- Email: [email protected]
Neurofibromatosis of the larynx causing stridor and sleep apnea
Pediatric Otolaryngology: Principles and practice –Neurofibromatosis of the larynx causing stridor and sleep apnea Dhave Setabutr M.D., Myrza Perez M.D., Mai Thy Truong M.D., Craig W. Senders M.D., Brian K. Rubinstein M.D. PII: DOI: Reference:
S0196-0709(14)00103-3 doi: 10.1016/j.amjoto.2014.04.009 YAJOT 1384
To appear in:
American Journal of Otolaryngology–Head and Neck Medicine and Surgery
Received date: Accepted date:
24 March 2014 26 April 2014
Please cite this article as: Setabutr Dhave, Perez Myrza, Truong Mai Thy, Senders Craig W., Rubinstein Brian K., Pediatric Otolaryngology: Principles and practice –Neurofibromatosis of the larynx causing stridor and sleep apnea, American Journal of Otolaryngology– Head and Neck Medicine and Surgery (2014), doi: 10.1016/j.amjoto.2014.04.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT
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Pediatric Otolaryngology: Principles and practice – Neurofibromatosis of the larynx causing stridor and sleep apnea
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Dhave Setabutr, M.D.,1 Myrza Perez, M.D.,2 Mai Thy Truong, M.D.,3 Craig W. Senders, M.D.,1 Brian K. Rubinstein, M.D.4 1
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Department of Otolaryngology, UC Davis Medical Center, Sacramento, CA USA 2 Division of Pediatric Pulmonology, Kaiser Permanente, Roseville, CA USA 3 Department of Head & Neck Surgery, Kaiser Permanente, Santa Clara, CA USA 4 Department of Head & Neck Surgery, Kaiser Permanente, Roseville, CA USA
No financial disclosures.
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Conflict of interest: None.
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Keywords: Neurofibroma, larynx, sleep apnea
Corresponding author: Dhave Setabutr, M.D.
University of California – Davis Medical Center 2521 Stockton Blvd., Suite 5200 Sacramento, CA 95816 Email: [email protected]
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Abstract
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Background: Neurofibromatosis type 1 can rarely present in the larynx. Patients typically do not present with complete obstructive symptoms, but partial obstruction and stridor. We review
SC
our health centers’ case series of two patients, the first of whom presented with persistent sleep
NU
apnea post tonsillectomy and adenoidectomy, and the second that presented with noisy breathing. Additionally, we will review the literature on the management and treatment options for children
ED
Methods: Retrospective case review.
MA
with this rare clinical entity.
Case Report & Results: A two-year old male underwent a sleep endoscopy following persistent
PT
evidence of obstructive sleep apnea on polysomnography after initial tonsillectomy and
CE
adenoidectomy. Family elicited concerns about noisy breathing at night and accompanying video documented stridor while sleeping during monitored polysomnography. Flexible fiberoptic
AC
laryngoscopy in the operating room revealed what appeared to be a cystic mass along the right aryepiglottic fold causing deviation of the laryngeal introitus towards the contralateral side. Subsequent direct laryngoscopy and excisional biopsy revealed pathology results consistent with a plexiform neurofibroma. A six-month-old patient with sterter and stridor was found to have a laryngeal mass, subglottic stensosis, and progressive airway obstruction due to plexiform neurofirboma in the supraglottis, subglottis, and trachea.
ACCEPTED MANUSCRIPT We present a series of two patients incidentally diagnosed with neurofibromatosis type 1 by way of a laryngealneurofibroma and review the literature on management options. Both patients were
T
found to have accompanying café au lait spots. Both patients required tracheostomy for airway
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management, and one was successfully decannulated.
SC
Conclusion: Laryngeal neurofibroma is a rare anomaly that can manifest with airway obstruction. Both patients presented here subsequently were noted to have café au lait spots on
NU
physical examination. The Otolaryngologist should be reminded of this anomaly when
MA
evaluating a child with evidence of a submucosal laryngeal mass. We present our series including that of a patient whose diagnosis was prompted by persistent sleep apnea following
ED
tonsillectomy and with airway obstruction and subglottic stenosis due to neurofibroma. The treatment of choice is complete excision of the neurofibroma while maintaining functionality of
AC
CE
PT
the larynx. This can lead to successful decannulation.
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Introduction:
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Von Recklinghausen neurofibromatosis, NF1 has a reported incidence of 1 in 3300 live births and a prevalence of 1 in 4000.1 Patients can develop tumors of neural origin at any age and at
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any location. Laryngeal involvement, however remains rare.2 Patients should have 2 or more of
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the following findings to diagnose NF1: 1. Six or more café au lait spots:
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a. 1.5 cm or larger in postpubertal individuals b. 0.5 cm or larger in prepubertal individuals
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2. Two more neurofibromas of any type or 1 or more plexiform neurofibroma
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3. Axillary or groin freckling 4. Optic glioma
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5. Two or more Lisch nodules (benign melanoti iris hamartomas)
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6. A distinctive bony lesion: a. Dysplasia of the sphenoid bone b. Dysplasia or thinning of long bone cortex 7. A first degree relative with NF1 Neurofibromas consist of a proliferation of Schwann cells, fibroblasts and perineural cells.3 In the advent of more aggressive management of children with persistent sleep apnea following tonsillectomy and adenoidectomy, we present two cases of a laryngeal neurofibroma diagnosed at our hospital. One was found following sleep endoscopy after persistent sleep apnea after tonsillectomy and adenoidectomy, while the other presented in a more obstructive manner.
ACCEPTED MANUSCRIPT Case 1: A 2-year-old male presented to the Pediatric Otolaryngologic clinic with symptoms consistent
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with sleep-disordered breathing. The patient underwent elective tonsillectomy and adenoidectomy in April of 2013 uneventfully. There were no noted abnormal laryngeal findings
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on laryngoscopy for intubation by the Anesthesia team. Following full recovery, the parents reported persistent symptoms of sleep disordered breathing and a decision was made by the
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Pediatric Pulmonologist to pursue a formal sleep study. Review of the sleep study video
MA
recording revealed evidence of stridor during supine sleep and an associated polysomnogram with an elevated AHI of 4.8. Both the Pediatric Pulmonologist and Otolaryngology physicians
ED
therefore recommended sleep endoscopy. Flexible fiberoptic laryngoscopy was performed revealing what appeared to be a cystic mass along the right aryepiglottic fold causing deviation
PT
of the laryngeal introitus towards the contralateral side. Given the patient’s lack of significant
CE
symptoms for obstruction, the decision was made for elective marsupialization of what was initially considered a saccular cyst. Interestingly, post operatively, the parents electively
AC
provided further information stating that the patient was also having dyspnea with exertion. The following week the patient returned to the operating room suite for excision and marsupialization of the cyst. Direct laryngoscopy was performed and initially aspiration with an 18-gauge needle was attempted which did not result in decompression (Figure 1). Incisions were made with both cold steel and the OmniGuide® (OmniGuide Surgical, Cambridge, MA) carbon dioxide (CO2) laser without successful un-roofing of the suspected cyst. Ultimately it was determined to be a solid mass and a biopsy was taken using a cupped forceps. The patient was intubated and taken to the radiology suite for magnetic resonance imaging (MRI) (Figure 2). MRI revealed a solid mass from the level of the vallecula that extended to the false cord on the right. The patient
ACCEPTED MANUSCRIPT electively underwent a tracheostomy and formal excision via an open approach following pathology reports confirming plexiform neurofibroma. (Figure 3)
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Case 2:
A 6-month-old female was referred to the Otolaryngology Head & Neck Clinic for evaluation of
SC
noisy breathing since birth. The patient had no prior medical history evident and an
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uncomplicated birth history was reported. The child was feeding well and gaining weight appropriately without evidence of any cyanotic episodes. Primary concerns elicited by the
MA
family included coughing and gagging, especially at night. A flexible fiberoptic laryngoscopy was performed revealing a right arytenoid mass that was submucosal in nature. The bulge
ED
extended into the post-cricoid region, but the patient maintained a patent airway. The patient was subsequently referred to the Pediatric Otolaryngologist who proceeded with repeat flexible
PT
laryngoscopy and CT imaging (Fig. 3). Microdirect laryngoscopy with endoscopic excisional
CE
biopsy was performed with pathology consistent with plexiform neurofibroma. Incidentally,
AC
postoperatively it was noted the patient had presence of multiple small cafe a lait spots on physical exam. The patient was observed closely in the Otolaryngology clinic and underwent repeat evaluations in the operating room as well as an initial MRI after diagnosis of neurofibromatosis type 1 (Fig. 4). Repeat airway evaluation subsequently revealed persistent swelling in the glossoepiglottic fold on the right and a Grade I subglottic stenosis. Following balloon dilation and a repeat biopsy of the tracheal wall revealing extension of tumor the patient ultimately underwent a repeat MRI and subsequent elective tracheostomy within twelve months of the initial diagnosis. Clinical examination, imaging and repeat biopsy had now confirmed separate evidence of neurofibroma in the tongue and distal airway including partial obstruction
ACCEPTED MANUSCRIPT of the left bronchus. The patient has remained tracheostomy tube dependent at this time given its unresectable status.
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Discussion:
Stridor in the neonate and infant population is most commonly secondary to laryngomalacia
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followed by unilateral vocal cord paresis.4 Other entities including laryngeal tumors, although
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rare, can present in a similar fashion. Apart from the laryngeal neurofibroma presented in our series, reports of laryngeal hamartomas have been similarly reported.5 Congenital cysts are
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typically located in the supraglottis and glottis proper. With increasing growth these lesions can cause complete obstruction of the airway, requiring tracheostomy.6 Lesions that are less
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prominent may present in less prominent situations such as stridor during the day and may solely cause sleep apnea. Obstructive sleep apnea syndrome affects 1% to 4% of the pediatric
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population in the United States.7-12 Although historically it has been stated that tonsillectomy
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and adenoidectomy routinely cured obstructive sleep apnea in children, recent studies have shown otherwise. Up to 75% of children undergoing tonsillectomy and adenoidectomy have
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some degree of residual sleep-disordered breathing after surgery.13 The astute otolaryngologist should consider neurofibromas in addition to laryngomalacia in the examination of children with sleep apnea evident on polysomnogram and persistent sleep apnea after adenotonsillectomy. Flexible laryngoscopy in the clinic or sleep endoscopy should be employed in these more complicated situations. Fishman et. al. have found that sleep endoscopy demonstrably guided therapy better than awake endoscopy.14 Neurofibromas are typically associated with NF-1 and NF-2 or as solitary lesions noted sporadically.15 Von Recklinghausen first reported on neurofibromatosis in 1882 and it is an
ACCEPTED MANUSCRIPT autosomal dominant disorder.16 The prevalence of NF-1 has been reported as 1 in 2500-3000 patients, while NF-2 is even rarer with an incidence of 1 in 40,000 live births.17 Chevalier
Chinn et. al. recently reviewed the literature
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described in the pediatric population.18-19
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Jackson first reported the laryngeal neurofibroma in 1930 and it was not until 1940 that it was
identifying 62 pediatric cases of laryngeal neurofibroma in the world literature presented as
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either case reports or case series.17 The average age reported was 4.1 years, they most
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commonly were found on the aryepiglottic fold and stridor was present in 44% of the cases they
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reviewed.17
The mucous membranes of the upper part of the larynx are innervated by the internal branch of
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the superior laryngeal nerve.18-19 Anastomosis occurs between the internal branch of the superior laryngeal nerve and the recurrent laryngeal nerve in the region of the aryepiglottic fold and
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therefore leads to the propensity for presentation at this anatomic subsite.20 One of the two
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patients presented had a laryngeal neurofibroma along the aryepiglottic fold.
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Direct visualization is the initial step to the diagnosis and management of laryngeal neurofibromatosis. Depending upon age, some patients may undergo flexible laryngoscopy in the outpatient clinical setting prior to definitive evaluation in the operating room. Once initial visualization is made, diagnostic imaging can be important in differentiating between various lesions and extent of the previously visualized entity. In both cases presented, magnetic resonance imaging (MRI) was completed under sedation given their age to further elucidate the involvement of adjacent structures. An MRI can provide superior soft tissue characterization and may delineate additional unsuspected tumors in patients with NF1 and NF2.21 T1 weighted images demonstrate iso- to hyperintense lesions while T2-weighted images may be hyperintense.22 After imaging is obtained, definitive diagnosis via endoscopic biopsy is
ACCEPTED MANUSCRIPT preferred. Given the benign nature of the disease entity, near total resection with preservation of laryngeal function was performed in our patients and is typically the treatment of choice.
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Endoscopic removal of a laryngeal neurofibroma was first reported by Bagwell in 1990 with he
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use of a CO2 laser.23 The open approach was chosen in Case 1 to provide wider exposure and the ability to achieve a greater resection than what was anticipated endoscopically. The patient
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in Case 2 had advanced involvement and extent that removal was not deemed a beneficial
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intervention and tracheostomy was deemed appropriate. Airway management is crucial and both of our aforementioned patients underwent elective tracheostomy tube placement during their
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treatment process. It however has been established that regardless of technique the likelihood of recurrence is elevated because of the infiltrative nature of neurofibromatosis.24-25 Because of the
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infiltrative growth pattern and poor margin control it is important to maintain close follow-up
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with patients so that less invasive procedures performed endoscopically can potentially be
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utilized. Our patients are followed closely every 4 to 6 months within the first year. Historically, well-known causes of persistent sleep apnea in children have included adenoid
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regrowth, tongue-base prolapse, and laryngomalcia. Stridor is commonly derived from laryngomalacia, vocal cord paresis, subglottic stenosis and croup. Although rare, benign tumors of the larynx, specifically neurofibromas of the larynx may precipitate the diagnosis of neurofibromatosis type 1 or 2 and cause both of the aforementioned entities. With persistent sleep apnea, patients should undergo either a repeat laryngoscopy in the clinic if tolerable or a sleep endoscopy in the operating room. Although Mueller’s maneuver could be attempted in the pediatric population, the utility of it has been brought into question.26 Ultimately both modalities have both positives and negatives with the extent of muscle relaxation in each state, although one should be employed in those patients with persistent sleep apnea.
ACCEPTED MANUSCRIPT References:
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1. Rahbar R, Litrovnik BG, Vargas SO, Robson CD, Nuss RC, Irons MB, McGill TJ, Healy GB. The biology and management of laryngeal neurofibroma. Arch Otolaryngol Head Neck Surg. 2004 Dec;130(12):1400-6. 2. Moussali N, Belmoukari S, Elmahfoudi H, Elbenna N, Abdelouafi A, Gharbi A. An uncommon cause of dyspnea in children. Plexiform neurofibroma of the larynx. Arch Pediatr. 2013 Jun;20(6):629-32. doi: 10.1016/j.arcped.2013.03.011. Epub 2013 Apr 28. 3. Chen YC, Lee KS, Yang CC, Chang KC. Laryngeal neurofibroma: case report of a child. Int J Pediatr Otorhinolaryngol. 2002 Sep 2;65(2):167-70. 4. Dobbie AM, White DR. Laryngomalcia. Pediatr Clin N America. (60) 2013. 893-902. 5. Kşlal FM, Acar M, Acar B, Karahan F. Laryngeal fibrous hamartoma presenting with airway obstruction at birth. J Craniofac Surg. 2013 Jul;24(4):e383-4. doi: 10.1097/SCS.0b013e31829031fd. 6. Saha D, Sinha R, Pai RR, Kumar A, Chakraborti S. Laryngeal cysts in infants and children--a pathologist's perspective (with review of literature). Int J Pediatr Otorhinolaryngol. 2013 Jul;77(7):1112-7. doi: 10.1016/j.ijporl.2013.04.012. Epub 2013 May 15. 7. Brietzke SE, Gllagher D. The effectiveness of tonsillectomy and adenoidectomy in the treatment of pediatric obstructive sleep apnea/hypopnea syndrome: a meta-analysis. Otolaryngol Head Neck Surg 2006; 134:979-984. 8. Tauman R, Gulliver TE, Krishna J. et. al. Persistence of obstructive sleep apnea syndrome in children after adenotonsillectomy. J Pediatr 2006; 149:803-808. 9. O’Brien LM, Sitha S, Baur LA, Waters KA. Obesity increases the risk for persisting obstructive sleep apnea after treatment in children. Int J Pediatr Otorhinolaryngol 2006; 70:1555-1560. 10. Mitchell RB. Adenotonsillectomy for obstructive sleep apnea in children: outcome evaluated by pre and postoperative polysomnography. Laryngoscope 2007; 117-18441854. 11. Shott SR. Evaluation and management of pediatric obstructive sleep apnea beyond tonsillectomy and adenoidectomy. Curr Opin Otolaryngol Head Neck Surg 19:449-454. 12. Chan DK, Truong MT, Koltai PJ. Supraglottoplasty for occult laryngomalacia to improve obstructive sleep apnea syndrome. Arch Otolaryngol Head Neck Surg. 2012; 138(1):5054. 13. Bhattacharjee R, Kheirandish-Gozal L, Spruyt K. et al. Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study. Am J Respir Crit Care Med. 2010; 182(5):676-683. 14. Fishman G, Zemel M, DeRowe A, Sadot E, Sivian Y, Koltai PJ. Fiber-optic sleep endoscopy in children with persistent obstructive sleep apnea: inter-observer correlation and comparison with awake endoscopy. Intl J Pediatr Otorhinolaryngol 2013. May;77(5):725-5. Epub 2013 Feb 22.
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15. White AK, Smith RJ, Bigler CR, Brooke WF, Schauer PR. Head and neck manifestations of neurofibromatosis. Laryngoscope 96 (1986) 732-737. 16. von Recklinghausen FD, Uber die multipen Fibromeder Haut und ihre Beziehung zuden multiplen Neuromen, A Hirschwald, Berlin, Germany, 1882. 17. Chinn SB, Collar RM, McHugh JB, Hogikyan ND, Thorne MC. Pediatric laryngeal neurofibroma: case report and review of the literature. Intl Jour of Pediatr Otorhinolaryngol. 78(2014)142-147. 18. Plantet MM, Hagay C, DeMaulmont C, Mahe E, Banal A, Gentile A, et. al. Laryngeal schwannomas. Eur J Radiol 1995;21:61-6. 19. Nishino H, Ishikawa K, Ishida T, Kitamura K. A case of laryngeal neurinoma with neurofibromatosis 2. Auris Nasus Larynx 1999;26:95-9. 20. Nagato T, Katada A, Toshizaki T, Kunibe I, et. al. Laryngeal plexiform schwannoma as first symptom in a patient with neurofibromatosis type 2. Clinical Neurology and Neurosurgery. 112(2010)505-508. 21. Rahbar R, LItrovnik BG, Vargas SO, Robson CD, Nuss RC, Irons MB, McGill TJ, Healy GB. The biology and management of laryngeal neurofibroma. Arch Otolaryngol Head Neck Surg. 2004;130:1400-1406. 22. Nakahira M, Nakatani H, Matsumoto S. Neurofibroma of the larynx in neurofibromatosis: preoperative computed tomography and magnetic resonance imaging. Arch. Otolaryngol. Head Neck Surg. 127 (2001) 325-328. 23. Bagwell CE. CO2 laser excision of pediatric airway lesions. J. Pediatric Surg. 25 (1990) 1152-1156. 24. Garabedian EN, Ducroz V, Ayache D, Triglia JM. Results of partial laryngectomy for benigh neural tumors of the larynx in children. Ann Otol Rhinol Laryngol. 1999; 108:666-671. 25. Figi FA, Stark DB. Neurofibroma of the larynx: presentation of five cases. Laryngoscope 63 (1953) 652-659. 26. Stuck BA, Mauer JT. Airway evaluation in obstructive sleep apnea. Sleep Med Rev 2008; 12:411-436. 27. Hoover WB. Benign tumors of the larynx, their diagnosis and treatment. Surg. Clin. North Am. 20(1940)697-719.
ACCEPTED MANUSCRIPT Figure 1. Laryngeal view of mass along the aryepiglottic fold causing obstruction of the glottis introitus. Figure 2. Sagittal MRI slice of laryngeal mass on T2 fat-suppression highlighting the laryngeal neurofibroma.
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Figure 4. Axial MRI reveals a right sided laryngeal mass on T2.
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Figure 3. Laryngeal view post excision at time of decannulation revealing a remnant suture.
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Fig. 1
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Fig. 2
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Fig. 3
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Fig. 4
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ACCEPTED MANUSCRIPT
S0196-0709(14)00103-3 doi: 10.1016/j.amjoto.2014.04.009 YAJOT 1384
To appear in:
American Journal of Otolaryngology–Head and Neck Medicine and Surgery
Received date: Accepted date:
24 March 2014 26 April 2014
Please cite this article as: Setabutr Dhave, Perez Myrza, Truong Mai Thy, Senders Craig W., Rubinstein Brian K., Pediatric Otolaryngology: Principles and practice –Neurofibromatosis of the larynx causing stridor and sleep apnea, American Journal of Otolaryngology– Head and Neck Medicine and Surgery (2014), doi: 10.1016/j.amjoto.2014.04.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
RI P
T
ACCEPTED MANUSCRIPT
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Pediatric Otolaryngology: Principles and practice – Neurofibromatosis of the larynx causing stridor and sleep apnea
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Dhave Setabutr, M.D.,1 Myrza Perez, M.D.,2 Mai Thy Truong, M.D.,3 Craig W. Senders, M.D.,1 Brian K. Rubinstein, M.D.4 1
ED
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Department of Otolaryngology, UC Davis Medical Center, Sacramento, CA USA 2 Division of Pediatric Pulmonology, Kaiser Permanente, Roseville, CA USA 3 Department of Head & Neck Surgery, Kaiser Permanente, Santa Clara, CA USA 4 Department of Head & Neck Surgery, Kaiser Permanente, Roseville, CA USA
No financial disclosures.
AC
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Conflict of interest: None.
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Keywords: Neurofibroma, larynx, sleep apnea
Corresponding author: Dhave Setabutr, M.D.
University of California – Davis Medical Center 2521 Stockton Blvd., Suite 5200 Sacramento, CA 95816 Email: [email protected]
ACCEPTED MANUSCRIPT
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Abstract
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Background: Neurofibromatosis type 1 can rarely present in the larynx. Patients typically do not present with complete obstructive symptoms, but partial obstruction and stridor. We review
SC
our health centers’ case series of two patients, the first of whom presented with persistent sleep
NU
apnea post tonsillectomy and adenoidectomy, and the second that presented with noisy breathing. Additionally, we will review the literature on the management and treatment options for children
ED
Methods: Retrospective case review.
MA
with this rare clinical entity.
Case Report & Results: A two-year old male underwent a sleep endoscopy following persistent
PT
evidence of obstructive sleep apnea on polysomnography after initial tonsillectomy and
CE
adenoidectomy. Family elicited concerns about noisy breathing at night and accompanying video documented stridor while sleeping during monitored polysomnography. Flexible fiberoptic
AC
laryngoscopy in the operating room revealed what appeared to be a cystic mass along the right aryepiglottic fold causing deviation of the laryngeal introitus towards the contralateral side. Subsequent direct laryngoscopy and excisional biopsy revealed pathology results consistent with a plexiform neurofibroma. A six-month-old patient with sterter and stridor was found to have a laryngeal mass, subglottic stensosis, and progressive airway obstruction due to plexiform neurofirboma in the supraglottis, subglottis, and trachea.
ACCEPTED MANUSCRIPT We present a series of two patients incidentally diagnosed with neurofibromatosis type 1 by way of a laryngealneurofibroma and review the literature on management options. Both patients were
T
found to have accompanying café au lait spots. Both patients required tracheostomy for airway
RI P
management, and one was successfully decannulated.
SC
Conclusion: Laryngeal neurofibroma is a rare anomaly that can manifest with airway obstruction. Both patients presented here subsequently were noted to have café au lait spots on
NU
physical examination. The Otolaryngologist should be reminded of this anomaly when
MA
evaluating a child with evidence of a submucosal laryngeal mass. We present our series including that of a patient whose diagnosis was prompted by persistent sleep apnea following
ED
tonsillectomy and with airway obstruction and subglottic stenosis due to neurofibroma. The treatment of choice is complete excision of the neurofibroma while maintaining functionality of
AC
CE
PT
the larynx. This can lead to successful decannulation.
ACCEPTED MANUSCRIPT
T
Introduction:
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Von Recklinghausen neurofibromatosis, NF1 has a reported incidence of 1 in 3300 live births and a prevalence of 1 in 4000.1 Patients can develop tumors of neural origin at any age and at
SC
any location. Laryngeal involvement, however remains rare.2 Patients should have 2 or more of
NU
the following findings to diagnose NF1: 1. Six or more café au lait spots:
MA
a. 1.5 cm or larger in postpubertal individuals b. 0.5 cm or larger in prepubertal individuals
ED
2. Two more neurofibromas of any type or 1 or more plexiform neurofibroma
PT
3. Axillary or groin freckling 4. Optic glioma
CE
5. Two or more Lisch nodules (benign melanoti iris hamartomas)
AC
6. A distinctive bony lesion: a. Dysplasia of the sphenoid bone b. Dysplasia or thinning of long bone cortex 7. A first degree relative with NF1 Neurofibromas consist of a proliferation of Schwann cells, fibroblasts and perineural cells.3 In the advent of more aggressive management of children with persistent sleep apnea following tonsillectomy and adenoidectomy, we present two cases of a laryngeal neurofibroma diagnosed at our hospital. One was found following sleep endoscopy after persistent sleep apnea after tonsillectomy and adenoidectomy, while the other presented in a more obstructive manner.
ACCEPTED MANUSCRIPT Case 1: A 2-year-old male presented to the Pediatric Otolaryngologic clinic with symptoms consistent
RI P
T
with sleep-disordered breathing. The patient underwent elective tonsillectomy and adenoidectomy in April of 2013 uneventfully. There were no noted abnormal laryngeal findings
SC
on laryngoscopy for intubation by the Anesthesia team. Following full recovery, the parents reported persistent symptoms of sleep disordered breathing and a decision was made by the
NU
Pediatric Pulmonologist to pursue a formal sleep study. Review of the sleep study video
MA
recording revealed evidence of stridor during supine sleep and an associated polysomnogram with an elevated AHI of 4.8. Both the Pediatric Pulmonologist and Otolaryngology physicians
ED
therefore recommended sleep endoscopy. Flexible fiberoptic laryngoscopy was performed revealing what appeared to be a cystic mass along the right aryepiglottic fold causing deviation
PT
of the laryngeal introitus towards the contralateral side. Given the patient’s lack of significant
CE
symptoms for obstruction, the decision was made for elective marsupialization of what was initially considered a saccular cyst. Interestingly, post operatively, the parents electively
AC
provided further information stating that the patient was also having dyspnea with exertion. The following week the patient returned to the operating room suite for excision and marsupialization of the cyst. Direct laryngoscopy was performed and initially aspiration with an 18-gauge needle was attempted which did not result in decompression (Figure 1). Incisions were made with both cold steel and the OmniGuide® (OmniGuide Surgical, Cambridge, MA) carbon dioxide (CO2) laser without successful un-roofing of the suspected cyst. Ultimately it was determined to be a solid mass and a biopsy was taken using a cupped forceps. The patient was intubated and taken to the radiology suite for magnetic resonance imaging (MRI) (Figure 2). MRI revealed a solid mass from the level of the vallecula that extended to the false cord on the right. The patient
ACCEPTED MANUSCRIPT electively underwent a tracheostomy and formal excision via an open approach following pathology reports confirming plexiform neurofibroma. (Figure 3)
RI P
T
Case 2:
A 6-month-old female was referred to the Otolaryngology Head & Neck Clinic for evaluation of
SC
noisy breathing since birth. The patient had no prior medical history evident and an
NU
uncomplicated birth history was reported. The child was feeding well and gaining weight appropriately without evidence of any cyanotic episodes. Primary concerns elicited by the
MA
family included coughing and gagging, especially at night. A flexible fiberoptic laryngoscopy was performed revealing a right arytenoid mass that was submucosal in nature. The bulge
ED
extended into the post-cricoid region, but the patient maintained a patent airway. The patient was subsequently referred to the Pediatric Otolaryngologist who proceeded with repeat flexible
PT
laryngoscopy and CT imaging (Fig. 3). Microdirect laryngoscopy with endoscopic excisional
CE
biopsy was performed with pathology consistent with plexiform neurofibroma. Incidentally,
AC
postoperatively it was noted the patient had presence of multiple small cafe a lait spots on physical exam. The patient was observed closely in the Otolaryngology clinic and underwent repeat evaluations in the operating room as well as an initial MRI after diagnosis of neurofibromatosis type 1 (Fig. 4). Repeat airway evaluation subsequently revealed persistent swelling in the glossoepiglottic fold on the right and a Grade I subglottic stenosis. Following balloon dilation and a repeat biopsy of the tracheal wall revealing extension of tumor the patient ultimately underwent a repeat MRI and subsequent elective tracheostomy within twelve months of the initial diagnosis. Clinical examination, imaging and repeat biopsy had now confirmed separate evidence of neurofibroma in the tongue and distal airway including partial obstruction
ACCEPTED MANUSCRIPT of the left bronchus. The patient has remained tracheostomy tube dependent at this time given its unresectable status.
RI P
T
Discussion:
Stridor in the neonate and infant population is most commonly secondary to laryngomalacia
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followed by unilateral vocal cord paresis.4 Other entities including laryngeal tumors, although
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rare, can present in a similar fashion. Apart from the laryngeal neurofibroma presented in our series, reports of laryngeal hamartomas have been similarly reported.5 Congenital cysts are
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typically located in the supraglottis and glottis proper. With increasing growth these lesions can cause complete obstruction of the airway, requiring tracheostomy.6 Lesions that are less
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prominent may present in less prominent situations such as stridor during the day and may solely cause sleep apnea. Obstructive sleep apnea syndrome affects 1% to 4% of the pediatric
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population in the United States.7-12 Although historically it has been stated that tonsillectomy
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and adenoidectomy routinely cured obstructive sleep apnea in children, recent studies have shown otherwise. Up to 75% of children undergoing tonsillectomy and adenoidectomy have
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some degree of residual sleep-disordered breathing after surgery.13 The astute otolaryngologist should consider neurofibromas in addition to laryngomalacia in the examination of children with sleep apnea evident on polysomnogram and persistent sleep apnea after adenotonsillectomy. Flexible laryngoscopy in the clinic or sleep endoscopy should be employed in these more complicated situations. Fishman et. al. have found that sleep endoscopy demonstrably guided therapy better than awake endoscopy.14 Neurofibromas are typically associated with NF-1 and NF-2 or as solitary lesions noted sporadically.15 Von Recklinghausen first reported on neurofibromatosis in 1882 and it is an
ACCEPTED MANUSCRIPT autosomal dominant disorder.16 The prevalence of NF-1 has been reported as 1 in 2500-3000 patients, while NF-2 is even rarer with an incidence of 1 in 40,000 live births.17 Chevalier
Chinn et. al. recently reviewed the literature
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described in the pediatric population.18-19
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Jackson first reported the laryngeal neurofibroma in 1930 and it was not until 1940 that it was
identifying 62 pediatric cases of laryngeal neurofibroma in the world literature presented as
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either case reports or case series.17 The average age reported was 4.1 years, they most
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commonly were found on the aryepiglottic fold and stridor was present in 44% of the cases they
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reviewed.17
The mucous membranes of the upper part of the larynx are innervated by the internal branch of
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the superior laryngeal nerve.18-19 Anastomosis occurs between the internal branch of the superior laryngeal nerve and the recurrent laryngeal nerve in the region of the aryepiglottic fold and
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therefore leads to the propensity for presentation at this anatomic subsite.20 One of the two
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patients presented had a laryngeal neurofibroma along the aryepiglottic fold.
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Direct visualization is the initial step to the diagnosis and management of laryngeal neurofibromatosis. Depending upon age, some patients may undergo flexible laryngoscopy in the outpatient clinical setting prior to definitive evaluation in the operating room. Once initial visualization is made, diagnostic imaging can be important in differentiating between various lesions and extent of the previously visualized entity. In both cases presented, magnetic resonance imaging (MRI) was completed under sedation given their age to further elucidate the involvement of adjacent structures. An MRI can provide superior soft tissue characterization and may delineate additional unsuspected tumors in patients with NF1 and NF2.21 T1 weighted images demonstrate iso- to hyperintense lesions while T2-weighted images may be hyperintense.22 After imaging is obtained, definitive diagnosis via endoscopic biopsy is
ACCEPTED MANUSCRIPT preferred. Given the benign nature of the disease entity, near total resection with preservation of laryngeal function was performed in our patients and is typically the treatment of choice.
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Endoscopic removal of a laryngeal neurofibroma was first reported by Bagwell in 1990 with he
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use of a CO2 laser.23 The open approach was chosen in Case 1 to provide wider exposure and the ability to achieve a greater resection than what was anticipated endoscopically. The patient
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in Case 2 had advanced involvement and extent that removal was not deemed a beneficial
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intervention and tracheostomy was deemed appropriate. Airway management is crucial and both of our aforementioned patients underwent elective tracheostomy tube placement during their
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treatment process. It however has been established that regardless of technique the likelihood of recurrence is elevated because of the infiltrative nature of neurofibromatosis.24-25 Because of the
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infiltrative growth pattern and poor margin control it is important to maintain close follow-up
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with patients so that less invasive procedures performed endoscopically can potentially be
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utilized. Our patients are followed closely every 4 to 6 months within the first year. Historically, well-known causes of persistent sleep apnea in children have included adenoid
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regrowth, tongue-base prolapse, and laryngomalcia. Stridor is commonly derived from laryngomalacia, vocal cord paresis, subglottic stenosis and croup. Although rare, benign tumors of the larynx, specifically neurofibromas of the larynx may precipitate the diagnosis of neurofibromatosis type 1 or 2 and cause both of the aforementioned entities. With persistent sleep apnea, patients should undergo either a repeat laryngoscopy in the clinic if tolerable or a sleep endoscopy in the operating room. Although Mueller’s maneuver could be attempted in the pediatric population, the utility of it has been brought into question.26 Ultimately both modalities have both positives and negatives with the extent of muscle relaxation in each state, although one should be employed in those patients with persistent sleep apnea.
ACCEPTED MANUSCRIPT References:
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1. Rahbar R, Litrovnik BG, Vargas SO, Robson CD, Nuss RC, Irons MB, McGill TJ, Healy GB. The biology and management of laryngeal neurofibroma. Arch Otolaryngol Head Neck Surg. 2004 Dec;130(12):1400-6. 2. Moussali N, Belmoukari S, Elmahfoudi H, Elbenna N, Abdelouafi A, Gharbi A. An uncommon cause of dyspnea in children. Plexiform neurofibroma of the larynx. Arch Pediatr. 2013 Jun;20(6):629-32. doi: 10.1016/j.arcped.2013.03.011. Epub 2013 Apr 28. 3. Chen YC, Lee KS, Yang CC, Chang KC. Laryngeal neurofibroma: case report of a child. Int J Pediatr Otorhinolaryngol. 2002 Sep 2;65(2):167-70. 4. Dobbie AM, White DR. Laryngomalcia. Pediatr Clin N America. (60) 2013. 893-902. 5. Kşlal FM, Acar M, Acar B, Karahan F. Laryngeal fibrous hamartoma presenting with airway obstruction at birth. J Craniofac Surg. 2013 Jul;24(4):e383-4. doi: 10.1097/SCS.0b013e31829031fd. 6. Saha D, Sinha R, Pai RR, Kumar A, Chakraborti S. Laryngeal cysts in infants and children--a pathologist's perspective (with review of literature). Int J Pediatr Otorhinolaryngol. 2013 Jul;77(7):1112-7. doi: 10.1016/j.ijporl.2013.04.012. Epub 2013 May 15. 7. Brietzke SE, Gllagher D. The effectiveness of tonsillectomy and adenoidectomy in the treatment of pediatric obstructive sleep apnea/hypopnea syndrome: a meta-analysis. Otolaryngol Head Neck Surg 2006; 134:979-984. 8. Tauman R, Gulliver TE, Krishna J. et. al. Persistence of obstructive sleep apnea syndrome in children after adenotonsillectomy. J Pediatr 2006; 149:803-808. 9. O’Brien LM, Sitha S, Baur LA, Waters KA. Obesity increases the risk for persisting obstructive sleep apnea after treatment in children. Int J Pediatr Otorhinolaryngol 2006; 70:1555-1560. 10. Mitchell RB. Adenotonsillectomy for obstructive sleep apnea in children: outcome evaluated by pre and postoperative polysomnography. Laryngoscope 2007; 117-18441854. 11. Shott SR. Evaluation and management of pediatric obstructive sleep apnea beyond tonsillectomy and adenoidectomy. Curr Opin Otolaryngol Head Neck Surg 19:449-454. 12. Chan DK, Truong MT, Koltai PJ. Supraglottoplasty for occult laryngomalacia to improve obstructive sleep apnea syndrome. Arch Otolaryngol Head Neck Surg. 2012; 138(1):5054. 13. Bhattacharjee R, Kheirandish-Gozal L, Spruyt K. et al. Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study. Am J Respir Crit Care Med. 2010; 182(5):676-683. 14. Fishman G, Zemel M, DeRowe A, Sadot E, Sivian Y, Koltai PJ. Fiber-optic sleep endoscopy in children with persistent obstructive sleep apnea: inter-observer correlation and comparison with awake endoscopy. Intl J Pediatr Otorhinolaryngol 2013. May;77(5):725-5. Epub 2013 Feb 22.
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15. White AK, Smith RJ, Bigler CR, Brooke WF, Schauer PR. Head and neck manifestations of neurofibromatosis. Laryngoscope 96 (1986) 732-737. 16. von Recklinghausen FD, Uber die multipen Fibromeder Haut und ihre Beziehung zuden multiplen Neuromen, A Hirschwald, Berlin, Germany, 1882. 17. Chinn SB, Collar RM, McHugh JB, Hogikyan ND, Thorne MC. Pediatric laryngeal neurofibroma: case report and review of the literature. Intl Jour of Pediatr Otorhinolaryngol. 78(2014)142-147. 18. Plantet MM, Hagay C, DeMaulmont C, Mahe E, Banal A, Gentile A, et. al. Laryngeal schwannomas. Eur J Radiol 1995;21:61-6. 19. Nishino H, Ishikawa K, Ishida T, Kitamura K. A case of laryngeal neurinoma with neurofibromatosis 2. Auris Nasus Larynx 1999;26:95-9. 20. Nagato T, Katada A, Toshizaki T, Kunibe I, et. al. Laryngeal plexiform schwannoma as first symptom in a patient with neurofibromatosis type 2. Clinical Neurology and Neurosurgery. 112(2010)505-508. 21. Rahbar R, LItrovnik BG, Vargas SO, Robson CD, Nuss RC, Irons MB, McGill TJ, Healy GB. The biology and management of laryngeal neurofibroma. Arch Otolaryngol Head Neck Surg. 2004;130:1400-1406. 22. Nakahira M, Nakatani H, Matsumoto S. Neurofibroma of the larynx in neurofibromatosis: preoperative computed tomography and magnetic resonance imaging. Arch. Otolaryngol. Head Neck Surg. 127 (2001) 325-328. 23. Bagwell CE. CO2 laser excision of pediatric airway lesions. J. Pediatric Surg. 25 (1990) 1152-1156. 24. Garabedian EN, Ducroz V, Ayache D, Triglia JM. Results of partial laryngectomy for benigh neural tumors of the larynx in children. Ann Otol Rhinol Laryngol. 1999; 108:666-671. 25. Figi FA, Stark DB. Neurofibroma of the larynx: presentation of five cases. Laryngoscope 63 (1953) 652-659. 26. Stuck BA, Mauer JT. Airway evaluation in obstructive sleep apnea. Sleep Med Rev 2008; 12:411-436. 27. Hoover WB. Benign tumors of the larynx, their diagnosis and treatment. Surg. Clin. North Am. 20(1940)697-719.
ACCEPTED MANUSCRIPT Figure 1. Laryngeal view of mass along the aryepiglottic fold causing obstruction of the glottis introitus. Figure 2. Sagittal MRI slice of laryngeal mass on T2 fat-suppression highlighting the laryngeal neurofibroma.
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Figure 4. Axial MRI reveals a right sided laryngeal mass on T2.
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Figure 3. Laryngeal view post excision at time of decannulation revealing a remnant suture.
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