Disease course of Neurofibromatosis Type 2; a 30-year follow-up study of 353 patients seen at a single institution

Abstract Background Limited data exists on the disease course of Neurofibromatosis Type 2 (NF2) to guide clinical trial design. Methods A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990–2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred and inheritance type. Interventions for NF2-related tumours were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death. Results Three-hundred-and-fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65 respectively per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting <16 and >40 years had poorer overall survival than those presenting at 26-39 years (P=0.03 and P=0.02 respectively) but those presenting between 16-39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P=0.004). Conclusion Understanding disease course improves prognostication, allowing for better informed decisions about care.

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Age at symptom onset and long-term survival in patients with neurofibromatosis Type 2

Journal of Neurosurgery ◽

10.3171/jns.2003.99.3.0480 ◽

2003 ◽

Vol 99 (3) ◽

pp. 480-483 ◽

Cited By ~ 62

Author(s):

Goro Otsuka ◽

Kiyoshi Saito ◽

Tetsuya Nagatani ◽

Jun Yoshida

Keyword(s):

Symptom Onset ◽

Survival Rates ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Vestibular Schwannomas ◽

Content Type ◽

Fine Print

Object. Neurofibromatosis Type 2 (NF2) is an intractable disorder predisposing to multiple, recurrent tumors of the central nervous system (CNS). To clarify the survival rate and characteristics that predict poor survival, we retrospectively reviewed clinical data in cases of NF2. Methods. From among 283 patients with neurofibromatosis who had been registered in a nationwide study in Japan between 1986 and 1987, 74 patients with bilateral vestibular schwannomas were analyzed. The mean duration of follow up after diagnosis was 121 months (range 2–287 months). Results of a Kaplan—Meier product-limit analysis indicated that overall 5-, 10-, and 20-year patient survival rates following diagnosis of NF2 were 85, 67, and 38%, respectively. Early onset of the initial symptom significantly compromised survival; 5-, 10-, and 20-year survival rates in patients with symptom onset at an age younger than 25 years were 80, 60, and 28%, respectively, whereas in patients with symptom onset at an age of 25 years or older the rates were 100, 87, and 62%, respectively. Patients with small vestibular schwannomas at diagnosis (< 2 cm in diameter) had better rates of survival. Other variables such as sex, additional tumors in the CNS, or dermal abnormalities did not significantly affect survival. Conclusions. This first report of long-term follow-up results concerning the survival of patients with NF2 indicates an adverse effect of early symptom onset.

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Sporadic unilateral vestibular schwannoma in the pediatric population

Journal of Neurosurgery Pediatrics ◽

10.3171/2009.3.peds08434 ◽

2009 ◽

Vol 4 (2) ◽

pp. 125-129 ◽

Cited By ~ 8

Author(s):

Brian P. Walcott ◽

Ganesh Sivarajan ◽

Bronislava Bashinskaya ◽

Douglas E. Anderson ◽

John P. Leonetti ◽

...

Keyword(s):

Facial Nerve ◽

Tumor Size ◽

Pediatric Population ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Nerve Function ◽

Facial Nerve Function ◽

Duration Of Symptoms

Object Vestibular schwannomas (VSs) are rare in the pediatric population. Most often, these lesions manifest as a bilateral disease process in the setting of neurofibromatosis Type 2. Even in the absence of additional clinical diagnostic criteria, the presentation of a unilateral VS in a young patient may be a harbinger of future penetrance for this hereditary tumor syndrome. Methods The authors retrospectively reviewed the charts of a cohort of 7 patients who presented with apparently sporadic, unilateral VSs. These patients had previously undergone surgery via translabyrinthine, retrosigmoid, or combined approaches. Clinical outcomes were reviewed with emphasis on facial nerve function and follow-up for signs and symptoms of a heritable disorder. Results All patients underwent microsurgical resection in a multidisciplinary effort by the senior authors. The average tumor size was 4.57 cm, with an average duration of symptoms prior to definitive diagnosis of 31.2 months. The tumor size at the time of presentation followed a trend different from reports in adults, while the duration of symptoms did not. At a follow-up average of 6.3 years (range 1–12 years), 100% of patients demonstrated good facial function (House-Brackmann Grade I or II). No patient in this cohort demonstrated symptoms, objective signs, or genetic analysis indicating the presence of neurofibromatosis Type 2. Conclusions Diagnosis and management of sporadic, unilateral VSs in children is complicated by clinical presentations and surgical challenges unique from their adult counterparts. Careful consideration should be given to a heritable genetic basis for sporadic unilateral VS in the pediatric population. Results of genetic testing do not preclude the necessity for long-term follow-up and systemic investigation. In patients who present with large tumors, preliminary experience leads the authors to suggest that a combined retrosigmoid-translabyrinthine approach offers the greatest opportunity for preservation of facial nerve function.

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Multiple schwannomas: schwannomatosis or neurofibromatosis type 2?

Journal of Neurosurgery ◽

10.3171/jns.1998.89.1.0036 ◽

1998 ◽

Vol 89 (1) ◽

pp. 36-41 ◽

Cited By ~ 55

Author(s):

Matti Tapio Seppälä ◽

Markku Alarik Sainio ◽

Matti Jouko Johannes Haltia ◽

Jaakko Jyri Kinnunen ◽

Kirsi Hannele Setälä ◽

...

Keyword(s):

Clinical Course ◽

Positive Family History ◽

Neurofibromatosis Type ◽

Magnetic Resonance Images ◽

Neurofibromatosis Type 2 ◽

Long Term Outcome ◽

Content Type ◽

Fine Print

Object. The aim of this study was to clarify the clinical outcome of schwannomatosis, a rare condition characterized by multiple nonvestibular schwannomas in the absence of meningiomas, intraspinal ependymomas, and other clinical signs of neurofibromatosis type 2 (NF2). Methods. Nine patients with schwannomatosis treated at one institution are presented and their clinical course during a median follow-up time of 9.9 years is discussed. The patients were typically middle-aged at the time of their first operation (median 43.5 years), none had a positive family history of schwannomatosis or NF2, and none showed cutaneous or ocular signs of NF2. On histopathological examination the tumors from the patients with schwannomatosis showed a lobular appearance and frequent Verocay bodies, signs indicating NF2, more often than 20 sporadic schwannomas that were investigated as controls. Two patients died of unrelated causes at 3.2 and 9.9 years, respectively, of follow up. Magnetic resonance images of the head and spine were obtained in seven patients at the end of the follow-up period. New spinal schwannomas were detected in one patient and a residual schwannoma in three. No germline mutations of the NF2 gene were found in these seven patients. Two additional patients originally included in the schwannomatosis group who were 8.6 and 11.7 years old at initial surgery had NF2. One was diagnosed at follow-up review and the other developed a fulminant disease that led to death in 4 years. Conclusions. The clinical course, long-term outcome, and genetic mechanism of schwannomatosis differ from that of NF2.

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Cochlear Implantation in the Neurofibromatosis Type 2 Patient: Long-Term Follow-up

The Laryngoscope ◽

10.1097/mlg.0b013e31804b1ae7 ◽

2007 ◽

Vol 117 (6) ◽

pp. 1069-1072 ◽

Cited By ~ 74

Author(s):

Brian A. Neff ◽

R Mark Wiet ◽

John M. Lasak ◽

Noel L. Cohen ◽

Harold C. Pillsbury ◽

...

Keyword(s):

Cochlear Implantation ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Long Term Follow Up

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Long-term Follow-up and Histological Correlation of Peripheral Nervous System Alterations in Neurofibromatosis Type 2

Clinical Neuroradiology ◽

10.1007/s00062-021-01102-5 ◽

2021 ◽

Author(s):

Tim Godel ◽

Philipp Bäumer ◽

Said Farschtschi ◽

Klaus Püschel ◽

Barbara Hofstadler ◽

...

Keyword(s):

Nervous System ◽

Peripheral Nerve ◽

Peripheral Nervous System ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Nerve Lesions ◽

Peripheral Nerve Lesions

Abstract Purpose To examine long-term alterations of the dorsal root ganglia (DRG) and the peripheral nerve in patients with neurofibromatosis type 2 (NF2) by in vivo high-resolution magnetic resonance neurography (MRN) and their correlation to histology. Methods In this prospective study the lumbosacral DRG, the right sciatic, tibial, and peroneal nerves were examined in 6 patients diagnosed with NF2 and associated polyneuropathy (PNP) by a standardized MRN protocol at 3 T. Volumes of DRG L3–S2 as well as peripheral nerve lesions were assessed and compared to follow-up examinations after 14–100 months. In one patient, imaging findings were further correlated to histology. Results Follow-up MRN examination showed a non-significant increase of volume for the DRG L3: +0.41% (p = 0.10), L4: +22.41% (p = 0.23), L5: +3.38% (p = 0.09), S1: +10.63% (p = 0.05) and S2: +1.17% (p = 0.57). Likewise, peripheral nerve lesions were not significantly increased regarding size (2.18 mm2 vs. 2.15 mm2, p = 0.89) and number (9.00 vs. 9.33, p = 0.36). Histological analyses identified schwannomas as the major correlate of both DRG hyperplasia and peripheral nerve lesions. For peripheral nerve microlesions additionally clusters of onion-bulb formations were identified. Conclusion Peripheral nervous system alterations seem to be constant or show only a minor increase in adult NF2. Thus, symptoms of PNP may not primarily attributed to the initial schwannoma growth but to secondary long-term processes, with symptoms only occurring if a certain threshold is exceeded. Histology identified grouped areas of Schwann cell proliferations as the correlate of DRG hyperplasia, while for peripheral nerve lesions different patterns could be found.

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Facial Nerve Outcomes After Vestibular Schwannoma Microsurgical Resection in Neurofibromatosis Type 2

Otolaryngology ◽

10.1177/0194599820954144 ◽

2020 ◽

pp. 019459982095414

Author(s):

Catherine Sobieski ◽

Daniel E. Killeen ◽

Samuel L. Barnett ◽

Bruce E. Mickey ◽

Jacob B. Hunter ◽

...

Keyword(s):

Facial Nerve ◽

Vestibular Schwannoma ◽

Tumor Volume ◽

Tumor Resection ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Tumor Diameter ◽

Microsurgical Resection

Objective The aim of this study is to investigate facial nerve outcomes after microsurgical resection in neurofibromatosis type 2 (NF2) compared to sporadic tumors. Study Design Single institutional retrospective chart review. Setting Tertiary referral center. Methods All adult patients with NF2 vestibular schwannoma (VS) or sporadic VS who underwent microsurgical resection from 2008 to 2019 with preoperative magnetic resonance imaging (MRI) and 1 year of postsurgical follow-up were included. The primary outcome measure was postoperative House-Brackmann (HB) facial nerve score measured at first postoperative visit and after at least 10 months. Results In total, 161 sporadic VSs and 14 NF2 VSs met inclusion criteria. Both median tumor diameter (NF2, 33.5 mm vs sporadic, 24 mm, P = .0011) and median tumor volume (NF2, 12.4 cm3 vs sporadic, 2.9 cm3, P = .0005) were significantly greater in patients with NF2. The median follow-up was 24.9 months (range, 12-130.1). Median facial nerve function after 1 year for patients with NF2 was HB 3 (range, 1-6) compared to HB 1 (range, 1-6) for sporadic VS ( P = .001). With multivariate logistic regression, NF2 tumors (odds ratio [OR] = 13.9, P = .001) and tumor volume ≥3 cm3 (OR = 3.6, P = .025) were significantly associated with HB ≥3 when controlling for age, sex, extent of tumor resection, translabyrinthine approach, and prior radiation. Conclusion Tumor volume >3 cm3 and NF2 tumors are associated with poorer facial nerve outcomes 1 year following microsurgical resection.

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STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2

Neurosurgery ◽

10.1227/01.neu.0000255340.26027.53 ◽

2007 ◽

Vol 60 (3) ◽

pp. 460-470 ◽

Cited By ~ 102

Author(s):

David Mathieu ◽

Douglas Kondziolka ◽

John C. Flickinger ◽

Ajay Niranjan ◽

Richard Williamson ◽

...

Keyword(s):

Stereotactic Radiosurgery ◽

Tumor Volume ◽

Gamma Knife Radiosurgery ◽

Neurofibromatosis Type ◽

Hearing Preservation ◽

Neurofibromatosis Type 2 ◽

Vestibular Schwannomas ◽

Factors Affecting

Abstract OBJECTIVE Vestibular schwannomas present significant management challenges in patients with neurofibromatosis Type 2 (NF2). We evaluated the results of gamma knife radiosurgery for the management of these tumors, focusing on tumor response, hearing preservation, and other factors affecting outcomes. METHODS Stereotactic radiosurgery was performed to manage 74 schwannomas in 62 patients. Ipsilateral serviceable hearing was present in 35% of tumors before the procedure. The mean tumor volume was 5.7 cm3. The mean margin and maximum dose used were 14 and 27.5 Gy, respectively. Cox regression analyses were performed to identify factors affecting outcomes. RESULTS The median follow-up period was 53 months, and two patients were lost to follow-up. Actuarial local control rates at were 85, 81, and 81% at 5, 10, and 15 years, respectively. Tumor volume was significant as a predictor of local control. Since 1992, using current radiosurgery techniques (magnetic resonance imaging scan targeting and reduced margin dose to 14 Gy or less), the actuarial serviceable hearing preservation rate is 73% at 1 year, 59% at 2 years, and 48% at 5 years after radiosurgery. Facial neuropathy occurred in 8% of tumors, trigeminal neuropathy occurred in 4%, and vestibular dysfunction occurred in 4%. Radiation dose and tumor volume were predictive of development of new deficits. No radiosurgery-associated secondary tumors or atypical or malignant changes were noted. CONCLUSION Stereotactic radiosurgery is a safe and effective management modality for neurofibromatosis Type 2 vestibular schwannomas. Although results do not seem to be as good as for patients with sporadic unilateral tumors, gamma knife radiosurgery results seem favorable and indicate that radiosurgery should be strongly considered for primary tumor management in selected patients.

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Age at Onset and Presenting Symptoms of Neurofibromatosis Type 2 as Prognostic Factors for Clinical Course of Vestibular Schwannomas

Cancers ◽

10.3390/cancers12092355 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2355

Author(s):

Isabel Gugel ◽

Florian Grimm ◽

Julian Zipfel ◽

Christian Teuber ◽

Ulrike Ernemann ◽

...

Keyword(s):

Hearing Loss ◽

Clinical Course ◽

Age At Onset ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Vestibular Schwannomas ◽

Speech Discrimination ◽

Predictive Values ◽

Presenting Symptoms

The presenting symptoms of the tumor suppressor gene syndrome neurofibromatosis type 2 (NF2) are often non-specific and unrelated to the disease hallmark bilateral vestibular schwannomas (VS). However, age at onset and presenting symptoms may have predictive values for the clinical course of VS. In this retrospective single-center study, we addressed this issue by reviewing 106 patients with 194 VS. Presenting symptoms attributable to VS commonly occur in 87% of adults and 31% of children. Age at onset significantly correlates with tumor volumes at presentation (p = 0.034). In addition, age at onset significantly correlates with pure-tone average (p = 0.0001), speech discrimination scores (p = 0.001), age at beginning of hearing loss (p = 0.0001), age at deafness (p = 0.0001), and age at first surgery (p = 0.0001). Patients presenting with VS related symptoms had significantly (p < 0.05) worse hearing values at presentation and after surgery. These patients also exhibited higher growth rates and tumor volumes compared to patients with non-VS related presenting symptoms, but this difference did not reach the significance level of p < 0.05. Due to the late appearance of these symptoms, the time of beginning hearing loss, surgery and deafness is significantly delayed (p < 0.05) compared to patients not presenting with VS. In summary, age at onset and type of presenting symptom provide excellent prognostic parameters for predicting VS- and hearing-related clinical course.

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Internal Auditory Canal Decompression for Hearing Maintenance in Neurofibromatosis Type 2 Patients

Neurosurgery ◽

10.1227/neu.0000000000001125 ◽

2015 ◽

Vol 79 (3) ◽

pp. 370-377 ◽

Cited By ~ 7

Author(s):

Daniele Bernardeschi ◽

Matthieu Peyre ◽

Michael Collin ◽

Mustapha Smail ◽

Olivier Sterkers ◽

...

Keyword(s):

Hearing Loss ◽

Internal Auditory Canal ◽

Neurofibromatosis Type ◽

Early Postoperative Period ◽

Neurofibromatosis Type 2 ◽

Hearing Level ◽

Speech Discrimination ◽

Unilateral Deafness

Abstract BACKGROUND: In neurofibromatosis type 2 (NF2), multiple therapeutic options are available to prevent bilateral hearing loss that significantly affects the quality of life of patients. OBJECTIVE: To evaluate the morbidity and functional results of internal auditory canal (IAC) decompression in NF2 patients with an only hearing ear. METHODS: Twenty-one NF2 patients operated on for IAC decompression in a 3-year period with a minimum follow-up of 1 year were included in this retrospective study. They presented unilateral deafness due to previous contralateral vestibular schwannoma removal in 16 patients or contralateral hearing loss due to the tumor in 5 patients. Hearing level was of class A (American Academy of Otolaryngology-Head and Neck Surgery classification) in 7 patients, B in 8 patients, C in 1 patient, and D in 5 patients. Pure-tone average and speech discrimination score evaluations were performed at 6 days, 1 year, and during the follow-up. Eight patients had postoperative chemotherapy. RESULTS: No case of facial nerve palsy was observed. In the early postoperative period; all patients maintained the hearing class of the preoperative period. At 1-year follow-up, all but 3 patients maintained their hearing scores; at last follow-up (mean follow-up, 23 + 8 months; range, 12-44 months), hearing classes remained stable with only 1 patient worsening from class B to C and 1 patient improving from class D to B. CONCLUSION: Decompression of IAC seems to be a useful procedure for hearing maintenance in NF2 patients, with very low morbidity. Ideal timing and association with chemotherapy should be evaluated in the future.

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Vestibular schwannoma growth in patients with neurofibromatosis Type 2: a longitudinal study

Journal of Neurosurgery ◽

10.3171/jns.2002.96.2.0223 ◽

2002 ◽

Vol 96 (2) ◽

pp. 223-228 ◽

Cited By ~ 76

Author(s):

Victor-Felix Mautner ◽

Michael E. Baser ◽

Sarang D. Thakkar ◽

Urs M. Feigen ◽

J. M. Friedman ◽

...

Keyword(s):

Growth Rates ◽

Age At Onset ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Spinal Tumors ◽

Content Type ◽

Gradient Gel Electrophoresis ◽

Temperature Gradient Gel Electrophoresis ◽

Fine Print

Object. The factors that determine the growth rates of vestibular schwannomas (VSs) in patients with neurofibromatosis Type 2 (NF2) are unknown. The authors undertook this study to determine if clinical factors or type of constitutional NF2 mutation were associated with VS growth rates in cases of NF2. Methods. The authors reviewed serial gadolinium-enhanced magnetic resonance (MR) images of the head and full spine of 37 patients with sporadic NF2 who had been observed over periods ranging from 0.2 to 8 years (median 3.9 years) at a specialized referral clinic for NF2. A box model was used to calculate VS volumes so that tumor growth rates could be estimated. Temperature-gradient gel electrophoresis was used to screen for constitutional NF2 mutations. The VS growth rates tended to decrease with increasing patient age at onset of signs or symptoms (r2 = 0.23, p = 0.003) and at the time the baseline gadolinium-enhanced MR image was obtained (r2 = 0.38, p < 0.001). The authors did not find significant associations between VS growth rates and the number of non-VS cerebral or spinal tumors or different types of constitutional NF2 mutations. Conclusions. There is considerable variability in growth rates of VSs in patients with NF2, but they tend to be higher in patients who are younger at onset of signs or symptoms.

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