Figure 12–1. Fixation of the right vocal fold secondary to cricoarytenoid joint fixation in a 53-year-old patient diagnosed with rheumatoid arthritis and receiving methotrexate.

Based on the aforementioned, most of the reports describe bilateral cricoarytenoid joint involvement in both acute and chronic RA. In the acute phase of inflammation, patients complain of neck pain, difficulty in swallowing and talking, referred pain to the ears, and hoarseness, whereas in the chronic phase patients present more with shortness of breath and obstructive airway symptoms. The report by Copeman exemplifies the various degrees of cricoarytenoid involvement in three RA patients.²⁸ In the first case, RA was moderate in intensity and patient reported hoarseness and difficulty in speaking loud, at times associated with shortness of breath. These symptoms were secondary to impaired mobility of the left vocal fold with evidence of peri-arthritic inflammation around the arytenoid cartilage that resolved with medical treatment. In the second case there was total fixation of the vocal fold with edema of the periarytenoid area that resulted in frequent attacks of hoarseness and shortness of breath. In the third case there was complete fixation of both vocal folds resulting in dysphonia and stridor. It is worth noting that despite the high rate of cricoarytenoid joint involvement in patients with RA, which ranges between 15 to 75%,^36–38 patients may not have vocal fold fixation and may not suffer from vocal symptoms. This can be attributed to the insidious onset of the disease that allows ample of time for patients to adapt. It is also important to note that impaired mobility of the vocal folds is not always secondary to CAJ involvement but may also be secondary to involvement of the recurrent laryngeal nerve or to cervicomedullary compression due to cervical spine involvement.^39–40 Demyelination of the recurrent laryngeal nerve with subsequent paralysis leading to stridor has been reported by Darke et al.³⁹

Other laryngeal findings in patients with RA include rheumatoid nodules. Laryngeal rheumatoid nodules were first described by Raven et al in 1948.⁴¹ Since then rheumatoid nodules have been reported in the larynx at various sites.^42–44 These are more likely to appear at pressure sites or areas subject to repeated trauma. To that end there have been reports of rheumatoid nodules in the cricoarytenoid joint, periarytenoid area, and vocal folds with the mid-membranous portion being the most common site.⁴⁵ Other authors have reported the presence of these nodules in the posterior third of the vocal folds. Woo et al in 1994 reported two cases of RA who presented with hoarseness secondary to involvement of the vocal folds. In the first case, there was evidence of decreased amplitude of the mucosal waves secondary to bilateral submucosal nodules that were resected through a cordotomy approach. The second case had bilateral subcordal masses that were also treated surgically.⁴⁴ Given the ubiquity of reports on laryngeal rheumatoid nodules, the American Rheumatism Association has included the presence of submucosal nodules in the criteria for classification of rheumatoid arthritis.⁴⁶ These lesions consist of focal areas of fibrinoid necrosis surrounded by palisading histiocytes with outer rims of fibrosis. See Figure 12–2. The treatment of these lesions is primarily aimed at restoring the function of the vocal folds while preserving its anatomical structure. When there is reduction in the mucosal waves resulting in dysphonia, surgical removal thru a cordotomy approach is often recommended.

Bamboo nodes of the vocal folds are also rare laryngeal manifestations of RA in addition to other autoimmune diseases. These have been described initially by Hosako et al in 1993 as transverse yellowish or whitish submucosal lesions of the vocal folds.⁴⁷ See Figure 12–3. These lesions occur mainly in patients with autoimmune diseases, primarily systemic lupus erythematosus, Sjogren’s syndrome, and rheumatoid arthritis. Unlike rheumatoid nodules which are well-rounded submucosal lesions, bamboo nodes are frequently fusiform in shape and have ill-defined margins that are hard to delineate.^48–51 These lesions consist of central necrosis surrounded by macrophages and inflammatory cells. In 2007 Immerman and Sulica reported a 24-year-old female who presented with hoarseness and effortful voice production that were secondary to bilateral vocal fold bamboo nodes. The patient was managed with systemic steroids with no recurrence at 4 months follow-up.⁵² A year later Hilgert et al reported another case of RA who had hoarseness with multiple submucosal cysts that were treated by logopedic speech therapy.⁵⁰ The management of these lesions varies according to the authors’ preference and availability of resources. One option is conservative and focuses on controlling the confounding variables and risk factors for dysphonia such as laryngopharyngeal reflux disease and allergy, in addition to vocal therapy for rehabilitation of the phonatory behavior.⁵⁰ The second option is surgical removal of these lesions under suspension microlaryngoscopy.

It is important to note that all the aforementioned laryngeal pathologies, namely, rheumatoid nodules and bamboo nodes seen on telescopic examination can be supplemented with stroboscopic imaging which provides further information on the malleability and behavior of the vocal fold cover. It can also assist in diagnosing mild mucosal changes and subtle submucosal lesions. Wojnowski et al described decrease in vibration amplitude and mucosal irregularities in two out of the three RA subjects.⁶ Hojna et al reported features of hypofunctional dysphonia confirmed by high-speed digital imaging and videokymography in RA patients with moderate activity of the disease.¹⁵ Similarly in a recent investigation by Puerta et al using videolaryngostrobosopy in patients with RA, abnormal findings were reported in almost two-thirds of the 36 patients examined. The most common findings were signs and symptoms of laryngopharyngeal reflux (64%), followed by muscle tension dysphonia (31%), and presence of bamboo node in one patient.²⁰

Other important diagnostic tests include computerized tomographic evaluation of the larynx and in particular of the cricoarytenoid joint and cricothyroid joint. The most common radiologic findings include narrowing of the joint, prominence, ankylosis, erosion, and increased soft tissue densities. The rate of CAJ abnormalities varies with the sensitivity of the imaging technique and resolution used. The figure can reach up to 72% with the presence of osseous destruction in close to 50% of the cases.⁵³ Other reported findings include sublaxation of the joint, joint irregularities, space narrowing, and joint irregularities.²² Interestingly, the presence of radiologic changes in the CAJ does not always correlate with the presence of symptoms. In a study by Grossman et al close to half of patients with radiologic findings were asymptomatic.¹⁶ On the other hand the study by Amernick in 2007 and the one by Hojna et al in 2015 showed a correlation between vocal disorders and radiologic changes.^5,15 It is also worth mentioning that not only the CAJ is amenable to involvement by RA but also the cricothyroid joint (CTJ). In a study by Berjawi et al on 11 patients with advanced RA receiving methotrexate, the CTJ abnormalities were investigated using high-resolution computerized tomography. The results indicated CTJ abnormalities in 10 out of the 11 patients. The involvement was mainly unilateral, with narrowing of the joint space (defined as decrease in volume) present in more than 2/3 of the cases. Other radiologic findings included changes in density (45.5% of the cases) and thickening of the vocal folds (27.3% of cases). See Figures 12–4, 12–5, 12–6, and 12–7. It is worth noting that these radiologic changes in the CTJ were commensurate with a decrease in vocal range in almost half the subjects.⁵⁴

The management of laryngeal manifestations of RA requires a multidisciplinary approach. The internist, the otolaryngologist, as well as the speech-language pathologist play a role. The internist needs to control the systemic disease using steroids in order to mitigate the development of permanent changes within the affected joints. Corticosteroids may also be delivered via intra or periarticular injections.^55,56 Dockery et al has reported five cases of RA with laryngeal manifestations who were treated successfully by systemic and intra-articular steroids. The symptoms of hoarseness, dysphagia, and shortness of breath improved following speech therapy. The authors highlighted the importance of early diagnosis and intervention in these cases.¹³ Simpson et al has reported 6 cases of RA who were treated successfully with periarticular injections and had adequate improvement. The authors highlighted the many added values of this mode of therapy, namely, the ease of performance, short duration of the procedure, and minimal training needed to perform such an injection.⁵⁵

In advanced cases that do not respond to steroid therapy, the use of methotrexate or Leflunomide might be indicated.^19,57 In these refractory cases securing the airway obstruction by performing a tracheotomy is often required. This is followed by a lateralization procedure to widen the glottis inlet permanently. Endoscopic laser arytenoidectomy is the most commonly used procedure with very promising results. Variations on its theme have been described over the last two decades, such as laser posterior partial cordectomy by Dennis and Kashima in 1989, endoscopic laser medial cordectomy by Crumley in 1993, or subtotal arytenoidectomy by Remacle et al in 1996.^58–60

Laryngeal Manifestations of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the deposition of autoantibodies in different sites in the body, namely, joints, pleura, kidneys, central nervous system, and less commonly in the larynx.⁶¹ Since the first description of laryngeal involvement in patients with SLE by Sacarpelli et al in 1959 there has been a growing number of cases in the literature.^62–64 Today laryngeal pathology is estimated to be present in one out of three patients with SLE with a reported incidence that ranges between 0.3 to 30% based on numerous studies.^63,64 The symptoms are many and can range from foreign body sensation, mild change in voice quality and throat discomfort, to life-threatening difficulty in breathing. In a review by Teitel et al of 97 patients with SLE, the most common reported symptoms were hoarseness, throat discomfort, dysphagia, and dyspnea.⁶⁵ Other rare manifestations include acute airway obstruction and respiratory distress often necessitating tracheotomy. Three possible mechanisms for laryngeal involvement have been suggested: One is the deposition of the immune complexes in the laryngeal structures such as muscles and mucosa,^65,66 second, is involvement of the recurrent laryngeal nerve either by reduction in its vascularity or by compression, last, is infection and diffuse chondritis of the thyroid cartilage and cricoid.^65,67–74 It is important to note that symptoms related to the laryngopharyngeal complex may not always prevail during the active stage of the disease. Korbet et al in 1984 reported a case of hoarseness and dyspnea in a patient with inactive SLE. The early detection of laryngeal involvement allowed adjustment of steroid dosage and thus spared the patient undue complications.⁷⁵

When phonatory symptoms are present, laryngeal findings are neither rare nor isolated.⁶⁵ These may range from mucosal changes such as edema, inflammation, and ulceration at the level of the arytenoids and or aryepiglottic folds, to vocal fold paralysis and life-threatening necrotizing vasculitis. These findings may be evident on radiologic imaging as shown in the two cases reported by Ozcan et al, where CT scan of the larynx showed thickening of the laryngeal mucosa at the aryepiglottic fold with evidence of arytenoid asymmetry.⁷⁶ Mucosal inflammation is usually the most common clinical finding in patients with SLE and may be present in almost one-third of the cases. In 1992 Martin et al in their review of 158 cases of SLE reported 4 cases of upper airway obstruction.⁷⁷ In rare cases patients may present with epiglottitis, diffuse mucosal edema, irregular shaped epiglottic mass, and/or superficial mucosal ulcerations as reported by Toomey et al.⁷⁸ Acute epiglottitis can be the sole presentation of the disease as reported by Charuvanij and Houghton in a 5-year-old girl who developed sepsis.⁷⁹ The most common pathogens in epiglottitis in patients with SLE are pneumococcal and Haemophilus influenzae.^79–81 When nonspecific laryngeal findings are present in patients with SLE, other causes such as infection laryngitis, smoke-induced injury, allergic angioedema, irradiation, and phonotrauma should be ruled out.^82,83 Less frequently encountered etiology presenting with laryngeal edema is relapsing polychondritis which results in laryngeal perichondritis often occurring with other connective tissue disorders and complicated by tracheomalacia.⁷⁸ Other laryngeal manifestations of SLE include the presence of vasculitis resulting in a polypoid or nodular lesion.^84,85 In cases of vasculitis, biopsy shows evidence of fibrinoid necrosis and inflammatory infiltrates with disruption of the submucosal arterial walls. Other reported findings include perivascular lymphocytic infiltrates, thickening of the vessel walls, and hyalinization.^62,86

Phonatory symptoms in patients with SLE can also be secondary to the presence of rheumatoid nodules or bamboo nodes in addition to the aforementioned laryngeal inflammatory changes. In 1993, Hosako et al was the first to describe the presence of a transverse yellowish submucosal lesion of the vocal folds in a patient with SLE in reference to its similarity to the bamboo and its nodes. The lesion was described as a “bamboo joint-like lesion.”⁸⁷ In 1996 Tsunoda and Soda reported a 51-year-old case who developed “bamboo joint-like nodules” as a result of lupus laryngitis, and improved on systemic therapy.⁸⁸ Five similar cases have been reported in the literature and the term was later modified to “vocal fold bamboo nodes” by Murano et al in 2001.⁸⁹ Another report on bamboo nodes was reported by Todic et al in 2014.⁹⁰ See Table 12–1. Although these lesions occur primarily in patients with SLE, other underlying autoimmune diseases such as Sjogren’s disease and progressive systemic sclerosis must be ruled out.^87,88,92,93 The management strategy for these lesions mandates steroid injection as a first line of treatment and surgery as the second line for those who fail to achieve the desired voice outcome. Schwemmle in 2007 was the first to report local steroid injection as a first line of therapy in a 43-year-old female patient with Sharp syndrome and bilateral bamboo nodes.⁹⁴ The injection was made locally in the vocal folds 4 times before taking the patient to the operating room for suspension microlaryngoscopy and excision. Intraoperatively there was fixation of the mucosal cover to the submucosal structures.⁹⁴

Vocal fold paralysis is also another less frequently encountered laryngeal manifestation of SLE that can result in dysphonia, aspiration, and dyspnea. There are many reports of unilateral and bilateral vocal fold paralysis that can be temporary or permanent with a prevalence rate of 11% according to Teitel et al.^{65-75,82,95,96} In 2001 Nanke et al was the first to report a case of overlap syndrome who had respiratory distress secondary to bilateral cricoarytenoid joint arthritis which mandated a tracheotomy.⁹⁷ In 2008 Lee et al has reported a 41-year-old female diagnosed with SLE who presented with hoarseness and dyspnea. Fiberoptic examination showed fixed left vocal fold in the paramedian position. The paralysis was confirmed using electromyography of the left thyroarytenoid muscle that revealed positive sharp waves and fibrillation at rest. Hypothesized etiologies included vasculitis of the vasa nervosa of the recurrent laryngeal nerve, thrombolytic events, pulmonary hypertension, and cricoarytenoid arthritis.⁹⁸ Karim et al has reported a 52-year-old female who presented with acute airway obstruction secondary to cricoarytenoid arthritis as the only presentation of SLE following several years of quiescence.⁹⁹ In 2009, Hughes and Hill reported a case of isolated left vocal fold palsy in the absence of cranial nerve deficit in a patient with SLE who developed hoarseness. The patient was treated with immunosuppression to partial avail.¹⁰⁰ A year later Jayachandran et al reported a 17-year-old girl with active SLE who presented with hoarseness and shortness of breath. On laryngeal exam she had bilateral vocal fold paralysis with oral ulcerations. The patient was treated with intravenous hydrocortisone with significant improvement in her condition.¹⁰¹ In 2013 Leszczynski and Pawlak-Bus also reported a case of a 38-year-old female patient diagnosed with SLE who presented with bilateral vocal fold paralysis. Her condition was complicated by the morbidities of other diseases, namely, myasthenia gravis and Hashimoto thyroiditis. She was managed with pulsed steroid intake and immunosuppressive therapy.¹⁰² It is important to note that vocal fold paralysis may also be drug induced as reported by Hari et al following the intake of Hydralazine.¹⁰³ Other airway manifestations of SLE include subglottic stenosis that again can be life threatening. Smith and Ferguson have reported a 63-year-old female with active SLE who presented with shortness of breath and dyspnea on exertion. Endoscopy revealed subglottic stenosis that failed medical therapy and dilatation and required tracheotomy.¹⁰⁴

With respect to treatment, unlike patients with rheumatoid arthritis, SLE patients with cricoarytenoid joint involvement respond to steroid therapy⁶³ and few may require a tracheotomy to secure the airway. The lack of mucosal changes such as inflammation or necrosis on laryngeal examination and the lack of response to steroid treatment make the etiology of arthritis and muscle inflammation unlikely. The presence of dilated pulmonary vessel on chest X-ray or echocardiography in the absence of any laryngeal lesions favors recurrent laryngeal nerve compression as the cause of the paralysis.

Laryngeal Manifestations of Sjögren’s Syndrome

Sjögren’s syndrome (SS) is an autoimmune disease characterized by the presence of lymphocytic infiltrates within the exocrine glands resulting in systemic dryness that affects several systems in the body.^105,106 These include the central nervous system, the respiratory and digestive systems, in addition to many organs such as the lacrimal and salivary glands. The clinical picture may vary from non-specific symptoms of ocular and oral dryness, to marked exacerbation of sicca-related symptoms.^107,108 When Sjögren’s syndrome coexists with other autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and scleroderma, it is referred to as secondary, otherwise it is considered primary. Secondary SS accounts for 60% of the cases whereas the overall prevalence of primary SS is 1% of the adult population, an underestimated figure given the large number of underdiagnosed cases.¹⁰⁸ Sjögren’s syndrome affects mainly women in their 4th and 5th decades and seems to be exacerbated by occupational factors and lifestyle. Pierce et al has reported in a large survey of 101 patients with SS that had vocally demanding jobs and exposure to inhalant irritants and dust, which are considered as significant risk factors that worsen the laryngeal symptoms in affected patients.¹⁰⁹ Other risk factors reported in this study are excessive jaw tension, neck tension, and history of lower airway disease such as pneumonia and bronchitis.

The etiology of SS remains unknown and many factors have been implicated such as viral infections and hormonal disturbances in addition to genetic predisposition.^110,111 A large array of antibodies has been incriminated in the pathophysiology of this disease among which is the antinuclear antibody (ANA) and rheumatoid factor (RA). The autoantibodies to the minor and major salivary glands and in particular to the glandular tissues in the laryngopharyngeal mucosa can cause severe reduction in the amount of saliva produced resulting in significant complaints. Irrespective of the culprit, the laryngeal symptoms in patients with SS are similar. These are usually gradual in onset with progression toward chronicity in 83% of the cases. The overall current prevalence of voice disorders can range between 41.9% up to 59.4% compared to a figure of 6.6% seen in the normal population.^109,112,113 In a study by Ruiz et al of 31 patients with SS, the disease was secondary in 87% of the cases. Associated symptoms of dysphagia and dysglossia were present in 70.9% and 35.4% of the cases, respectively.¹¹³ The prevalence of these symptoms correlated with the severity of the disease but not with age, gender, duration of the disease, and its associated co-morbidities.¹⁰⁹ When present, the laryngeal symptoms of Sjogren’s syndrome affect the quality of life to variable degrees. In a study by Heller et al of 11 patients with SS, the Voice Handicap Index scores were mild to moderate with a mean of 43 and a SD of 23.¹¹⁴ Similarly Salturk et al has reported a higher Voice Handicap Index score in 10 women with SS patients compared to controls.¹¹⁵ In a large study by Tanner et al on 101 patients with SS who completed interviews using Voice-Related Quality of Life (V-RQOL) and the general health-related quality of life short Form 36 (SF-36) questionnaire, the results indicated that patients with vocal symptoms had a higher burden on quality of life, and those with specific symptoms such as throat clearing, soreness, and vocal discomfort had significantly reduced SF-36 scores.¹¹⁶ The results of this large cohort study not only supports the strong association between autoimmune diseases and voice but also substantiates the mild to moderate reduction in quality of life of patients with SS irrespective whether patients had voice disorders or not. Nevertheless, despite the aforementioned, only a few affected individuals seek medical attention (15.8%). This has been attributed either to the fact that the overall disease severity may mask or shadow the vocal symptoms, or to the shortage in education and level of awareness regarding the management modalities readily available for the treatment of these symptoms.

The symptoms in patients with SS are mainly related to physical sensations in the laryngopharyngeal complex. These include throat clearing, throat dryness, hoarseness, increased effort to talk, vocal fatigue, and dysphagia.^{113,114,117,118} The phonatory symptoms are not always substantiated by disturbances in the acoustic parameters as shown on spectral and speech analysis. Heller et al has reported a significant difference in the fundamental frequency and perturbation parameters in her study of 11 patients with SS compared to normative values.¹¹⁴ Similarly Ruiz et al has reported abnormalities in one or more of the acoustic parameters in 28 patients with SS.¹¹³ These findings were further corroborated by Ogut et al who has reported a significant difference in all the voice quality parameters except for the noise to harmonic ration (NHR) in patients with SS compared to controls.¹¹⁸ According to the authors, these findings were attributed to the aperiodic vibration of the vocal folds and to inadequate adduction. On the other hand, Salturk et al failed to show any significant difference in any of the acoustic or aerodynamic measures in his study on 10 patients with SS.¹¹⁵

In parallel with the aforementioned phonatory and swallowing symptoms, patients with Sjogren’s syndrome exhibit diverse laryngeal pathology. These include impaired mobility of the vocal folds secondary to fixation of the cricoarytenoid joint or recurrent laryngeal nerve palsy,¹¹⁹ presence of granulomatous and non-granulomatous nodules,^120–124 vocal nodules,¹²⁵ lymphocytic infiltrates,¹²⁶ lesions such as bamboo nodes,¹²⁷ dryness and crusting, and erythema and edema. In 2005 Seve et al reported a rare case of a 50-year-old female with SS who presented with dysphonia and oral dryness. On videostroboscopy she had cricoarytenoid joint (CAJ) arthritis with joint fixation that was managed successfully with prednisolone.¹²⁸ Arthritis of the CAJ has also been previously reported by Montgomery in 1963 and by Gresham and Kellaway in 1958.^129,130 Prytz reported the case of a 31-year-old female teacher who had persistent dysphonia following removal of bilateral vocal fold nodules. The patient was later diagnosed with SS and the recurrence of her vocal symptoms was attributed to edema and hyperemia of the vocal folds that resolved with medical treatment.¹²⁵ Ito et al reported a case who had recurrent swelling of the false vocal folds that necessitated repeated excisions of the false cords to alleviate obstructive airway symptoms. The pathology revealed atrophic glandular changes and cystic dilation suggestive of SS.¹³¹ Korst has also reported another laryngotracheal manifestation of SS in a 61-year-old women who complained of dyspnea and stridor that was attributed to a circumferential narrowing of the subglottic region 3 cm below the true vocal folds. The patient was managed by subglottic resection and reconstruction of the mucosal membrane after excision of the stenotic segment. The pathology was consistent with mucosal associated lymphoid tissue lymphoma.¹²⁶

The edema and erythema of the laryngeal mucosa most commonly seen in patients with SS can be secondary either to the effect of the disease itself on the seromucinous glands of the laryngeal mucosa or to precipitation and worsening of pre-existent or silent laryngopharyngeal reflux disease.^{113,125,127,128,132–135} Patients with SS are more predisposed to reflux symptoms because of deficiencies in their anti-reflux barriers in addition to the inherent susceptibility of the laryngeal and pharyngeal mucosa to the refluxate material. The limited buffering of the saliva in patients with SS makes the esophagus more vulnerable to acid. Confounded with further reduction in acid clearance, there is exacerbation and worsening of the reflux symptoms as reported by Belafsky and Postma in 2003.¹³² In a study by Ogut et al on 77 patients with SS, both the Reflux Symptoms Index and Reflux Finding Scores were statistically significantly higher compared to the control group.¹¹⁸

Despite the description of an array of laryngeal pathologies in patients with SS, in many instances patients present with vocal symptoms in the absence of frank or gross laryngeal pathology on endoscopy. Instead patients present with subtle abnormalities hardly perceived on routine examination. Using the Stroboscopy Evaluation Rating Form (SERF), Salturk et al has reported that the smoothness, straightness, regularity, and closure of the vocal folds in patients with SS differed significantly from normal subjects.¹¹⁵ Similarly in a study by Ruiz et al on 31 subjects with SS, 41.9% of whom had dysphonia, vocal fold mucosal changes and reduced amplitude have been reported in 90% of the cases and altered nasopharyngeal and laryngeal mucosa in 77.41% of the cases. The most common mucosal changes were hyperemia and thick secretions. In parallel with the phonatory symptoms there was dysphagia in 70.9% and abnormalities in swallowing mechanism in 90.3%.¹¹³ A study by Heller et al revealed mild reduction in the laryngeal function with normal vibratory behavior and mobility of the vocal folds.¹¹⁴

Treatment of SS is frustrating both to the patient and to the physician. There is no cure for this disease and the treatment consists of controlling the symptoms. Most commonly used regimens include topical lubricants, use of nebulizers, and cholinergic medications. The use of nebulizers has gained popularity because of the known effect of local hydration on the voice in addition to systemic hydration. Hydration correlates with the phonatory threshold pressure (PTP) which is the pressure needed to set the vocal folds into vibration, and subsequently with the phonatory effort. Subjects who are well hydrated have lower PTP and need less effort to phonate compared to subjects who are poorly hydrated. Similarly, osmotically induced dehydration as reported by Chan and Tayama and by Finkelhor et al increases vocal fold stiffness and viscosity.^136,137 This correlation has also been demonstrated in regard to systemic dehydration.^138–141 As the vocal fold surface consists of water and mucus, humidifiers, nasal breathing, and use of nebulizers assist in replenishing surface tissue hydration which secures epithelial cell homeostasis and helps protect the existing mucus of the vocal folds from external irritants.^142–144 Various concentrations of nebulized saline have been prescribed for the treatment of autoimmune related symptoms of the upper and lower airway.^145–149 Tanner et al has recently reported the effects of nebulized saline in a longitudinal study on eight patients with SS. Cepstral Spectral Index of Dysphonia improved by 20% during treatment and worsened with withdrawal. Patients on treatment had less vocal effort, less laryngeal dryness, and better voice production. Thus, nebulized saline has been recommended by the authors as a topical hydration treatment for the vocal folds that can be used temporary and intermittently.¹⁵⁰

Laryngeal Manifestations of Relapsing Polychondritis

Relapsing polychondritis (RP) is an inflammatory disease that affects cartilaginous structures and connective tissues in the body leading to functional disorders and disabilities.¹⁵¹ It has multiple systemic manifestations among which are arthritic, vascular, and ocular, often leading to degenerative changes and deformities. It was first described as polychondropathy by Jaksch-Wartenhorst in 1923 and later coined as relapsing polychondritis in view of the relapsing and episodic nature of the disease.¹⁵² All ethnic groups are affected and the prevalence is around 3.5 cases per million, affecting almost equally men and women between their fourth to sixth decades of life. Its association with cancer has been reported in two cases by Quinsat et al in 1989.¹⁵³ The etiology is believed to be autoimmune based on the high prevalence of other autoimmune diseases present in almost one out of three patients and on the high titers of circulating antibodies to type II collagen in two out of three affected individuals.¹⁵⁴ In a study by Buckner et al, T cells against CII were identified in patients with RP and the cloning of which was specific for CII peptide 261–273.¹⁵⁵ To that end, Navarro et al has reported the successful use of oral CII in the treatment of a child with relapsing polychondritis.¹⁵⁶ More so, studies by Lang et al and later by Zeuner et al have documented the presence of HLA-DR4 antigen in patients with RP.^157,158

In view of its overlap with many autoimmune diseases, the diagnosis of the otolaryngologic manifestations of RP can be masked by non-specific symptoms. The otolaryngologic manifestations are many with chondritis being the hallmark feature of the disease and a key diagnostic feature. It may present in one out of two patients, and is usually limited to the ear, nose, and laryngotracheal structures. The ears are affected first in 40% to 90% of the cases. Patients usually complain of ear pain, redness, and severe tenderness upon slight touching which often is mistaken for an acute infection.^159,160 The recurrent bouts of inflammation often lead to collapse, calcification, and cauliflower deformity in 10% of the cases.¹⁶¹ Audiovestibular manifestations can also be present in up to 40% of the cases with a sudden onset of sensorineural hearing loss. Nasal chondritis is the second most common presentation of this disease. It affects primarily the dorsum or bridge of the nose with subsequent, atrophy of the cartilage, and nasal septal collapse. Nasal crusting, pain, and epistaxis are the primary symptoms of nasal chondritis which is present in one out of four patients with RP. Repeated episodes of nasal inflammation may result in destruction of the nasal cartilage with subsequent saddle nose deformity. Systemic vasculitis has been reported to be a poor prognostic indicator of nasal involvement

Laryngotracheal manifestations of RP can occur in one out of two patients along the course of the disease often leading to fatal complications.¹⁶² The associated symptoms are usually present in 25% of the cases as reported by Isaak et al in 1986 in his cohort study of 112 patients. When the larynx is affected patients often report a change in voice quality, cough, difficulty in breathing, wheezing, neck pain at the site of the laryngotracheal complex, and choking.¹⁶⁰ What is alarming is that the airway symptoms may be the initial symptoms in affected patients. Childs et al reported three cases of laryngeal manifestation of relapsing polychondritis, all of whom presented with airway symptoms that necessitated aggressive medical therapy and or surgical intervention.¹⁶² Similarly the summary article by Kent et al on the clinical manifestations of RP indicated that almost half the subjects had respiratory tract symptoms, namely, wheezing, stridor, and dyspnea in addition to change in voice quality.¹⁶³ These results were further corroborated by numerous studies indicating the high prevalence of airway and phonatory symptoms in patients with relapsing polychondritis.^164–166 Hong and Kim have reported that in patients with airway involvement, the larynx is affected in 25% of the cases.¹⁶⁵ In Michet et al’s review of 112 cases, airway involvement was the cause of death in 10% of the cases.¹⁶⁶ The laryngotracheal symptoms have been attributed to inflammatory changes, cicatricial formation with subsequent subglottic stenosis, infection of the proximal and distal airway, and last to collapse of the airway, all of which lead to obstruction of the endolaryngeal or tracheal lumen. The rheumatologic manifestations of the disease in patients with airway involvement have been reported by Hong and Kim in 2013 in their review of 12 patients with RP and airway involvement. In addition to the tracheal and laryngeal involvement in 100% and 25%, respectively, other rheumatologic manifestations included the nose, ears, and eyes.¹⁶⁵

The diagnosis of RP is based on meeting 3 out of the 6 criteria set by McAdam’s criteria which represent a compilation of signs and symptoms of chondritic and inflammatory changes in various organs of the body.¹⁵⁴ Additional histologic features and extent of response to therapy were later added to these diagnostic criteria by Damiani and Levine.¹⁶⁷ Based on the aforementioned, for a patient to be diagnosed with RP he or she has to have not only 3 out of the 6 diagnostic criteria set by McAdam but also histologic confirmation of one or more of McAdam’s signs, and response to therapy, namely, steroids and or Dapsone. Laryngotracheal manifestations of relapsing polychondritis mandate proper assessment not only of the static extent of involvement in terms of site and severity but also of the dynamic impairment of affected patients given the pliability of the airway during inspiration and expiration. Numerous diagnostic methods have been used, including flow-volume loop studies to assess extra-thoracic airway obstruction and resistance, plain radiography such as laryngotracheograms, or more advanced radiologic imaging such as computerized tomography which allows three-dimensional reconstruction of the airway while breathing. Krell et al in 1986 reported on the utility of pulmonary function testing (PFT) in 5 patients with RP. In three out of the five patients the PFT showed evidence of both inspiratory and expiratory obstruction, findings that were not reflected or evident on bronchoscopy during quiet breathing.¹⁶⁸ Mohsenifar et al has also advocated the usefulness of maximal expiratory and inspiratory flow-volume in the assessment of the dynamic nature of the tracheobronchial tree in patients with RP and airway symptoms.¹⁶⁹

The treatment of relapsing polychondritis is individually based on the patient’s condition, and extent and severity of the disease. It is invariably tailored given the disparities in the clinical presentation and the response to therapy. The mainstay medication given chronically or as bolus is glucocorticoid steroids. The dosage in patients with laryngotracheal manifestations is 1mg/kg/day that is tapered over time.^{151,170–172} In the study by McAdam on 23 patients, three-fourths were on corticosteroid therapy, the effect of which was promising except in cases of severe respiratory tract involvement.¹⁷³ Less commonly used medications include colchicine and Dapsone, the intake of which mandates close observation in view of their adverse effects. In severe cases, immunosuppressive agents such a methotrexate are advocated with caution regarding hematologic complications.¹⁷¹ In the investigation of the clinical characteristics of patients with RP and airway involvement, Hong and Kim recommended the use of both steroid and methotrexate as a therapeutic option.¹⁶⁵ Childs et al also reported the usage of steroids with methotrexate in two patients with hoarseness and dyspnea, one of whom needed laser treatment for the control of the laryngeal mass.¹⁵⁴ Biologic agents such as infliximab have been used experimentally but several patients experienced fatal infections.¹⁷⁴ Infliximab is a monoclonal antibody that has been used successfully for the treatment of disease mediated by tumor necrosis factors. Mpofu et al has described the usage of infliximab in the treatment of a 51-year-old female with RP who had relapse following cessation of methyl prednisolone therapy and had developed methemoglobinemia following administration of Dapsone.¹⁷⁵

Laryngeal Manifestations of Sarcoidosis

Sarcoidosis is a slowly progressive disease characterized by the occurrence of non-caseating granuloma in various sites of the body. It rarely occurs below the age of 15 years and is most common in the third to fifth decade of life affecting women more than men, and African Americans more than Caucasians.^176,177 Based on the ACCESS study (A Case Control Etiologic Study of Sarcoidosis) designed to characterize sarcoidosis in the United States, women are likely to suffer from neurologic and ocular involvement whereas men are more likely to develop hypercalcemia. The study has also shown that Blacks were more likely to have skin, liver, eye, and bone marrow involvement.¹⁷⁸ The etiology of sarcoidosis is still unknown. Many theories have been suggested, none of which are confirmative. These include infectious, toxic, and abnormal immune regulation.^176,179 For a subject to develop sarcoidosis, three elements must coincide: a stimulus or an allergen be it environmental or infectious, a genetic predisposition, and a host reaction that is most likely immunologic. Today there is limited understanding of the gene-environment interactions in sarcoidosis as in many other disease entities. An external stimulus can modulate gene expression and similarly a genetic variant is context-dependent, meaning it is only expressed upon exposure to the right stimulus.¹⁸⁰ The notion that sarcoidosis is familial has been supported by the increased odds ratio among siblings by five and by the presence of familial clustering.¹⁸¹ HLA-related genes have also been suggested in the genetic predisposition in some of the affected patients, namely, the HLA-DQB1 in African-American families, alluding to racial differences.^180–182 To that end, sarcoidosis has an inherited susceptibility and future genotyping may further elucidate the true genetic makeup of affected patients.¹⁸²

The starting point in the histology of sarcoidosis is a granuloma that forms as a reaction to an antigenic agent that leads to the clustering of different inflammatory cells as an immune mediated response. Several antigens such as mycobacteria or Propionibacteria have been incriminated as stimuli and “Interferon-gamma” and cytokines such as TNF-alpha, IL-12 and IL-18^183,184 have been suggested to play a role in the formation of the granuloma. A recent study by Moller supported the notion that Mycobacterium tuberculosis catalase-peroxidase protein (mKatG) is an antigenic stimulus in a subset of sarcoidosis patients.¹⁸⁴ His results were in accordance with a recent review that further substantiates that infectious agents, namely, mycobacteria and proprionibacteria are considered to be etiologic antigens in some cases of sarcoidosis.¹⁸⁵ Once exposed to these antigens, there is an immune-mediated response. These include “reduced lymphocyte blastogenesis, circulating immune complexes or delayed hypersensitivity reactions.”¹⁸⁵ However, it is important to note that whether the autoimmune response is primary or secondary remains a controversial issue.

The course of the disease is characterized by remissions and relapses often leading to functional impairment. At times it can be self-attenuating within one to three years leaving behind residual end organ damage.¹⁷⁹ The disease has a predilection for lungs and chest lymph nodes. Other organs less likely to be involved are spleen, liver, skin, bones, and nervous system.^{178,186–189} The otolaryngologic manifestations of this disease may be present in 10 to 15% of patients with sarcoidosis with involvement of the nasopharynx, nose, paranasal sinuses, tongue, tonsils, and larynx.^{176,179,183,189} Laryngeal sarcoidosis is a rare entity with the first case being reported by Poe in 1940.¹⁹⁰ Since then the estimated prevalence of laryngeal sarcoidosis is 0.5 to 1.4% within the context of otolaryngologic manifestations of this disease which is within the range of 9 to 15%.^189,191 Laryngeal sarcoidosis is invariably accompanied by systemic manifestations such as relapsing fever, polyarthritis that is migratory, fatigue, and weight loss. When accompanied by head and neck manifestations, symptoms such as nasal crusting, bleeding, and multiple cranial neuropathies related to central nervous system involvement may prevail. A limited number of isolated laryngeal sarcoidosis have been reported in the literature.^192,193 In the review of the Mayo Clinic by Neel and McDonald in 1982, almost half the patients with laryngeal sarcoidosis had systemic manifestations and similarly in the review of Benjamin et al of five cases of laryngeal sarcoid, only one had disease not confined to the larynx.^193,194 Nevertheless, before stating that sarcoidosis is isolated to the larynx, a systematic inquiry must be made and a long-term follow-up is needed to ensure that no other organ is involved.¹⁹⁵

The clinical presentation of sarcoidosis is mosaic as demonstrated in the report of 4 cases by Mayerhoff et al.¹⁹⁶ Although the symptoms of laryngeal sarcoidosis are invariably confined to the laryngopharyngeal complex, these can vary in nature and severity. The most common symptoms reported are cough, change in voice quality, difficulty in swallowing, and airway obstruction.^194,197 Based on a report of 13 cases of laryngeal sarcoidosis by Neel and McDonald, the most common symptoms by order of frequency were hoarseness followed by dysphagia and dyspnea.¹⁹⁴ This order of frequency of symptoms was confirmed by numerous studies with an estimated presence of hoarseness in 70 to 85% of the cases followed by dysphagia in up to 85%, dyspnea in 47% to 60%, and non-specific symptoms such as globus and cough in one out of 10 patients. Note that up to 18% of patients with laryngeal sarcoidosis may be asymptomatic.^{191,194,197,198} Indeed in the report by Neel and McDonald one patient out of the 13 had incidental findings of laryngeal sarcoidosis in the absence of any symptoms.

All the aforementioned reports alluded further to the heterogeneity of the laryngeal findings in patients with sarcoidosis. The most common site of laryngeal involvement is the supraglottis in 80% of cases, followed by subglottis in 15 to 20% of the cases, and the true vocal folds in 1%.^{192,194,197,198} In the review by Neel and McDonald the supraglottis was the site most commonly involved in 9 out of 13 patients, followed by the subglottis in two patients and the vocal folds in one.¹⁹⁴ The sites most commonly involved in the supraglottis are the epiglottis, aryepiglottic folds, and false vocal folds.¹⁹¹ The rarity of involvement of the true vocal folds is due to the scarcity of lymphatics and lymphoid tissue within these structures. Nevertheless, the report by Bower et al revealed abnormalities in the vocal folds in 24% of the cases.¹⁹⁷ When affected, non-specific findings of inflammatory changes in the anteroinferior segments are present.

Despite the presence of edema, inflammation, and diffuse mucosal thickening in any area of the larynx,¹⁹⁹ the classic appearance of an epiglottic rim that is fully rounded with a turban-like thickening is pathognomonic of laryngeal sarcoidosis.¹⁹⁵ Note that laryngeal involvement may not be limited to one laryngeal segment but instead multiple laryngeal sites can be involved as reported by Sims and Thakkar in 2007, where two-thirds of patients with laryngeal sarcoidosis had extensive disease necessitating surgical management.²⁰⁰ When these lesions are sporadic and non-specific the otolaryngologist must also rule out allergic reactions and infectious diseases such as tuberculosis, blastomycosis, histoplasmosis, or syphilis. It is also important to keep in mind that similar mucosal changes may be found following irradiation or in patients with connective tissue disorders such as amyloidosis.²⁰¹ A less frequently encountered finding is an exophytic lesion well localized, mimicking laryngeal neoplasms.^192,202,203 Sakamato et al has reported a rare case of laryngeal sarcoidosis presenting as a polypoid mass pedunculated arising from the right arytenoid and aryepiglottic fold in a 45 year women who presented with stridor.²⁰³ In similar cases, the otolaryngologist must rule out other neoplastic lesions and laryngeal malignant tumors such as lymphoma or cartilaginous neoplasms.

Sarcoidosis may also cause unilateral or bilateral vocal fold paralysis as reported by many authors.^204–209 The paralysis can be isolated or in combination with multiple cranial neuropathies involving the facial and optic nerves in addition to the hypoglossal, trigeminal, spinal accessory, auditory, and vagal nerves. When present in the absence of polyneuritis, the etiology is usually compression of the recurrent laryngeal nerve along its course in the chest. Significant hilar or peritracheal lymphadenopathy is usually present on computerized tomography of the chest. Based on a literature review only eight cases of vocal fold paralysis have been reported with the majority being unilateral and on the left side given the long course of the recurrent laryngeal nerve on the left.^204–209 Only two cases of bilateral vocal fold paralysis have been reported, one by Witt attributed to both polyneuritis and compression of the recurrent laryngeal nerve and one by Coffey et al that was attributed to intrathoracic lymphadenopathy, a common finding in patients with sarcoidosis present in up to 90% of the cases.^206–209 The majority of these patients improve on corticosteroid therapy within few days after the initiation of therapy.

In the absence of systemic complaints and when the disease is confined to the larynx the diagnosis of laryngeal sarcoidosis may be challenging to the Otolaryngologist. It is more so when the laryngeal findings are non-specific, which mandates a good index of suspicion in order to make the proper diagnosis. It should be based on clinical findings, exclusion of other infectious and inflammatory diseases that have similar presentations, and on histopathologic confirmation. To that end a complete workup to assess the extent of the disease systemically and to assess the response to treatment is crucial. This includes laboratory studies to check for abnormal protein electrophoresis, the presence of hyperglobulinenia, hypercalcemia, hypercalciuria in case of abnormal vitamin D3 metabolism, decreased albumin, and abnormal electrophoresis, in addition to electrocardiogram and chest x-ray to rule out the presence of hilar, paratracheal or mediastinal lymphadenopathy, and/or the presence of pulmonary infiltrates.^179,210 Other required tests include PPD skin testing to exclude tuberculosis, and last pulmonary function testing which may show signs of upper airway obstruction in cases of laryngeal involvement.^191,195,197 Gallium-67 citrate may be used to detect granulomatous inflammation in other sites of the body such as the salivary glands that may not be clinically apparent at the time of presentation.^{194, 211} The Kveim test to elicit an allergic reaction at the site of injection is not commonly used in view of its low accuracy and the difficulty in procuring the antigen of right consistency.^{194, 195, 212}

The diagnosis is confirmed on histologic examination with the presence of noncaseating nonnecrotic granuloma formation that consists of inflammatory cells such as epithelioid cells, Langerhans’ giant cells, macrophages, and lymphocytes. With time, there is hyalinization, fibrosis, and scarring. That is why a biopsy taken late in the course of the disease may be non-diagnostic and reveals only non-specific inflammatory infiltrates. It is preferable to have more than one laryngeal biopsy in order to demonstrate the presence of noncaseating granulomatous lesion. Cultures for acid-fast bacilli and fungus in addition to Ziehl-Neelsen staining must be taken to exclude other infections and disease entities. However, if the clinical picture is typical and the laryngeal findings are highly suggestive, biopsies taken from other sites of the body showing noncaseating granulomatous disease may be used to make the diagnosis as reported by Neel and McDonald.¹⁹⁴ The physician must also exclude other disease entities as discussed earlier in this chapter.

The management of laryngeal sarcoidosis aims at restoring the airway while preserving good voice quality. To that end, it is empirical to remain conservative as much as possible. The mainstays of medical treatment are corticosteroids and cytotoxic agents such as methotrexate and cyclophosphamide.^{191,202,213,214} Fortune and Courey have reported the successful management of a 28-year-old woman diagnosed with sarcoidosis with systemic steroids. The patient had severe supraglottic swelling that resulted in dysphagia, shortness of breath, and dysphonia. All the symptoms improved on systemic steroids that was tapered over the course of three weeks.¹⁹² In another report, Hensderson et al discussed the treatment of a 50-year-old man who had failed steroid therapy with methotrexate 10 mg/week. The methotrexate resulted in marked improvement of both cutaneous and nasolaryngeal lesions.²⁰²

Given the natural course of the disease, namely, remission and relapse with spontaneous regression, sometimes it is very hard to assess the effect of medical treatment in particular the use of glucocorticoids. Nevertheless, steroids still are recommended as the first line of treatment for systemic manifestations such as pulmonary disease, ocular myasthenia gravis (MG), central nervous system or skin involvement. Steroids may also be used as intralesional injections in patients with localized laryngeal lesions.^191,198 A report by Gallivan and Landis of two teachers who presented with a “honking” voice secondary to laryngeal sarcoidosis with the typical pathognomonic appearance were successfully treated with intralesional steroid injection. This mode of therapy in addition to early diagnosis of laryngeal involvement of this disease may spare the patient unnecessary morbidity such as tracheotomy.¹⁹¹ Similarly Dean et al has reported successful treatment of a 64-year-old female case of sarcoidosis with laryngeal intralesional steroid injections in addition to steroid inhalers. Three months after initiation of therapy, the patient had marked improvement in both voice quality and breathing.¹⁹⁸

Surgical resection is also an alternative that is mainly performed endoscopically. James and Simpson have reported a 60-year-old woman who failed intralesional steroid and dilation and presented with symptoms of airway obstruction. The stenotic area was treated successfully with CO₂ laser followed by the application of mytomycin C (0.4 mg/mL saline).²¹⁵ More aggressive and extensive lesions that fail conservative transoral or microlaryngeal resection may require surgery through open approaches such as laryngofissure for excision of subglottic lesions or supraglottic laryngectomy. Low-dose irradiation confined to the site of the lesion is also a viable alternative. Additionally, tracheotomy may be considered as a last resort in order to secure the airway.

Laryngeal Manifestations of Wegener’s Granulomatosis

Wegener’s granulomatosis, initially named after Friedreich Wegener in 1939, is a necrotizing granulomatous inflammatory disease characterized by vasculitis that involves small and medium-sized blood vessels. Recently, the preferred name has been changed to granulomatosis with polyangiitis. Also described as granulomatosis with polyangiitis (GPA), Wegener’s granulomatosis affects 3 out 100,000 individuals in the United States with a predilection for whites compared to blacks.^216,217 Information on geographic variation is conflicting despite the numerous reports indicating a higher prevalence in Europe compared to the United States.^216,218-220 Patients are usually in their 5th, 6th, and 7th decades of life.^216,217 Unlike adults, when children are affected, the course of the disease may be undulant with life-threatening dyspnea and respiratory distress.²²¹

Wegener’s granulomatosis can present either as a syndrome with the classic involvement of the respiratory tract, kidneys, and lungs, or as a local disease affecting mainly the upper and lower airway. When the disease is systemic, patients present with systemic complaints such as malaise, arthritic pain, generalized weakness, myalgia, and night sweats, in addition to the presence of cutaneous lesions mainly on the lower extremities. When the lungs are involved, which occurs in 50 to 90% of cases, hemoptysis and cough are the most common symptoms. Evidence of pulmonary cavitated parenchymal lesions are often mistaken for fibrosis or pulmonary vascular diseases on radiologic imaging.^222,223 When the kidneys are affected the prognosis is worse and patients present with hematuria and protenuria secondary to necrotizing glomerulonephritis.²¹⁷ Criteria for distinguishing GPA from other systemic vasculitis have been defined by the American College of Rheumatology. Two of the following 4 criteria must be present in order to make the diagnosis: (1) “sinus involvement, (2)“lung radio-graph demonstrating nodules, fixed infiltrates, or cavities,” (3) abnormal urine cytology, and (4)” histologic evidence of granulomas in or around an artery or arteriole.”²²⁴ Depending on the severity of the disease, the Birmingham Vasculitis Activity Score can be used to grade the extent of the disease.²²⁵

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