Neurofibromatosis type 2 and auditory brainstem implantation

Abstract

Neurofibromatosis type 2 (NF-2) is one of the most common single gene disorders in the nervous system. For approximately 96% of patients with NF-2 present with bilateral Schwannomas involving the eighth cranial nerves, which may be accompanied by Schwannomas involving other cranial, spinal or peripheral nerves, NF-2 is also referred to as “bilateral acoustic neuromas”.1 Due to progression of tumors, surgery or radiotherapy, patients with bilateral acoustic neuromas will eventually suffer profound or total hearing loss, resulting in decrease of quality of life (QOL). In this article, we report the clinical data of 3 patients within one family suffering from NF-2. Of the two patients who received surgeries for resection of bilateral acoustic neuromas, one received auditory brainstem implant (ABI) aiming to restore some degree of his auditory function, and the anticipant outcome was obtained. Based on our experience and data in relevant literatures, we explore the clinical characteristics and management strategies of NF-2 as well as the clinical value of ABI application CLINICAL DATA Patients Patient 1, a 52-year-old woman, was the index case. She was initially referred to Queen Mary Hospital, University of Hong Kong Medical Centre, Hong Kong, China in 1987, having noticed bilateral progressive hearing loss, tinnitus and disequilibrium for 3 years. Computed tomography (CT) scans showed bilateral acoustic neuromas and spinal cord tumor within T4-T5 region. The bilateral acoustic neuromas were removed by retro-sigmoid and middle fossa approach, respectively. The spinal cord tumor was removed as well. All these tumors were Schwannomas confirmed by pathologic examination. Postoperatively, she suffered from total, bilateral deafness and facial paralysis, although she could walk independently. Since March 2004, she suffered from progressive disequilibrium accompanied by frequent tumble once again. Then pure-tone audiometry showed a total, bilateral hearing loss. And no waveform could be recorded in auditory brainstem response testing (ABR). Facial nerve function (according to the House-Brackman classification): right: VI grade; left: III grade. Muscle strength: superior limbs: 4/5; inferior limbs: 5/5. No cerebella sign could be noticed. But step width was amplus. CT scan revealed atrophy of the left cerebellar hemisphere, meningioma in the right frontal lobe, enlargement of cerebral ventricles and recurrence of bilateral acoustic neuromas. Then craniocerebral magnetic resonance imaging (MRI) confirmed the recurrence of bilateral acoustic neuromas (Fig. 1). Moreover, spinal cord MRI revealed extramedullary and paraspinal mass with spinal cord compression. Therefore, in the subsequent October, she received surgery for resection of the spinal cord tumor which was schwannoma confirmed by postoperative pathologic examination. Two sons of the patient, with age of 22 and 20 years respectively, have not noticed any symptom or positive sign of NF-2 to date.Fig. 1.: Enhanced craniocerebral MRI of patient 1 showing bilateral acoustic neuromas with bursa, left: 2.2 cm×3.5 cm, right: 1.2 cm×1.9 cm.Patient 2, died at 67 years of age, was the mother of the proband. Since 1971, she suffered from bilateral, progressive tinnitus and gradual hearing loss subsequently. Until 1991, the hearing loss was profound and accompanied by disequilibrium and infrequent tumble. Then CT examination revealed bilateral acoustic neuromas. Due to heart disease and chronic obstructive pulmonary disease (COPD), she could not receive any surgery for tumors removal and died from respiratory failure resulted from pulmonary infection in 1993. The patient had a daughter and four sons, and the daughter and the oldest son are patient 1 and patient 3 reported in this study, respectively. Patient 3, a 50-year-old man, was a younger brother of the proband. In 1993, due to the death of his mother, he took examination for NF-2 on the suggestion of the doctor. And CT scan revealed bilateral acoustic neuromas although without any symptom. Since 1998, he suffered from progressive hearing loss at his left ear which became a complete one until 2001. Since October 2003, he suffered from powerless of inferior limbs, disequilibrium, pain at bilateral tempus, infrequent nausea and vomiting and dizziness, but without any unconsciousness. Since March 2004, he suffered from hearing loss at his right ear which developed rapidly and became completely in the end of the subsequent April. Physical examination showed equal size of the pupils which were reactive to light, no facial paralysis, no cerebella sign, normal muscle strength of the superior and inferior limbs and disequilibrium with obliquity to the left side. Pure-tone audiometry showed total, bilateral deafness. ABR testing could not educe any waveform. Electrically auditory brainstem response (EABR) could record wave V at the right ear. Craniocerebral MRI revealed bilateral acoustic neuromas with slight encephaledema (Fig. 2). Spinal cord MRI revealed extramedullary and paraspinal mass at T12/L1 level at the right side. Since the end of April 2004, he received speech therapy and train for lip-reading and sign language. In the middle of May, he underwent a retro-sigmoid approach to remove the left acoustic neuroma. And in the front of July, the spinal cord tumor was removed. Both the tumors were Schwannomas confirmed by postoperative pathologic examination. Then in the font of October, he received ABI at the time of partial removal of the right acoustic neuroma by a retro-sigmoid/suboccipital approach.Fig. 2.: Enhanced craniocerebral MRI of patient 3 showing bilateral acoustic neuromas with inhomogeneous enhancement, left: 4.0 cm×4.6 cm, right: 3.6 cm×2.3 cm.ABI device and the surgical procedures The ABI device used for patient 3 was a C40+ABI device (Med-EL Corporation, Austria). Its implantable portions consist of receiver/stimulator, microcoiled electrode wires, electrode array, and reference electrode. The electrode array consists of 12 platinum disk electrodes arranged in three diagonally offset rows on one face of a silicone carrier (5.5 mm ×3 mm). The surgical procedures were aiming to place the electrode array into the lateral recess of the fourth ventricle to directly stimulate the cochlear nuclear complex in the brainstem. Therefore, the search for the opening of the lateral recess of the fourth ventricle (foramen of Luschka) was the critical procedure of the surgery.2 Normally intact choroid plexus mark the entrance to the lateral recess. And just inferior to the foramen is the root of the glossopharyngeal ninth nerve; superior to the foramen is the root entry and exit zones of the vestibulocochlear and facial nerves. When unfolding the choroid plexus, egress of cerebrospinal fluid can be noted. After identifying the opening to the foramen of Luschka, the carrier was passed into the lateral recess with the electrodes facing superiorly. During the implantation, electrophysiologic monitoring of the VII and IX cranial nerves was performed to determine the electrodes position in minimizing nonauditory side effects. Then the carrier was secured by a small piece of fat tissue packed into the meatus of the lateral recess to prevent migration of the electrodes. In addition, a brick-shaped dacron mesh connecting to the electrodes was used to enhance the immobility. Immediately after the placement, the ABI device was stimulated to confirm the position of the electrodes over the nucleus by recording the presence of EABR. Speech training and speech perception The patient 3 received speech training 4 weeks after the implantation with a frequency of 2–3 times per week. Speech perception was ongoing every three months, including vowel, consonant, spondee, bisyllabic, open-set sentence and environment sound. Postoperative fitting of the ABI Four weeks after the surgery, X-ray of the skull showed no migration of the electrodes (Fig. 3). Then the initial stimulation of the ABI device took place 8 weeks after implantation. During the course, the patient stayed in the intensive care unit (ICU) where medical monitoring equipment were accessible because of remote possibility of stimulating other structure of the brainstem resulting in vital signs change. Firstly, the threshold and the maximum comfort level of each electrode were obtained. Electrodes that produced non-auditory side effects would be deactivated. For our patient, none of the 12 electrodes produced non-auditory side effect. Subsequently, pitch scaling and ranking of the electrodes took place. During the course of pitch scaling, the pitch was reported as low, middle, high or uncomforting by the patient undergoing the stimulation at maximum comfort level. During the course of pitch ranking, electrodes were randomly activated in pairs to determine their positions. Based on the data, speech processing strategies was made using the continuous interleaved sampler (CIS) strategies.Fig. 3.: X-ray of the skull of patient 3 showing the position of the electrodes.Speech perception Over time, the patient made progress in recognizing vowel, consonant, word, open-set sentence and environment sound. Some of the results are list follow: he scored 40% in vowels confusion 12 months after surgery, as compared with that of 3 months (24%) and 9 months (28%); scored 15% in words recognition 6 months after surgery, 20% at 9 months and 25% at 12 months; scored 20%, 25% and 30% in open-set sentences discrimination when the postoperative time was 6, 9 and 12 months, respectively. DISCUSSION Clinical characteristics of NF-2 The hallmark of NF-2 is bilateral acoustic neuromas (in about 96% of gene carriers), which may be accompanied by Schwannomas involving other cranial, spinal or peripheral nerves, gliomas, meningiomas and ependymomas.1 Patients with NF-2 have a tendency to recur, and approximately 50% of their offspring will be affected for NF-2 is an autosomal dominant disorder. The early symptoms of NF-2 usually present at aural region, such as hearing loss, tinnitus, dizziness and disequilibrium. The growth pattern of the tumors is unpredictable: some tumors grow slowly over many years, whereas others may enlarge rapidly. Nearly all of NF-2 patients initially visit ENT clinicians, calling for great vigilance of the clinician: bilateral acoustic neuromas must be ruled out in any patient present with bilateral hearing loss, tinnitus and disequilibrium, especially being accompanied by symptoms of other cranial nerves. All the patients reported in this study became symptomatic older than 30 years and initially manifest aural symptoms. Patient 1 and patient 3 developed meningiomas and spinal cord tumors as well as bilateral acoustic neuromas. Patient 1 recurred bilaterally after tumors removal. All the above manifestations are consistent with the clinical characteristics of NF-2. Considering the inherited law of NF-2, all individuals within this family should receive genetic counseling and be followed up for being ruled out or identified at an early stage which resulting in early management. Assistant procedures for diagnosis of NF-2 For patients with NF-2, pure-tone audiometry often shows a bilateral sensorineural hearing loss mainly affecting the high frequency (HF), usually with poor discrimination. At early stage, prolongation of incubative stage of waves III, IV, V and intervals of wave I—III and I-V can be identified in ABR testing. However, no waveform can be educed by ABR at advanced stage, 3 such as that of patient 1 and patient 3 reported in this study. Therefore, ABR can be used for a screening procedure for NF-2 and assist the early diagnosis of NF-2. To make a definite diagnosis of bilateral acoustic neuromas, craniocerebral CT and MRI are the essential procedures rather than biopsy. The main intracranial manifestation of NF-2 is bilateral acoustic neuromas, being followed by meningiomas. Tumors involving other cranial nerves can be seen in minority of NF-2 patients. Li et al4 found that approximately 30% of acoustic tumors are localized in internal auditory canal (IAC), resulting in possible missing diagnosis by CT scan for their small size. CT is a better technique in detecting calcification, such as calcification of choroid plexus and cerebellar cortex, whereas MRI is better in detecting localized tumors in IAC and meningiomas on the skull base or the convexity of the brain. The typical intraspinal manifestations of NF-2 are ependymoma, extramedullary and paraspinal Schwannoma and neurofibromatosis.4 Both case 1 and case 3 reported in this study typically developed intraspinal tumors or meningiomas at the time of being diagnosised as NF-2. The etiological gene for NF-2 has been located to the center of the long arm of chromosome 22 (22q12.2). Recently, genetic diagnosis methods have been set up to identify asymptomatic patients and monitor their families.5 Management of NF-2 The treatment planning of NF-2 is influenced by tumor size at the time of diagnosis and their effect to auditory function, patients' age and physical status, the condition of brainstem compression, intracranial pressure and the function of the facial nerves, and on. Considering the patients condition and the principle of individual management, Miyamoto et al1 proposed six basic management strategies for patients with bilateral acoustic neuromas: ① Hearing preservation surgery-total tumor removal, for patients with small tumors involving IAC or cerebellopontine angle (CPA). ② Observation without surgical intervention, for patients with a small tumor in an only-hearing ear or bilateral tumors too large for hearing preservation. ③ Middle fossa craniotomy-internal auditory canal decompression without tumor removal, for patients undergoing observation who experience fluctuation or progression of hearing loss. ④ Retro-sigmoid partial tumor removal, for patients aiming in preservation of the seventh and eighth nerves by removing only those portions of the tumors farthest from the nerves. ⑤ Nonhearing preservation-total removal, for the goal of total tumor removal and facial nerve preservation undergoing translabyrinthine or retro-sigmoid approach. ⑥ Stereotactic radiosurgery (gamma knife) is also an alternative. The indication and the advantage or disadvantage of the above six management strategies must be under consideration when determine the treatment planning in a specific individual. ABI: the exclusive option for hearing rehabilitation after bilateral acoustic neuromas removal The progression of bilateral acoustic neuromas and their removal may cause total, bilateral deafness. These patients can not benefit from cochlear implants because they have lost integrity of the auditory nerves between the spiral ganglion of the cochlea and the cochlear nuclei in the brainstem. However, ABI can provide them with a therapeutic option for hearing rehabilitation. ABIs function similarly to cochlear implants in terms of device hardware and signal processing, but different in the placement of the stimulate electrodes: the ABI directly stimulates the “cochlear nucleus complex” by implanting the electrodes to the lateral recess of the 4th ventricle, whereas the cochlear implant stimulates the neurofibra within the cochlea.2 In 1979, the House Ear Institute firstly performed a single-channel auditory brainstem implant for a patient with NF-2 and obtained promising outcomes. To date, more than 300 patients have received ABI over the world. Most of these patients obtained significant auditory sensation which assist lip-reading and enhanced their quality of life. A few patients attained open-set speech understanding and were able to do some degree of telephone conversation.6 Our patients made progress in recognizing vowel, word, open-set sentence and environment sound as time going. ABI is mainly designed for patients with NF-2 as well as some of other tumors involving the IAC or cerebellopontine angle.2 Additionally, Colletti et al7 recently reported promising outcomes of ABI implantation applied in patients with failure of cochlear implant. However, as compared with that of multi-channel cochlear implant, the auditory sensation provided by ABI cannot be satisfactory. The difference is mainly produced by the irregular arrangement of the neurons in the auditory nucleus. Therefore, further studies to the auditory nucleus will promote improvement in designs of ABI and their functions. The precise placement of the ABI device was the critical factor for the success of the implantation. It is confirmed by surgery and anatomy that the lateral recess of the fourth ventricle is the optimal site for the placement of the ABI electrode array.2 However, the intraoperative location of the auditory nucleus is far more difficult than that of cochlear implantation. The location may be hampered by distortion of the brainstem caused by the tumors, tissues adherence due to previous surgery or radiotherapy and the experience of the operator. Meanwhile, intraoperative monitoring of the VIIth and IXth cranial nerves is of great importance in correct placement of the electrodes,8 for it assists location of the foramen of Luschka as well as prevention of activating the nerves at the time of stimulating the ABI device. In addition, intraoperative EABRs can confirm whether the auditory pathway is activated at the time of intraoperative ABI device stimulation. EABR responses typically comprise of two or three visible waves (corresponding to waves III, IV and V of a conventional ABR). However, some patients with poor EABRs obtained intraoperatively could obtain auditory sensation at the time of postoperative initial ABI stimulation.8 The possible reasons may be related to the magnetic interfere origined from the equipment in the operating room and the influence caused by the blood or effusion in the wound. Therefore, the results of the EABR response are only references rather than essentiality in determining whether the ABI implantation is successful.