Mandibular Patterns of Chronic Ischemic Bone Disease (CIBD) Assessment of a High Risk Cadaver Cohort American Academy of Oral Medicine, Atlanta, Georgia April, 2016 J. E. Bouquot, DDS, MSD Director of Research, The Maxillofacial Center for Education and Research, Morgantown, West Virginia Wesley E. Shankland, DDS, MS Director, Facial Pain Clinic, Columbus, Ohio Firoozeh Samim, DDS, MS University of British Columbia, Vancouver, British Columbia, Canada

CIBD: The Oldest Bone Disease Osteonecrosis = earliest diagnosable bone disease (cavitations found in 90,000,000 year old diving dinosaurs, & a few land ones) First paper on hip osteonecrosis: Fothergill, 1794 (England) First paper on jaw osteonecrosis : Noel, 1868 (United States) -- Called it “bone caries” or “osteitis” Considered to be extremely rare -- Because it was reported under 72 different names (usually the surgeon’s name who first reported it)

CIBD: Like Osteomyelitis, but Not So Much Called “aseptic osteomyelitis” – looked like infection but no micro- organisms cultured Some called it “cardiac disease of the hip” -- thought it was a blood flow/infarction phenomenon, but couldn’t prove it Knew that bone cavitations were unique to this particular disease Term bone “cavitation” was coined for this disease in 1932 Along came Arlet and Ficat

CIBD: Like a Brand New Disease Ficat and Arlet (France): -- Said it’s all one disease (a marrow disease more than a bone disease) -- Has a wide microscopic spectrum, called Grades I – IV -- Not seen easily with available imaging technology -- Is a physiologic problem of ↓ blood flow in marrow Now classified under of several microscopic dxs: -- Ischemic osteonecrosis -- Bone marrow edema -- Transient/regional ischemic osteoporosis -- Other names Not rare: responsible for 30-40% of hip replacements Diagnosed by MRI more than by histopathology

CIBD: Since Like A Brand New Disease Up to 80% of cases were associated with hypercoagulation states -- Small clots predominate, but marrow and brain are both susceptible to capillary bed thrombosis Three other very unique features: -- Usually bilateral (up to 80% of cases) -- In affected bone: multiple involved areas, separated by normal marrow -- It’s poorly visualized on radiographs, but shows up well on bone scans (scintigraphy) Thrombus Tech 99 MDP scan

Residual socket (filled with collagen) 14 years after extraction Jawbone CIBD More likely to be missed because dentists assume tooth or sinus causes of pain, don’t look further Seem to be more painful than other locations -- Pain diminished greatly with anticoagulants Might be triggered by surgery/extraction, but pain doesn’t develop for decades Low-grade inflammation/infection is often present Same hypercoagulation states (72-80% of cases) Positive bone scan (97% accurate) Positive dx anesthesia test (98% accurate) Positive quantitative ultrasound (98% accurate) Residual socket (filled with collagen) 14 years after extraction

BME in patient diagnosed with atypical facial neuralgia Jawbone CIBD My name (1989) = NICO (Neuralgia-inducing cavitational osteonecrosis) My name (2002) = CIBD -- Bone marrow edema -- Regional ischemic osteoporosis -- Ischemic cavitation In 2010: Bouquot, McMahon classification systems for jawbone CIBD and osteomyelitis -- Available in the BouquotToGo Dropbox files BME in patient diagnosed with atypical facial neuralgia

CHRONIC ISCHEMIC BONE DISEASE (CIBD) Classification Ischemic marrow diseases: Bone marrow edema -- Ischemic myelofibrosis -- Reticular fatty degeneration -- Marrow congestion (dilated vessels) -- Regional ischemic osteoporosis Intramedullary fibrous scar Ischemic marrow atrophy (honeycombed bone) Ischemic osseous cavitation -- Traumatic bone cyst Ischemic bone diseases: Partially nonviable bone Ischemic osteonecrosis (avascular necrosis) -- BRONJ (bisphosphonate-related osteonecrosis of the jaws (biopsy shows acute osteomyelitis) -- Osteoradionecrosis Ischemic osteosclerosis -- Bone scar -- Condensing osteitis Poorly forming new bone Focal osteoporotic marrow defect Ischemic myelofibrosis Intramedullary fibrous scar Bone marrow edema Bouquot, McMahon, Annual meeting, American Academy of Oral & Maxillofacial Pathology, 2010

Chronic fibrosing osteomyelitis Chronic granulomatous osteomyelitis Inflammatory Jawbone Disease Classification per Bouquot & McMahon, 2012 * Acute osteomyelitis: Periapical abscess Periodontal abscess Periapical granuloma, suppurative Acute/subacute osteomyelitis -- Actinomycosis Chronic nonsuppurative osteomyelitis: Periapical granuloma, nonsuppurative Chronic fibrosing osteomyelitis -- Cemental tear -- Intramedullary fibrous scar, inflamed? Garré's osteomyelitis Chronic granulomatous osteomyelitis -- Tuberculous, syphilis, fungus -- Intramedullary foreign body reaction -- Sarcoidosis Chronic sclerosing osteomyelitis -- Diffuse -- Focal (condensing osteitis) Chronic fibrosing osteomyelitis Chronic granulomatous osteomyelitis * Bouquot J, Qari H, McMahon R. Chronic fibrosing osteomyelitis (CFO) – new or long forgotten jawbone disease? OOOO 2012; 114:e39

The Problem Medical pathologists get the entire femoral head to study, oral pathologists get bits and pieces (curettage is the Rx) Medicine has proven the multifocal nature of CIBD, dentistry has not Medicine has correlated histopathology with various gross appearances, dentistry has not Dentistry has found ischemic/inflammatory bone disease in the majority of implant sites CIBD, mandible Normal mandible

Investigative Objective Chronic ischemic bone disease (CIBD) has very unique histopathologic, imaging and gross anatomic characteristics, including multi-site involvement and bone cavitations. While the gross appearances are well established in long bones, they remain largely unknown for the jaws, despite the fact that jaws are among the most commonly affected bones. The purpose of this investigation was to characterize CIBD in mandibles from a cadaver cohort representing patients with high risk of chronic systemic ischemia.

Investigative Protocol Hemi-mandibles were obtained from cadaver material in the Department of Anatomy, WV School of Osteopathic Medicine, Lewisburg, WV Gender, age at death, cause of death and additional health records as available were reviewed Only cadavers from persons with chronic illnesses likely to be associated with systemic ischemia were accepted -- Cardiovascular disease, stroke, cancer/chemotherapy, chronic lung disease, kidney failure, liver failure, etc. Only well preserved cadavers were selected, but no special embalming procedures were performed Lateral jaw radiographs were obtained and then samples were slowly decalcified in a 1:1 solution of formalin and formic acid Once decalcified, each mandible was incised by scalpel blade along its long axis. Cut surfaces were examined grossly and via magnification, spatula-tested for firmness and texture, and photographed

Investigative Protocol Representative transverse and cross-sectional samples were taken from all abnormal regions for microscopic evaluation Similar samples were also taken routinely from the #32, #29, #26 areas Tissue samples were processed via research-grade procedures for bone evaluation, cut at 7 μ, and stained with hematoxylin and eosin Microscopic features searched for were those in the orthopedic literature for ischemic osteonecrosis (IO), bone marrow edema (BME) and osteomyelitis Ischemic and inflammatory diagnoses were taken from the classification systems described by Bouquot & McMahon (2010, 2012) Abnormal marrow Normal fatty marrow Normal fatty marrow

Investigative Results 66 hemi-mandibles were processed 62.2% (n = 46) from females Average age at death = 69.0 years (66.2 for males; 71.3 for females) Range, age at death = 42-91 years 24 were edentulous; 11 of the others had no posterior teeth Overall, 24 (33.4%) mandibles showed 34 grossly abnormal areas of medullary bone Terminal Disease Type Number % (N) with Gross Abnormality Autoimmune disease 6 50.0 (3) Cancer 22 45.5 (10) Heart disease 18 22.2 (4) Stroke 19 36.8 (7) Total: 66 33.4 (24)

Investigative Results N = 34 Lesions Average lesional size = 1.4 x 0.4 cm. -- Range: 0.5 x 0.3 mm –- 8.1 x 2.7 cm. 8 mandibles had multiple lesions: -- 2 had 3 separate sites -- 6 had 2 separate sites Brown discoloration =79.3% (n = 23), Typically very soft or “mushy” (n = 20)

Investigative Results N = 34 Lesions in 24 Mandibles Bone cavitations in 26.5% (N = 9) -- 2 with surrounding discoloration Dense focal sclerosis in 11.8% (n = 4) Cavitation in vivo

Investigative Results N = 34 Lesions in 24 Mandibles 79.5% (n =27) of lesions were touching or surrounding the inferior mandibular nerve Normal Remember: no other bones have sensory nerves inside

Investigative Results N = 34 Lesions in 24 Mandibles 40.7% (n = 14) of positive gross sites showed CIBD microscopically Proteinaceous & calcific necrotic marrow detritus Ischemic marrow atrophy

Investigative Results N = 34 Lesions in 24 Mandibles 40.7% (n = 14) of positive gross sites showed CIBD microscopically Oil Cyst Bone marrow edema

Investigative Results N = 34 Lesions in 24 Mandibles 17.6% showed chronic fibrosing osteomyelitis

Investigative Results N = 34 Lesions in 24 Mandibles 11.2% (n = 4) of lesions were easily localized via radiographs

Investigative Results N = 34 Lesions in 24 Mandibles 11.2% (n = 4) of lesions were easily localized via radiographs

Investigative Results N = 34 Lesions in 24 Mandibles 11.2% (n = 4) of lesions were easily localized via radiographs

Investigative Results N = 34 Lesions in 24 Mandibles Conclusions: CIBD is seen in 1/3 of cadaver mandibles from individuals who have died in presumably ischemic states. The lesions are typically in the molar/premolar region and 1/3 of affected persons had multiple sites of involvement. Radiographs are not helpful in localizing most lesions.