Otologic Seminar 2002-06-26
Primary “Autoimmune” Inner Ear Disease
R2 Juen-Haur Hwang
Introduction
1.Blood-Labyrinthine barrier:
Lack of lymphatic drainage
Immunoglobulins: 1/1000 of the titer present in serum
2.The primary point of entry of leukocytes : spiral modiolar vein.
3.1944, De Kleyn, first published the first group of patients with
“idiopathic” sensorineural hearing loss (SHL).
4.1979, McCabe, real recognition of autoimmune disorder in inner-ear
nonhealing mastoidectomy wound, progressive bilateral but
asymmetric SNHL, mild or absent vestibulopathy, vasculitis, steroid
5.It’s hard to establish such a diagnosis:
/ The variability in the clinical course and laboratory tests.
/ The difficulty of human organ biopsy for immunopathologic survey.
Suspicion of immune-mediated inner ear disease
1.SNHL is bilateral (particularly when rapidly progressive)
2.It occurs in an only-hearing ear
3.Systemic immune disease is present
Organ-specific or systemic disorder
Primary “autoimmune” inner ear disease
Temporal arteritis
Wegener’s granulomatosis
Cogan’s syndrome
Polyarteritis nodosa
Delayed contralateral endolymphatic hydrops
Disease manifestations
1.Typical patients was middle-aged women: 63%~65% women
2.Rapid progressive SNHL over several weeks.
3.Bilateral involvement: 79%
4.No associated vestibular symptoms: 1/3(+)
5.Occasionally, concomitant serous otitis media.
6.Fluctuation of hearing and presence of dizziness and aural fullness:
about 1/4 to 1/2 (-->Meniere's disease)
7.Coexistence of other systemic autoimmune disease: 29%
Pathology
1.Schuknecht, 1991.
/ Bilateral progressive SNHL and systemic eosinophilia.
/ Temporal bone findings after death
*hydrops
*mononuclear and plasma cell infiltrates in the scalae
*osteoneogenesis in the scala tympani adjacent to the round
window membrane
*perivascular infiltrates surrounding the spiral modiolar veins
2.Veldman, 1986.
/ Progressive polyneuropathy with bilateral severe SNHL after tetanus
toxoid vaccination on a 46-year-old man
/ Circulating cross-reacting antibodies with spiral ganglion cells of
human temporal bones of unrelated dead newborns.
Diagnostic tests ( finding a specific marker)
1. Arnold et al, 1985. Cadaveric temporal bone sections as an antigenic
source for immunohistochemical assay.
Problems: controls, nonspecific staining, technical difficulties
2.Berger et al., 1989; Hughes et al, 1994. Lymphocyte transformation test
(blastogenesis) against inner ear antigen.
Problems: non organ-specific, insensitive
3.Western blot immunoassay
*Harris & Sharp, 1990.
Against 68-kD inner-ear antigen, organ-specific(?)
/ This antigen in all tissue components of membranous inner ear
structure.
/ Associated with renal tissue, heat shock protein-70.
/ 19/54 (35%) positive in progressive SNHL
No hearing loss (5%), RA or SLE (7%), Healthy woman (8%)
/ female predominance (63%)
/ Specific (95%) but insensitive(up to 89 % with active disease)
/ Responsive to steroid: 75 % (Positive) v.s. 18% (Negative)
*Veldman & Hanada, 1993.
/ Three groups: Rapidly progressive SNHL: over weeks to months
Sudden deafness: within hours to days
Mixed: over several months to years
Table 1:
Table 2:
/ In rapidly progressive SNHL group
11/15 (73%) positive
68 kD band (IgG or IgA; never IgM): specific
*Mayot, 1993
Fig 1
/ Autoimmune pattern: 30%
/ Anti-cochlear antibodies were mostly directed to the membrana
tectoria.
4.Others: non-specific, non-sensitive
/Antigen-nonspecific serologic tests
/Autoantibodies (ANA, anticardiolipin, anti-smooth muscle, antiendoplasmic reticulum): non-specific, increasing positive with age.
/Acute phase reactants: sedimentation rate, C-reactive protein, etc
Meniere’s disease: autoimmune ?
Elevated immune complexes: 54%~96% (healthy individuals2.9%)
Anti-68 kD autoantibody: 32%
Immune complexes (IgG) in the endolymphatic sac: relationship ?
Live cytomegalovirus injection into the endolymphatic sac
endolymphatic hydrops and hearing loss
viral replication within the sac epithelial cells
Otosyphilis:
endolymphatic hydrops;
round-cell infiltrates surrounding the endolymphatic duct
MHC class I HLA allele CW7: highly significant association
Autoimmune inner-ear disease
9.Delayed endolymphatic hydrops: Western bolts positive (6/7)
Against 68 kd or 35-36 Kd antigen in cow cochlear inner ear.
Treatment
1.Steroids
* Prednisolone (glucocorticoid)
/Contraindications/ Careful monitoring:
pregnancy, peptic ulcer disease, glaucoma, diabetes,
hypertension, inactive tuberculosis, osteoporosis,
recent vaccination
/ 1-2 mg/kg/day for 1 month, first
/ Improved hearing: evident after three weeks.
/ Maintenance on alternate-day therapy as low a dose as possible, as
long as hearing is maintained.
*Aldosterone (mineralocorticoid; no immune suppressive function)
/ Only enhancing sodium transport of stria vascularis
/ As effective as the prednisolone in restoring cochlear function in
lupus autoimmune mice
2.Cyclophosphamide (2-5 mg/kg/day)
/ for no response to steroids ; for not of childbearing age.
/ Contraindications/ Careful monitoring:
Bone marrow suppression, Hemorrhagic cystitis
3.Low-salt diet: 2-4g sodium/kg
4.Hydrochlorothiazide (25 mg): diuretic therapy, k-sparing
*1# qd with fruit juice
In conclusion
1.Not all unexplained form of progressive SNHL or sudden deafness
should be assumed to be (auto) immune.
2.Additional analyses are needed to characterize the antigenic epitopes
with a molecular weight of interest and to identify their exact tissue
location.
References
1.Hughes GB, Freedman MA, Haberkamp TJ, and Guay ME. Sudden
sensorineural hearing loss. Otolaryngologic Clinics of North America
1996; 29: 393-405.
2.McCabe BF. Autoimmune sensorineural hearing loss. Ann Oto Rhinol
Laryngol 1979; 88: 585-589.
3.Schuknecht H. Ear pathology in autoimmune disease. In Pfaltz CR,
Arnold W, Kleinsasser O, editors. Bearing of basic research on clinical
otolaryngology, 1991.
4.Veldman JE. Cochlear and retrocochlear immune-mediated inner ear
disorders: Pathogenetic mechanisms and diagnostic tools. Ann Otol
Rhinol Laryngol 1986; 95: 535-540.
5.Arnold W, Pfaltz R, Altermatt HJ. Evidence of serum antibodies against
inner ear tissues in the blood of patient with certain sensorineural
hearing disorders. Acta Otolaryngo (Stockh) 1985; 99: 437-44.
6.Berger P, et al. The lymphocyte transformation test for detecting
immunologic inner ear deafness. HNO 1989; 37: 153-157.
7.Hughes GB, Moscicki RA, Barna BP, San Martin JE. Laboratory
diagnosis of immune inner ear disease. Am J Otol 1994; 15: 198-202.
8.Harris JP, Sharp P. Inner ear autoantibodies in patients with rapidly
progressive sensorineural hearing loss. Laryngoscope 1990; 100: 516524.
9.Billings PB, Keithley EM, Harris JP. Evidence linking the 68-kd antigen
associated with progressive sensorineural hearing loss with the highly
inducible hsp 70. Ann Otol Rhinol Laryngol 1995; 104: 181-188.
10.Derebery MJ, et al. Meniere’s disease: an immune complex-mediated
illness ? Laryngoscope 1991; 101: 225-229.
11. Gottschlich S. Billings PB. Keithley EM. Weisman MH. Harris JP.
Assessment of serum antibodies in patients with rapidly progressive
sensorineural hearing loss and Meniere's disease. Laryngoscope 1995;
105:1347-1352.
12.Harris JP, Aframiam D. Role of autoimmunity in contralaterall delayed
endolymphatic hydrops. Am J Otol 1994; 15: 710-716.
13.Veldman JE, Hanada T, Meeuwsen F. Diagnostic and therapeutic
dilemmas in rapidly progressive sensorineural hearing loss and sudden
deafness. Acta Otolaryngol (Stockh) 1993; 113: 303-306.
14.Mayot D, Bene MC, Dron K, et al. Immunologic alterations in Patients
with sensorineural hearing disorders. Clinical Immunology and
immunopathology. 1993; 68: 41-45.
15.Trune DR, Kempton JB. Aldosterone and prednisolone control of
cochlear function in MRL/MpJ-Fas(lpr) autoimmune mice. Hearing
research 2001; 155: 9-20.