Clinical Analysis of small Acoustic neuromas With Initial Neurological Symptoms


 Background

Initial neurological manifestations involved with Acoustic neuromas (ANs) are easily misdiagnosed due to nonspecific symptoms. The objective is to investigate and describe the clinical features of small ANs presenting with initial neurological manifestations, to allow earlier diagnosis and more well-timed interference for patients with this disease.
Methods

This was a retrospective cross-sectional study that included 22 patients. The detailed clinical information with initial symptoms of neurological manifestations caused by small ANs between January 2010 and May 2020 were retrospectively analyzed. The collected data included symptoms, signs, neuroimaging results, and pathologic diagnoses.
Results

There were 9 males and 13 females, and their ages ranged from 22 to 74 years. Dizziness/vertigo was the most common initial presenting symptom in 9 of the 22 patients. Headache was the second most frequent initial presenting symptom in 8 of 22. Neuro-physical examination found that the facial nerve and auditory nerve were the most involved cranial nerves, with remaining positive signs involving abnormalities of the optic nerve, trigeminal nerve and abducens nerve as well as ataxia and nystagmus. More than half of the patients underwent microsurgery and had postoperative clinical symptom improvement. The patients who chose the observation method showed no change in tumor size at follow-up.
Conclusions

Dizziness/vertigo and headache are the most common initial neurological symptoms of small ANs and should be considered in the differential diagnosis of patients. The results suggest that MRI is the best tool in diagnosis for small ANs. Observation and microsurgery are safe and common methods for the treatment.


Introduction
Acoustic neuromas (ANs), or vestibular schwannomas, which were first identified in 1777 by Eduard Sandifort [1] , represent a type of benign brain tumor of Schwann cells that mostly arises from the vestibular nerve [2] . ANs represent one of the most common intracranial tumors with an incidence from 1 to 20 per million, and ANs accounts for approximately 6% of all intracranial tumors [3] .
Additionally, the incidence of acoustic neuromas is slightly increasing worldwide. [4,5] . In the cerebellopontine angle (CPA) area, facial (VI), acoustic and vestibular (VIII) nerves run across it to the internal auditory meatus, and the trigeminal (V) nerve is located at the apex of the cerebellopontine angle. The base region of the cerebellopontine angle contains the lower cranial nerves (IX, X, and XI) [6] . Consequently, the initial symptoms of ANs are often vague and imperceptible, especially in cases of small tumors. The general inspection offers little diagnostic information, resulting in misdiagnosis and mistreatment. Unilateral progressive hearing loss is the most common initial symptom of ANs, but ANs may have other uncharacteristic presentations. As a result of the atypical neurological presentations, patients are inclined to consult in neurology departments. Neurological symptoms may be caused by ANs compressing the brainstem or by raised intracranial pressure in the cerebellopontine angle. It is vital to detect, diagnose and treat small ANs at an early stage. We retrospectively investigated the clinical features of small ANs, primarily focusing on those with initial neurological symptoms, to improve awareness of the disease among neurologists.

Study Design and Setting
A retrospective cross-sectional study was performed in the Second Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, China. Approval was obtained from the Institutional Review Board and Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University. The need for individual consent was waived by the committee because of the retrospective nature of the study.

Study Participants and Data Source
Data were collected after review of the electronic medical records of all patients who initially presented to the neurology department and then were treated by the otolaryngology or neurosurgery department of the Second Affiliated Hospital of Wenzhou Medical University from January 2010 to January 2020.

Variables and Measures
Two investigators independently used the term "Acoustic neuromas (ANs)" or "Vestibular schwannomas" or a diagnosis code in the International Classification of Diseases, 10th edition, Clinical Modification of D33.3 in the electronic medical record discharge registration to obtain the basic information of patients who had presented with neurological symptoms and who were diagnosed with ANs. The following detailed information was extracted: age, sex, residential status, admission time, visit history, initial symptoms, clinical manifestations, type of treatment, discharge status, personalized medication, radiologic examination, postoperative complications and follow-up records.
Patients with stage 1 (in the internal auditory meatus) or 2 (in the internal auditory meatus and cerebellar pontine angle without contact with the brainstem) Koos classification [7] were included, based on each patient's initial magnetic resonance imaging (MRI) scan. Tumor size was measured with the longest diameter (mm) in the CPA [8] and classified according to the 1995 American Academy of Otolaryngology-Head and Neck Surgery guidelines [9] . Disagreements were resolved through consultation with a third experienced-investigator (CBB). The exclusion criteria were patients who had type 2 neurofibromatosis, Koos classification 3 or 4, and patients with incomplete or unavailable medical records as well as patients without follow-up records.

Statistical Analysis
No statistical inferences were conducted in this study. The proportion of clinical symptoms to the total was presented as percentages. Microsoft Excel was used to assist in gathering the data.

Results
We retrieved medical records, and a total of 102 patients were diagnosed with ANs during the study period. Patients in whom the initial symptoms were non-neurological manifestations (n = 63), Koos classification 3 or 4(n = 6), and patients with a pathological diagnosis of another tumor (n = 6), missing follow-up records or incomplete clinical data (n = 5) were excluded, resulting in a total of 22 patients (9 males, 13 females). Figure 1 demonstrates the sample inclusion and exclusion criteria.
Overall, patients were aged from 22 to 74 years, with an average age of 53.5 ± 13.2 years (Table 1), and 8 had ANs on the left side and 14 on the right side. The symptomatology was usually nonspecific and the average lag time for the diagnosis of ANs was (11.06 ± 11.27) months. Table 2 revealed that dizziness/vertigo was the most frequent initial neurological symptom (9/22), and headache was the second most common neurological symptom in our study (8/22) (One patent's initial presenting symptom was both dizziness and headache), occurring in the form of frontal, occipital, intermittentthrobbing or paroxysmal headache. The third most common initial neurological symptom was facial symptoms, such as numbness and pain. The remaining initial neurological symptoms included walking problems. The total clinical symptoms of the 22 patients accompanied by 6 cases of hearing loss, 7 cases of ear symptoms (5 tinnitus,1 aural fullness,1 deafness) and 3 cases of visual disturbances (Table 3). Upon neurological examination, 2 patients had optic nerve palsy, 1 had trigeminal nerve abnormalities, 1 had abducens nerve palsy, 4 had facial nerve abnormalities, 5 had auditory nerve abnormalities, 1 had ataxia, and 2 had nystagmus. The remaining 9 patients of the total 22 had a normal neurological examination in this study. With regard to the imaging scans,4 subjects had only CT scans of the brain, 6 had MRI only scans, and 12 underwent both CT and MRI scans. In our study, all of the patients underwent MRI to detect the extension of ANs during the follow-up. Seven patients in our study experienced surgery via the translabyrinthine approach, 6 underwent craniotomy via the retrosigmoid approach, and 8 underwent observation. One patient underwent surgery via a left suboccipital approach.   Representative Case Hg. His pain was measured by the visual analogue scale and was scored as grade 6. Neurological examination showed round, regular, equal pupils and sensitivity upon light reflex testing. Cranial nerve examination was negative as well as the Romberg test (-) and Heel-knee-tibia test (-). Initially, the proposed treatment was to reduce pain using 20 mg carbamazepine twice a day. In the follow-up period, the symptoms were alleviated slightly but still occurred continuously. A neurologist who supervised the case proposed an imaging examination. Mastoid CT: the left internal auditory canal was slightly widened compared with the normal meatus on the right (Fig. 2). MRI revealed a round mass with a size of 1.3 × 1.0 cm in the left CPA region (Fig. 3). The lesion was hypointense on T1-

Discussion
Acoustic neuromas are the most common type of tumor in the region of the internal auditory canal with a higher prevalence in females than in males [3] . Our study found the same trend, with a larger prevalence of ANs in women (n = 59.1%) than in men (n = 40.9%). Dizziness is a shared complaint among patients presenting to primary care physicians, accounting for 30% of people suffering at different points [10] . Dizziness is divided into four subtypes: vertigo, disequilibrium, presyncope, and psychological dizziness. Vertigo is a sensation of rotation or movement of one's self or of one's surroundings in any place, and vertigo is classified as peripheral or central [11] . In AN patients, vertigo strongly influences quality of life. The true incidence of vertigo in the AN patient population is controversial, from 10%--70% [12][13][14]. In our practice, vertigo is present in 41% of patients at baseline. When these patients consult in the neurology department, they are commonly first diagnosed with peripheral vestibular vertigo, such as benign paroxysmal positional vertigo, Meniere's disease, or persistent postural-perceptual dizziness. As they arise from the vestibular nerve, ANs can grow into the internal auditory canal and impinge on the eighth cranial nerve, cerebellum, or pons.
Furthermore, ANs can cause secondary hydrocephalus and vestibular changes, which can result in vertiginous episodes. However, we found that it is difficult to observe or detect vestibular abnormalities. The average lag time for diagnosis is 37.25 months. A previous study suggested that tumor size may be associated with the severity of vertigo [15] . Because ANs grow slowly and undergo sensory substitution, there is adequate time for the occurrence of vestibular compensation and adjustment. In addition, some have argued that the symptom of dizziness is related to patient age [16,17] . Nilsen.et.al explained that central compensation leads to a slight decrease in dizziness over time in patients with diagnosed AN and counteracts the effects of aging [18] . It is vital to detect vestibular dysfunction at the early stage of AN. In patients with non-specific vertigo, unexplained unilateral VHIT and VEMP asymmetry should alert neurologists to perform imaging [12] .
Headache is among the most common causes in patients seeking medical attention in neurology departments. Headache resulting from acoustic neuromas generally belongs to the category of secondary headache. To date, most studies have focused on headaches after surgery, including microsurgical resection and retrosigmoid craniotomy [19][20][21] . Patients with postoperative headache syndrome appear to be directly associated with the presence of occipital nerve damage and occipital nerve excision can provide relief [22] . Despite the connection between headache in patients with ANs and substantial physical and emotional burdens, this condition remains unnoticed. One study discovered that the prevalence of headache in patients was surprisingly 60%, with varying degrees of headache before treatment, and 19% recorded a positive history of migraine [23] . RyzenHman and colleagues suggested that headache was the second most common symptom in 17.6% of patients with small tumors [24] . In our study, headache was also the second most common neurological symptom in AN patents who consulted in the neurology department. Acoustic neuromas generally do not cause headaches until they are large enough to compress the fifth cranial nerve or until they cause obstructive hydrocephalus resulting from fourth ventricle effacement. Mechanisms of headache include increased intracranial pressure, venous outflow obstruction, and pain associated with dura sensitivity or meningeal vasculature as well as intracranial sensory nerves such as the trigeminal nerve, facial nerve, glossopharyngeal nerve, and vagus nerve. [25] . Another explanation for headache caused by small ANs is dural traction within the internal auditory canal. In addition, occipital neuralgia is a type of headache that is partly related to a peripheral nerve-mediated mechanism. In terms of neuroanatomical observations of the trigeminal system, C2 and C3 projections are to the ventral posteromedial nucleus rather than to the ventral posterolateral nucleus, leading to headaches with occipital origin extending to the V1 distribution [26] . The condition is often misdiagnosed as migraine, trigeminal neuralgia, or tension headache due to the different potential presentations of ANs; for example, there have been 5 cases where patients report that they were misdiagnosed with migraine, 1 case was tension headache.
Imaging is a crucial tool in the evaluation, treatment and management of patients with ANs, including magnetic resonance imaging (MRI) imaging and computerized tomography (CT). A previous study suggested that if the hearing threshold is worse than 70 dB, patient management should directly proceed to CT [27] . However, MRI with gadolinium enhancement is now widely accepted as the 'gold standard' inspection for acoustic neuromas [28] because it is superior for identifying soft-tissue structures, whereas CT can provide resolution of bone structures and detect moderate-large ANs. A further advantage of using MRI as the primary screening procedure is its ability to identify small tumors [29] .T1-weighted sequences of mucoceles reveal hypointensity of the mass, whereas T2weighted sequences show equal intensity or hyperintensity with significant enhancement. Some MRIs reveal a high signal intensity on both T1-weighted sequences and T2-weighted sequences because of the associated bleeding. Enhanced MRI scans show the most uneven patchy enhancement and ipsilateral auditory nerve thickening and strengthening, which are characteristics of neoplastic processes [30] . Therefore, MRI was the best diagnostic and detection method in our cohort study.
Three treatment options are available for AN patients: observation, radiotherapy (RT) and microsurgery (MS) via hearing preservation retrosigmoid or middle fossa approach or translabyrinthine approach. The choice of treatment depends on several criteria such as age, comorbidity, tumor size and location, hearing status, expected treatment outcomes and complications, and patient preference. For small ANs, especially in elderly patients, the "wait and see" controlling method has been advised [31] .The appropriate and proactive option for patients who hope for hearing preservation is microsurgery [32] or rehabilitation with translabyrinthine surgery and hearing aids. Multi-option management for small ANs has been found to be an effective strategy in terms of hearing outcomes [33] .
We recognize some limitations of this study. First, our study is a retrospective data analysis. All relevant information was documented from electronic medical records. Second, the investigation lacked complete information about the exact neurological outcomes because the patients were discharged from the Department of Otolaryngology or Neurosurgery, and they did not have a routine neurological examination. Furthermore, the follow-up time was not long enough to obtain the terminal outcomes, and some patients who underwent the "wait-and-see" did not continue follow-up to identify the delayed treatment.

Conclusions
Although the majority of patients with acoustic neuromas present with classic, progressive, unilateral hearing loss, the neurological symptoms of ANs are becoming more universal. As our findings confirmed, these atypical initial neurological symptoms are more frequent in small lateral neuromas.
Neurologists must consider the possibility of AN when patients with other etiologies of headache, vertigo, and facial symptoms and especially hearing loss and tinnitus present to the neurology department or neurological emergency department. The next step is referral to the ENT or neurosurgery department for investigative imaging and audiological examination. Therefore, a better understanding of this disease by neurologists, as well as otolaryngologists and neurosurgeons is essential for early diagnosis and prompt surgical treatments in order to avoid misdiagnosis and mistreatment.

Ethics approval and consent to participate
Approval was obtained from the Institutional Review Board and Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University. The need for individual consent was waived by the committee because of the retrospective nature of the study.

Consent for publication
Not applicable.

Competing interests
None.

Availability of data and materials
Anonymized and statistical information of all the participants was made available to and shared only among qualified investigators.

Funding
None.

Authors' contributions
Ke-Yang Chen drafting initial manuscript, manuscript revision, study design, data acquisition, data