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Neurofibromatosis type 2

Neurofibromatosis type 2 (NF2), a neurogenetic condition that can manifest as intracranial, spinal, ocular and cutaneous lesions (Peripheral nerve sheath tumors (PNST) throughout the neuroaxis, with vestibular schwannomas, meningiomas, and spinal ependymomas).

Several Familial Tumor Syndrome of the Central Nervous systems are characterized by increased meningioma risk, and the genetics of these syndromes provides mechanistic insight into sporadic disease. The best defined of these syndromes is neurofibromatosis type 2, which is caused by a mutation in the NF2 gene and has a meningioma incidence of approximately 50%. This finding led to the subsequent discovery that NF2 loss-of-function occurs in up to 60% of sporadic tumors.

Leptomeningeal angiomatosis has been described with this tumour predisposition syndrome 1).

High-grade gliomas are not a feature of NF2 in the unirradiated patient and should be excluded from the diagnostic criteria 2).


It is a genetic disorder with autosomal dominant pattern, with germline mutation of NF2/Merlin.

Mutations in the NF2 gene cause neurofibromatosis type 2. The NF2 gene provides instructions for making a protein called merlin.

Lakshiminarasimhaiah et al, has a anaesthetic management of a paediatric patient with neurofibromatosis 2 for multiple spinal and thoracic tumour decompression 3).

Patients with neurofibromatosis type II are the initial candidates for auditory midbrain implantation; the appropriate surgical approach should allow for tumor removal and electrode implantation in the same surgical setting.


The nature of this devastating genetic disease requires ongoing MRI for the patient's lifespan.

Today, most auditory brainstem implants require removal of the magnet that connects the internal device to the external speech processor to undergo imaging as their disease progresses. Patients have the option of having a short procedure to have the magnet taken out and replaced each time, or alternately using a headband to secure the processor over the receiver coil of the internal device. Novel magnet technology has led to the development of a freely rotating magnet that can be used inside the magnetic field of an MRI scanner without losing magnet strength and without being displaced from the body of the device. We report one of the first patients implanted with a Med-El Synchrony ABI in the United States who subsequently underwent successful imaging with MRI 1.5 tesla to follow for other existing schwannomas 4).

Ultrasound patterns of peripheral nerve pathologies are described for the first time in a large cohort of patients with NF1 and NF2. It is a suitable screening tool and enables targeted MRI analysis 5).


Risk factors of progressive disability include younger age of onset, positive family history, positive treatment history, and specific neurological deficits 6).

In Guy's and St. Thomas' NHS Trust, London, UK NF2 patients undergo annual MRI brain and internal auditory meatus imaging. They noted incidental intracranial aneurysms in some patients and sought to determine the prevalence of intracranial aneurysms in there cohort of NF2 patients. They conducted a retrospective audit of the MRI images of 104 NF2 patients from 2014 to 2016. Axial T2 brain MRI images were assessed for vascular abnormalities by two neuroradiologists blinded to patient's clinical details. Intracranial aneurysms were detected in four patients and an aneurysm clip related to previous surgery was noted in one additional patient. Using standard MRI imaging sequences alone we provide evidence of intracranial aneurysms in 4.4% of our cohort. This compares with an estimated overall prevalence of 3% in the general population. We discuss these findings as well as other evidence for a vasculopathy associated with NF2 7).


It is a devastating disease with no well-accepted management guidelines. Better understanding of the disease process provides the basis for how or when to initiate treatment.

In neurofibromatosis type 2 (NF2), multiple therapeutic options are available to prevent bilateral hearing loss in vestibular schwannomas that significantly affects the quality of life of patients.

It is also important to consider that the management of vestibular schwannomas in NF2 is complex and decision-making is determined by many factors, not just the need to preserve hearing 8).

Experimental treatment

Paldor et al. examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiotherapy (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2 9).

Case series


In a retrospective cohort study of the Japanese national NF2 registry between 2009 and 2013, clinical data (demographic, history, oncologic, and neurologic) of 807 patients with a diagnosis of NF2 were analyzed. The overall severity of neurologic disability was assessed using a comprehensive 25-point scoring system encompassing a wide variety of neurologic deficits. In 587 patients in whom longitudinal disability data were available, multivariate logistic regression was performed to identify risk factors for significant progression of disability.

The clinical characteristics of the Japanese NF2 population were heterogeneous. The median age of onset was 24 years (range, 1-80 years), the male:female ratio was 1:1.29, and the initial severity score was 4 (range, 0-22) out of 25 points. A family history of NF2 was present in 33% of the patients. Most frequent clinical features were bilateral cranial nerve VIII nerve sheath tumor (NST) in 87%, spinal NST in 80%, hearing loss in 65%, spinal dysfunction in 50%, intracranial meningioma in 49%, and facial paresis in 36%. The disability score progressed by ≥5 points in 6.1% of patients over the study period. Based on multivariate logistic regression analyses, the significant independent risk factors of progression (P value) included age of onset <25 years (P = 0.015), positive family history (P = 0.007), positive treatment history (P = 0.026), hearing loss (P = 0.014), facial paresis (P = 0.015), blindness (P = 0.011), and hemiparesis (P = 0.025).

The Japanese NF2 population has heterogeneous clinical features. Risk factors for progressive disability include younger age of onset, positive family history, positive treatment history, and specific neurologic deficits 10).


Twenty-one NF2 patients operated on for internal auditory canal 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.

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.

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 11).

Case reports


Two Cases of Spinal Tanycytic Ependymoma Associated with Neurofibromatosis Type 2 12).

A 12-year-old girl presented with headache and ataxia for four months. Kawsar et al. examined and found a lump in the right side of her abdomen. On magnetic resonance imaging (MRI) of brain, a bilateral VS at the cerebellopontine (CP) angle was detected, and on computerized tomography (CT) scan and ultrasonography of her abdomen a large retroperitoneal schwannoma was revealed in the right side of her abdomen. At first, the right-sided CP angle tumour and two months later, the left-sided lesion was operated. After some days, she became mute and incontinent, and was found to have hydrocephalus on CT scan. We introduced a ventriculoperitoneal shunt. Then we operated the abdominal lump, which was histologically proven as schwannoma. The association of these three tumours is rare and untiring surgical approaches made her better. The patient recovered well except bilateral mild facial and vestibulocochlear deficit 13).

Naik S, Shetty GS, Kumar S, Phadke RV. Leptomeningeal Angiomatosis in a Case of Neurofibromatosis Type 2: An Unusual Finding. Pediatr Neurosurg. 2015 Oct 29. [Epub ahead of print] PubMed PMID: 26510155.
King AT, Rutherford SA, Hammerbeck-Ward C, Lloyd SK, Freeman SM, Pathmanaban ON, Rodriguez-Valero M, Thomas OM, Laitt RD, Stivaros S, Kellett M, Evans DG. High-Grade Glioma is not a Feature of Neurofibromatosis Type 2 in the Unirradiated Patient. Neurosurgery. 2017 Jul 21. doi: 10.1093/neuros/nyx374. [Epub ahead of print] PubMed PMID: 28973691.
Lakshiminarasimhaiah G, Jagannatha AT, Pai KR, Varma RG, Hegde AS. Anaesthetic management of a child with neurofibromatosis type 2 for multiple tumour decompressions. J Clin Diagn Res. 2013 Dec;7(12):3004-5. doi: 10.7860/JCDR/2013/6881.3828. Epub 2013 Dec 15. PubMed PMID: 24551709.
Shew M, Bertsch J, Camarata P, Staecker H. Magnetic Resonance Imaging in a Neurofibromatosis Type 2 Patient with a Novel MRI-Compatible Auditory Brainstem Implant. J Neurol Surg Rep. 2017 Jan;78(1):e12-e14. doi: 10.1055/s-0036-1597588. Review. PubMed PMID: 28210535; PubMed Central PMCID: PMC5309127.
Winter N, Rattay TW, Axer H, Schäffer E, Décard BF, Gugel I, Schuhmann M, Grimm A. Ultrasound assessment of peripheral nerve pathology in neurofibromatosis type 1 and 2. Clin Neurophysiol. 2017 May;128(5):702-706. doi: 10.1016/j.clinph.2017.02.005. Epub 2017 Feb 20. PubMed PMID: 28315612.
Iwatate K, Yokoo T, Iwatate E, Ichikawa M, Sato T, Fujii M, Sakuma J, Saito K. Population rCharacteristics and Progressive Disability in Neuofibromatosis Type 2. World Neurosurg. 2017 Jul 15. pii: S1878-8750(17)31136-1. doi: 10.1016/j.wneu.2017.07.036. [Epub ahead of print] PubMed PMID: 28720529.
Afridi SK, Thomson S, Connor SEJ, Walsh DC, Ferner RE. Aneurysms in neurofibromatosis type 2: Evidence for vasculopathy? Am J Med Genet A. 2017 Jun;173(6):1562-1565. doi: 10.1002/ajmg.a.38221. Epub 2017 Apr 21. PubMed PMID: 28429859.
Lloyd SKW, King AT, Rutherford SA, Hammerbeck-Ward CL, Freeman SRM, Mawman DJ, O'Driscoll M, Evans DG. Hearing optimisation in neurofibromatosis type 2: A systematic review. Clin Otolaryngol. 2017 Apr 1. doi: 10.1111/coa.12882. [Epub ahead of print] PubMed PMID: 28371358.
Paldor I, Abbadi S, Bonne N, Ye X, Rodriguez FJ, Rowshanshad D, Itzoe M, Vigilar V, Giovannini M, Brem H, Blakeley JO, Tyler BM. The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma. J Neurooncol. 2017 Jul 22. doi: 10.1007/s11060-017-2567-9. [Epub ahead of print] PubMed PMID: 28735458.
Iwatate K, Yokoo T, Iwatate E, Ichikawa M, Sato T, Fujii M, Sakuma J, Saito K. Population Characteristics and Progressive Disability in Neurofibromatosis Type 2. World Neurosurg. 2017 Oct;106:653-660. doi: 10.1016/j.wneu.2017.07.036. Epub 2017 Jul 16. PubMed PMID: 28720529.
Bernardeschi D, Peyre M, Collin M, Smail M, Sterkers O, Kalamarides M. Internal Auditory Canal Decompression for Hearing Maintenance in Neurofibromatosis Type 2 Patients. Neurosurgery. 2016 Sep;79(3):370-7. doi: 10.1227/NEU.0000000000001125. PubMed PMID: 26579965.
Tao XG, Hou ZG, Hao SY, Zhang JT, Liu BY. Two Cases of Spinal Tanycytic Ependymoma Associated with Neurofibromatosis Type 2. Chin Med J (Engl). 2017 Apr 5;130(7):872-873. doi: 10.4103/0366-6999.202732. PubMed PMID: 28345553; PubMed Central PMCID: PMC5381323.
Kawsar KA, Haque MR, Chowdhury FH. Abdominal schwannoma in a case of neurofibromatosis type 2: A report of a rare combination. Asian J Neurosurg. 2017 Jan-Mar;12(1):89-91. doi: 10.4103/1793-5482.145347. PubMed PMID: 28413544; PubMed Central PMCID: PMC5379816.
neurofibromatosis_type_2.txt · Last modified: 2018/11/24 12:10 by administrador