Neurofibromatosis type 2

Neurofibromatosis type 2

What is Neurofibromatosis type 2 (NF2)?

Neurofibromatosis type 2 (NF2) is a genetic disorder that causes tumours to form on the nerves of the brain and spinal cord. These tumours can lead to hearing and vestibular loss by affecting the nerves responsible for hearing and balance. It may also cause vision loss and many other neurological problems. A typical presentation and near diagnostic sign is a patient presenting with vestibular schwannoma on both sides (bilateral) (1). Vestibular schwannoma (VS) are benign tumours that grow on the nerve responsible for balance and hearing in the inner ear.

Bilateral vestibular schwannoma (*) in NF2
Bilateral vestibular schwannoma (*) in NF2

Neurofibromatosis is a general term encompassing three conditions: Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and the rare schwannomatosis. Although NF1 is by far the most commonly occurring of the three, it will not be discussed further as it does not involve the hearing and balance function of the patient commonly (2).

Epidemiology of neurofibromatosis type 2

The incidence of NF2 varies between 1: 25 000 to 1: 44 000 people, occurring equally in males and females. All races are similarly affected. The condition usually becomes apparent during puberty and nearly always before the age of 30 years (3).

Genetics of neurofibromatosis type 2

NF2 is an autosomal dominant inherited condition, meaning an abnormal gene must only be inherited from one parent to develop the condition. Mutations of normal genes cause mosaic expressions. The expression in a patient may vary and depends on which stage of embryonic development the mutation occurs.

The abnormal gene located at 22q12.2 of chromosome 22 causes an abnormality of the protein Merlin that acts as a tumour suppressor. The net result is that numerous tumours originate on nerve tissue in the brain, spinal cord and peripheral nerves (4).

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Diagnostic criteria of neurofibromatosis type 2

Bilateral vestibular schwannoma occur in over 90% of  patients. Patients with a positive family history and a single schwannoma or a combination of other tumours  may still suffer from NF2 (5).

Clinical presentation

Typical presenting symptoms include (6):

  • Hearing loss
  • Balance problems and sometimes vertigo
  • Tinnitus
  • Facial nerve twitching or weakness
  • Eye problems, including cataracts and visual loss
  • Headaches
  • Weakness in an arm or leg
  • Other cranial nerve problems include but are not limited to numbness of the face, swallowing difficulties, hoarseness, shoulder weakness and weakness of the tongue
  • In the late stage, patients may present with increased pressure on the brain

Special tests in Neurofibromatosis type 2

Magnetic resonance imaging (MRI) is still the gold standard of examination. MRI of the whole nervous system must be performed. Imaging should include the brain, spinal cord, and any other anatomical area that may be clinically affected. Once the diagnosis is confirmed, a brain MRI should be performed annually, and if no symptoms are present, a spinal MRI should be performed every three years.

Computed tomography (CT) and then, preferably, cone-beam CT, is essential when involvement and destruction of bone are suspected. Cone beam CT offers the advantage of less radiation, an important factor when imaging children.

Diagnostic audiometry with speech discrimination and basic vestibular testing in videonystagmography(VNG) are indicated in all patients with vestibular schwannomas. Patients with bilateral vestibular involvement may require rotation chair testing. Auditory brainstem response audiometry(ABR) and vestibular myogenic potential testing (VEMP) may help define the auditory and vestibular neural involvement. The vestibular function should be regularly monitored even if no obvious symptoms occur. Bilateral vestibular failure typically presents with an insidious onset.

Patients may also develop facial nerve tumours; if facial nerve symptoms are present, electromyography and other nerve conduction studies may be required.

Since visual problems are so familiar, it is indicated that all patients consult with an ophthalmologist. All patients with NF2 should consult with a neurosurgeon, regardless of symptomatology.

Therefore, consulting with a clinical geneticist is advised because many questions arise regarding genetic susceptibility.

The treatment of neurofibromatosis type 2

Currently, there is no curative treatment for NF 2. Treatment focuses on managing symptoms and complications associated with the condition to improve quality of life for affected individuals.

Patients with NF2 must be managed in multidisciplinary teams due to the complexity of the condition.

Medical treatment of neurofibromatosis type 2

Avastin, also known as Bevacizumab, is a medication that inhibits the growth of blood vessels, which can be beneficial in treating certain types of tumours. In the case of NF2, Avastin can be used as a treatment option for VS (10).

Studies have shown that Avastin can help reduce the size of vestibular schwannomas and improve hearing in patients with NF2. This medication is typically administered intravenously, usually every 2-3 weeks, under the supervision of a healthcare provider.

While Avastin may be effective in shrinking tumours and improving symptoms in some patients with NF2, it is essential to note that this treatment may not be suitable for everyone and can have potential side effects. It is crucial to discuss the risks and benefits of using Avastin with an oncologist before starting treatment.

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Surgical treatment

The surgical treatment of neurofibromatosis type 2 involves the removal of tumours that are causing symptoms or affecting the quality of life. Surgery may include the removal of vestibular schwannoma. Surgery may also be performed to remove other tumours that are pressing on the spinal cord or brain. Surgery aims to alleviate symptoms, restore function, and prevent further complications. The success of surgery depends on the location and size of the tumours, as well as the overall health of the patient. Follow-up care and monitoring are essential to managing potential complications and recurrence of tumours.

 Patients with hearing loss may benefit from hearing aids, cochlear implantation, and even, in some cases, auditory brainstem implants (ABI) (7,8,9). More than ten patients have already been implanted in South Africa and over 1000 patients worldwide. ABI surgery is currently only offered in Johannesburg and Cape Town.

Auditory brainstem implant (ABI) showing the part that fits in the brainstem (credit: MEDEL)
Auditory brainstem implant (ABI) showing the part that fits in the brainstem (credit: MEDEL)

Vestibular implants for bilateral vestibular loss are currently still under investigation. It has been performed successfully in trials, and I am sure it will be commercially available in South Africa within 5-7 years.

Patients with facial nerve damage may benefit from facial nerve grafting, re-animation surgery, botulinum toxin injection, fillers and other cosmetic surgery.

Eye problems like cataracts may benefit from ophthalmological surgery.

Radiation for neurofibromatosis type 2

Radiation therapy treats tumours associated with NF2 by targeting and shrinking the tumours. This treatment can help to control tumour growth in growing tumours and alleviate symptoms. However, the potential risks and long-term effects of radiation therapy should be carefully monitored.

Future possibilities

Future treatment possibilities include gene therapy and molecular treatment.  Gene therapy involves targeting the mutated gene responsible for developing tumours in the nervous system. Researchers are exploring methods to replace the faulty gene with a healthy copy or to correct the mutation within the patient’s cells.

Molecular treatments for NF2 may involve using small molecules or antibodies to target the signalling pathways involved in tumour growth specifically. These therapies aim to inhibit tumour growth and reduce symptoms associated with NF2. While these approaches are still in the early stages of development, they offer promising potential for more effective and targeted treatments for individuals with NF2 (4,11).

References

1. Jiramongkolchai P, Schwartz MS, Friedman RA. Management of Neurofibromatosis Type 2-Associated Vestibular Schwannomas. Otolaryngol Clin North Am. 2023 Jun;56(3):533-541. doi: 10.1016/j.otc.2023.02.012. Epub 2023 Mar 22. PMID: 36964092.

2. Tamura R. Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis. Int J Mol Sci. 2021 May 29;22(11):5850. doi: 10.3390/ijms22115850. PMID: 34072574; PMCID: PMC8198724.

3. Tiwari R, Singh AK. Neurofibromatosis Type 2. [Updated 2022 Oct 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470350/#

4. Ghalavand MA, Asghari A, Farhadi M, Taghizadeh-Hesary F, Garshasbi M, Falah M. The genetic landscape and possible therapeutics of neurofibromatosis type 2. Cancer Cell Int. 2023 May 23;23(1):99. doi: 10.1186/s12935-023-02940-8. PMID: 37217995; PMCID: PMC10204202.

5. Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genet Med. 2022 Sep;24(9):1967-1977. doi: 10.1016/j.gim.2022.05.007. Epub 2022 Jun 9. PMID: 35674741.

6. Coy S, Rashid R, Stemmer-Rachamimov A, Santagata S. An update on the CNS manifestations of neurofibromatosis type 2. Acta Neuropathol. 2020 Apr;139(4):643-665. doi: 10.1007/s00401-019-02029-5. Epub 2019 Jun 4. Erratum in: Acta Neuropathol. 2019 Aug 20;: PMID: 31161239; PMCID: PMC7038792.

7. 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 Dec;42(6):1329-1337. doi: 10.1111/coa.12882. Epub 2017 Apr 26. PMID: 28371358.

8. North HJD, Lloyd SKW. Hearing Rehabilitation in Neurofibromatosis Type 2. Adv Otorhinolaryngol. 2018;81:93-104. doi: 10.1159/000485526. Epub 2018 Apr 6. PMID: 29794459.

9. Colletti L, Shannon R, Colletti V. Auditory brainstem implants for neurofibromatosis type 2. Curr Opin Otolaryngol Head Neck Surg. 2012 Oct;20(5):353-7. doi: 10.1097/MOO.0b013e328357613d. PMID: 22886036.

10. Fujii M, Ichikawa M, Iwatate K, Bakhit M, Yamada M, Kuromi Y, Sato T, Sakuma J, Saito K. Bevacizumab Therapy of Neurofibromatosis Type 2 Associated Vestibular Schwannoma in Japanese Patients. Neurol Med Chir (Tokyo). 2020 Feb 15;60(2):75-82. doi: 10.2176/nmc.oa.2019-0194. Epub 2020 Jan 3. PMID: 31902875; PMCID: PMC7040431.

11. Prabhakar S, Beauchamp RL, Cheah PS, Yoshinaga A, Haidar EA, Lule S, Mani G, Maalouf K, Stemmer-Rachamimov A, Jung DH, Welling DB, Giovannini M, Plotkin SR, Maguire CA, Ramesh V, Breakefield XO. Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2. Mol Ther Methods Clin Dev. 2022 Jun 22;26:169-180. doi: 10.1016/j.omtm.2022.06.012. PMID: 35846573; PMCID: PMC9263409.