and eventually died. Autopsy findings suggested that the eighth nerve tumors had enlarged considerably since the original diagnosis and may have contributed to her death. All five conservatively treated patients were diagnosed at relatively late ages (average age 44 years, range 31 to 50 years). One Operation. Cases 6 and 7 (Fig. 2) underwent unilateral operations. In each case, the first tumor was removed in the era before CT scanning was available. One patient (Case 6) survived for 20 years, dying at 79 years of age, although it is probable that the second tumor was ultimately the cause of death. The other patient (Case 7) remains generally well 25 years after operation while still suffering from some trigeminal neuralgia. As this patient is now only 50 years of age and her remaining tumor is large, it seems likely that a second operation will become necessary. Two Operations. The remaining 12 patients (Fig. 2) had both of their tumors removed, although not all of them at this institution. Patient age at diagnosis ranged from 11 to 40 years (average 23 years). In cases managed at this hospital, a conservative approach to surgery was followed and intervention undertaken on one side only when progressive neurological deficit or raised intracranial pressure was apparent. In no case was an attempt made to preserve hearing by early operation on a small tumor, as recommended by the National Institutes of 912
Health consensus document. "~The operative results are shown in Fig. 2, where the interval between operations is represented graphically. Intervention was necessary, at the time of diagnosis in eight patients and was delayed for between 1 and 5 years (average 388 years) in four others. In two patients (Cases 8 and 19), each of whom was operated on elsewhere, both tumors were removed at the time of hospital admission. In one patient (Case 19), operation on the second side was confined to a subtotal removal; the patient underwent total tumor removal on the same side 10 years later at our institution. In the remaining patients, an interval of between 3 months (Case 17) and 9 years (Case 15) elapsed between the first and second operation, the latter of which entailed total removal in all patients except Case 16 (see below). A problem arises when surgery becomes necessary, and the larger or only remaining tumor is on the side of residual hearing which, even at very low levels, may assist the patient with lip reading. Subtotal removal with opening of the internal auditory meatus to decompress the cochlear nerve, as suggested by Martuza and Ojemann, J6 was attempted under these circumstances in two patients (Cases 10 and 17) but failed, the patients being rendered completely deaf by this conservative operation. In each case, conservative management was followed shortly after by total removal. In Case 16, subtotal removal relieved severe trigeminal neuralgia and resulted in preservation of poor hearing in the ear for another 12 years. Although now totally deaf, this patient has not required further surgery and his facial function on the side of the residual tumour remains normal. Radiosurgery was employed in one patient (Case 15), but failed to prevent progressive loss of hearing on the side of the second tumor which, after 2 years, had enlarged and was excised. This technique is an attractive solution in such difficult cases but its efficacy in preventing progressive hearing loss is not impressive, as reported by Nor6n, et al. ~
Results
Role of Tumor Growth Evidence of tumor growth was available in 15 cases: from serial CT scanning in 13 patients, from repeated vertebral arteriography in one (Case 14), and at autopsy in one (Case 5). Four patients have shown no discernible increase in size of their small or medium-sized bilateral tumors over periods of 4 to 5 years; in one patient (Case 16), the remaining large tumor remained static following a subtotal removal carried out 12 years previously. In nine patients there was a demonstrable increase in size which occurred at a variable rate. In a patient (Case 8) with a history of maternal inheritance, and who presented at the age of 11 years, enormous tumor growth occurred over 4 years (Fig. 3). In two patients (Cases 10 and 15), a contralateral tumor grew J. Neurosurg. / Volume 74~June, 1991
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Fl(;. 3. Computerized tomography (CT) suans in Case 8. I+(!fi and U('lller. Air-CT scans showing bilateral acoustic nerve tumors at age of It ~cars, Ri~,kt 1.eft-sided enhanced ( T scan showing enormous t u m o r growth 4 ,,'cats later,
from being initially invisible on a first-generation CT scanner image to being large (> 2 cm in diameter) 9 and 8 years later, respectively. As with unilateral tumorsY =27 rates of growth are variable.
Patient Morla/it), Three patients in this series died. One patient (Case 5) did not undergo operation and lived for 6 years after diagnosis. Another patient (Case 6) died in old age having survived her first operation for 20 years. The third patient (Case 14) died at 26 years of age as a consequence of paraplegia, 10 years after diagnosis and after total resection of both tumors and a laminectomy for multiple spinal neurofibromas. No deaths were attributable to surgery. It is probable that the acoustic nerve tumor(s) contributed to the death of the first two patients, although one (Case 5) also had an intramedullary cervical cord glioma.
Hearing Loss Of the four survivors in the group without surgery, one has good hearing unilaterally, two have some residual hearing, and one is totally deaf. The two patients (Cases 6 and 7) undergoing unilateral resection became completely deaf in the unoperated ear within a few years of surgery. The 12 survivors of bilateral operations were followed for periods ranging from 1 to 12 years (average 4.5 years). All are now completely deaf, either through natural progression or due to surgery; however, one patient (Case 16) retained some hearing for 12 years after subtotal removal of a tumor. All tumors in this patient group were large. The outlook for hearing in these patients has, therefore, been dismal.
Facial Nerve D~:/icil The facial nerve, which was at risk 26 times in this series, fared somewhat better. Both patients with unilateral tumors removed prior to microsurgical techJ. ,,\r~,ttrostlr~./ Vohtme 74/June. 1991
niques had facial paralyses treated by faciohypoglossal anastomosis. Of the 12 patients with bilateral operalions, two underwent both operations and four underwent one operation elsewhere. Three of these eight facial nerves have maintained fair function. In operations carried out by us, 16 nerves were at risk. Seven nerves were preserved with the following results: normal function in one patient (Case 16) undergoing subtotal removal, minimal recovery in one patient, and fair function (considerable weakness and synkinesis) in five patients. Five other facial nerves were repaired with a sural nerve graft which failed in one patient, and provided minimal recovery, in one and fair recovery in another. In Case 18, bilateral facial nerve tumors and grafts resulted in fair function on one side and minimal recovery on the other. Altogether, therefore, nine of these 20 facial nerves were preserved and maintained some function. Adding to these the four nerves which recovered in part after nerve grafting, 13 of the 20 nerves functioned and two of the 12 patients who had bilateral operations either here or elsewhere have some bilateral facial movement. Five faciohypoglossal anastomoses were performed; however, it would seem wise to avoid this procedure in neurofibromatosis type 2 because a further cranial nerve has to be sacrificed.
General Resull,~ Aside from total deafness and facial palsies, the clinical results of treatment in the survivors were better than one might have expected. Four of the unoperated patients are alive and leading normal lives. One patient who underwent unilateral resection leads a restricted but independent life. Of the l 1 survivors of bilateral operations, five are independent although restricted and six are leading satisfactory lives; one (Case 19) is a practicing radiologist, one (Case 15) runs a building company, and a third (Case 10) now works for a real 913
D. Baldwin, et al. estate agency, being no longer able to practice as a barrister. Another patient, a young girl (Case 18), is taking a college course, and two others (Cases 12 and 16) have returned to their former occupations. Additional Operations
Six additional operations of the central nervous system were required in five patients and are indicated by closed triangles in Fig. i. Two cervical laminectomies were carried out for the diagnosis of intramedullary glioma, one cervical laminectomy for the removal of a large foramen magnum neurinoma arising on the C-2 nerve root, one lumbar laminectomy for multiple neurofibromas, one posterior fossa exploration for a cystic astrocytoma of the medulla, and one shunt placement for hydrocephalus. Discussion
Central neurofibromatosis, or neurofibromatosis type 2, affects about one in 50,000 individuals, compared to one in 4000 for yon Recklinghausen's disease, or neurofibromatosis type l.lS The frequency with which patients with bilateral tumors are encountered, compared to those with unilateral tumors, varies in different r e p o r t s , 3"9"14'22 with ratios ranging from 1:108 to 1:50. 26 Our 19 cases occurred among a group of 444 acoustic nerve tumors, comprising 4% of the total, or at a ratio of 1:23. It is clear that the condition is rare and no surgeon, even one in a unit specializing in the treatment of unilateral tumors, is likely to see many cases, which aggravates the difficulty of deciding on treatment. In recent years, the earlier gloom surrounding these cases has somewhat lifted but the problems remain clear. Patients face the possibility of total hearing loss; surgery is likely to hasten this possibility and there is a higher than average chance of producing facial paralysis. It has been observed by Martuza and Ojemann ~6that the facial nerve may be engulfed by the lesion in cases of bilateral acoustic nerve tumors, making nerve preservation impossible. In our series, four tumors (one each in Cases 9 and 19, and both in Case 18) demonstrably arose from the facial nerve, a circumstance to which neurofibromatosis type 2 is probably disposed. ,2 Therefore, at least four tumors arose from the facial nerve, a rate of 15% of all bilateral tumors operated upon. This rate is much higher than that observed in unilateral acoustic nerve tumors (between 1% and 2%'J), or even lower if cases of neurofibromatosis type 2 are excluded. The observation of Martuza and Ojemann could be explained by the nerve of origin of the neurinoma rather than the biological behavior of a tumor that is not histologically different from a unilateral acoustic nerve tumor. A similar explanation may account for the contention that it is impossible to preserve the cochlear nerve at surgery for bilateral tumors. ,3 However, this is not always the case as hearing has been successfully preserved in previously reported 914
cases of bilateral acoustic nerve tumors. 7~1~ Other tumors, both intrinsic, especially in the cervical cord, and extrinsic, may require treatment, thereby adding to the morbidity. Diagnosis has been made much easier with CT and MR imaging, which may reveal an unsuspected tumor on the other side in an apparently unilateral problem. In five of our cases, most of them presenting before the availability of CT and MR imaging, the bilateral nature of the disease was not recognized; however, such a possibility should always be considered in patients presenting under the age of 25 years. The majority of our cases had large tumors at the time of diagnosis. This may not be the case in the future, since fairly small tumors can be detected by MR imaging (Fig. 4), and if careful follow-up examinations and screening of the offspring of known cases are performed, diagnosis may be apparent before the patient's hearing is seriously affected. In the present state of our ability to preserve hearing in patients with unilateral acoustic nerve tumors, early detection may present a dilemma, the resolution of which has already been suggested: ~ namely, an attempt may be made to remove one tumor while hearing is normal on both sides. If successful, removal of the opposite tumor could follow. This approach requires a good deal of courage on the part of both surgeon and patient; indeed, one may doubt whether it is justified by the present results. In cases of large bilateral tumors, a more conservative approach, such as that practiced here, may be considered since symptoms progress at a variable rate. Our findings suggest that delaying surgery, even if the tu-
FIG. 4. Magnetic resonance image with gadolinium administration in Case 2 revealing an intracanalicular tumor and a left-sided medium-sized tumor (arrowheads). Hearing was poor on the right side but normal on the left. J. Neurosurg. / Volume 74/June, 1991
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mors are of considerable size and especially if hearing is good in at least one ear, is reasonable and allows some patients the benefit of residual auditor}, function for a number of years. The problem associated with early diagnosis of bilateral tumors is that of heating preservation, and the techniques needed to accomplish this can only be developed by operating on the more common unilateral lesions. Careful follow-up examinations of patients' offspring, probably requiring MR imaging rather than repeated audiometry only, may allow early surgery, and hearing preservation. 2 However, cranial nerve function may be threatened even then as, in our experience, some o f these tumors arise on the facial nerve and others may possibly be of cochlear nerve origin.
Acknowledgments The authors are indebted to Dr. T. H. Koeze for Figs. 1 and 2, and to Mr. John Firth who generously provided followup information regarding Case 8. References 1. Barker D, Wright E, Nguyen K, et al: Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science 236:1100-1102, 1987 2. Dutcher PO Jr, House WF, Hitselberger WE: Early detection of small bilateral acoustic tumors. Am J Otol 8: 35-38, 1987 3. Edwards CH, Paterson JH: A review of the symptoms and signs of acoustic neurofibromata. Brain 74:144-190, 1951 4. Eldridge R: Central neurofibromatosis with bilateral acoustic neuroma, in Riccardi VM, Mulvihill JJ (eds): Advances in Neurology, Volume 29: Neurofibromatosis. New York: Raven Press, 1981, pp 57-65 5. Frykholm R: Treatment of bilateral acoustic tumors. Report of six cases operated on, with a review of thirteen cases from the literature. Acta Chir Scand 92:451-469, 1945 6. Gardner WJ, Frazier CH: Bilateral acoustic neurofibroma. A clinical study and field survey of a family of five generations with bilateral deafness in thirty eight members. Arch Neurol Psychiatry 23:266-302, 1930 7. Glasscock ME III, Woods CI, Jackson CG, et ai: Management of bilateral acoustic tumors. Laryngoscope 99: 475-484, 1989 8. Henschen F: Zur Histologie und Pathogenese der KleinhirnbNckenwinkeltumoren. Arch Psychiatry Nervenkn 56:21-[22, 1915 9. Hitselberger WE, Hughes RL: Bilateral acoustic tumors and neurofibromatosis. Arch Otolaryngol 88:700-711, 1968 10. Kanter WR, Eldridge R, Fabricant R, et al: Central neurofibromatosis with bilateral acoustic neuroma. Genetic, clinical and biochemical distinctions from peripheral neurofibromatosis. Neurology 30:851-859, 1980
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11. King TT, Morfison AW: Primary facial nerve tumors within the skull. J Nenrosurg 72:1-8, 1990 12. Laasonen EM, Troupp H: Volume growth rate of acoustic neurinomas. Neuroradiology 28:203-207, 1986 13. Linthicum FH Jr, Brackmann DE: Bilateral acoustic tumors. A diagnostic and surgical challenge. Arch Otolaryngol 106:729-733, 1980 14, Malis LI: Acoustic Neuroma Surgery. Randolph, Mass: Codman & Shurtlett, 1987 15, Martuza RL, Eldridge R: Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318: 684-688, 1988 16. Martuza RL, Ojemann RG: Bilateral acoustic neuromas: clinical aspects, pathogenesis, and treatment. Neurosurgery 10:1-12, 1982 17. Moyes PD: Familial bilateral acoustic neuroma affecting 14 members from four generations. J Neurosurg 29: 78-89, 1968 18. National Institutes of Health Consensus Development Conference: Neurofibromatosis. Conference statement. Arch Neurol 45:575-578, 1988 19. Nor6n G, Arndt J, Hindmarsh T, et al: Stereotactic radiosurgical treatment of acoustic neurinomas, in Lunsford LD (ed): Modern Stereotactic Neurosurgery. Boston: Martinus Nijhoff, 1988, pp 481-489 20. Olivecrona H: The neurinomas, in Olivecrona H, T6nnis W (eds): Hundbueh der Neurochirurgie, Vol IV. Berlin: Springer-Verlag, Teil IV, 1960, pp 221-223 21. Pool JL, Pava AA: Acoustic Nerve Tumours, ed 2. Springfield, Ilk Charles C Thomas, 1970, p 84 22. Revilla AG: Neurinomas of the cerebellopontine recess. A clinical study of one hundred and sixty cases including operative mortality end results. Bull Johns Hopkins Hosp 80:254-296, 1947 23. Rouleau GA, Wertelecki W, Haines JL, et at: Genetic linkage of bilateral neurofibromatosis to a DNA marker on chromosome 22. Nature 329:246-248, 1987 24. Seizinger BR, Martuza RL, Gusella JF: Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma. Nature 322:644-677, 1986 25. Seizinger BR, Rouleau G, Ozelius LJ, et al: Common pathogenetic mechanism for three tumor types in bilateral acoustic neurofibromatosis. Science 236:317-319, 1987 26. Tos M, Thomsen J, Harmsen A: Acoustic neuroma surgery: results of translabyrinthine tumour removal in 300 patients. Discussion of choice of approach in relation to overall results and possibility of preserving hearing. Br J Neurosurg 3:349-360, 1989 27. Valvassori GE, Guzman M: Growth rate of acoustic neuromas. Am J Otol 10:174-176, 1989 28. Wertelecki W, Rouleau GA, Duane W, et al: Neurofibromatosis 2: clinical and DNA linkage studies of a large kindred. N Engl J Med 319:278-283, 1988 29. Wishart JL: Case of turnouts in the skull, dura mater and brain. Edinburgh Med Surg J 18:393-397, 1822 Manuscript received August 8, 1990. Accepted in final form December 19, 1990. Address reprint requests to: T. T. King, F.R.C.S., Department of Neurosurgery, The Royal London Hospital, Whitechapel, London E1 1BB, England.
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