Laryngeal involvement in systemic lupus erythematosus

Laryngeal

Involvement

in Systemic

Lupus Erythematosus

By Ariel D. Teitel, C. Ronald MacKenzie, Richard Stern, and Stephen A. Paget Laryngeal involvement in systemic lupus ery thematosus (SLE) can range from mild ulcerations, vocal cord paralysis, and edema to necrotizing vasculitis with airway obstruction. In this report, four cases showing the range of severity of this disease manifestation are presented, accompanied by a comprehensive review of the literature. The clinical course of 97 patients with laryngeal involvement with SLE are reviewed, of whom 28% had laryngeal edema and 11% had vocal cord paralysis. In the majority of cases, symptoms such as hoarseness, dyspnea, and vocal cord paralysis resolved with corticosteroid therapy. Other, less common causes of this entity included subglottic stenosis, rheumatoid

T

HE FIRST CASE of laryngeal involvement in systemic lupus erythematosus (SLE) was published more than 30 years ago.’ Since that initial report, additional examples of this often serious complication of SLE have been reported sporadically. The presence of laryngeal involvement is now believed to occur in as many as one third of patients with SLE.2 Despite the frequency and life-threatening potential of this disease manifestation, it remains a clinical observation that probably is not appreciated by many physicians caring for patients with SLE. In this report, we present a comprehensive review of the literature concerning this manifestation of SLE and supplement it with four previously unreported case histories of patients with SLE-related laryngeal involvement. The broad range of pathological entities within the larynx of these patients, the differential diagnosis, and the approach to therapy are discussed. PATIENTS AND METHODS The Hospital for Special Surgery, a 200-bed tertiary referral center located in New York City, has an SLE population of approximately 200 patients who account for 800 average annual patient visits. The four cases described herein all met the American College of Rheumatology criteria for SLE3 and were cared for by one of the authors (cases 1 through 3) or by a current fellow (case 4) at our institution between 1987 and 1991.

nodules, inflammatory mass lesions, necrotizing vasculitis, and epiglottitis. The clinical presentation of laryngeal involvement in patients with SLE follows a highly variable course, ranging from an asymptomatic state to severe, lifethreatening upper airway compromise. With its unpredictable course and multiple causations, this complication remains a diagnostic and therapeutic challenge to physicians involved in the care of patients with SLE. Copyright o 1992 by W. B. Saunders Company INDEX WORDS: Systemic lupus erythematosus; larynx; vocal cord.

Case 1

A 37-year-old black man with newly diagnosed SLE was admitted in April 1987 with fever (40°C) and a several-week history of progressive hoarseness and dysphagia. Laryngoscopy revealed diffuse laryngeal edema and left vocal cord paralysis. The next day, mild respiratory stridor developed and repeat endoscopy showed new areas of edema in the left arytenoid and left aryepiglottic fold. A computed tomography (CT) scan of the neck showed diffuse soft tissue edema; no mass, abscess, or foreign body was seen (Fig 1). Subsequent laryngeal cultures were negative. High-dose intravenous methylprednisolone therapy greatly ameliorated the symptoms. Repeat laryngoscopy 48 hours after the institution of treatment showed markedly diminished edema and normal vocal cord mobility. He has not experienced laryngeal symptoms during the subsequent 5 years of observation, despite the occurrence of multiple exacerbations of his disease. He is currently on dialysis therapy after failing to respond to pulse cyclophosphamide therapy.

From the Department of Medicine and Rheumatology, The Hospital for Special Surgety, New York, NY Address reprint requests to Stephen A. Paget, MD, The Hospital for Special Surgery, 535 E 70 St, New York, NY 10021. Copright 0 1992 by W. B. Saunders Company 0049-0172/92/2203-0007$5.OOlO

Seminars in Arthritis and Rheumatism, Vol 22, No 3 (December), 1992: pp 203-214

203

TEITEL ET AL

Fig 1:

Scan taken at the

level of the false vocal cord (FVC) showing soft tissue swelling with deviation of that structure to the

right.

(ThC), and

The

thyroid

arytenoid

cricoid

(CrC)

(Arc), carti-

lages are indicated.

Case 2 A 26-year-old black man with an l&month history of SLE was admitted in January 1988 with distal leg pain and swelling to rule out deep venous thrombosis. His disease had been previously characterized by malaise, myalgias, arthritis, and discoid lesions. Four months before admission he developed a right popliteal vein thrombosis and was treated with intravenous heparin. Results of tests for the lupus anticoagulant and anticardiolipin antibodies were negative.

Fig 2: level

Scan taken at the of the

true

vocal

cords (TVC) showing intubation. Diffuse soft tissue edema has narrowed

the

laryngeal ventricle (LV) around the tube. The thyroid (ThC) and cricoid (CrC) cartilages are indicated.

Thirty-six hours after admission the patient complained of a sore throat. During the next 5 hours he developed marked tonsillar enlargement, compression of the uvula, and inspiratory stridor which rapidly progressed to total upper airway obstruction. Urgent nasotracheal intubation was life-saving. A CT scan of the neck showed diffuse soft tissue edema with obliteration of airway patency (Fig 2). Broad-spectrum antibiotic and high-dose corticosteroid therapy were instituted, and a tracheostomy was performed. All blood and laryngeal cultures were

LARYNGEAL

INVOLVEMENT

IN SLE

negative, and over the next 4 days the laryngeal swelling resolved. He has had no recurrence of laryngeal symptoms. Case 3

A 29-year-old Hispanic woman had a 6-year history of SLE with focal proliferative glomerulonephritis, nephrotic-range proteinuria, arthritis, leukopenia, thrombocytopenia, seizures, myositis, and vasculitis. In April, August, and October 1988 she received intravenous pulse methylprednisolone therapy for worsening azotemia and proteinuria. In November 1988, fever and progressive stridor developed over a period of several hours, and she was admitted to the hospital. Otolaryngological consultation confirmed the presence of acute epiglottitis and diffuse laryngeal edema. An emergency intubation was performed in the operating room. Broad-spectrum antibiotic and high-dose corticosteroid therapy were administered intravenously, resulting in rapid resolution of the laryngeal and epiglottal inflammation. Laryngeal and blood cultures were negative. She has not subsequently experienced further laryngeal symptoms, despite several exacerbations of the disease manifested by skin vasculitis, pericarditis, and progressive renal failure leading to dialysis. Case 4

A 26-year-old Hispanic women had SLE diagnosed in December 1989 when she presented with arthritis, fever, and hoarseness of 2 months’ duration. She was antinuclear antibody and double-stranded DNA positive with hypocomplementemia. Laryngoscopy showed slight edema of the vocal cords with normal motion. Her symptoms improved rapidly with beclomethasone dipropionate inhaler, potassium iodide, and 30 mg of prednisone per day. She subsequently experienced several episodes of pleuropericarditis. In February 1991 the patient presented with pleuritic pain, arthritis, and pharyngitis of 1 week’s duration. Wheezing but no true stridor was noted on physical examination. Laryngoscopy showed vocal cord edema and hyperemia with good mobility although the epiglottis was normal; a diagnosis of laryngitis with laryngotracheal bronchitis was made. The patient’s pred-

205

nisone dosage was increased from 5 to 30 mg/d, and trimethoprim sulfamethoxazole therapy was started. Laryngeal cultures were negative, and symptoms resolved within 10 days. During a lo-month follow-up, the disease, including the laryngeal manifestation, has been quiescent. REVIEW

OF THE

LITERATURE

Table 1 summarizes the study population, which is composed of 97 patients with laryngeal involvement with SLE. The different denominators reported in the data reflect the fact that some information was not available for all cases. Half of the patients were on corticosteroid therapy at the time of laryngeal involvement (11/22), and laryngeal involvement was not an isolated manifestation of the disease in most cases (21/24). Nearly all patients had established SLE (93/97); however, two with druginduced lupus, one with discoid lupus, and one with isolated vocal cord nodulosis who eventually developed SLE also are included. Hoarseness was the most frequent symptom (17/25), and dyspnea was noted in 14 of 25 patients. Dysphagia was infrequent (2/25), as was odynophagia (3/25). On clinical examination, the most common laryngeal findings were edema (27/97) and vocal cord paralysis (11/97). Oral ulceration was noted in 7 of 25 patients; in 5 patients it was concurrent, while in 4 patients it occurred 10 days to 2 months before the episode of laryngeal involvement. Two patients experienced both concurrent and prior oral ulceration along with laryngeal involvement. Three patients had had a prior episode of laryngeal involvement with increasing disease activity (case 4 and references 4 and 19). Based on our review of the reported literature, laryngeal involvement in SLE can be divided into nine overlapping categories. These groupings, along with a corresponding differential diagnosis, are presented below. Micosal Inflammation

Oral ulceration, laryngeal erythema, and edema were the most common gross clinical findings. Generally these findings resolved rapidly with corticosteroid therapy. Although this response to therapy strongly suggests that the underlying SLE was the cause of the laryngeal process, the clinician should be aware of other

206

TEITEL ET AL

Table 1: Laryngeal involvement

Author Teitel et al

Age hr)/

SLE

Laryngeal

Gender

Features

Disease

37/M

Arthritis; anemia x6 mo; NSAlDs

in SLE Patients

Therapy

Hoarseness; dysphagia;

High-dose MP IV

Outcome RI resolved 48 h later; NR over 3

x1

mo; E; RI; cul-

yr; on dialysis

tureTeitel et al

26/M

18 mo discoid le-

Pharyngitis; sud-

sions; arthritis;

den laryngeal

20 mgld pred-

edema; culture-

AB; high-dose MP; intubation

Resolution of E over 4 d; NR over 2 yr

nisone Teitel et al

29/F

6 yr GN; arthritis; CNS; 8 mg/d MP

Stridor; suddenonset laryngeal

AB; high-dose MP; intubation

edema; culture-

Resolution of E over 4 d; no recurrence over 1 yr; dialysis

Teitel et al

26/F

Smith et alzO

36/F

2 yr arthritis; se-

Pharyngitis x 1 wk;

rositis; 5 mg/d

H; VC; E; ery-

prednisone

thema; culture-;

1 yr hepatitis; skin;

arthritis; 2-3 g/d

Dg Pharyngitis; H x 1 mo; E; slow VC

AB; 30 mg/d prednisone

Unknown dose steroid

Asa

Resolution of Ph; H; no recurrence

Resolution of Ph. H but several recurrences per year

Korbet et all2

51/F

1 mo anemia; ar-

1 wk DOE; H; Rl;

Unknown dose ste-

Resolution of H,

thralgias;

E; arytenoid car-

roid; steam inha-

DOE, Rl over 2

azotemia; GN 60

tilage

lation

wk

mg/d prednisone Gilliam et all6

24/F

1 mo arthritis; U;

1 mo H; S; E of

myositis; GN;

VCs; M; oral ul-

prednisone/CP

cers; culture-

Trach; prednisone; CP

Inflammation on biopsy; resolution of symptoms

Chatelanat et al7

49/M

Discoid LE only

Scarpelli et al1

21/M

1 yr serositis; ar-

H; edema

Unknown

Necrotizing vascu-

Sudden D; facial,

Unable to intubate

Death; possible

xl8yr

litis on biopsy

thritis; GN; un-

laryngeal edema

laryngeal vascu-

known medica-

litis on biopsy

tions Burgess et ala

59/F

Azotemia; anemia;

H; E; U; pharyngeal M; drooling;

NSAID

Feeding tube; trach; steroids

RI

Inflammation on biopsy; H, M, E improved; permanent RI

50/M

Petri et al5

1 yr CNS; GN;

2 wk dysphagia;

prednisone/CPM

AB; IV steroids

Recurrent fever;

pharyngitis;

Nocardia,

hoarseness

lated; SXs re-

iso-

solved Montgomery

et all9

25/F

7 mo on Asa; arthritis; U; leuko-

H; Ph; 0; E;
20 mgld pred-

Resolution of

nisone

symptoms

Excision of VC

Sicca 12 mo; SLE

penia Schwartz et ail8

28/F

No diagnosis of SLE

H xmo; rheumatoid nodules on vc

Continued on next page

nodules

16 mo later

LARYNGEAL INVOLVEMENT IN SLE

207

Table 1: Laryngeal Involvement

Author roomey et al4

in SLE Patients (Cont’d)

Age (vr) 1

SLE

Laryngeal

Gender

Features

Disease

45/M

6 mo GN; arthritis;

H x4 mo; acute S;

Trach; inflamma-

oral ulcers; on

U; edema of epi-

tion on biopsy

steroids

glottis

lNeiser et al6

60/M

6 mo hydralazine

Ph, H x2 mo; epi-

Smith et alI5

63/F

3 yr serositis; GN;

Subglottic stenosis

prednisone

x6yr

Babich et all7

45/F

1 yr symptoms;

Dyspnea;

glottic mass

Espana et al9

27/F

Therapy

therapy un-

odynophagia;

known

edema; mass

3 mo NSAID; arthritis; GN; oral

H x2 wk; Rl; oral ulcers

Outcome Cultured Bacillus sp; died; CNS bleed 1 mo

Vasculitis on biopsy Normal on biopsy;

D/C hydralazine; resolution H, M Tracheostomy

prednisone Trach

Fistula; necrosis of cartilage; death

Prednisone, azathioprine

Permanent VC paralysis

ulcers Baluja et all3

35/F

2 yr arthritis

Stridor x 1 wk; bilateral VC paraly-

Trach; steroids; chloroquine

VCs mobile 1 mo later

s/s eszkenasy et allo

41/F

6 yr pulmonary hy-

D, H x3 wk; VC

Diuresis; steroids

RHF; death; com-

pertension; ar-

paralysis; dilated

pressed right

thritis; steroids

pulmonary arter-

laryngeal nerve

ies 4sherson et al”

28/F

2 yr steroids; arthritis

24/F

7 yr steroids; serositis

DOE; H; VC paraly-

Unknown

sis SOB; H; VC paraly-

Pulmonary artery pressure 55 mm

IV captopril

sis

Hg Pulmonary artery pressure 55/25 mm Hg

Maxwell et all4

63/F

7 yr hydralazine; 2 yr arthritis

4 mo H; oral ul-

Prednisone

cers; stridor;

Normal VC mobility 3 mo later

fixed VCs Minchina et al**

-

Unknown disease

Hoarseness; acute

manifestations

laryngitis in 6;

Steroid inhalation; antibiotics

2 Died; 6 biopsies showed perivas-

corditis in 13 E;

cular inflamma-

chronic laryngitis

tion

in 4; VC paralysis in 2 Raz et aI*’

29/F

6 yr arthritis, GN;

Stridor; diffuse

Intubation; ste-

therapy un-

edema; normal

roids; inhaled

known

Cl -; esterase

epinephrine

inhibitor 22/F

Anemia; arthritis; oral ulcers

Ph; laryngeal, arytenoid E

Extubated 48 h later; 9 recurrences, 5 intubations next 2 yr

Prednisone 200

E resolved 3 wk

mg/d; inhaled

later; recurrence

epinephrine

days later requiring trach, IV CP

Abbreviations: SLE, systemic lt~puserythematosus; NSAID, nonsteroidalantiinflammatory drug; IV, intravenous;Ab, antibiotics; Asa, aspirin; CNS, central nervous system; CP, cyclophosphamide; D, dyspnea; Dg, dysphagia; DL, discoid lupus; DOE, dyspnea on exertion; E, edema; GN, glomerulonephritis; H, hoarseness; M, mass; MP, methylprednisolone; NR, no recurrence; 0, odynophagia; Ph. pharyngitis; R, recurrence; RHF, right-sided heart failure: Rl, unilateral vocal cord paralysis: R2, bilateral vocal cord paralysis; S, stridor; SOB, shortness of breath; St, steroids; Tr, tracheostomy; VC, vocal cord. *72 SLE patients reported by Minchina et al.

TEITEL ET AL

208

conditions which may result in the similar findings. Differential diagnosis. Subacute or chronic laryngitis occurs both in the normal host and in patients with SLE. Overall, the most common causes of chronic laryngitis and leukoplakia are cigarette smoking and alcohol abuse. Leukoplakia usually affects the vocal cords and causes hoarseness.22 Reflux laryngopharyngitis due to incompetence of the gastroesophageal sphincter and Zenker’s diverticulum with reflux must also be considered before attributing chronic laryngitis to lupus activity.*” Certain chemicals used in the home or at work, such as ammonia and oven cleaners, may cause chronic laryngitis.24 Acute mucosal ulceration may also be seen in pemphigus vulgaris of the larynx. In this condition the affected mucosal surface is covered by a white membrane that is free of bleb formation. Diagnosis is made by biopsy and immunofluorescence studies. Mucous membrane pemphigoid is also seen in the larynx. This bullous disease usually has a more chronic indolent course than pemphigus. The lesions begin as vesicles, which develop into erosions and heal with scarring. Occasionally fibrosis of the larynx results in eventual stenosis.25 Laryngeal edema is a nonspecific reaction provoked by a variety of insults: trauma, infection, cigarette use, radiation therapy, and voice abuse.2h,27 Allergic angioedema may be provoked by food, inhalants, and drugs. Aspirin is the most common medication, followed by iodine and penicillin. Chicken, beef, bee stings, house dust, and cosmetics are also frequent causes. Recurrent episodes of laryngeal edema occasionally associated with cutaneous urticaria are typical in hereditary angioneurotic edema (HANE). This condition, which results from a Ci-esterase inhibitor deficiency, leads to activation of the complement cascade after slight provocation such as minor trauma, infection, or emotional stress.z8 This autosomal dominant disorder has an approximate mortality rate of 25%, and cases of concurrent HANE and SLE have been reported.29 Laryngeal perichondritis may cause mucosal edema and erythema. This condition, involving inflammation of tissues covering the laryngeal cartilages, is most frequently a sequela of radia-

tion therapy. Relapsing polychondritis involves the larynx in more than 50% of cases. This poorly understood illness is manifested by recurrent cartilage inflammation and is sometimes seen in patients with connective tissue disorders such as rheumatoid arthritis and lupus. The pinna of the ear is affected in more than 75% of patients. Tracheomalacia or stenosis of the larynx may result even if the disease is treated with steroids4 Infection

Laryngeal inflammation and edema were responsive to steroid therapy, except in those cases in which infection was documented. Of the eight patients who had laryngeal cultures performed, two yielded organisms. One of these infections was bacterial (Bacillus species; Toomey et a14)and the other was fungal (Nocurdia; Petri et a15). It was not noted whether antibiotics were used for the patient with laryngeal Bacillus infection. Antimicrobial therapy was administered to the patient with Nocardia, resulting in rapid improvement in symptoms and in laryngeal erythema and edema. Although there was no distinguishing feature in the patient reported by Toomey et ak4 mucopurulent drainage was noted with the Nocardiu infection. The patient with laryngeal Nocurdiu experienced recurrent fever and worsening laryngeal symptoms while on broad-spectrum antibiotic therapy and an increased corticosteroid dosage. Shorter duration of symptoms did not correlate with the presence of laryngeal infection. Cases 2 and 3 both had sudden onset of profound laryngeal edema, but laryngeal cultures were negative. Differential diagnosis. Infections of the larynx commonly cause acute mucosal ulceration with or without edema. Whereas viruses such as influenza or adenovirus are usually implicated, secondary infection often occurs with group A @hemolytic streptococci, Staphylococcus uureus and Hemophilus influenzue.24 Other infections that can involve the larynx include diphtheria, tuberculosis (almost always associated with advanced pulmonary disease), trichinosis (spontaneously resolving within 3 weeks), syphilis, and leprosy. Scleroma of the larynx is a chronic granulomatous infection caused by Klebsiellu rhinoscleromutis; more than 90% of cases have

LARYNGEAL

INVOLVEMENT

IN SLE

209

associated nasal involvement. Prolonged antimicrobial therapy with frequent relapses is common.30 Fungal laryngitis can range from granulomas of the vocal cords to inflammatory involvement with scarring. Commonly implicated fungi include Histoplasma, Coccidiodes, Blastomyces, Candida, Actinomyces, Gyptococcus, and Aspergillus. 4

Nocardia,

Vasculitis

Definitive evidence of vasculitis was found in only two cases. Weiser et al6 described a patient with drug-induced SLE who developed hoarseness. Direct laryngoscopy showed small polypoid vocal cord lesions and a 1 x 1.5cm nodule on the lingual surface of the epiglottis. An epiglottal biopsy revealed a necrotizing ulcer with fibrinoid necrosis and an inflammatory infiltrate in the walls of deeper blood vessels, characteristic of vasculitis. The second case of Chatelenat and Rauch7 was a 49-yearold man with an l&year history of discoid lupus involving the face who developed progressive hoarseness. Laryngeal biopsy of an inflamed left vocal cord showed an inflammatory infiltrate and fibrinoid necrosis with disruption of the intima and media of a submucosal artery. The patient had no recurrent laryngeal symptoms or evidence of systemic lupus after a 16month follow-up. Seven other patients had biopsy results compatible with but not diagnostic of vasculitis. The patient reported by Scarpelli et al’ had sudden onset of profound edema of the face and upper airway and suffered a fatal respiratory arrest. Diffuse laryngeal edema was noted before unsuccessful attempts at endotracheal intubation. Microscopic examination of the larynx at autopsy showed an inflammatory infiltrate in the lamina propria, fibrinoid degeneration of collagen, and occasional arterioles with perivascular lymphocytic infiltrates. Six other laryngeal biopsies with features of vasculitis were noted by Minchina et al.* These authors performed laryngoscopic examinations on 72 patients with SLE, 25 of whom had laryngeal symptoms (35%). Biopsy specimen were obtained from two patients who had acute laryngitis and died and four patients with chronic laryngitis. Blood vessel walls were thickened and hyalinized. Perivascular edema and cellular infiltration also

were seen, although no necrosis or destruction of the elastic lamina was described. Differential diagnosis. Vasculitis associated with connective tissue disorders such as rheumatoid arthritis, polyarteritis nodosa, and relapsing polychondritis could affect the larynx, as has been reported in a patient with Wegener’s granulomatosis.27 Vocal Cord Paralysis

Vocal cord paralysis was found in 11 patients, although the clinical outcome was reported in only six: two had transient unilateral palsy, two had permanent unilateral paralysis, and two had temporary bilateral vocal cord paralysis. The resolution of vocal cord palsy with immunosuppressive therapy took variable amounts of time. The patient reported by Korbet et all2 developed increasing hoarseness and dyspnea while steroids were being tapered. Two weeks after her steroid dosage was increased her vocal cords regained normal mobility. In one of our patients (case l), vocal cord mobility was regained within 48 hours of institution of highdose steroid therapy. The patient reported by Burgess and Renders developed a left vocal cord paresis that did not resolve 9 months after institution of corticosteroid therapy. Initial laryngoscopy showed bilaterally edematous vocal cords and paralysis of the left cord. The duration of respiratory symptoms before the institution of immunosuppressive therapy is not reported. The patient reported by Espana et al’ developed hoarseness over a period of days and was noted to have a right vocal cord paralysis. This patient was treated with 120 mg of prednisone daily, which was gradually tapered after the addition of azathioprine. No improvement in vocal cord palsy was noted at follow-up examination 12 months later. The patient reported by Saluja et alI3 developed respiratory distress due to bilateral vocal cord palsy. Laryngoscopy showed bilateral vocal cord paralysis with passive mobility of both cords. The patient was treated with prednisolone (1.5 mg/kg daily) for 3 weeks, and a repeat laryngoscopy showed sluggish movement of both cords. Three pulses of dexamethasone (100 mg IV every other day) were then adminis-

TEITEL ET AL

210

tered, and 1 week later both vocal cords regained active mobility. Maxwell and SilverI reported a patient with hydralazine-induced lupus who developed bilateral vocal cord paralysis. After 2 years of arthritis, hoarseness, painful oral ulceration, and a vasculitic lower extremity rash occurred. Stridor subsequently developed in the setting of newonset glomerulonephritis. Laryngoscopy showed thickened vocal cords, fixed in midposition. Hydralazine was discontinued, and the patient was given 60 mg of prednisone per day followed by a tapering course over a 2-month period. A rapid resolution of the laryngeal symptoms was followed by normalization of vocal cord mobility 3 months later. Asherson and Hughes” previously have speculated that the association of pulmonary hypertension and vocal cord palsy might be explained by compression of the recurrent laryngeal nerve by an enlarged pulmonary artery. This explanation was later confirmed by Aszkenasy et al,‘” who reported a patient with SLE, pulmonary hypertension, and vocal cord palsy. A work-up for dysphonia and dyspnea showed left vocal cord paralysis; dilated proximal pulmonary arteries were found on CT. Pulmonary hypertension was confirmed by catheterization with pulmonary arterial pressure measurements (135/58 mm Hg). Prednisolone, 60 mg/d, resulted in improvement of dysphonia, but rapidly progressive right heart failure led to the patient’s death. On postmortem examination the left recurrent laryngeal nerve was found to be compressed by a dilated left pulmonary artery. There was no evidence of vasculitis in multiple sections of the nerve. Interestingly, of patients with unilateral paralysis, almost all (6/7) had the left vocal cord affected. Only the left recurrent laryngeal nerve is in contact with the ipsilateral pulmonary artery, and three of these six patients had documented pulmonary hypertension. Thus the literature shows that in four of six cases in which an outcome is given, vocal cord paralysis in SLE patients was responsive to corticosteroid therapy. It is unknown whether the patient reported by Burgess and Render8 had pulmonary hypertension, a condition that generally would not be expected to improve with corticosteroid therapy. There is no distinguishing feature of the case reported by Espana

et al’; the patient received prompt immunosuppressive therapy but did not respond. Although vasculitis of the vasa nervorum has been proposed as the cause of steroid-responsive vocal cord palsy in these patients, there has been no documented case of vasculitis involving the recurrent laryngeal nerve of an SLE patient. The presence of lupus anticoagulant activity in the case reported by Saluja et al’” and anticardiolipin antibodies in one of the cases reported by Asherson and Hughesi’ raises the possibility of a thromboembolic event. However, a causative role for these antibodies in the pathogenesis of recurrent laryngeal nerve palsy in SLE patients is purely speculative. Differential diagnosis. Unilateral vocal cord paralysis is most commonly caused by virally induced inflammation of the recurrent laryngeal nerve. In such cases, function usually returns within 1 year. Other causes include intraoperative injury to the nerve, bronchogenic carcinoma of the left lung, and pulmonary hypertension. In the last instance, the presumed pathophysiology (verified at autopsy by Aszkenasy et allO) is compression of the left recurrent laryngeal nerve by an enlarged left pulmonary artery. Aneurysmal aortic dilatation may also compress the left recurrent laryngeal nerve. Causes include syphilis, arteriosclerosis, Marfan’s disease, and trauma. Other causes of unilateral vocal cord paralysis include multiple sclerosis, diabetic neuropathy, syringomyelia, alcoholic polyneuropathy, and sarcoid. Bilateral recurrent laryngeal nerve palsy also has a long differential diagnosis including polio, cerebrovascular accident, multiple sclerosis, amyotropic lateral sclerosis, Parkinson’s disease, trauma, and thyroid and esophageal malignancies.“’ Vasculitis has been shown to cause recurrent laryngeal nerve palsy and vocal cord paralysis in Wegener’s granulomatosis, but in general, laryngeal involvement with necrotizing granulomae and vasculitis usually occurs in the subglottic region.27 Cricoarytenoid Arthritis Although cricoarytenoid arthritis was not definitively noted in the cases reviewed here, it may have been overlooked on laryngeal exami-

LARYNGEAL

INVOLVEMENT

211

IN SLE

nation and may be a particular concern in overlap patients with rheumatoidlike arthritis. Di#hwztiul diagnosis. Cricoarytenoid arthritis can cause hoarseness, dysphagia, and odynophagia. Diminished movement or even paralysis of the vocal cord may result. Infections such as mumps and gonorrhea can affect the joint. Although rheumatoid arthritis is well known to affect the cricoarytenoid joint, several other arthritic syndromes such as gout and Reiter’s syndrome also should be considered. Rheumatoid arthritis may result in fixation of the arytenoids, necessitating arytenoidectomy because this involvement usually is not responsive to steroid therapy. Tietze’s syndrome (costochondritis) has been associated with cricoarytenoid arthritis that was responsive to salicylate therapy. Traumatic cricoarytenoid arthritis also has been documented in the literature.19 The “passive mobility” test during laryngoscopy is helpful in diagnosing cricoarytenoid involvement. If diminished vocal cord mobility is caused by cricoarytenoid arthritis, external compression of the larynx will show immobility of the arytenoid cartilage on the affected side. Other causes of vocal cord immobility have good passive motion of the arytenoid cartilages.32 Subglottic Stenosis

Subglottic stenosis was noted by Smith and Ferguson15 in a patient 3 years before SLE was diagnosed. Exertional dyspnea did not improve despite numerous dilations over a 2-year period, and temporary tracheostomy was performed. The stenosis was noted to extend 4 cm below the cords into the trachea. The vocal cords were normal, and a biopsy specimen from the stenotic area showed granulomatous inflammation. Serositis, anemia, and glomerulonephritis prompted corticosteroid therapy although the dose and duration are not noted. Two years later an evaluation of recurrent dyspnea confirmed persistent subglottic stenosis, and permanent tracheostomy was necessary. Laryngoscopy again demonstrated normal vocal cords and biopsy revealed only squamous epithelium. Differential diagnosis. Subglottic stenosis has a broad differential including congenital causes, tracheomalacia (may be caused by relapsing

polychondritis), tumor, infection (tuberculosis, scleroma, histoplasmosis, syphilis, diphtheria), trauma, lye/acid ingestion, and thermal or chemical inhalation.33 Inj?ammatory Mass An inflammatory “mass” was noted in the larynx of two patients, leading to the death of one. A third had a hypopharyngeal mass that responded to immunosuppressive therapy. Two of the three patients with odynophagia had an inflammatory mass; one mass was laryngeal. The patient reported by Gilliam and Cheatum16 had a mass posterior to the cricoid, which on biopsy showed only nonspecific inflammation. This mass initially increased in size while the patient was on corticosteroid and oral cyclophosphamide therapy. Cultures were negative, tracheostomy was required, and improvement eventually occurred. Babich and Taranovl’ described a patient with an inflammatory mass involving the right hemilarynx. A biopsy of the right false vocal cord showed subacute inflammation with some granulation tissue. Treatment is not mentioned, and the patient developed a fistula to the esophagus and died. Autopsy revealed complete destruction of the right arytenoid cartilage with soft tissue necrosis. The condition of blood vessels, specifically whether vasculitis was present, was not noted. Burgess and Render8 described a large necrotic mass projecting from the posterior wall of the lower hypopharynx in their patient. Biopsy showed inflammatory changes, and a rapid response to steroid therapy was observed. Differential diagnosis. Laryngeal mass formation and infiltration may result from diseases such as amyloidosis or sarcoidosis.34 Hoarseness and obstruction may result from an amyloid nodule, which is most commonly located in the laryngeal vestibule, ventricular folds, aryepiglottic folds, or subglottis. 35The extent of laryngeal involvement in the 5% of sarcoid patients affected is proportional to the degree of systemic disease. A circumscribed granuloma is often seen, which can cause hoarseness, dyspnea, or dysphagia. Supraglottic involvement can lead to erythematous, diffuse enlargement in the vicinity of the false vocal cords.36 Addison’s disease rarely causes vocal weakness, while hypothyroidism can lead to thicken-

212

ing of the vocal cords with polypoid changes.23-37 Acromegaly may lead to a deeper voice due to increased laryngeal growth and mucosal hyperplasia. Rheumatoid Nodules

The patient reported by Schwartz and Grishmani had nodular excrescences on both vocal cords. Biopsy revealed a central zone of fibrinoid necrosis bordered by a mononuclear cell infiltrate that was oriented in a palisading arrangement, typical of a rheumatoid nodule. Direct immunofluorescence disclosed the presence of immunoglobulin (1g)G and IgA. Cultures, including acid-fast and fungal, were negative, as was polarized microscopic examination for amyloid deposits. Sixteen months after the biopsy of the nodules the patient developed serositis, arthritis, malar rash, and serological and renal involvement diagnostic of SLE. Differential diagnosis. Although the pathology of the rheumatoid nodule is quite specific for this disease, it is noteworthy in the context of this report that rheumatoid nodules are seen in 5% of patients with SLE. This phenomenon usually is seen in association with rheumatoid like changes in the joints.“s,39 Epiglottitis

Epiglottic involvement was specifically noted in three cases. The patient reported by Toomey et al4 had chronic hoarseness and superficial mucosal ulceration of the hard palate. He presented to the emergency department 3 weeks later with fever and rapidly progressive dyspnea. Immediate tracheotomy was performed, and laryngoscopy revealed an inflamed epiglottis of three times normal thickness. The contiguous portions of both aryepiglottic folds were similarly involved. The epiglottic biopsy specimen contained necrotic epithelium and a dense inflammatory infiltrate in the connective tissue. Although Bacillus species grew from the epiglottic specimen, the patient’s respiratory symptoms improved. It was not noted whether antibiotics or steroids were administered during the epiglottitis. He died 2 weeks later of continuing multisystem involvement of his SLE. This case substantiates the observation that oral mucosal ulceration may herald an increase of overall disease activity.40 Weiser et alh noted a hypertensive 60-year-

TEITEL ET AL

old man who developed arthralgias 3 months after beginning hydralazine therapy. Three months later, pharyngitis and hoarseness developed. Laryngoscopy disclosed vocal cord polyps and a 1 x 1.5cm irregularly shaped mass on the lingual surface of the epiglottis. A biopsy of the area revealed a necrotic ulcer with fibrinoid necrosis and an inflammatory infiltrate in blood vessel walls characteristic of vasculitis. The patient’s hoarseness subsided after a l-week course of prednisone. Six months after discontinuation of hydralazine therapy, follow-up laryngoscopy showed resolution of the epiglottic “pseudotumor.” Case 3 was noted to have acute epiglottitis in addition to diffuse laryngeal edema. Cultures were negative, and epiglottic swelling resolved after 4 days of intubation and high-dose corticosteroid therapy. Differential diagnosis. Epiglottitis in children is predominantly caused by Haemophilus inpuenzae B, whereas staphylococcal and streptococcal infections are the primary cause in adults.4’ TREATMENT

Of the 97 cases reviewed, only a few included precise data concerning therapy. Of the seven cases in which steroid dosage was reported, five were receiving a daily prednisone dose of less than 20 mg at the time of laryngeal involvement. The actual response to therapy was noted in three of these: two responded to high doses of corticosteroids (cases 2 and 3) and one responded to 30 mg of prednisoneid (case 4). Two patients had a delayed response to high corticosteroid dosages. The patient reported by Gilliam and Cheatumlh developed stridor and laryngeal edema after 3 weeks of 60 mg of prednisoneid. This was prescribed in conjunction with cyclophosphamide (100 mgid), and eventual improvement did occur. The patient reported by Raz et al” required more than 3 weeks of prednisone therapy (200 mg/d) given with epinephrine inhalation before laryngeal edema resolved. However, it was not noted whether laryngeal cultures were performed. Although cytotoxic medication was used in three patients, only in one (Raz et a12’) was it added for laryngeal disease that was refractory to steroid therapy. Azathioprine was added for its steroid-sparing effect in the patient of Es-

LARYNGEAL

INVOLVEMENT

213

IN SLE

pana et aL9 and cyclophosphamide was used as initial therapy for the patient reported by Gilliam and Cheatum.16 The only other cases in which laryngeal symptoms failed to improve after steroid therapy were in patients with pulmonary hypertension (Aszkenasy et allo) or infection (Petri et a15). PATHOPHYSIOLOGY

OF LARYNGEAL IN SLE

DISEASE

The pathophysiology of laryngeal inflammation in SLE is not well understood. Oral mucosal immunoglobulin and complement deposition has previously been described. In one series, immunoglobulin deposition was noted in two of three patients with mucosal ulceration of the hard palate. IgM, C3, and C4 were deposited at the junction of the epithelium and the lamina propria in one patient; the other had IgG and IgM. Immunoglobulin deposition in blood vessel walls was observed in two of the biopsy specimens. One patient had IgG, the other had both IgG and IgM.40 Gilliam and Cheatuml’j found IgG, IgM, and C3 deposition along the laryngeal basement membrane as well as on the epidermal basement membrane in a simultaneously obtained skin biopsy specimen from the same lupus patient. It may be that antigen-antibody complexes diffuse to the basement membrane and are indicative of high levels of circulating immune complexes and overall disease activity. There is evidence to suggest that skin basement membrane immunoglobulin deposition correlates with the presence and severity of renal disease and general disease activity.42 As men-

tioned earlier, oral mucosal ulceration in SLE patients has been found to correlate with increased overall disease activity.40 Tissue deposition of immune complexes leads to complement activation and eventual neutrophi1 and mononuclear cell infiltration, resulting in localized inflammation. It is unknown why some patients have deposition of immune complexes at certain sites. Their laryngeal basement membranes may be better suited to binding immune complexes of a particular size or charge. Alternatively, they may have particular laryngeal antigens that lead to localized formation of immune complexes. CONCLUSIONS

The number of cases presented herein is too small to allow definitive conclusions concerning the characteristics and outcome of patients with SLE who develop significant laryngeal involvement. However, it seems clear that laryngeal symptoms can herald an impending disease exacerbation in a manner similar to other symptoms more traditionally associated with increasing disease activity. Patients with mild symptoms such as pharyngitis should be examined carefully for oral ulceration. Consideration should be given to increasing immunosuppressive medications while evaluating and treating for possible infection. Those with more severe symptoms such as hoarseness or dyspnea may need prompt otolaryngological consultation and endoscopy. Patients with evidence of vasculitis on laryngeal biopsy should be evaluated for systemic vasculitis and treated accordingly.

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et al: The band test.