Abstract
Background/Aim: Refractory rhinorrhea is common after total laryngectomy (TL). Because botulinum toxin injection and ipratropium bromide nasal spray have shown success in it, suggesting a hyperactive parasympathetic tone may play a role. Therefore, we sought to evaluate whether endoscopic posterior nasal neurectomy (ePNN) to include more nasal secretomotor fibers is a treatment option for laryngectomy-associated rhinorrhea. Patients and Methods: Laryngectomized patients with persistent rhinorrhea who underwent ePNN at both the middle and inferior meatus were enrolled. We evaluated the changes in 2-week Total Nasal Symptoms Score (TNSS) and rhinorrhea subscore over 6 and 12 months post ePNN treatment, as well as self-rated rhinorrhea using the visual analogue scale (VAS) at pretreatment and 12 months post-treatment. Adverse events, post-procedure medication reliance, and patient satisfaction were recorded. Results: Five males (mean age, 62.4 years) with elapsed time from TL of 97.56±89.91 months were identified. ePNN significantly improved the average rhinorrhea subscore of TNSS at six months (p=0.037, Wilcoxon sign-rank test) and twelve months (p=0.047) compared to baseline. There were marginally significant improvements between baseline and at 12 months for overall TNSS (6.60±2.30 to 2.00±1.22, p=0.056) and VAS for rhinorrhea (7.80±0.84 to 2.00±1.58, p=0.062). No adverse event was reported, and four patients had excellent outcomes. Conclusion: Endoscopic posterior nasal neurectomy is a safe and efficient alternative treatment for laryngectomy-associated rhinorrhea, with lasting improvement over one year. However, a large-scale study with more comprehensive measurements is needed to verify its long-term efficacy.
Total laryngectomy (TL) has shown promise in treating locally advanced laryngeal and hypopharyngeal cancers. However, it often leads to increased rhinological symptoms, especially rhinorrhea (1, 2). The pathophysiology of laryngectomy-associated rhinorrhea remains unknown (1, 2). Of interest, in contrast to other rhinology conditions, the inflammatory processes in the sinus mucosa of laryngectomized patients were paradoxically reduced (3). Despite these challenges, two studies have found treatments of botulinum toxin injection (4) and ipratropium bromide (IB) nasal spray (5) were beneficial in treating this condition. Because these drugs work by acting on the cholinergic synapse and blocking the release of acetylcholine, we hypothesized that the dysregulation of the autonomic nervous system might be involved in causing laryngectomy-associated rhinorrhea.
Endoscopic posterior nasal neurectomy (ePNN) and vidian neurectomy help control rhinorrhea by reducing the hyperactive parasympathetic ton (6-9). ePNN was preferred over vidian neurectomy because it provided comparable therapeutic results with fewer ophthalmologic complications, such as dry eye and keratitis (6-9). However, the results of ePNN could vary depending on the surgical method used. Takahara et al. (9) have shown that the number of branches of the posterior nasal nerve removed affected the outcome of the procedure. Bleier et al. (10) further suggested the management of the accessory posterolateral nerves in the middle- and inferior- meatus might also impact the effectiveness. A recent study on cryoablation for rhinitis otherwise demonstrated that treatment on middle and inferior meatuses was safe and showed promising short-term results (11). However, the impact of extending the extent of ePNN on laryngectomy-associated rhinorrhea has yet to be studied.
This feasibility study aimed to put insight into the long-term effects of ePNN on laryngectomy-associated rhinorrhea. We sought to follow up with participants for 12 months to assess the feasibility and efficacy of the procedure by analyzing multiple patient-reported symptom measurements.
Patients and Methods
Study design and patient eligibility. We retrospectively identified five laryngectomized patients with persistent rhinorrhea who underwent ePNN under general anesthesia between June 2020 and December 2021. This Institutional Review Board of Kaohsiung Veterans General Hospital approved this study (KSVGH 22-CT12-03).
Endoscopic findings and surgical procedures. The typical endoscopic findings of these patients are illustrated in Figure 1A, showing wrinkled and pale mucosa of the inferior turbinate and nasal septum.
The surgical procedures of endoscopic posterior nasal neurectomy. (A) The pre-surgical endoscopic view shows the edematous, pale, and wrinkled mucosa of the inferior turbinate (IT) and nasal septum (SP). (B) Several nerve fascicles (white arrowheads) traverse the perpendicular plate of the palatine bone within the middle meatus. (C) Nerve fibers (white arrowheads) are found within the inferior meatus (inferior turbinate bone marked with an asterisk). (D) The branch of the posterior nasal nerve (white arrowheads) is clearly seen after opening the periosteum covering the sphenopalatine artery (yellow arrowheads). IT: Inferior turbinate; SP: septum; PB: perpendicular plate of the palatine bone.
The procedure started with bilateral sphenopalatine nerve blocks being administered. A vertical mucosal incision was made behind the posterior fontanelle and a mucoperiosteal flap was raised to reach the ethmoidal crest of the palatine bone to expose the sphenopalatine foramen (SPF) and the sphenopalatine neurovascular bundle.
The entire perpendicular plate of the palatine bone and posterior inferior turbinate bone were exposed by further elevating the flap posteriorly up to the anterior wall of the sphenoid sinus and inferiorly to the nasal floor. After obtaining wide exposure of the entire posterolateral nasal wall, all visible neurovascular fascicles traversing through the palatine bone were removed to include both the middle and inferior meatus (Figure 1B and C).
Furthermore, the sphenopalatine artery (SPA) was carefully skeletonized by opening the covering periosteum, and its integrity was maintained to avoid bleeding. The main branches (e.g., anteroinferior branch, posterosuperior branch) of the posterior nasal nerve associated with the sphenopalatine artery were meticulously isolated from the SPA using the angled probe (Figure 1D) and then resected using the grasping forceps.
Monopolar suction diathermy was applied to control bleeding and cauterize the perpendicular foramina to reinforce the denervation. At the end of the procedure, the mucoperiosteal flap was re-draped to the lateral nasal wall and surgical® was placed over the mucosal edge for homeostasis.
Main outcomes measures. Measurements included 1) Overall rhinitis symptoms accessed using Total Nasal Symptoms Score (TNSS), which consists of 5 symptoms with 4-scaled answers, based on perception within 2 weeks. Rhinorrhea was specifically evaluated using the rhinorrhea subscore, which was measured at the pretreatment baseline and 6 and 12 months after ePNN. Patients rated the severity of symptoms as 0 (None), 1 (Mild), 2 (Moderate), or 3 (Severe); 2) Pre- and post-surgical 10-point visual analogue scale (VAS) for rhinorrhea; 3) Patient’s overall satisfaction categorized into three categories: ‘excellent’ indicating that patients were satisfied with the postoperative outcomes; ‘improved’ showing that patients noticed some improvement compared to preoperative status; or ‘failure’ showing that patients felt their rhinorrhea got worse or remained unchanged.
Statistical analysis. Continuous values are presented as mean±standard deviation (SD). The Wilcoxon Sign-Rank test was used to assess the outcome differences between different time points. All statistical analyses were performed using SPSS Statistics, version 21 (IBM Corp, Chicago, IL, USA). All statistical tests were two-sided, and statistical significance was set at p-value <0.05.
Results
Baseline characteristics. This study included five men with an average age of 62.4 years (range=50-67 years) and the mean±SD time elapsed from the total laryngectomy was 97.56±89.91 months (range=10-215.3 months) (Table I). Four patients had received a regular nasal spray with or without oral anti-histamine agents for at least two months leading up to the operation; two of them had been using the medications for over two years. The baseline data showed that the average total TNSS score was 6.6, with 3 points for rhinorrhea and a mean rhinorrhea VAS of 7.80±0.84 (Table I). The scores for the other TNSS subdomains were nasal congestion (1.0±1.0), nasal itching (0.2±0.45), sneezing (1.60±0.89), and difficulty sleeping (0.8±1.3), respectively.
Demographic and baseline features of 5 laryngectomized patients.
Effectiveness of ePNN. Figure 2 illustrates the mean values of TNSS, rhinorrhea subscore, and VAS of rhinorrhea assessed at each time point relative to those at baseline. The results showed that after ePNN, the TNSS improved from 6.6±2.3 at baseline to 2.0±1.0 six months after procedure (p=0.056, Table II). The improvement remained marginally significant at 12 months post-procedure (p=0.058). Further subdomain analysis showed significant improvement in the rhinorrhea subscore, which reduced from 3 to 1 at six months (p=0.037, Table II), and was stable at 12 months with an average score of 0.8 (p=0.047). There was also a marginally significant improvement observed in the rhinorrhea VAS between baseline (7.80±0.84) and 12 months post-procedure (2.00±1.58) (p=0.062, Table II).
Changes in total nasal symptoms score (TNSS), Rhinorrhea SubScore, and Rhinorrhea visual analogue scale (VAS) over time. Graphs of TNSS total score, rhinorrhea subscore, and rhinorrhea VAS at baseline, 6-month- and 12-month- post endoscopic posterior nasal neurectomy. The error bars represent the standard deviation.
Patient total nasal symptom score (TNSS), Rhinorrhea subscore, and Rhinorrhea visual analogue scale (VAS) after ePNN.
All of the patients had uneventful post-procedural courses after ePNN treatment. Four participants, except for the fourth patient listed in Table I, reported excellent outcomes. Two patients were able to stop using medical treatments, while the third patient (Table I) showed improvement in sneezing (score 3 at baseline to score 1 at six months- and 12 months-post-operatively) but still required reduced doses of antihistamine to relieve symptoms.
Discussion
The study found that ePNN could significantly improve the rhinorrhea subscore for laryngectomized patients over time. These results suggested that an overactive parasympathetic tone might be the possible cause of laryngectomy-associated rhinorrhea, and ePNN can be a safe, effective, and long-lasting treatment option for patients with this refractory condition.
Studies have consistently demonstrated an increased incidence of nasal symptoms in patients undergoing TL. Ayoub et al. (1) reported patients who have undergone TL are more likely to experience rhinorrhea, olfactory disturbance, postnasal drips, and nasal congestion than non-laryngectomized controls. Similarly, Sesterhenn et al. (2) revealed a significant difference in rhinorrhea in 104 patients before and after TL. The exact mechanisms behind the increased incidence of rhinorrhea are not fully understood, but some research suggested an increase in mucociliary clearance (MCC), a process by which the respiratory tract clears mucus from the airways, may be a contributing factor (12, 13). Deniz et al. (12) found laryngectomized patients have faster MCC than normal controls even after subgroup analysis for smoking and diabetes. Kocak and his colleagues (13) found the effect of TL on MCC appears to vary at different times, with a significant difference observed in MCC at postoperative six and 12 months but not at one month post-procedure compared to the pretreatment baseline. Contrary to expectations, local inflammation does not seem to be a significant factor. Skoloudik et al. (3) revealed that laryngectomized patients characteristically have significantly lower sinonasal inflammatory responses compared to controls.
There have been few reports on the treatment of laryngectomy-associated rhinorrhea, with a case showing success with intra-nasal botulinum toxin injection onto bilateral inferior turbinates (4), and a randomized investigation by Magardino et al. (5) found that using 0.06% ipratropium bromide nasal spray twice daily reduced the severity and duration of rhinorrhea (55% and 51%, respectively) compared to saline placebo. Because these agents target cholinergic synapses to attenuate the parasympathetic tone, we hypothesize that an imbalance between parasympathetic and sympathetic nasal innervation may partially contribute to the development of laryngectomy-associated rhinorrhea.
ePNN has been proven effective in controlling rhinorrhea in both allergic and nonallergic rhinitis by suppressing the parasympathetic efferent trafficking to the nasal mucosa (6-8). A preclinical investigation by Nishijima et al. (6) found that PNN suppressed allergic nasal secretion by deleting the nerve fiber, choline acetyltransferase, and neuropeptides without affecting the immune profiles of the nasal mucosa. However, a clinical study has demonstrated that ePNN improves rhinorrhea and hypersensitivity symptoms in allergic rhinitis by modulating local cytokine production (7). For nonallergic rhinitis, ePNN has been found to alleviate rhinorrhea by reducing nasal gland density and inflammation (8). The success of cryoablation in the middle meatus has provided further evidence of the efficacy of ePNN on rhinorrhea, with two prospective studies reporting significant improvements in rhinorrhea and nasal congestion and quality of life, with the effects lasting up to 9 months (14) and two years post-operation, respectively (15).
The treatment efficacy of ePNN for laryngectomy-associated rhinorrhea can be influenced by numerous factors, such as the number of branches removed during the procedure and the management of posterolateral neurovascular fascicles (9, 10). A study by Takahara et al. (9) found that patients with perennial allergic rhinitis who received more than two branch resections had significantly more improvements in TNSS than those who received fewer branch resections. This suggested that more nerve branch resections might offer better results for laryngectomy-associated rhinorrhea. The posterolateral neurovascular fascicles, which originated directly from the pterygopalatine ganglion or greater palatine nerve, contained postganglionic parasympathetic pathways that do not traverse the sphenopalatine foramen but instead traveled through the perpendicular plate of the palatine bone near the attachment of the inferior turbinate (10). Because of the high incidence ratio of approximately 90% in the normal population and that 40% of them were independent of the anastomosis from SPF (10), proper treatment of these fascicles might improve outcomes. Based on these findings, we theorized that the effectiveness of ePNN for laryngectomy-associated rhinorrhea might be improved by treating the middle and inferior meatus treatments, removing more parasympathetic nerve fibers. An observational study (11) supported this assumption by finding that multiple sites cryoablation significantly improved various patient-reported outcomes in chronic rhinitis patients despite a control group not being included for comparison.
Our findings suggest that ePNN may be a promising treatment option for laryngectomized patients suffering from persistent rhinorrhea, which could have significant implications for improving their quality of life. However, the limited sample size of our study is a significant limitation, and larger investigations are needed to better understand the long-term benefits and risks of ePNN for this patient population. Another limitation is that our study was retrospective, and we were unable to obtain data on the TNSS changes in patients who received medical treatment alone. Additionally, the unavailability of the drug IB in our study made it difficult to compare the efficacy of ePNN with standard medical therapy for this condition.
Conclusion
In conclusion, our study suggested that rhinorrhea could have a negative impact on laryngectomized patients. When medical therapy is ineffective, ePNN can provide significant relief from symptoms. The study showed that the benefits were durable for one year without significant adverse effects, making ePNN a potentially safe and effective strategy for treating laryngectomy-associated rhinorrhea.
Acknowledgements
This study was supported by Yen Tjing Ling Medical Foundation (CI-112-24) and Kaohsiung Veterans General Hospital (KSVGH110-048 and KSVGH112-013).
Footnotes
Authors’ Contributions
LYH designed the work; LYH and HCY acquired the data; LYH analyzed the data and provided statistical analysis; LYH drafted the manuscript. Both Authors reviewed the manuscript.
Conflicts of Interest
There are no conflicts of interest related to this study.
- Received July 4, 2023.
- Revision received August 7, 2023.
- Accepted August 8, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
