Perspectives in Otology

From the Medical University of South Carolina's 9th Annual Charleston Magnolia Conference

D. Bradley Welling, MD, Professor and Chairman, Department of Otolaryngology  —  Head and Neck Surgery, Ohio State College of Medicine

Educational Objectives

The goals of this program are to improve reconstruction techniques for the middle ear and to advance treatment of Meniere's Disease (MD) and vestibular schwannoma (VS). After hearing and assimilating this program, the clinician will be better able to:

1.   Assess and treat patients in need of middle ear reconstruction.

2.   Discuss definite, probable, and possible definitions for MD.

3.   Explain surgical options, such as intratympanic aminoglycosides, endolymphatic shunt, and intratympanic ste­roids, for the treatment of MD.

4.   Describe the underlying genetic and molecular etiology of VS.

5.   Discuss mechanisms and outcomes of drug  and radiation therapy for VS.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose. In his lectures, Dr. Welling discusses the off-label or investigational use of a therapy, product, or device.

Acknowledgments

Dr. Welling was recorded at 9th Annual Charleston Magnolia Conference, held June 5-6, 2009, in Charleston, SC, and sponsored by the Medical University of South Carolina's Department of Otolaryngology  –  Head and Neck Surgery and Office of Continuing Medical Education. The Audio-Digest Foundation thanks Dr. Welling and the Medical University of South Carolina for their co­operation in the production of this program.

Challenges in Middle Ear Reconstruction

Overview: treatment advice based on personal experience and several retrospective studies; tympanic perforation  —meatal incision made in skin of canal, then moving post-auricularly, turn ear forward for good exposure; save loose connective tissue overlying temporalis fascia (makes natural-looking tympanic membrane [TM]); remaining squa­mous epithelium peeled off malleus; rim freshened and flaps moved down in canal; adrenaline-soaked compressed sponge (Gelfoam) placed in middle ear; advantages of large graft  —  does not pull away from anterior edge where reperforation most likely; gives area for vascular supply from canal skin; flaps laid back down over fascia graft and external canal filled with antibiotic ointment (Polysporin); compression sponge  —  consider using for edge of perfo­ration before filling with antibiotic ointment; most will drain within 3 wk postoperatively

Nonsurgical alternatives (Japanese study): used fibroblast growth factor on compressed sponge and covered with fibrin glue; 99 of 100 healed after several applications, many after first

Surgical Cases

Case 1: man 35 yr of age with left chronic otitis media; 2 yr progressive hearing loss; no otalgia or otorrhea; physical examination  —  eroded incus; retracted TM; tympanosclerosis; preoperative audiography  —  excellent speech dis­crimination; operative findings  —  eroded long process of incus with mobile remnant; intact stapes and malleus; TM did not contact stapes

Treatment options: sculpted incus  —  does not erode through TM; well tolerated; partial ossicular replacement prosthesis (PORP)  —  convenient; can cause irritation of TM; Applebaum prosthesis  —  cartilage covering pre­vents erosion through TM if retraction occurs; lip heavy and sometimes falls away from incus; speaker has not had good results; bone cement (eg, OtoMimix)  —build bridge with narrow gap; placement between incus and sta­pes gives firm fixation; works well if no retraction; over time, irritates TM in manner similar to hydroxyapatite; bone cement retrospective study  —  mainly used for incus erosion; also used for securing prostheses and incus augmentation after stapedectomy; not successful for recontouring external auditory canal (if mucosal inflamma­tion present, can become infected)

Case 2: child 6 yr of age with history of otorrhea; left cholesteatoma removed 6 mo ago; incus absent; no vestibular symptoms; audiogram  —  large conductive loss; re-exploration  —  no residual cholesteatoma; mobile malleus;  stapes superstructure fixed (tympanosclerosis)

Treatment options: 1) hearing aid; 2) stapedectomy with oval window graft and total ossicular replacement prosthe­sis (TORP); 3) stapedectomy with oval window graft and third stage TORP; 4) stapedotomy and malleus-to-foot­plate prosthesis; 5) prosthesis to fixed footplate; avoid altering footplate in pediatric patients; retrospective study of pediatric stapedectomies  —  shows middle ear problems likely in future; consider using prosthesis to close some of gap; titanium prostheses have good acoustic properties, but not as stable as polyethylene shaft with hy­droxyapatite head; results similar to those of adults for juvenile otosclerosis or congenital stapes fixation without cochlear anomaly; for tympanosclerosis, 10 to 20 dB air-blown gap; children more likely to have sensorineural hearing loss (SNHL)

Case 3: woman 28 yr of age; right chronic otorrhea (6 yr); intermittent discomfort and mild conductive hearing loss (CHL); mobile, "beefy red" TM and external auditory canal

Treatment options: chronic myringitis  —  challenging to treat; acid alcohol irrigations, powdered antibiotic or anti­fungal topical application, topical steroids, ciprofloxacin/dexamethasone, or other combinations; surgical options include local debridement (50% effective) and homograph myringoplasty; external auditory canal stenosis  —  blunted lateralized TM; increases CHL (use hearing aid); transcanal tympanoplasty and skin graft (first option); postauricular canaloplasty and split-thickness skin graft (better exposure); homograft tympanoplasty; canal wall down mastoidectomy widens canal and prevents scarring and reblunting; bone anchored hearing aid (bypasses CHL without reconstruction)

Case 4: moderate CHL; facial nerve overhanging 75% of oval window; firmly fixed stapes footplate

Treatment options: hearing aid; stapedotomy; laser stapedotomy; stapes mobilization not helpful; retrospective study  —  with thickened soft tissue and aberrant facial nerve over oval window, if crura stop in soft tissue and are mobile, best left alone

Case 5: patient 42 yr of age; had left stapedectomy 2 yr earlier, with stainless steel shaft and platinum ribbon wire prosthesis; initial results excellent, but gap reappeared; piston lateralized and pushed out of stapedotomy; incus narrowed; seen in 9% of patients with prosthesis

Treatment options: hearing aid; replace platinum prosthesis with nitinol piston; bone cement can secure; cup prosthesis  —  not useful if incus narrow

Meniere's Disease (MD) Update

MD definitions: other causes excluded; definite  —  2 spontaneous episodes of vertigo lasting ³20 min;  change in hearing audiometrically documented at least once; tinnitus or aural fullness; certain MD involves temporal bone donation; possible (1 of these)  —  episodic vertigo of Meniere's type with no hearing loss; fluctuating SNHL (pri­marily low frequency) with or without dysequilibrium, but no definite vertigo; probable  —  1 definite episode of true vertigo; documented fluctuation in hearing at least once; tinnitus or aural fullness

Trends in surgical management: use of intratympanic gentamicin increasing; vestibular neurectomy decreasing; en­dolymphatic sac surgery remains popular

Intratympanic aminoglycosides: dosing, delivery, treatment schedules, and end points vary

Double-blinded randomized placebo-controlled trial: 22 patients ³6 mo follow-up; end points measured before each injection of gentamicin (30 mg/mL); number of treatments  —  1.5 in gentamicin group (vs 2.7 in placebo; not significant); vertiginous attacks per year  —  before gentamicin 74 vs 0 after; for placebo, 25 before vs 11 after (also statistically significant); vertigo  —  12 gentamicin-treated patients reported no vertigo for 6 wk after last treatment; significant reduction in placebo group; caloric response (degrees/sec) and hearing loss  —  high degree of variability; not significant in either group

Chia et al (2004): review of »980 patients in 27 studies; dosing categories  —  multiple daily, weekly, low-dose, con­tinuous microcatheter infusion, and titration; overall complete vestibular control  —  73% of patients (wide varia­tion); more aggressive dosing regimens may be most effective; titration method produced greater complete vertigo control (81%) when compared to other methods (eg, 67% in low-dose group); overall hearing loss  —  »25% of patients had some SNHL; multiple daily dosing, 34%; other methods less but not statistically signifi­cant; profound SNHL in 6% of patients; vertigo control  —  with complete ablation of vestibular response, 92% of patients had control of vertigo; partial control seen in 74% when partial ablation occurred (not statistically signif­icant); hearing loss  —  with complete vestibular ablation, 37% vs 24% with partial ablation; take-home message  —  titration method best for complete and effective vertigo control; less aggressive treatment may be ap­propriate; degree of vestibular ablation not associated with degree of vestibular control or hearing loss

Cohen-Kerem (Laryngoscope 2004): meta-analysis; high dose over short period not more beneficial than low dose over extended period; avoid short high-dosing schedules

Endolymphatic shunt: significant vertigo control; meta-analysis  —  nonablative nature advantage; vertigo control  —87% (class A or B); »79% class A; 7% fail; revisions  —common; hearing loss  —  »5% at time of surgery; 20% of patients improved hearing; 20% improvement in tinnitus; long-term  —  no protective benefit; vertigo control better with gentamicin, and hearing loss equal over time

Intratympanic steroids (Johns Hopkins retrospective study): 129 patients using dexamethasone (12 mg/mL); fol­lowed for 2 yr; acceptable vertigo control 91%; more frequent dosing  —  spreads drug throughout length of cochlea (also true for gentamicin); control of vertigo  —  37% with 1 injection; 20% with 2; 14% with 3; 70% needed no fur­ther injections by time of publication; 26% ongoing; 4% failed steroids and went on to gentamicin

Vestibular Schwannomas (VS): Pathogenesis and Treatment

Genetic and molecular etiology: neurofibromin 2 (NF2) gene  —  underlying cause; encodes protein “merlin” (moe­sin ezrin radixin-like gene); merlin  —  in 4.1-related protein family; N-terminal domain similar (globular region fol­lowed by coiled alpha-helical segment); carboxy terminus  —  charged; differs from others in family; 4.1-related proteins  —  attach actin cytoskeleton to plasma membrane; most growth permissive, but merlin growth inhibitory; phosphorylated merlin at carboxy end  —  open configuration; growth permissive; in cytoplasm; dephosphorylated  —  closes on itself, moves to plasma membrane and becomes growth inhibitory through interac­tion with cell membrane-associated proteins; tumor NF2 analysis  —  mutations spread throughout, except in exons 16 and 17

Merlin functions and pathways: inhibits cell motility, spreading, and invasiveness; affects growth of Schwann cells and meningiomas; coordinates receptor signaling; expression  —  neural tube formation in early embryogenesis; reti­nal pigment epithelium and trigeminal ganglion

Drug Therapy

OSU-0312 in vitro studies: pyruvate dehydrogenase isoenzyme 1 (PDK1) inhibitor derived from cyclooxygenase 2 inhibitor (methyl group responsible for cardiac side effects not present); treatment  —  required dose much lower than lethal dose; dose-dependent inhibition of serine-threonine kinase phosphorylation; increase in apoptosis (24-48 hr) in malignant and benign schwannoma cells; xenograft mouse model  —  65% decrease in malignant tumor vol­ume; drug crosses blood-brain barrier; treating meningiomas  —   72% of pediatric patients have lost NF2 gene; in vitro study shows drug kills grade III malignant meningioma cells in dose-dependent fashion

Other potential therapeutic agents: inhibitors of mitogen-activated protein kinase, ErbB2, vascular endothelial growth factor (VEGF), or combination; VEGF  —  testing in patients with end-stage NF2 tumors; some drugs may decrease required radiation;  bevacizumab (Avastin)  —  VEGF inhibitor; in 9 of 10 patients, decrease in tumor size; 6 of 10 had ³20% decrease in tumor volume; improved speech discrimination score in some; uncommon side ef­fects, eg, bowel perforation, hemorrhage; most encouraging therapeutic to date; given intravenously (IV)

Treatment modalities: observation  —  acceptable for elderly patients with small tumors; »33% of patients; remainder receive surgery or radiation therapy; tumor growth rates  —estimates vary from »33%  to 85%; usually ³2 mm; studies not volumetric ; further treatment not necessarily warranted, even in patients with some growth

Stereotactic Radiation Therapy

Overview: also called gamma knife therapy; goal to stop tumor growth, but often uncertain which tumors actively growing; »50%  grow over 2 to 3 yr; radiation  —  effective compared to observation; likely causes decrease in vas­cular supply to tumors;  quality of life  —  excellent; patients return to work quickly; short-term outcomes  —  eg, tu­mor control, reduced cranial neuropathies; long-term control  —uncertain; must use balanced approach; malignant change  —  1 in 1000; of patients who develop malignant tumors after irradiation,  »50% have NF2 (further radiation not recommended); swelling after irradiation  —  »23% of patients; do not assess tumor growth for 1 to 2 yr; average growth 2 to 4 mm but may reach 10 mm; post-irradiation changes  —  vascular changes, interstitial fibrin; viable Schwann cells still present

Single-dose vs fractionated radiation therapy: 5-yr progression-free rate  —  single dose, 95% of patients; fraction­ated dosing, 94%; hearing loss  —  similar; on average, 15 to 20 dB decline over several years; serviceable hearing  —  cannot tell difference; facial nerve outcome  —  acceptable for both; permanent facial nerve palsy in 5% of patients; if £16 Gray (Gy), 15%; £13 Gy, 0% to 10%; fractionated, 6%; actuarial growth  —  81% control rate at 15 yr; 35% with serviceable hearing pretreatment had 48% preservation rate at 5 yr

Cystic schwannomas: 5% of speaker's patients; cystic pockets  —  poor response to stereotactic radiation; malignant changes in 0.1% worldwide; 8000 cases treated since 1969; 3 cases of tumors that became malignant without irra­diation; Japanese patient  —  incomplete tumor resection at 26 yr of age; remnant irradiated; regrew and became ma­lignant; identified p53 mutation not present at first resection; 30-yr follow-up may be necessary

Take-home points: useful tool with potential to reduce morbidity; can combine with surgery  —  avoid incomplete re­sections in young patients; long-term effects uncertain

Case Examples

Case A: boy 11 yr of age; family history of NF2; enhancement on lateral auditory canal; enhancement of facial nerve and geniculate ganglion suggesting facial nerve schwannomas; ependymoma in pons; facial nerve tumor and ab­normal internal auditory canal; T2-weighted image  —  lack of spinal fluid in internal auditory canal; small amount of fluid outside of tumor; audiography  —  satisfactory speech discrimination; consider treatment over observation

Hearing preservation strategies: resect most favorable tumor first to preserve hearing in that ear; if successful, re­sect second tumor; if failed to save hearing in first ear but cochlear nerve intact, consider cochlear implant after hearing gone in second ear; if unable to save hearing in either ear  —  consider auditory brainstem implant (useful for sound awareness but not for open-set speech discrimination); open-set speech understanding in