Sensorineural Hearing Loss as the Prominent Symptom in Meningeal Carcinomatosis

Sensorineural hearing loss (SNHL) has been reported rarely in patients with meningeal carcinomatosis (MC). We summarized the clinical data of eight MC patients with SNHL and 35 patients reported from publications. In the eight patients with SNHL, the medium onset age was 48 (range from 37 to 66) years and six (75%) were male. Seven (87.5%) suffered from headaches as the initial symptom, and they experienced SNHL during the first two months after the occurrence of headaches (0.5 to 2 months, average 1.5 months). The audiogram configuration was flat in three patients (37.5%) and showed total deafness in five patients (62.5%). The damage of cranial nerves VI (abducens) was observed in six patients (75%), and four patients (50%) had cranial nerves VII (facial) injury during the disease course. The percentage of damage of cranial nerves was higher than the patients without SNHL (VIth, 75.0% vs. 13.3%, p = 0.002 and VIIth 50.0% vs. 6.7%, p = 0.012). Four (50%) patients suffered from lung adenocarcinoma as primary tumor, two (25%) experienced stomach adenocarcinoma, one had colon cancer, and one patient was unknown. The symptom of SNHL improved after individualized therapy in four patients (focal radiotherapy and chemotherapy for three patients and whole brain radiotherapy for one patient), but all passed away from 2 to 11 months after diagnosis. Total deafness and flat hearing loss in audiogram were the common types of SNHL resulting from MC. MC patients with SNHL were more likely to suffer from the damage of other cranial nerves, especially to cranial nerves VI and VII. Treatment might improve SNHL, but not improve the case fatality rate.


Introduction
Meningeal carcinomatosis (MC), also known as carcinomatous meningitis or leptomeningeal carcinomatosis (LMC), is characterized by diffuse infiltration of cancer cells to the leptomeninges and cerebrospinal fluid (CSF) from solid tumors, commonly from lung and breast cancer, melanoma, and lymphoma [1,2]. The symptoms of MC are typically widespread, involving central and peripheral nervous systems.
The damage of cranial nerves III (oculomotor), IV (trochlear), VI (abducens), and VII (facial) occurred frequently during the disease course [3]. However, cranial nerves VIII (vestibulocochlear) lesions had been reported rarely in patients with MC [3]. In our study, we analyzed the clinical data of eight MC patients in our hospital, and 35 MC patients identified through a review of the literature with sensorineural hearing loss (SNHL) as the prominent symptom, and compared the clinical characteristics of patient with SNHL and without SNHL.

Patients
The clinical information of 38 MC patients in Department of Neurology, Xuanwu Hospital, Capital Medical University from September 2013 to September 2019, were col-lected, retrospectively. All patients underwent the lumbar puncture, and malignant cells were observed in CSF analysis to define the diagnosis of MC. We performed a long-term follow-up investigation for these 38 patients. Among these patients, 10 patients had the complaint of hearing loss. While 2 patients had a history of deafness for many years, the remaining 8 patients developed hearing loss during the disease course. All 8 patients were diagnosed as sensorineural hearing loss (SNHL) by pure tone audiometry (PTA) and were included in this study. Written informed consent was obtained from all patients' dependents for collection of clinical information and the publication of articles.

Identification of SNHL
Pure tone audiometry (with air and bone conduction thresholds) differentiated conductive from sensorineural loss and defined the severity of hearing loss, and all 8 patients met the diagnostic criteria of sensorineural hearing loss (SNHL). Audiometry results were analyzed using four contiguous frequency pure-tone average (500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz). All hearing loss was defined as any hearing loss above 20 dB, ranging from mild to complete in severity (Mild hearing loss, 20-

Clinical Data
We collected and analyzed the detailed clinical data, including demographics, clinical manifestation, auxiliary examination, treatments, and prognosis. All patients were followed 6 months to 3 years after discharge. Treatment effect was evaluated by the Modified Rankin score (mRS), progression-free survival (PFS), and overall survival (OS). The outcome of SNHL was evaluated by pure tone audiometry (PTA) with average thresholds ≥ 15 dB during follow-ups defined as efficacious. Then, we compared the clinical characteristics, such as the ratio of male to female, age, initial symptom, other symptoms, and damage of cranial nerves, of patients with and without SNHL.

Systematic Review and Data Extraction
We performed a PubMed search to identify the relative publications regarding meningeal carcinomatosis with sensorineural hearing loss by using the keywords of meningeal carcinomatosis (carcinomatous meningitis or leptomeningeal carcinomatosis) and sensorineural hearing loss. A total of 35 patients from 27 published articles were included in this study. We summarized the clinical data, including age, gender, and side of SNHL, as well as the primary tumor of MC.

Statistical Analysis
All statistical analyses were performed with the SPSS version 19.0 (SPSS Inc., Chicago, IL, USA). Univariate analysis of nominal and interval variables were performed using the Mann-Whitney test, McNemar test, and Pearson's Chi-squared or Fisher exact test, respectively.

Demographics
Among the 38 MC patients from our hospital, 20 (52.6%) were male, and the median onset age of MC was 45 (range from 15 to 66) years. Nine patients had a history of hypertension, five had diabetes, two patients had coronary heart disease, and one patient suffered from chronic valvulopathy. Of 38 MC patients, eight patients (21.1%) developed sensorineural hearing loss (SNHL). In these eight patients, the medium onset age of MC was 48 (range from 37 to 66) years and six of them (75%) were male. Compared the demographics information of patients with and without SNHL, there was no statistical difference of the gender and age between two groups (Table 1).
Eight patients developed SNHL in early stage of disease (six with bilateral SNHL and two with right sided SNHL), seven (87.5%) suffered from headaches as the initial symptom. The patients experienced SNHL during the first two months after occurrence of the headaches (0.5 to 2 months, average 1.5 months). The damage of cranial nerves III (oculomotor) occurred in two patients (25%), cranial nerves VI (abducens) in six patients (75%), and cranial nerves VII (facial) in four patients (50%), and the percentage of damage of cranial nerves was higher than the patients without SNHL (VIth, 75.0% vs. 13.3%, p = 0.002 and VIIth 50.0% vs. 6.7%, p = 0.012).

Auxiliary Examination
Subjective pure tone audiometry (PTA) and the air conduction thresholds of eight patients were shown in Table 2. The audiogram configuration was flat in three patients (37.5%) and showed total deafness in five patients (62.5%).
Brain gadolinium-enhanced MRI showed different degrees of meningeal reinforcement in 26 (68.4%) patients, and for the patients with SNHL, brain MRI revealed that the thickening and enhancement of both vestibulocochlear nerves in four (50%) patients (cases 2, 4, 6, and 7). All these four patients with VIIIth nerve involvement developed bilateral SNHL, and the magnitude of hearing loss was worse than those patients without VIIIth nerve enhancement on brain MRI (Table 2). Among these four patients, the patterns of hearing loss was total deafness in three patients and another was flat.

Treatment and Prognoses
Most patients were treated with chemotherapy or radiotherapy according to the different condition. The patients were followed up 1 month to 1 year through consultation or telephone calls after discharged; five patients were lost to follow-up and the remaining (33 patients) had accomplished. Despite chemotherapy and/or radiotherapy, 28 (73.7%) patients' condition quickly deteriorated, and they passed away between 1 and 6 months after diagnosis; the remaining died between 6 months and 1 year after diagnosis.
The median PFS was 3.35 months (95% CI 2.91-4.73 months), and the median OS of all patients was 5.25 months (95% CI 4.80-6.63 months). Considering deaths from all causes, 29 patients died from dyscrasia or neurologic involvement caused by MC, and others died of acute coronary syndrome (two patients), severe pneumonia (one patient) or acute cerebral hemorrhage (one patient).
For the patients with SNHL, symptoms of hearing loss were improved after therapy in 4 (50%) patients (focal radiotherapy and chemotherapy for three patients (case 1, 5 and 8) and whole brain radiotherapy for one patient (case 3)). The median PFS was 2.25 months (95% CI 1.19-5.31 months), and the median OS of MC patients with SNHL was 4.30 months (95% CI 3.52-7.08 months).

Systematic Literature Review
As seen in Table 3, the clinical data of 35 MC patients with SNHL reported in the literature were collected . The age was 61 (42, 77) years and ratio of male to female was 4:3. In total, 71.4% of patients developed bilateral SNHL. Hearing loss as the initial symptom was found in eight patients (22.9%) and it often accompanied by symptoms of vertigo (24 patients, 68.6%), tinnitus (10 patients, 28.6%) and unsteadiness (13 patients, 37.1%). Damage of cranial nerves VIIth was not common in MC patients with SNHL, and seven patients (20%) suffered from facial palsy during the disease course. Moreover, brain MRI revealed swelling and increased signal intensity on T2WI/FLAIR images of unilateral or bilateral vestibulocochlear nerves in 10 patients (28.6%) and involvement of internal auditory meatus (IAM) in 17 patients (48.6%).
In terms of the primary tumor leading to MC, lung cancer (22.9%, 8/35), esophagus adenocarcinoma (14.2%, 5/35), and gastric cancer (14.2%, 5/35) were the major causes related to the development of MC. In addition, we collected the treatments and outcomes of MC patients with SNHL from publications. Treatment options were very limited. A majority of patients continued to deteriorate, and only two cases responded well to the treatments of a combination of radiation therapy and chemotherapy [25,31].

Discussion
MC, defined as the invasion of subarachnoid spaces by malignant cells from a primitive cancer, is a rare and complex neurological disorder. It tends to be more susceptible to elderly and middle-aged patients, which extensively affects nervous systems [3]. SNHL is an atypical and uncommon symptom in patients with MC. In the present study, we collected the clinical information of eight MC patients suffering from SNHL during the disease course. In total, 87.5% patients presented with headaches as the initial symptom. Hearing loss was often the subsequent symptom after headaches, with an interval of 1.5 months. Moreover, MC patients with SNHL were more likely to develop the damage of other cranial nerves, especially to the cranial nerves VIth and VIIth, but fewer problems on urinary retention, as well as limb weakness and numbness.
We summarized the clinical information of a total of 35 MC patients with SNHL reported in the literature . A majority of patients suffered from bilateral SNHL; fewer developed one-sided hearing loss. As for the primary tumor leading to MC, lung cancer was the main cause, followed by esophagus adenocarcinoma, and gastric cancer. Due to limited access to audiogram data of some of the literature, the type of SNHL from most publications was total deafness. In our study, the audiogram configuration was flat in three patients (37.5%) and showed total deafness in five patients (62.5%), which was consistent with the literature reports.
For the treatment of MC, a combination of radiotherapy and intrathecal chemotherapy were the first-line therapy. However, disease severity and rapid deterioration of MC contributed to a poor prognosis. The median survival of untreated patients was about 4-6 weeks, and in some patients can be prolonged to 4-6 months for survival after aggressive treatment [3,21]. In our study, though half of patients had improved symptoms of SNHL after treatment, the median OS was only 5.05 months. However, most encouragingly, two cases reported by de Mones del Pujol E and Nakashima K et al. responded very well to the treatments of radiation therapy associated with chemotherapy (Methotrexate or Pembrolizumab) [25,31]. Thus, further studies need to focus on the rare MC cases with good prognosis, and explore the best individualized treatment to prolong the survival time of patients.

Conclusions
SNHL is an atypical symptom in MC. Total deafness and flat hearing loss in audiogram were the common types of SNHL caused by MC. MC patients with SNHL were more likely to suffer from the damage of cranial nerves, especially to cranial nerves VIth and VIIth. Treatments might improve SNHL, but not improve the case-fatality rate. Thus, we should be alert to the possibility of MC in patients with SNHL, and the suspected patients will benefit from early brain MRI, cytology in CSF, as well as the tumor screening. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study and written informed consent has been obtained from the patients and their family to publish this paper.

Data Availability Statement:
Data is contained within the article.