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OTOSCLEROSIS — A COMPREHENSIVE 50-MARK ESSAY

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TABLE OF CONTENTS

1. Introduction & Definition
2. Historical Background
3. Epidemiology
4. Etiopathogenesis
5. Histopathology
6. Classification
7. Clinical Features
8. Investigations
9. Differential Diagnosis
10. Management
11. Complications
12. Recent Advances
13. Summary Flowcharts & Diagrams

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1. INTRODUCTION & DEFINITION

Terminological note: The term otospongiosis (Politzer, 1894) is histologically more accurate as the active lesion is vascular and spongy, while otosclerosis refers to the later sclerotic stage. Clinically, the term otosclerosis is universally retained.

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2. HISTORICAL BACKGROUND

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3. EPIDEMIOLOGY

• Prevalence (histological): ~10% of white Caucasians have microscopic foci; ~1% develop clinical disease
• Prevalence (clinical): 0.3–0.4% of white adults
• Gender: Female:Male = 2:1; hormonal factors implicated
• Race: Predominantly Caucasian; rare in Africans and Asians
• Laterality: Bilateral in 70–80% of cases (asymmetric)
• Age of onset: 2nd–4th decade; rarely before puberty
• Family history: Present in 25–40% of cases
• Inheritance: Autosomal dominant with 25–40% penetrance

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4. ETIOPATHOGENESIS

4.1 Genetic Factors

• Autosomal dominant with incomplete penetrance (~25–40%)
• Multiple loci identified: OTSC1 (15q25–26), OTSC2 (7q34–36), OTSC3 (6p21–22), OTSC4 (16q21–23), OTSC5, OTSC7, OTSC8
• COL1A1 gene mutations (Type I collagen) — most consistently linked; associated with vulnerability of enchondral bone
• TGF-β1 gene polymorphisms — linked to abnormal bone remodeling
• RELN gene (encoding Reelin) — recent candidate

4.2 Viral Theory — Measles Virus

• Measles (Rubeola) virus is the strongest environmental trigger
• Viral RNA, antigens, and virus-like particles demonstrated in otosclerotic foci (McKenna & Mills, 1989)
• Anti-measles antibody titers elevated in perilymph of otosclerotic patients
• Measles infects enchondral bone, triggering aberrant remodeling
• MMR vaccination: Studies (Niedermeyer, 2001) showed declining incidence of otosclerosis in countries with high measles vaccination coverage — suggesting a causal link
• The virus may act as an environmental "second hit" in genetically susceptible individuals

4.3 Hormonal Factors

• Female predominance and onset at puberty, pregnancy, menopause — estrogen implicated
• Estrogen may accelerate bone remodeling in otic capsule
• Oral contraceptive use and pregnancy are known to accelerate progression
• Fluoride (sodium fluoride) antagonizes this by inhibiting osteoclastic activity

4.4 Autoimmune Theory

• Type II collagen autoantibodies found in otosclerosis patients
• Abnormal expression of HLA antigens (HLA-A, HLA-B)
• Immune complexes deposited in otic capsule
• Activation of complement and macrophages triggers osteoclast recruitment

4.5 Bone Metabolism Dysregulation — The Central Mechanism

PATHOGENETIC CASCADE:
─────────────────────────────────────────────────────────
Genetic susceptibility (COL1A1, TGF-β1)
         +
Environmental trigger (Measles virus)
         +
Hormonal acceleration (Estrogen)
         ↓
Activation of OSTEOCLASTS at otic capsule
         ↓
Resorption of dense enchondral bone
         ↓
Replacement by vascular spongy bone (OTOSPONGIOSIS)
         ↓
Fibroblast proliferation → NEW ABNORMAL BONE deposition
         ↓
SCLEROSIS — dense avascular bone
         ↓
STAPES FOOTPLATE FIXATION → CHL
+/- Cochlear endosteum involvement → SNHL
─────────────────────────────────────────────────────────

4.6 Role of Growth Factors

• TGF-β1 (Transforming Growth Factor-β1): Overexpressed in otosclerotic foci; stimulates osteoblasts; key mediator
• BMP (Bone Morphogenetic Protein): BMP-2, BMP-4 elevated; promotes ectopic ossification
• VEGF (Vascular Endothelial Growth Factor): Drives the vascularity of active foci
• IGF-1: Promotes osteoblast proliferation
• RANKL/OPG axis: RANKL upregulation → osteoclast activation; OPG (osteoprotegerin) deficiency

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5. HISTOPATHOLOGY

Histological Zones:

Microscopic Features:

1. Haversian system disruption — disorganized vascular channels
2. "Blue mantles" (Manasse) — newly formed woven bone with deep blue staining
3. Osteoclastic lacunae (Howship's lacunae) surrounded by large, multinucleated osteoclasts
4. Mosaic pattern of lamellar bone (mature lesion)
5. Vascular spaces filled with red marrow-like tissue in active phase
6. Fibrous stroma with inflammatory cells

Sites of Predilection (in order of frequency):

1. Fissula ante fenestram (anterior to oval window) — 90%
   (PRIMARY site; between oval window and cochleariform process)
2. Round window margin — 30%
3. Anterior cochlear wall near helicotrema
4. Posterior to oval window
5. Semicircular canals (rare)

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6. CLASSIFICATION

6.1 By Clinical Type

6.2 By Footplate Appearance (Surgical Classification — Shea)

6.3 Pearce Classification (Scott-Brown)

• Grade I: Localized focus at fissula ante fenestram
• Grade II: Complete footplate involvement
• Grade III: Obliterative — total bony closure of oval window

6.4 Activity Classification

• Active (otospongiotic) — progressive, fluorescent imaging positive
• Inactive (otosclerotic) — stable, sclerotic

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7. CLINICAL FEATURES

7.1 Symptoms

• Progressive, bilateral, asymmetric CHL — insidious onset
• Typically begins in 2nd–3rd decade
• Initially low-frequency CHL (due to stapes mass/fixation)
• Progression: 1–2 dB per year on average
• Paracusis Willisii: Paradoxical improvement in hearing in noisy environments — pathognomonic; occurs because others raise their voice in noise while the masking background noise does not penetrate the fixed ossicular chain as much as it does for normal-hearing individuals

• Present in ~75% of patients
• Usually low-frequency, pulsatile or hissing
• Correlates with active disease

• Present in ~25% of patients
• Usually mild; due to perilymphatic involvement
• Severe vertigo rare — suggests vestibular otosclerosis

7.2 Signs

• External ear canal: Normal
• Tympanic membrane: Intact, normal in appearance

• Pinkish/reddish hue seen through the tympanic membrane
• Caused by increased vascularity of the active otosclerotic focus over the promontory
• Indicates active, rapidly progressive disease
• Seen in ~10–15% of patients
• Clinical significance: Patients with Schwartze sign benefit most from sodium fluoride therapy (Dhingra, 7th Ed.)

Gelle's Test Negative = Pathognomonic of stapes fixation (Dhingra; Zakir Hussain)

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8. INVESTIGATIONS

8.1 Pure Tone Audiometry (PTA)

AUDIOMETRIC PATTERN IN OTOSCLEROSIS:
─────────────────────────────────────────────────────────────
dB  250  500  1000  2000  4000  8000 Hz
 0   ─────────────────────────────────  (Normal)
10
20                                        AC ─ ─ ─ ─
30        ●────────────────●             BC ●────●
40           ↑ Carhart Notch             
             at 2000 Hz
─────────────────────────────────────────────────────────────
• Air-Bone Gap (ABG): 20–65 dB
• Carhart Notch: mechanical notch at 2000 Hz in BC curve
  (NOT true SNHL — disappears after successful stapedectomy)
• Low-frequency CHL predominantly (early stages)

• Dip in bone conduction at 2000 Hz (often 5 dB at 500 Hz, 10 dB at 1000 Hz, 15 dB at 2000 Hz, 5 dB at 4000 Hz)
• Mechanical artifact due to stapes resonance frequency interruption, NOT true cochlear SNHL
• Disappears after successful stapedectomy — confirms mechanical nature
• (Carhart, 1950; Cummings 7th Ed.)

8.2 Tympanometry (Impedance Audiometry)

"The acoustic reflex is absent in otosclerosis and present in inner-ear conductive hearing loss — this distinction is critical." (Harrison's Principles, 21st Ed., p. 1040)

8.3 Speech Audiometry

• Speech Discrimination Score (SDS): Normal (>90%) in pure fenestral otosclerosis
• Reduced in cochlear otosclerosis

8.4 High-Resolution CT (HRCT) Temporal Bone

• Investigation of choice for surgical planning and cochlear otosclerosis
• CT Findings:
  • "Halo sign" (double ring sign) — hypodense halo around cochlear lumen; pathognomonic of cochlear otosclerosis
  • Oval window narrowing/obliteration
  • Thickened stapes footplate
  • Pericochelar lucency (active focus)
  • Biscuit footplate — thick, dense footplate on CT

HRCT GRADING OF COCHLEAR OTOSCLEROSIS (Rotteveel):
Grade 1 — Isolated fenestral otosclerosis
Grade 2a — Double-ring around cochlea (incomplete)
Grade 2b — Double-ring around cochlea (complete)
Grade 3 — Confluent capsule involvement

8.5 MRI

• Less useful than CT
• Gadolinium enhancement of active foci on T1 (due to vascularity)
• Rules out retrocochlear pathology

8.6 Electrocochleography (ECoG)

• Identifies endolymphatic hydrops in cochlear otosclerosis

8.7 Vestibular Function Tests

• Caloric tests — may show hypofunction in vestibular otosclerosis

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9. DIFFERENTIAL DIAGNOSIS

Van der Hoeve Syndrome: Triad of blue sclerae + otosclerosis + osteogenesis imperfecta (Stell & Maran; Dhingra)

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10. MANAGEMENT

MANAGEMENT ALGORITHM FOR OTOSCLEROSIS:
──────────────────────────────────────────────────────────────
                    CONFIRMED OTOSCLEROSIS
                           │
              ┌────────────┴────────────┐
         Active disease           Stable/inactive
         (Schwartze sign +)           disease
              │                        │
      Sodium Fluoride           Assess hearing
      therapy first                   │
              │              ┌─────────┴────────┐
              └──────────────►   ABG ≥ 20–25 dB?
                                       │
                           ┌───────────┴───────────┐
                          YES                      NO
                           │                        │
                   SURGICAL                   Hearing Aid /
                   CANDIDATE?                 Observation
                  │                  
          ┌───────┴───────┐          
       FIT for           NOT FIT     
       surgery           surgery     
          │                │         
    STAPEDECTOMY/    Hearing Aid /   
    STAPEDOTOMY      Cochlear Implant
          │          (cochlear otosclerosis)
    Successful? ──► Amplification PRN
──────────────────────────────────────────────────────────────

10.1 MEDICAL MANAGEMENT

• Mechanism:
  • Converts hydroxyapatite → fluorapatite — more resistant to enzymatic degradation
  • Inhibits lysosomal enzymatic activity of osteoclasts
  • Reduces activity of alkaline phosphatase
  • Stabilizes otospongiotic foci → prevents further SNHL progression
• Indications:
  • Active disease (Schwartze sign positive)
  • Predominantly SNHL (cochlear otosclerosis)
  • Progressive SNHL in known otosclerosis
  • Pre/post operative (some surgeons use perioperatively)
• Dose: Sodium fluoride 20–40 mg/day PO for 2 years (some continue longer)
• Monitoring: Serum fluoride levels, urine fluoride, dental fluorosis
• Side effects: GI upset, dental mottling, skeletal fluorosis (with excess), osteosclerosis of other bones
• Contraindications: Renal failure, pregnancy, children
• Efficacy: Arrests/slows SNHL progression in ~70%; does NOT improve CHL

• Risedronate, alendronate — experimental
• Inhibit osteoclast-mediated bone resorption
• Limited evidence; not standard of care

• Theoretical interest given viral etiology
• MMR vaccination — public health role in prevention

• Avoid OCP / progesterone in progressive disease
• No direct hormonal therapy established

10.2 HEARING AID

• Patient unfit for/refuses surgery
• Cochlear otosclerosis with SNHL
• Elderly patients
• Unilateral good hearing
• Very mild ABG (<20 dB)

10.3 SURGICAL MANAGEMENT

Pre-operative Assessment:

• PTA — establish ABG ≥ 20–25 dB (most surgeons use ≥30 dB)
• SDS ≥ 60% (ensures cochlear reserve)
• Tuning fork tests (512 Hz Rinne negative)
• HRCT temporal bone
• General fitness for surgery under GA/LA
• Better ear operated last (or only if CHL is significant)
• Counsel re: risk of dead ear (1–2%)

STAPEDECTOMY vs STAPEDOTOMY:

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SURGICAL PROCEDURE — STAPEDOTOMY (Step-by-Step)

1. INCISION — Endaural / Postaural
2. ELEVATION of tympanomeatal flap (TM flap raised posterosuperiorly)
3. EXPOSURE of middle ear — identify ossicular chain
4. CONFIRM STAPES FIXATION — probe mobility of incus/malleus (mobile)
   and stapes (fixed)
5. MEASURE prosthesis length — from incus to footplate (typically 4.5 mm)
6. DIVIDE stapedius tendon (cut)
7. DIVIDE posterior crus (laser / microchisel)
8. FRACTURE and remove stapes superstructure
9. STAPEDOTOMY — create 0.6–0.8 mm fenestra in center of footplate
   using: Microdrill / CO2 laser / KTP laser / Er:YAG laser
10. PROSTHESIS PLACEMENT — piston prosthesis (e.g., Teflon piston,
    titanium piston) placed through fenestra, crimped onto incus
11. SEAL GRAFT — fat/blood/vein graft over fenestra
12. REPLACE tympanomeatal flap
13. PACK external canal with gelfoam

• Teflon piston (Shea) — classic
• Stainless steel/platinum wire + Teflon piston (Robinson)
• Titanium piston — current preference (MRI compatible, lighter)
• NITINOL (shape-memory alloy) self-crimping piston — latest
• Diameter: 0.4–0.6 mm; Length: 4.0–4.5 mm

COMPLICATIONS OF STAPEDECTOMY/STAPEDOTOMY:

• Only hearing ear
• Severe cochlear reserve loss (SDS <50%)
• Active infection (AOM, CSOM)
• Previous surgery on better ear with poor results
• Patient's refusal

• Occupation (divers, pilots — risk of barotrauma)
• Pregnancy
• Contralateral dead ear
• Obliterative/biscuit footplate (increased risk)

REVISION STAPEDECTOMY:

• Indicated for: Prosthesis displacement, granuloma, incus necrosis
• Higher complication risk than primary surgery
• HRCT temporal bone mandatory pre-operatively

10.4 COCHLEAR IMPLANTATION

• Indicated in bilateral cochlear otosclerosis with:
  • Severe-profound SNHL
  • Failed hearing aids
  • SDS <50%
• Challenges:
  • Obliteration of cochlear lumen by new bone → difficult electrode insertion
  • Partial insertion may be needed
  • Drill-out of cochlear lumen (Steenerson technique) in complete obliteration
  • CT essential pre-operatively to map cochlear patency
• Results: Comparable to non-otosclerosis cochlear implant outcomes if full insertion achieved

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11. FLOWCHART: COMPREHENSIVE DIAGNOSTIC AND MANAGEMENT PATHWAY

PATIENT WITH PROGRESSIVE BILATERAL HEARING LOSS
                    │
                    ▼
         CLINICAL EVALUATION
    (History: family Hx, pregnancy, OCP use,
     Paracusis Willisii, tinnitus, vertigo)
                    │
                    ▼
         OTOSCOPY: Normal TM
         Schwartze sign? (Flamingo pink)
                    │
          ┌─────────┴────────┐
         YES               NO
          │                 │
     Active disease    Proceed to tests
          │
          ▼
    TUNING FORK TESTS
    Rinne –ve / Weber lateralizes
    Gelle's –ve (pathognomonic)
                    │
                    ▼
    PURE TONE AUDIOMETRY
    CHL ± Carhart notch at 2 kHz
    ABG 20–65 dB
                    │
                    ▼
    IMPEDANCE AUDIOMETRY
    Type As tympanogram + Absent reflex
                    │
                    ▼
         HRCT TEMPORAL BONE
    (surgical planning / cochlear involvement)
                    │
          ┌─────────┴────────────┐
     Fenestral                Cochlear
     (CHL dominant)          (SNHL dominant)
          │                        │
          ▼                        ▼
    ABG ≥ 25–30 dB?          Sodium Fluoride
    SDS ≥ 60%?               Hearing Aid / CI
          │
    ┌─────┴──────┐
   YES           NO
    │             │
 SURGERY       Medical Rx +
 (Stapedotomy)  Hearing Aid

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12. OTOSCLEROSIS AND PREGNANCY

• Pregnancy accelerates progression — estrogen effect
• Cochlear decompensation may occur post-partum
• OCP may similarly accelerate disease
• Surgery is deferred during pregnancy
• Sodium fluoride is contraindicated in pregnancy
• Hearing aid recommended during pregnancy

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13. VAN DER HOEVE SYNDROME

1. Blue sclerae (thin sclerae — transparency of choroidal pigment)
2. Otosclerosis (stapes fixation, CHL)
3. Osteogenesis imperfecta (brittle bones)

• COL1A1 mutation shared with both OI and otosclerosis
• Surgery technically difficult (fragile, bleeding bone)
• Same surgical principles apply

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14. COCHLEAR OTOSCLEROSIS — Special Consideration

• Spongiotic foci encroach on scala media endosteum
• Release of toxic enzymes → cochlear hair cell damage → SNHL
• Histamine, proteolytic enzymes from vascular foci damage spiral ligament
• CT: "Halo sign" (lucent halo around cochlea)
• Treatment: Sodium fluoride + hearing aid → cochlear implant if severe

COCHLEAR OTOSCLEROSIS PATHOMECHANISM:
─────────────────────────────────────────────────
Spongiotic foci near scala media
         │
Vascular channels breach endosteum
         │
Toxic metabolites (histamine, proteases)
enter perilymph/endolymph
         │
Hair cell degeneration
         │
Stria vascularis atrophy
         │
Progressive SNHL (irreversible)
─────────────────────────────────────────────────

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15. RECENT ADVANCES

15.1 Genetic Research

• Genome-wide association studies (GWAS): Identified multiple SNPs near RELN, BMP2, and TGF-β1 genes
• Epigenetics: DNA methylation patterns in otosclerotic tissue differ significantly from normal otic capsule
• Next-generation sequencing — identifying novel pathogenic variants in OTSC loci

15.2 Measles Vaccination Effect

• Large epidemiological studies (Niedermeyer et al., Chole et al.) confirm declining otosclerosis incidence correlating with MMR vaccination programs
• Supports viral etiology and potential preventive role of vaccination

15.3 Molecular Targets — Future Therapies

• Anti-TGF-β1 agents — losartan (TGF-β1 antagonist) investigated in animal models
• Bisphosphonates — risedronate studies ongoing; inhibit osteoclast activity
• Statin therapy — inhibits mevalonate pathway; preliminary reports of slowing progression
• BMP antagonists — Noggin, sclerostin — experimental

15.4 Laser Stapedotomy

• CO₂ laser (OtoLAM™): Non-contact; precise; minimal mechanical trauma; current gold standard
• KTP (532 nm) laser: Excellent hemostasis; good for vascular obliterative footplates
• Er:YAG laser: Minimal thermal damage; precise
• Meta-analyses confirm laser stapedotomy = better hearing outcomes and lower SNHL risk vs. mechanical methods (Wegner et al., 2021)

15.5 Robotic and Minimally Invasive Ear Surgery

• Robot-assisted stapedotomy (RobOtol™, France): Sub-millimeter precision; reduced hand tremor
• Proof-of-concept studies show safety; clinical adoption expanding
• (Miroir et al., 2019; Nguyen et al., 2023)

15.6 Endoscopic Ear Surgery (EES)

• Endoscopic stapedotomy increasingly reported
• Single-port, no postauricular incision
• Equivalent audiological outcomes; faster recovery
• (Poe, 2016; Marchioni et al., 2020)

15.7 3D-Printed Prostheses

• Customized 3D-printed titanium prostheses for unusual anatomy
• Research stage; promising for revision cases

15.8 Gene Therapy

• SiRNA targeting TGF-β1 and RANKL — experimental (animal models)
• Intratympanic delivery of viral vectors — theoretical approach to halt progression

15.9 Fluoride Therapy Revisited

• Systematic reviews confirm sodium fluoride stabilizes SNHL in cochlear otosclerosis
• Optimal dose refinement: 40 mg/day (Shambaugh) vs. lower doses (20 mg) — evidence supports lower dose with fewer side effects
• Combination therapy: Fluoride + bisphosphonate — under investigation

15.10 MRI in Cochlear Implant Planning

• 4D-MRI flow studies assess cochlear patency pre-CI in cochlear otosclerosis
• Gadolinium-enhanced MRI identifies active foci and predicts sodium fluoride response

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16. SUMMARY TABLE — OTOSCLEROSIS AT A GLANCE

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KEY REFERENCES

1. Scott-Brown's Otorhinolaryngology, Head and Neck Surgery, 8th Ed. — Vol. 3 (Otology), Chapter on Otosclerosis
2. Cummings Otolaryngology: Head and Neck Surgery, 7th Ed. — Chapter 145 (Otosclerosis), p. 2152–2170
3. Dhingra's Diseases of Ear, Nose and Throat, 7th Ed. — Chapter: Otosclerosis, pp. 82–93
4. Hazarika P., ENT Head and Neck Surgery, 4th Ed. — Otosclerosis
5. Zakir Hussain, Textbook of ENT and Head & Neck Surgery — Otosclerosis
6. Stell and Maran's Head and Neck Surgery, 5th Ed. — Otosclerosis and Stapes Surgery
7. Harrison's Principles of Internal Medicine, 21st Ed. — p. 1040 (Acoustic Reflex in Otosclerosis)
8. Bailey and Love's Short Practice of Surgery, 28th Ed. — p. 780 (Histopathology)
9. Schuknecht HF — Pathology of the Ear, 2nd Ed.
10. Shea JJ Jr (1998) — 40 years of stapes surgery. Am J Otol 19:52–55
11. Niedermeyer HP et al. (2001) — Measles virus and otosclerosis. Adv Otorhinolaryngol 59:68–74
12. Wegner I et al. (2021) — Laser versus non-laser stapedotomy: systematic review. Cochrane Database
13. Marchioni D et al. (2020) — Endoscopic stapedotomy outcomes. Otol Neurotol
14. Rotteveel LJC et al. (2004) — CT grading of cochlear otosclerosis. Eur Arch ORL
15. GWAS on OTSC loci — McKenna MJ et al., various, 2011–2023

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Examiner's Note: For a 50-mark answer, all sections above should be covered. Emphasis should be placed on: (1) Multifactorial etiopathogenesis with the measles–genetics–hormonal triad; (2) Histopathological zones and Manasse blue mantles; (3) Systematic clinical features including Gelle's test, Schwartze sign, Carhart notch; (4) Complete audiological battery; (5) Surgical technique of stapedotomy with prosthesis types; and (6) Recent advances including laser, endoscopic, robotic surgery, and gene therapy.