Characteristics of mucosal glottic wave analyzed with HSDI- kymography, regional FFT, and red-color pattern after recurrent respiratory papillomatosis treated with laser surgery and intra-lesion bevacizumab injection

Raul M. Cruza,b , Krzysztof Izdebskia,b,c* (corresponding author) , Yuling Yanc

aOtolaryngology, Head & Neck Surgery, Kaiser Permanente Medical Center, Oakland, CA, USA

bPacific Voice and Speech Foundation, San Francisco, CA, USA

cBioengineering, Santa Clara University, Santa Clara, CA, USA

ABSTRACT

Recurrent Respiratory Papillomatosis (RRP) is a devastating disorder- especially in a performing professional voice user. The mainstay of treatment is based on immaculate serial removal of regrowing papillomas, usually with a laser. Repetitive laser excisions can cause significant scarring and webbing. The risks of post-operative sequela are exponentially increased with anterior location of papilloma clusters. The resultant dysphonia is not amenable to physiological voice therapy protocols. Additional or adjunctive treatments are eagerly sought by patients to avoid complications. Many of these treatments remain unproven. Recently, bevacizumab (Avastin) has been advocated as potentially useful. Consequently, we report a case treated with KTP lasering of papillomas with adjunctive intralesional bevacizumab injections. Current outcome of the case is analyzed with both traditional LVS and High Speed Digital Imaging (HSDI).

Keywords:papilloma, bevacizumab = Avastin®, laser surgery, HSDI, laryngo-videostroboscopy, vocal folds, professional voice user

1. INRODUCTION

Recurrent respiratory (laryngeal) papillomatosis (RRP) is a devastating disease usually requiring long-term repeated meticulous surgical removals. The high recurrence rates are associated with staggering costs and often lead to post-operative scarring of the vocal fold(s) resulting in different types of dysphonia1-3. To improve surgical outcomes, and to reduce the potential risk of scarring, medical therapies are often given concurrently4-9. These have included, α-interferon given intravenously, intralesional Cidofivir injections, vaccines to DNA viruses and mumps, oral indole 3-carbinaol, Cimetidine, or proton pump inhibitors, or with Celecoxib & Erlotinib combination therapy. Most recently adjuvant intralesional bevacizumab (Avastin) injection coupled with the use of 532-nm pulsed potassium titanyl phosphate (KTP) laser10 and adjuvant Gardasil injection protocol coupled with CO2 laser removal11,12. Ironically, to date, all these adjuvant therapies produce disappointing or only marginal improvement12. The basic surgical debulking techniques are often effective when aggressive but may result in tissue scarring and webbing, reducing the mucosal wave in a devastating complication to the professional voice user1,2,4,11.

Hoping to improve laser surgical results, our patient elected to couple bevacizumab intralesional injections with pulsed KTP lasering of the lesions. The hope was to potentially reduce the size of recurrences (and resultant amount of lasering), reduce the frequency of recurrences, and even induce complete remissions. We reviewed surgical results objectively with laryngovideostroboscopy (LVS) and with advanced HSDI technology and analysis of obtained images. This plan, utilizing an unproven investigational medication and the most advanced diagnostic imaging technology available was of significant potential value to a professional voice user very concerned about voice outcome.

2. CASE REPORT

Approximately three years ago, the lead singer of an alternative rock/hip-hop band was involved in an altercation in which he was choked. He noted a resulting loss of upper vocal range and occasional voice breaks. After three months
he sought medical consultation and was initially told he had a vocal fold nodule. Subsequent referral to our Voice Disorder Clinic after an additional month, led to a provisional diagnosis of recurrent respiratory papillomatosis (See Figure 1.)

Figure 1: Location of papilloma clusters in the anterior commissure as seen on diagnostic evaluation. This still was taken from a LVS exam.

This was confirmed by the ensuing MDL biopsy and KTP laser removal of the papillomas. He has had five additional laser procedures performed at intervals of three, five, three, four, and two months. The last three procedures were accompanied by submucosal vocal fold injection of bevacizumab. Approximately one ml of 25-mg/ml solution was injected under the location of papilloma removal and any areas of anterior commissure involvement. Since his last MDL, he has remained disease free for 13 months. While able to maintain a full performance schedule, he subjectively reports a slight loss of vocal power especially in his lower pitches. At regular intervals including postoperative visits, he underwent routine LVS studies as previously described11. In addition, at the last follow-up appointment, he was examined using the Kay-Pentax HSDI system (Model 9710, Montvale, NJ, USA) obtaining transoral visual images of the glottis during production of the most comfortable sustained pitch production. F0 levels above the most comfortable pitch levels were not examined as the patient reported his comfortable and lower pitch levels were more troublesome than higher pitches when singing. A 90-degree transoral rigid scope inserted without topical anesthesia was used to record images at 2000 frames/second with 512 x 512 image resolution. The collected data comprising 8000 consecutive frames was subjected to subsequent detailed analysis including kymography, point FFT, and red-color analysis.

3. RESULTS

Visual inspection of the glottis area either by conventional stroboscopy or by HSDI did no showed any visible papilloma clusters. (See Figure 2 R)

Figure 2: No visible papilloma clusters per LVS (L) or HSDI (R)

Characteristics of the mucosal wave were observed in both exams, but glottal area wave function was calculated exclusively from the HSDI and details of voice initiation and termination were observed only in the HSDI recordings.
Visual inspection suggested asymmetrical mucosal wave documented by both LVS and HSDI systems, but HSDI provided objective documentation of vibratory phase differences and gave more detailed assessment of specific areas of the vocal fold with reduced mucosal wave amplitude. Additionally, while glottic competence with full vocal fold approximation was noted on traditional LVS, HSDI revealed a subtle lack of full contact between the vocal folds.
Kymography analyzes motion by extracting a time sequence of a single scan lines from consecutive frames of video and provides analysis of aperiodicity, left-to-right vocal fold asymmetry, cycle-to-cycle variability, and frequency & phase differences between the vocal folds. Kymographic analysis was performed using four areas of segmentation of which three corresponded to the location of the papilloma at last surgery and the fourth location corresponded to the posterior portion of the vibrating vocal folds (Figure 3).

Figure 3: Kymographic analysiis showing reduced amplitue of the glottic cycle on the R TVC, but the differences in frequancy are negligible.

Results showed only mild out of phase vibratory activity with mildly reduced amplitude of the mucosal wave in the anterior portion of the glottis, the area with highest preoperative concentration of the papilloma clusters.

Point FFT analysis (Figure 4) showed reduction in F0 in the area of the last operating field vis a vis non-affected areas.

Figure 4: Point FFT analysis showed only mnimal differences between the vibratory activity of the L and the R (operated) VF

Red-color analysis was performed (Figure 5) since normal laryngeal mucosa shows as light tissue and affected tissue, papilloma, edema) and scarring correlated with increased vascularization showing predominance of red tint. No significant (but a non-statistically obtained values) observation was made between the operated and non-operated field, though the operated area was more “red” than the non-operated area.

Figure 5: Red color analysis showing 5 % difference between the operated (R, R=679% ) and non-operated upon vocal fold (L, R=64%)

4. Summary and Conclusions

We do not have sufficient data to claim efficacy of bevacizumab in the treatment of RRP of the larynx. However, we can conclude that in this case of a professional performing voice, the anterior glottis location of papilloma could have severe consequences to his performance abilities. Following six serial surgeries with the final three procedures combined with intra-lesion bevacizumab injections, his disease free interval has extended to 13 months with no recurrence noted on recent exam with LVS and HSDI. Moreover, HSDI showed minimal and acoustically insignificant asymmetry in the vibratory pattern within and between the operated and non-operated portions of the vocal folds. This is a rewarding outcome, especially given his prolonged disease free interval and preserved singing voice. This case also demonstrates the trials and tribulations of caring for a professional vocalist afflicted with this chronic and potentially devastating condition. We will continue to follow him closely to ensure early detection of recurrent disease.

5. ACKNOWLEDGEMENTS

We wish to thank Ms. Emma Marriott and Ms. Laura Vaughan for their editorial work of this manuscript. Research on this subject was supported in part by PVSF (www.pvsf.org ) internal funding and from SCU Bioengineering Department (Dr. Yan, www.scu.edu).

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