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Neuropathic pain in maxillofacial osteonecrosis

Identifieur interne : 006F42 ( Istex/Corpus ); précédent : 006F41; suivant : 006F43

Neuropathic pain in maxillofacial osteonecrosis

Auteurs : Jerry E. Bouquot ; Robert E. Mcmahon

Source :

RBID : ISTEX:E06A16BDBF0CFED02FED442EE72E29A187690AA4

English descriptors


Url:
DOI: 10.1053/joms.2000.8744

Links to Exploration step

ISTEX:E06A16BDBF0CFED02FED442EE72E29A187690AA4

Le document en format XML

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<term>Bone marrow disease</term>
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<term>Local anesthesia</term>
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<term>References abbreviations</term>
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<term>Antiphospholipid syndrome</term>
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<term>Biopsy</term>
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<term>Clinical suspicion</term>
<term>Coagulation</term>
<term>Craniomandib pract</term>
<term>Current concepts</term>
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<term>Deep bone pain</term>
<term>Degeneration</term>
<term>Degenerative changes</term>
<term>Dent</term>
<term>Dent assoc</term>
<term>Dental parameters</term>
<term>Diagnostics research</term>
<term>Edema</term>
<term>Endodontic therapy</term>
<term>Estrogen</term>
<term>Estrogen replacement therapy</term>
<term>Exogenous estrogen</term>
<term>Extraction sites</term>
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<term>Facial neuralgia</term>
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<term>Hypercoagulable state</term>
<term>Idiopathic</term>
<term>Idiopathic trigeminal neuralgia</term>
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<term>Imaging techniques</term>
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<term>Ischemic marrow damage</term>
<term>Ischemic osteonecrosis</term>
<term>Ischemic osteoporosis</term>
<term>Jawbone</term>
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<term>Local anesthesia</term>
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<term>Multifocal nature</term>
<term>Myelin</term>
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<term>Necrosis</term>
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<term>Nerve damage</term>
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<note>*Director of Research, The Maxillofacial Center for Diagnostics & Research, Morgantown, WV; Consultant, New York Eye and Ear Infirmary, New York, NY.</note>
<note>†Private Practice, Oral Surgery Group, Valparaiso, IN; Clinical Investigator, The Maxillofacial Center for Diagnostics & Research, Morgantown, WV; Clinical Investigator, Residual Infection in Bone (RIIB) Project, Indiana University Medical Center, Indianapolis, IN.</note>
<note>Address correspondence and reprint requests to Dr Bouquot: The Maxillofacial Center, 165 Scott Ave, Suite 100, Morgantown, WV 26508; e-mail: bouquot@@aol.com</note>
<note type="content">Section title: Clinical Controversies in Oral and Maxillofacial Surgery: Part One</note>
<note type="content">Table 1: LOCALIZED AND SYSTEMIC DISEASES AND PATHOPHYSIOLOGIC PROCESSES ASSOCIATED WITH ISCHEMIC OSTEONECROSIS</note>
<note type="content">Table 3: COAGULATION DISORDERS FOUND IN PATIENTS WITH ISCHEMIC OSTEONECROSIS OF THE HIPS, KNEES, AND JAWS</note>
<note type="content">Table 4: INTERNATIONAL CLASSIFICATION FOR THE STAGING OF ISCHEMIC OSTEONECROSIS (APPLIES PREDOMINANTLY TO HIP LESIONS AND ENDS OF LONG BONES); PATIENTS AT ALL STAGES MAY OR MAY NOT HAVE PAIN</note>
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<ce:table id="tab1" colsep="0" rowsep="0" frame="topbot">
<ce:label>Table 1</ce:label>
<ce:caption>
<ce:simple-para id="sp0010">LOCALIZED AND SYSTEMIC DISEASES AND PATHOPHYSIOLOGIC PROCESSES ASSOCIATED WITH ISCHEMIC OSTEONECROSIS</ce:simple-para>
</ce:caption>
<tgroup cols="4">
<colspec colname="col1" colsep="0"></colspec>
<colspec colname="col2" colsep="0"></colspec>
<colspec colname="col3" colsep="0"></colspec>
<colspec colname="col4" colsep="0"></colspec>
<thead>
<row rowsep="1" valign="bottom">
<entry>Disease or Etiologic Factor</entry>
<entry align="center">Subcategories</entry>
<entry align="center">Disease or Etiologic Factor</entry>
<entry align="center">Subcategories</entry>
</row>
</thead>
<tbody>
<row>
<entry>Alcohol abuse</entry>
<entry align="center">Cirrhosis</entry>
<entry align="center">Hypercoagulable state, systemic</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center">Pancreatitis</entry>
<entry align="center"></entry>
<entry align="center">Antiphospholipid antibody syndrome</entry>
</row>
<row>
<entry>Arthritis</entry>
<entry align="center">Subchondral cyst</entry>
<entry align="center"></entry>
<entry align="center">Factor V
<ce:sup>Leiden</ce:sup>
gene mutation</entry>
</row>
<row>
<entry></entry>
<entry align="center">Subchondral marrow edema</entry>
<entry align="center"></entry>
<entry align="center">Hyperhomocystinemia</entry>
</row>
<row>
<entry>Atmospheric pressure variations</entry>
<entry align="center"></entry>
<entry align="center"></entry>
<entry align="center">Homozygosity for MTHFR or CBS</entry>
</row>
<row>
<entry></entry>
<entry align="center">Caisson's disease</entry>
<entry align="center"></entry>
<entry align="center">Protein C deficiency</entry>
</row>
<row>
<entry></entry>
<entry align="center">Deep sea diving</entry>
<entry align="center"></entry>
<entry align="center">Protein S deficiency</entry>
</row>
<row>
<entry>Blood dyscrasias</entry>
<entry align="center">Disseminated intravascular coagulation</entry>
<entry align="center">Hyperlipidemia and embolic fat</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center">Leukemia</entry>
<entry align="center"></entry>
<entry align="center">Diabetes mellitus</entry>
</row>
<row>
<entry></entry>
<entry align="center">Sickle cell anemia</entry>
<entry align="center"></entry>
<entry align="center">Dysbaric phenomena</entry>
</row>
<row>
<entry>Cancer</entry>
<entry align="center">Chemotherapy for cancer</entry>
<entry align="center"></entry>
<entry align="center">Fracture of bone</entry>
</row>
<row>
<entry></entry>
<entry align="center">Cancer-induced hypercoagulation</entry>
<entry align="center"></entry>
<entry align="center">Hemoglobinopathies</entry>
</row>
<row>
<entry></entry>
<entry align="center">Lymphoma</entry>
<entry align="center"></entry>
<entry align="center">Osteomyelitis, acute</entry>
</row>
<row>
<entry></entry>
<entry align="center">Metastatic intraosseous carcinoma</entry>
<entry align="center">Hypersensitivity reactions</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center">Radiation therapy for cancer</entry>
<entry align="center"></entry>
<entry align="center">Allograft organ rejection</entry>
</row>
<row>
<entry>Chronic inactivity</entry>
<entry align="center">Bedridden</entry>
<entry align="center"></entry>
<entry align="center">Anaphylactic shock</entry>
</row>
<row>
<entry></entry>
<entry align="center">Full body cast</entry>
<entry align="center"></entry>
<entry align="center">Immune globulin therapy</entry>
</row>
<row>
<entry></entry>
<entry align="center">Paraplegic</entry>
<entry align="center"></entry>
<entry align="center">Shwartzman reaction to endotoxin</entry>
</row>
<row>
<entry>Corticosteroids</entry>
<entry align="center">Hypercortisolism</entry>
<entry align="center"></entry>
<entry align="center">Transfusion reactions</entry>
</row>
<row>
<entry></entry>
<entry align="center">Inflammatory bowel disease</entry>
<entry align="center">Hypertension</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center">Lupus erythematosus</entry>
<entry align="center">Hypothyroidism</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center">Transplants</entry>
<entry align="center">Inflammation, intraosseous</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Estrogen</entry>
<entry align="center">Birth control pills</entry>
<entry align="center"></entry>
<entry align="center">Infection, bacterial and viral</entry>
</row>
<row>
<entry></entry>
<entry align="center">Estrogen replacement therapy</entry>
<entry align="center"></entry>
<entry align="center">Trauma (mild or severe)</entry>
</row>
<row>
<entry></entry>
<entry align="center">Fertility drugs</entry>
<entry align="center"></entry>
<entry align="center">Autoimmunity/hypersensitivity</entry>
</row>
<row>
<entry></entry>
<entry align="center">Pregnancy</entry>
<entry align="center">Lupus erythematosus</entry>
<entry align="center">With corticosteroid therapy</entry>
</row>
<row>
<entry></entry>
<entry align="center">Prostate chemotherapy</entry>
<entry align="center"></entry>
<entry align="center">Without corticosteroid therapy</entry>
</row>
<row>
<entry></entry>
<entry align="center">Transient ischemic osteoporosis</entry>
<entry align="center">Neurodamage</entry>
<entry align="center">Brain injury/surgery</entry>
</row>
<row>
<entry>Gaucher disease</entry>
<entry align="center"></entry>
<entry align="center">Osteoporosis</entry>
<entry align="center">Regional or generalized</entry>
</row>
<row>
<entry>Hemodialysis</entry>
<entry align="center"></entry>
<entry align="center">Starvation</entry>
<entry align="center">Anorexia nervosa</entry>
</row>
<row>
<entry>Hypercoaguable state, local</entry>
<entry align="center"></entry>
<entry align="center">Storage diseases</entry>
<entry align="center">Gaucher's disease</entry>
</row>
<row>
<entry></entry>
<entry align="center">Acute infection/inflammation</entry>
<entry align="center">Tobacco use</entry>
<entry align="center">Tobacco smoking</entry>
</row>
<row>
<entry></entry>
<entry align="center">Chronic infection/inflammation</entry>
<entry align="center">Vascular occlusive disease</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center">Increased intramedullary pressures</entry>
<entry align="center"></entry>
<entry align="center">Atherosclerosis</entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center">Vasculitis</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center">Vasoconstriction</entry>
<entry align="center">Local anesthetic use</entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center"></entry>
<entry align="center">Raynaud phenomenon</entry>
</row>
<row>
<entry namest="col1" nameend="col4"></entry>
</row>
</tbody>
</tgroup>
<ce:legend>
<ce:simple-para id="sp0015">NOTE. Data in this table taken from references
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9">
<ce:sup>1-9</ce:sup>
</ce:cross-refs>
.</ce:simple-para>
<ce:simple-para id="sp0020">Abbreviations: MTHFR, methylene tetrahydrofolate reductase; CBS, cystathionine beta-synthetase.</ce:simple-para>
</ce:legend>
</ce:table>
<ce:table id="tab3" colsep="0" rowsep="0" frame="topbot">
<ce:label>Table 3</ce:label>
<ce:caption>
<ce:simple-para id="sp0025">COAGULATION DISORDERS FOUND IN PATIENTS WITH ISCHEMIC OSTEONECROSIS OF THE HIPS, KNEES, AND JAWS</ce:simple-para>
</ce:caption>
<tgroup cols="4">
<colspec colname="col1" colsep="0"></colspec>
<colspec colname="col2" colsep="0"></colspec>
<colspec colname="col3" colsep="0"></colspec>
<colspec colname="col4" colsep="0"></colspec>
<thead>
<row rowsep="1" valign="bottom">
<entry></entry>
<entry align="center">Normal Population (%)</entry>
<entry align="center">Deep Vein Thrombosis (%)</entry>
<entry align="center">Osteonecrosis (%)</entry>
</row>
</thead>
<tbody>
<row>
<entry>Thrombophilia</entry>
<entry align="center"></entry>
<entry align="center"></entry>
<entry align="center"></entry>
</row>
<row>
<entry>
<ce:hsp sp="1.0"></ce:hsp>
Hereditary types*</entry>
<entry align="center">2-5</entry>
<entry align="center">5-9</entry>
<entry align="center">50-70</entry>
</row>
<row>
<entry>
<ce:hsp sp="1.0"></ce:hsp>
Acquired types</entry>
<entry align="center">3-7</entry>
<entry align="center">20-50</entry>
<entry align="center">33</entry>
</row>
<row>
<entry>Hypofibrinolysis</entry>
<entry align="center"></entry>
<entry align="center"></entry>
<entry align="center"></entry>
</row>
<row>
<entry>
<ce:hsp sp="1.0"></ce:hsp>
Hereditary types*</entry>
<entry align="center"><1</entry>
<entry align="center">5-15</entry>
<entry align="center">18-22</entry>
</row>
<row>
<entry>
<ce:hsp sp="1.0"></ce:hsp>
Acquired types</entry>
<entry align="center"><1</entry>
<entry align="center">20-25</entry>
<entry align="center">50</entry>
</row>
<row>
<entry>Total (includes multiple coagulopathies)</entry>
<entry align="center">5-9</entry>
<entry align="center">20-50</entry>
<entry align="center">65-87</entry>
</row>
<row>
<entry namest="col1" nameend="col4">*Usually autosomal dominant.</entry>
</row>
</tbody>
</tgroup>
<ce:legend>
<ce:simple-para id="sp0030">NOTE. These are compared with the proportions found in patients with deep vein thrombosis of soft tissues and with the normal population.</ce:simple-para>
<ce:simple-para id="sp0035">Modified and reprinted with permission from Mosby from Bouquot JE, LaMarche MG: Ischemic osteonecrosis under fixed partial denture pontics: Radiographic and microscopic features in 38 patients with chronic pain. J Prosthet Dent 81:148-158, 1999.</ce:simple-para>
</ce:legend>
</ce:table>
<ce:table id="tab4" colsep="0" rowsep="0" frame="topbot">
<ce:label>Table 4</ce:label>
<ce:caption>
<ce:simple-para id="sp0040">INTERNATIONAL CLASSIFICATION FOR THE STAGING OF ISCHEMIC OSTEONECROSIS (APPLIES PREDOMINANTLY TO HIP LESIONS AND ENDS OF LONG BONES); PATIENTS AT ALL STAGES MAY OR MAY NOT HAVE PAIN</ce:simple-para>
</ce:caption>
<tgroup cols="4">
<colspec colname="col1" colsep="0"></colspec>
<colspec colname="col2" colsep="0"></colspec>
<colspec colname="col3" colsep="0"></colspec>
<colspec colname="col4" colsep="0"></colspec>
<thead>
<row rowsep="1" valign="bottom">
<entry>Stage</entry>
<entry align="center">Findings</entry>
<entry align="center">Techniques Needed for Diagnosis</entry>
<entry align="center">Proportion Requiring Eventual Surgery (%)</entry>
</row>
</thead>
<tbody>
<row rowsep="1">
<entry>0</entry>
<entry align="center">All techniques normal or nondiagnostic</entry>
<entry align="center">Open biopsy</entry>
<entry align="center">69</entry>
</row>
<row>
<entry>1</entry>
<entry align="center">Radiographs and CT scans are normal; positive results from at least 1 of tests to right</entry>
<entry align="center">
<ce:sup>99m</ce:sup>
Technetium radionuclide scan</entry>
<entry align="center">69</entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center">MRI scan</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center">Marrow blood flow studies</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center">Open biopsy</entry>
<entry align="center"></entry>
</row>
<row rowsep="1">
<entry>2</entry>
<entry align="center">Radiographs show mottled radiolucencies, osteoporosis, intramedullary cavitations/cysts, and/or focal sclerosis; no collapse of cortex</entry>
<entry align="center"></entry>
<entry align="center"></entry>
</row>
<row>
<entry>3</entry>
<entry align="center">Radiographs as above, also show subcortical fracture lines (early collapse); no gross change in external bone shape</entry>
<entry align="center">Radiographs</entry>
<entry align="center">82</entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center">CT scan as needed</entry>
<entry align="center"></entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center">MRI scan as needed</entry>
<entry align="center"></entry>
</row>
<row rowsep="1">
<entry>4</entry>
<entry align="center">Radiographs as above, also flattening or collapse of cortex</entry>
<entry align="center"></entry>
<entry align="center">90</entry>
</row>
<row>
<entry>5</entry>
<entry align="center">As for stage 4, with narrowing of the joint space</entry>
<entry align="center">Radiographs</entry>
<entry align="center">94</entry>
</row>
<row>
<entry></entry>
<entry align="center"></entry>
<entry align="center">CT scans as needed</entry>
<entry align="center"></entry>
</row>
<row>
<entry>6</entry>
<entry align="center">As for stage 5, with destruction and advanced degenerative changes of the joint/bone (collapse)</entry>
<entry align="center"></entry>
<entry align="center"></entry>
</row>
<row>
<entry namest="col1" nameend="col4"></entry>
</row>
</tbody>
</tgroup>
<ce:legend>
<ce:simple-para id="sp0045">NOTES. Osteonecrosis appears to be the only bone disease with a stage 0. Data in this table taken from references
<ce:cross-refs refid="bib4 bib5 bib6 bib9">
<ce:sup>4-6,9</ce:sup>
</ce:cross-refs>
.</ce:simple-para>
</ce:legend>
</ce:table>
</ce:floats>
<head>
<ce:article-footnote>
<ce:label></ce:label>
<ce:note-para>*Director of Research, The Maxillofacial Center for Diagnostics & Research, Morgantown, WV; Consultant, New York Eye and Ear Infirmary, New York, NY.</ce:note-para>
</ce:article-footnote>
<ce:article-footnote>
<ce:label>☆☆</ce:label>
<ce:note-para>†Private Practice, Oral Surgery Group, Valparaiso, IN; Clinical Investigator, The Maxillofacial Center for Diagnostics & Research, Morgantown, WV; Clinical Investigator, Residual Infection in Bone (RIIB) Project, Indiana University Medical Center, Indianapolis, IN.</ce:note-para>
</ce:article-footnote>
<ce:article-footnote>
<ce:label></ce:label>
<ce:note-para>Address correspondence and reprint requests to Dr Bouquot: The Maxillofacial Center, 165 Scott Ave, Suite 100, Morgantown, WV 26508; e-mail:
<ce:inter-ref xlink:href="mailto:bouquot@aol.com">bouquot@@aol.com</ce:inter-ref>
</ce:note-para>
</ce:article-footnote>
<ce:dochead>
<ce:textfn>Clinical Controversies in Oral and Maxillofacial Surgery: Part One</ce:textfn>
</ce:dochead>
<ce:title>Neuropathic pain in maxillofacial osteonecrosis</ce:title>
<ce:author-group>
<ce:author>
<ce:given-name>Jerry E.</ce:given-name>
<ce:surname>Bouquot</ce:surname>
<ce:degrees>DDS, MSD
<ce:sup>*</ce:sup>
</ce:degrees>
</ce:author>
<ce:author>
<ce:given-name>Robert E.</ce:given-name>
<ce:surname>McMahon</ce:surname>
<ce:degrees>DDS
<ce:sup></ce:sup>
</ce:degrees>
</ce:author>
</ce:author-group>
</head>
<body>
<ce:sections>
<ce:para id="p0010">Ischemic osteonecrosis (IO) is not so much a disease in its own right as it is the natural consequence of a wide variety of systemic and local factors capable of compromising marrow blood flow (Table 1).
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9">
<ce:sup>1-9</ce:sup>
</ce:cross-refs>
<ce:float-anchor refid="tab1"></ce:float-anchor>
It is the condition for which the term
<ce:italic>cavitation</ce:italic>
was coined in the orthopedic literature, and it is one of a select group of interrelated diseases able to deteriorate and hollow out medullary spaces (Fig 1)
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib10">
<ce:sup>1-10</ce:sup>
</ce:cross-refs>
: First described in 1794 in a case of septic necrosis of the femoral head, this enigmatic disease is as old as the dinosaurs, but it has been poorly understood and has such subtle radiographic changes that until recently it was seldom diagnosed before end-stage damage.
<ce:cross-refs refid="bib11 bib12 bib13">
<ce:sup>11-13</ce:sup>
</ce:cross-refs>
<ce:display>
<ce:figure id="fig1">
<ce:label>Fig. 1</ce:label>
<ce:caption>
<ce:simple-para id="sp0050">Cavitations in maxillofacial osteonecrosis.
<ce:italic>A,</ce:italic>
Normal mucosa in retromolar pad area, with third molar long extracted;
<ce:italic>B,</ce:italic>
After decortication, dark-walled intramedullary cavitation extends from cortex to cortex;
<ce:italic>C,</ce:italic>
Old extraction socket and a very thin, stringy, fibrosed, neurovascular bundle are visible in posterior mandible after decortication;
<ce:italic>D,</ce:italic>
Completely empty cortex-to-cortex cavitation. (Photos A-C courtesy of James Shen, DDS, and Rily Young, DDS, Huntington Beach, CA)</ce:simple-para>
</ce:caption>
<ce:link locator="gr1"></ce:link>
</ce:figure>
</ce:display>
Contemporary research has so enhanced our understanding of its basic pathophysiology that it now bears little resemblance to the entity once known as “aseptic osteomyelitis.”</ce:para>
<ce:para id="p0015">Heightened awareness and improved imaging techniques have confirmed this once rare disorder to be one of the most common of bone disorders. In certain diseases, such as lupus erythematosus, almost a third of patients may be affected.
<ce:cross-ref refid="bib9">
<ce:sup>9</ce:sup>
</ce:cross-ref>
IO is able to affect any bone of the human skeleton and is represented by a large number of orthopedic diseases now seen as simple anatomic and age-related variations of intramedullary ischemia and infarction.
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib9 bib14 bib15">
<ce:sup>1-5,9,14,15</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0020">The old, overly simplified histopathologic definition of IO as massive loss of osteocytes without pus is now substantially expanded to include specific and often subtle signs of ischemic marrow damage, which may not even include obviously dead tissues (Fig 2).
<ce:cross-refs refid="bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib14 bib15 bib16">
<ce:sup>2-9,14-16</ce:sup>
</ce:cross-refs>
<ce:display>
<ce:figure id="f0010">
<ce:label>Fig. 2</ce:label>
<ce:caption>
<ce:simple-para id="sp0055">Maxillofacial ischemic osteonecrosis.
<ce:italic>A,</ce:italic>
Fatty microvesicles and coalesced pools of liquefied fat (oil cysts), with almost complete loss of adipocyte nuclei (viable cortex is on right);
<ce:italic>B,</ce:italic>
Pallor, loss of nuclei, and oil cyst formation with few inflammatory cells, residual hematopoietic/fatty marrow in lower left;
<ce:italic>C,</ce:italic>
Coalesced dead adipocytes with thrombosed capillaries in surrounding marrow (overlying cortex is viable);
<ce:italic>D,</ce:italic>
Higher magnification of
<ce:italic>C</ce:italic>
shows serous ooze (plasmostasis) and dilated capillary (upper left) with pale staining, degenerated erythrocytes (ghost erythrocytes).</ce:simple-para>
</ce:caption>
<ce:link locator="gr2"></ce:link>
</ce:figure>
</ce:display>
Histopathologically, less severe or nascent involvement has begun to be consolidated under a common diagnostic term
<ce:italic>bone marrow edema</ce:italic>
(BME, Table 2), and the disease is now known primarily as a vascular disorder readily influenced by a variety of risk factors or trigger events (“hits”) that promote thrombosis.
<ce:cross-refs refid="bib7 bib9 bib17 bib18 bib19 bib20 bib21">
<ce:sup>7,9,17-21</ce:sup>
</ce:cross-refs>
<ce:display>
<ce:table id="t0010" colsep="0" rowsep="0" frame="topbot">
<ce:label>Table 2</ce:label>
<ce:caption>
<ce:simple-para id="sp0060">ALTERNATIVE DIAGNOSTIC NAMES USED FOR BONE MARROW EDEMA AND ISCHEMIC OSTEONECROSIS</ce:simple-para>
</ce:caption>
<tgroup cols="2">
<colspec colname="col1" colsep="0"></colspec>
<colspec colname="col2" colsep="0"></colspec>
<thead>
<row rowsep="1" valign="bottom">
<entry>Bone Marrow Edema</entry>
<entry align="center">Ischemic Osteonecrosis</entry>
</row>
</thead>
<tbody>
<row>
<entry>Arlet type I osteonecrosis</entry>
<entry align="center">Aseptic necrosis</entry>
</row>
<row>
<entry>Bone compartment disease</entry>
<entry align="center">Aseptic osteomyelitis</entry>
</row>
<row>
<entry>Bone marrow edema syndrome</entry>
<entry align="center">Aseptic osteonecrosis</entry>
</row>
<row>
<entry>Chronic traumatic edema</entry>
<entry align="center">Avascular necrosis</entry>
</row>
<row>
<entry>Medullary engorgement pain syndrome</entry>
<entry align="center">Bone infarction</entry>
</row>
<row>
<entry></entry>
<entry align="center">Coronary disease of bone</entry>
</row>
<row>
<entry>Migratory osteolysis</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Migratory osteoporosis</entry>
<entry align="center">Ischemic necrosis</entry>
</row>
<row>
<entry>NICO</entry>
<entry align="center">NICO</entry>
</row>
<row>
<entry>Posttraumatic painful osteoporosis</entry>
<entry align="center">Osteochondrosis desiccans</entry>
</row>
<row>
<entry>Posttraumatic reflex dystrophy</entry>
<entry align="center">Perthes disease</entry>
</row>
<row>
<entry>Primary algodystrophy</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Regional ischemic osteoporosis</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Regional osteoporosis</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Roentgenologic transient osteoporosis</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Sudeck disease (RSD)</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Transient bone marrow edema syndrome</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Transient demineralization</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Transient ischemic osteoporosis</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Transient marrow edema</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Transient osteoporosis</entry>
<entry align="center"></entry>
</row>
<row>
<entry>Transitory demineralization in pregnancy</entry>
<entry align="center"></entry>
</row>
<row>
<entry namest="col1" nameend="col2"></entry>
</row>
</tbody>
</tgroup>
<ce:legend>
<ce:simple-para id="sp0065">NOTE. Data in this table taken from references
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib14 bib15 bib16">
<ce:sup>1-9, 14-16</ce:sup>
</ce:cross-refs>
</ce:simple-para>
<ce:simple-para id="sp0070">Abbreviations: NICO, neuralgia-inducing cavitational osteonecrosis; RSD, reflex sympathetic dystrophy.</ce:simple-para>
</ce:legend>
</ce:table>
</ce:display>
Persons with multifocal IO are more likely to suffer from systemic risk factors than those with single site involvement, and most patients have inherited or acquired a systemic tendency toward fibrin generation (Table 3), which predisposes them to microinfarction (Fig 3) and ischemic marrow damage.
<ce:cross-refs refid="bib8 bib9 bib15 bib16 bib17 bib18 bib19 bib20 bib21 bib22">
<ce:sup>8,9,15-22</ce:sup>
</ce:cross-refs>
<ce:float-anchor refid="tab3"></ce:float-anchor>
<ce:display>
<ce:figure id="f0015">
<ce:label>Fig. 3</ce:label>
<ce:caption>
<ce:simple-para id="sp0075">Intravascular thrombi.
<ce:italic>A,</ce:italic>
Two fibrin thrombi (
<ce:italic>arrows</ce:italic>
) in dilated capillaries;
<ce:italic>B,</ce:italic>
Infarcted capillaries with lumina plugged with fibrin/platelet aggregates, with perivascular hemorrhage around one and with ischemic myelofibrosis of the marrow.</ce:simple-para>
</ce:caption>
<ce:link locator="gr3"></ce:link>
</ce:figure>
</ce:display>
</ce:para>
<ce:para id="p0025">Usually associated with pain, IO can nevertheless show a surprising capacity to remain painless until great destruction has occurred, even to the point of joint collapse for hip lesions. There is little correlation between the degree of bone involvement and the intensity of the associated pain.
<ce:cross-refs refid="bib5 bib9">
<ce:sup>5,9</ce:sup>
</ce:cross-refs>
The pain can take on a neuralgic character, but its cause is primarily a function of intraosseous fluid dynamics and inflammatory mediators rather than damaged nerves, as discussed later.
<ce:cross-refs refid="bib4 bib5 bib9 bib11 bib14 bib15 bib16">
<ce:sup>4,5,9,11,14-16</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:section id="s0010">
<ce:section-title>Maxillofacial osteonecrosis—historical review</ce:section-title>
<ce:para id="p0030">IO of the maxillofacial region is not new to dentistry. During the preantibiotic era, “phossy jaw” and other forms of “chemical osteomyelitis” resulted from environmental pollutants such as lead and the phosphorus used in safety matches, as well as from popular medications containing mercury, arsenic, or bismuth.
<ce:cross-refs refid="bib23 bib24 bib25 bib26 bib27 bib28">
<ce:sup>23-28</ce:sup>
</ce:cross-refs>
In his classic 1898 text, Barrett
<ce:cross-ref refid="bib29">
<ce:sup>29</ce:sup>
</ce:cross-ref>
described “caries” and “necrosis” of bone with cellular “devitalization” and “inhibition of nutrient currents,” characterized by a slowly progressive “breaking down” of the “territory” of marrow tissues receiving those nutrients and resulting in little or no production of granulation tissue. Thirty years earlier and more than a century ahead of his time, Noel
<ce:cross-ref refid="bib30">
<ce:sup>30</ce:sup>
</ce:cross-ref>
separated bone caries into 2 distinct categories: “bone death” and the less intense “reduced vitality.”</ce:para>
<ce:para id="p0035">G.V. Black,
<ce:cross-ref refid="bib31">
<ce:sup>31</ce:sup>
</ce:cross-ref>
the father of modern dentistry, described in 1915 an osteomyelitis look-alike disease that he called “chronic osteitis.” He described slow bone death “cell by cell” with the creation of alveolar intramedullary “cavities” up to 5 cm in size and wondered about its unique ability to produce extensive bone destruction without pus, without redness and swelling of the overlying tissues, without an increase in the patient's body temperature, and often without pain. His suggestion to curette diseased bone reiterated the treatment first proposed by Ferguson
<ce:cross-ref refid="bib32">
<ce:sup>32</ce:sup>
</ce:cross-ref>
in 1868.</ce:para>
<ce:para id="p0040">Wilensky
<ce:cross-ref refid="bib24">
<ce:sup>24</ce:sup>
</ce:cross-ref>
and Hankey
<ce:cross-ref refid="bib25">
<ce:sup>25</ce:sup>
</ce:cross-ref>
suggested that persistent regional necrosis in osteomyelitis of the jaws was secondary to vascular insufficiency, while Brosch
<ce:cross-ref refid="bib26">
<ce:sup>26</ce:sup>
</ce:cross-ref>
described the potential for hollow medullary spaces to enlarge and coalesce one with another. Thoma
<ce:cross-ref refid="bib33">
<ce:sup>33</ce:sup>
</ce:cross-ref>
was likely the first to specifically correlate this “residual infection” or “osteitis” with
<ce:italic>old extraction sites,</ce:italic>
many of which showed focal “necrotic exudates,” fibrosis, and “osteoclastic resorption” of surrounding bone. His observations were affirmed in 1955 by Box,
<ce:cross-ref refid="bib34">
<ce:sup>34</ce:sup>
</ce:cross-ref>
who reported a very large series of limited intraosseous cavitations or “vacuolations” in old extraction sites, with no production of pus or bony sequestra. Box was especially intrigued by the radiographic subtlety of the disease (Fig 4), by its multifocal nature, its localized tenderness without inflammatory signs, and the neuralgia-like nature of accompanying pain.
<ce:display>
<ce:figure id="f0020">
<ce:label>Fig. 4</ce:label>
<ce:caption>
<ce:simple-para id="sp0080">Radiographic examples of NICO.
<ce:italic>A,</ce:italic>
Hollow tuberosity, that is, poorly outlined radiolucency;
<ce:italic>B,</ce:italic>
Retromolar cavitation (
<ce:italic>arrows</ce:italic>
), moderately well-demarcated radiolucency with thin sclerotic rimming of some areas;
<ce:italic>C,</ce:italic>
“Eagle's nest” radiolucency with irregular trabeculae producing sun-burst pattern from center of lesion;
<ce:italic>D,</ce:italic>
“Bullseye lesion” with mild diffuse sclerosis of central area surrounded by a ring of slight radiolucency that is, in turn, surrounded by a mild, poorly defined radiopacity;
<ce:italic>E,</ce:italic>
Residual sockets (laminar rain) with needle pushed through cortex to floor of cavitation;
<ce:italic>F,</ce:italic>
Radiograph of cadaver case, Figure 8D.</ce:simple-para>
</ce:caption>
<ce:link locator="gr4"></ce:link>
</ce:figure>
</ce:display>
</ce:para>
<ce:para id="p0045">The 1970s and 1980s saw a strong emphasis placed on the associated neuralgic pain, an influence embodied in the currently popular diagnostic name
<ce:italic>NICO (neuralgia-inducing cavitational osteonecrosis).</ce:italic>
<ce:cross-refs refid="bib35 bib36 bib37 bib38 bib39 bib40 bib41 bib42 bib43 bib44">
<ce:sup>35-44</ce:sup>
</ce:cross-refs>
Significant or complete pain reduction was achieved in patients treated for chronic “idiopathic” facial neuralgia by decortication and curettage of damaged alveolar bone (Fig 5), supporting the contention by neural researchers that persistent odontogenic and osseous disease can be important contributing factors for such neuralgias.
<ce:cross-refs refid="bib45 bib46 bib47 bib48 bib49 bib50">
<ce:sup>45-50</ce:sup>
</ce:cross-refs>
<ce:display>
<ce:figure id="f0025">
<ce:label>Fig. 5</ce:label>
<ce:caption>
<ce:simple-para id="sp0085">Proportion (%) of NICO patients experiencing complete or significant pain reduction after decortication and curettage of diseased bone. Data in this figure taken from references 35-44, 92.</ce:simple-para>
</ce:caption>
<ce:link locator="gr5"></ce:link>
</ce:figure>
</ce:display>
None of these investigations included a control group, nor has
<ce:italic>any</ce:italic>
facial neuralgia follow-up study. Ethical considerations and the ever-present potential for silent or subclinical disease will likely prevent valid control groups from being identified, but a 1995 NICO follow-up investigation confirming earlier surgical successes went so far as to guarantee patient anonymity, to use a well-established pain evaluation instrument instead of surgeon records to determine outcomes, and to use a third party to collect and analyze data to reduce potential biases.
<ce:cross-ref refid="bib44">
<ce:sup>44</ce:sup>
</ce:cross-ref>
</ce:para>
<ce:para id="p0050">Microorganisms cultured from many NICO lesions, and occasional facial pain relief with antibiotic therapy, caused these cases to be diagnosed and treated as chronic osteomyelitis; yet, a significant number of patients did not respond in a fashion appropriate to that diagnosis, leading investigators to seek alternative interpretations for the biologic behavior and histopathology. A critical shift in perspective (return to the original concepts?) occurred in 1989 when this odd alveolar disease began to be viewed primarily as a problem of compromised medullary blood flow driven by progressive thrombosis rather than as a unique infection unknown to other bones.
<ce:cross-refs refid="bib44 bib51 bib52 bib53">
<ce:sup>44,51-53</ce:sup>
</ce:cross-refs>
</ce:para>
</ce:section>
<ce:section id="s0015">
<ce:section-title>Oral manifestation of systemic disease</ce:section-title>
<ce:para id="p0055">This new perspective as a maxillofacial manifestation of IO provided, for the first time, a logical explanation for the curiously multifocal nature of the disease; its frequent intermingling of ischemically damaged and normal marrow (also influenced by the perfusion irregularities of fatty marrow
<ce:cross-ref refid="bib54">
<ce:sup>54</ce:sup>
</ce:cross-ref>
); its frequent lack of inflammatory cells; its remarkably chronic and recurring character; its deep bone pain and varied pain syndromes; its relatively high failure rate with local interventions; and its primary localization at the ends of the arterial inflow (retromolar and subcrestal alveolar regions) where weak, irregular blood flow favors the formation of intravascular thrombi.
<ce:cross-refs refid="bib5 bib7 bib9 bib14 bib15 bib55">
<ce:sup>5,7,9,14,15,55</ce:sup>
</ce:cross-refs>
This is not to say that intraosseous microorganisms do not represent a significant risk factor or triggering mechanism for thrombosis in these stagnant zones of cancellous bone. Affected bone is ideal fodder for periodontal and periapical bacteria chronically stimulating inflammatory and immune responses.
<ce:cross-refs refid="bib56 bib57 bib58">
<ce:sup>56-58</ce:sup>
</ce:cross-refs>
Impaired medullary circulation prevents proper healing in these instances and the chronic infection, in turn, enhances local and systemic clotting. This further exacerbates the medullary ischemia and initiates a slow, ever-increasing spiral of thrombosis and microinfarction, with progressively elevating intramedullary pressures, additional thrombosis, and frequent propagation of spontaneous pain. Prothrombotic factors, especially fibrinogen, also allow increased adherence of bacteria to thrombin-activated endothelial cells.
<ce:cross-ref refid="bib59">
<ce:sup>59</ce:sup>
</ce:cross-ref>
</ce:para>
<ce:para id="p0060">Once it became clear that this disease of the jaws resembled avascular necrosis of other bones, investigators used newly available laboratory tests, including allele-specific polymerase chain reaction, to identify heritable disorders predisposing to adverse thrombotic events in NICO patients. At least 72% proved to be afflicted with a variety of such disorders, as compared with 65% to 87% for patients with IO of the hip and knee (
<ce:cross-ref refid="tab3">Table 3</ce:cross-ref>
).
<ce:cross-refs refid="bib9 bib19 bib20 bib21 bib60 bib61 bib62">
<ce:sup>9,19-21,60-62</ce:sup>
</ce:cross-refs>
This was seen as a major breakthrough, eventuating in the use of anticoagulants (without surgery or antibiotics) in persons with NICO and hip IO.
<ce:cross-refs refid="bib63 bib64 bib65 bib66">
<ce:sup>63-66</ce:sup>
</ce:cross-refs>
Although not all affected individuals benefited, the significant pain relief experienced by a large proportion of treated patients confirmed an association in those persons between the symptoms of IO and the hypercoagulable disorders.
<ce:cross-refs refid="bib64 bib66">
<ce:sup>64,66</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0065">Viewing NICO as the oral manifestation of a systemic disease also allowed application of the clinicopathologic qualities of long bone disease to maxillofacial cases, especially the use of diagnostic imaging techniques such as technetium Tc 99m-methylene diphosphonate (
<ce:sup>99m</ce:sup>
Tc-MDP) scintigraphy, and single proton emission computed tomography (SPECT) scans, instead of the indium and gallium scans typically used for bone infections (Fig 6).
<ce:cross-refs refid="bib53 bib67 bib68 bib69">
<ce:sup>53,67-69</ce:sup>
</ce:cross-refs>
<ce:display>
<ce:figure id="fig6">
<ce:label>Fig. 6</ce:label>
<ce:caption>
<ce:simple-para id="sp0090">Scintigraphy scans in patients with false-negative radiographs.
<ce:italic>A & B,</ce:italic>
<ce:sup>99m</ce:sup>
Tc-MDP scans shows multiple hot spots in patients with trigeminal neuralgia of 2 divisions;
<ce:italic>C,</ce:italic>
<ce:sup>99m</ce:sup>
Tc-MDP scan shows massive involvement of maxilla and zygoma in patient with atypical facial neuralgia/pain of right midface;
<ce:italic>D,</ce:italic>
SPECT scan shows mandibular and maxillary hot spots in patient with atypical facial neuralgia/pain.</ce:simple-para>
</ce:caption>
<ce:link locator="gr6"></ce:link>
</ce:figure>
</ce:display>
The small number of chronic inflammatory cells found in NICO lesions makes radioisotopes that attach to leukocytes much less useful than those that attach to new or exposed bone matrix. There is usually a small amount of ongoing healing in IO lesions and so they present as “hot spots” of increased radioisotope uptake, with “cold spots” of extremely reduced uptake in the occasional severely desiccated lesion. Newly developed
<ce:sup>99m</ce:sup>
Tc isotopes directed at fibrin α-chain peptide may prove useful for patients actively forming microclots.
<ce:cross-ref refid="bib70">
<ce:sup>70</ce:sup>
</ce:cross-ref>
</ce:para>
<ce:para id="p0070">A substantial proportion (25% to 35%) of scans will be falsely negative because the disease has long periods during which no bone is destroyed or regenerated, even as symptoms and marrow damage progress. This holds true regardless of the affected bone, but maxillofacial involvement suffers from an unexpected false-negative phenomenon: radiologists not attuned to jawbone ischemia often interpret a hot spot of alveolar bone as “normal,” presuming it to relate to ubiquitous dental and periodontal disease. Therefore, it is recommended that the surgeon review all films interpreted as negative.</ce:para>
<ce:para id="p0075">Thin-sliced spiral computed tomography (CT) scans and ultrasonic scans also have proved effective in localizing NICO, although they require very careful evaluation (Fig 7).
<ce:cross-ref refid="bib71">
<ce:sup>71</ce:sup>
</ce:cross-ref>
<ce:display>
<ce:figure id="f0030">
<ce:label>Fig. 7</ce:label>
<ce:caption>
<ce:simple-para id="sp0095">Thin-sliced CT scans of atypical facial neuralgia/pain patient.
<ce:italic>A,</ce:italic>
Panoramic view of maxilla shows multiple cystic radiolucencies and an area of ghost marrow (mild ground glass radiopacity) of right incisor region with central cavitation;
<ce:italic>B,</ce:italic>
Horizontal slice shows mottled ghost marrow and radiolucencies;
<ce:italic>C,</ce:italic>
Vertical slice shows 2 radiolucencies of anterior palate; posterior lesion has cortical perforations into sinus;
<ce:italic>D,</ce:italic>
Ultrasonic scan shows area of missing and dry (black) bone adjacent to normal, moist bone/marrow (gray); image is usually in color.</ce:simple-para>
</ce:caption>
<ce:link locator="gr7"></ce:link>
</ce:figure>
</ce:display>
<ce:display>
<ce:figure id="fig8">
<ce:label>Fig. 8</ce:label>
<ce:caption>
<ce:simple-para id="sp0100">Cadaver examples of maxillofacial osteonecrosis.
<ce:italic>A,</ce:italic>
Relatively normal mandibular marrow with small cavitations, normal pink/white neurovascular bundle, and no hemorrhagic discoloration;
<ce:italic>B,</ce:italic>
Hollow mandible with no residual alveolar canal, a somewhat translucent, desiccated, atrophic fatty marrow, and chalky white dry spots of inferior cortex;
<ce:italic>C,</ce:italic>
Darkly discolored, irregular area of infarction surrounds discolored, fibrillar neurovascular bundle extending into ramus. Also, note the chalky white, dry, spots in the cortex;
<ce:italic>D,</ce:italic>
Darkly discolored area of infarction of mandibular angle, with cavitation (yellow-orange walls) beneath alveolar nerve.</ce:simple-para>
</ce:caption>
<ce:link locator="gr8"></ce:link>
</ce:figure>
</ce:display>
Magnetic resonance imaging scans are valuable for the rounded ends of bones but, in our experience, are of little benefit in alveolar cases.
<ce:cross-refs refid="bib72 bib73">
<ce:sup>72,73</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0080">In a similar fashion, the more contemporary histopathologic features of IO and BME (mild IO), often overlooked by or unfamiliar to oral pathologists, could be applied to maxillofacial examples, with the notable caveat that there are no features of cortical collapse in jaw lesions and odontogenic infections are often superimposed.
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib52">
<ce:sup>1-9,52</ce:sup>
</ce:cross-refs>
Additionally, microscopic evaluation of maxillofacial biopsy samples is made
<ce:italic>much</ce:italic>
more difficult by the small number and size of available curettage fragments, especially when an intramedullary cavitation exists, in contradistinction to the large specimens available for study after resection and core biopsies of long bone cases.</ce:para>
</ce:section>
<ce:section id="s0020">
<ce:section-title>Age and the ischemic jaw</ce:section-title>
<ce:para id="p0085">Ischemic damage to the jawbones may be quite common, especially when it is understood that it may not necessarily be a painful condition, and that it may remain for years as an asymptomatic or subclinical process. Age-related ischemic loss of osteocytes has been shown in the jaws of monkeys and in other bones of humans.
<ce:cross-refs refid="bib74 bib75">
<ce:sup>74,75</ce:sup>
</ce:cross-refs>
Graff-Radford et al
<ce:cross-ref refid="bib76">
<ce:sup>76</ce:sup>
</ce:cross-ref>
identified numerous small intramedullary cavitations in the cadaver jawbones of elderly humans, and one of us (J.E.B., unpublished data) has found microscopic and gross evidence of ischemic damage in almost a third of 35 consecutively processed cadaver mandibles (
<ce:cross-ref refid="fig8">Fig 8</ce:cross-ref>
). Any portion of the marrow can be affected, but ischemic conditions are most often found in the subcortical marrow as age brings on diminishing periosteal nutrition and increasingly centrifugal and sluggish blood flow from the central arteries.
<ce:cross-refs refid="bib4 bib14 bib15">
<ce:sup>4,14,15</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0090">Age-related degenerative vascular alterations of the alveolar arteries are well documented and include increased tortuosity, luminal narrowing, atherosclerosis, and loss of rami.
<ce:cross-refs refid="bib77 bib78 bib79 bib80">
<ce:sup>77-80</ce:sup>
</ce:cross-refs>
These changes are especially pronounced in edentulous areas and are positively correlated with the length of time since extraction and the extent of alveolar ridge resorption. Moreover, the increased speed of blood flowing through narrowed arteries tends to propagate thrombi by inducing the formation of platelet microvesicles (procoagulant membrane particles).
<ce:cross-ref refid="bib81">
<ce:sup>81</ce:sup>
</ce:cross-ref>
Significant increases in the prothrombotic influences of hyperhomocystinemia and circulating antiphospholipid antibodies also have been linked to increasing age.
<ce:cross-refs refid="bib82 bib83">
<ce:sup>82,83</ce:sup>
</ce:cross-refs>
These phenomena, along with the rather high frequency (at least 7%) of inherited hypercoagulable disorders in the population and the strong correlation established between IO and such disorders, serve to suggest a common—perhaps a
<ce:italic>very</ce:italic>
common—risk of chronic jaw marrow ischemia. Subclinical or otherwise, this risk is likely to increase as susceptible individuals age, as blood flow becomes less efficient, and as additional risk factors (
<ce:cross-ref refid="tab1">Table 1</ce:cross-ref>
) are added to the multifactorial equation.</ce:para>
<ce:para id="p0095">Every IO-involved bone has its unique age and gender predilection because different risk factors favor certain environments and are sometimes strong enough to overwhelm the influences of age.
<ce:cross-ref refid="bib9">
<ce:sup>9</ce:sup>
</ce:cross-ref>
The rather young age of NICO patients, 30 to 55 years, suggests that environmental factors are at work, as does the strong female predilection (more than 80% of patients are female). Estrogen is the most logical factor, but there also must be undefined case-selection biases operating, perhaps relating to the greater tendency of women than men to seek medical attention for pain.
<ce:cross-refs refid="bib62 bib84 bib85">
<ce:sup>62,84,85</ce:sup>
</ce:cross-refs>
Unpublished data (J.E.B.) do support an increasing prevalence rate with increasing age: women 65 years and older have a rate more than twice that of those 25 to 65 years of age: 1/1,000 population versus 1/2,500 population, respectively (biopsy cases only).</ce:para>
<ce:para id="p0100">It is important when evaluating risk to remember that the hips and jaws are the two bones most susceptible to ischemic marrow damage, the former because of powerful weight-bearing pressures and anatomically compromised epiphyseal arterial inflow and the latter because of the significant risk of infection (odontogenic and sinus-related) and trauma (extractions, endodontic therapy, periodontal surgery). Even mild noxious stimuli from low-grade infection and inflammatory responses from minor surgery are capable of enhancing local coagulation and diminishing regional blood flow for extended periods of time.
<ce:cross-refs refid="bib86 bib87 bib88">
<ce:sup>86-88</ce:sup>
</ce:cross-refs>
Damaged unmyelinated autonomic nerves and neurogenic inflammatory responses can further diminish the flow.
<ce:cross-refs refid="bib89 bib90">
<ce:sup>89,90</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0105">These influences are a natural advantage to normal injury and healing but can be catastrophic to someone with prothrombotic or hypofibrinolytic tendencies. We already appreciate this for bone rendered ischemic by radiation therapy and sickle cell thrombosis, but perhaps we should be concerned in other settings, such as when a patient with an innate clotting tendency uses estrogen replacement therapy, a combination that can increase the risk of venous thrombosis by a factor of 80.
<ce:cross-refs refid="bib62 bib84 bib85">
<ce:sup>62,84,85</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0110">The jaws are subject to another unique ischemic phenomenon: the repeated use of local anesthesia for routine dental restorative procedures. The anesthetic typically contains a potent vasoconstrictor capable of severely decreasing regional blood flow, a benefit for the procedure itself but a potentially serious risk for persons with already compromised medullary circulation. With poor medullary outflow, the vasoconstrictor effect may, furthermore, continue much longer than normal.</ce:para>
<ce:para id="p0115">More research is needed to confirm these observations, but a patient with age-related alterations of the alveolar vasculature or a hypercoagulable state would seem to be a logical candidate for ischemic marrow damage, especially after secondary and tertiary “hits” from estrogen replacement therapy, corticosteroid therapy, alcohol abuse, tobacco smoking, infection, trauma, or the repeated use of vasoconstrictors.</ce:para>
</ce:section>
<ce:section id="s0025">
<ce:section-title>Ischemic disease in the facial pain patient</ce:section-title>
<ce:para id="p0120">Just as we lack the appropriate data to know how many jaws are ischemic and contain subclinical bone cavities, we also do not know the proportion of chronic “idiopathic” facial pain patients with inflammatory or ischemic bone disease. However, available clinical research indicates that medullary disease may be quite common in such patients. Several investigations have reported localized areas or “zones” of alveolar tenderness or elevated mucosal temperature in most patients with chronic idiopathic facial pain or headache.
<ce:cross-refs refid="bib91 bib92 bib93">
<ce:sup>91-93</ce:sup>
</ce:cross-refs>
Chronic inflammatory cells, presumably related to neuropeptide release by sensitized nerves, also have been shown in the stroma of the attached mucosa in zones of tenderness.
<ce:cross-refs refid="bib92 bib94 bib95 bib96 bib97 bib98">
<ce:sup>92,94-98</ce:sup>
</ce:cross-refs>
Neuropathic pain abatement with local anesthesia or cold laser therapy substantiates a relationship between diseased intramedullary tissues and the symptoms in these patients, but more significantly, all tissue samples obtained from the underlying bone marrow in 46 consecutive patients showed the microscopic features of ischemia or chronic inflammation.
<ce:cross-ref refid="bib92">
<ce:sup>92</ce:sup>
</ce:cross-ref>
</ce:para>
<ce:para id="p0125">Using
<ce:sup>99m</ce:sup>
Tc SPECT scans, a primary diagnostic tool for bone infarcts and new bone formation, Denucci et al
<ce:cross-ref refid="bib99">
<ce:sup>99</ce:sup>
</ce:cross-ref>
found localized “hot spots” in 75% of painful quadrants in idiopathic facial pain patients. No biopsies were performed, but a more recent study using routine
<ce:sup>99m</ce:sup>
Tc-MDP scintigraphy scans has reported hot spots in 57% of areas shown by later biopsy to be osteonecrosis or chronic osteomyelitis.
<ce:cross-ref refid="bib69">
<ce:sup>69</ce:sup>
</ce:cross-ref>
Cases from the latter investigation were identified through a national biopsy service and, therefore, are not directly comparable with those of Denucci et al, but unpublished data (J.E.B.) has tentatively confirmed the high proportion of positive cases using scintigraphy on more than 100 consecutively evaluated cases of chronic facial pain (
<ce:cross-ref refid="fig6">Fig 6</ce:cross-ref>
).</ce:para>
</ce:section>
<ce:section id="s0030">
<ce:section-title>Pain in maxillofacial osteonecrosis</ce:section-title>
<ce:para id="p0130">Maxillofacial osteonecrosis is notably identified with deep bone pain. In contrast to other bones, the medullary environment of the maxilla and mandible is innervated by major branches of the nerve (trigeminal) with the largest ganglion and the most extensive innervating zone of all peripheral nerves in humans.
<ce:cross-ref refid="bib100">
<ce:sup>100</ce:sup>
</ce:cross-ref>
Presumably, this has profound influences on the nature and intensity of associated pain, but it is extremely important to understand that damage to sensory nerves is
<ce:italic>not</ce:italic>
central to the explanation of pain in IO and that elevated intramedullary pressures and ischemia are most often the dominant pain stimulators.
<ce:cross-refs refid="bib9 bib14 bib15 bib16 bib101">
<ce:sup>9,14-16,101</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0135">Involved bones routinely maintain pain-producing intramedullary pressures 2 to 4 times greater than normal, usually because of poor outflow.
<ce:cross-refs refid="bib9 bib14 bib15">
<ce:sup>9,14,15</ce:sup>
</ce:cross-refs>
This reduced outflow phenomenon is so unique that it has led to the development of a “stress test” in long bones, whereby saline injected into the femoral head causes an immediate increase in pressure and pain. Conversely, more than half of all painful ischemic hips show dramatic and rapid, often instant, pain relief when decortication or core decompression allow pressure release, as do most NICO patients after alveolar decortication and curettage.
<ce:cross-refs refid="bib9 bib15 bib35 bib36 bib37 bib38 bib39 bib40 bib41 bib42 bib43 bib50">
<ce:sup>9,15,35-43,50</ce:sup>
</ce:cross-refs>
The relief experienced with anticoagulants also substantiates an association with an unusual intramedullary fluid environment.
<ce:cross-refs refid="bib9 bib63 bib64">
<ce:sup>9,63,64</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0140">Additional factors may influence symptoms: intramedullary venous distension; diminished or sluggish flow through capillary beds, including the vasa nervorum; infarction or microinfarction after complete, abrupt blockage of marrow blood vessels, again including the vasa nervorum; slow, continuous release of neuropeptides and other mediators of inflammation; formation of traumatic neuromas and nerve tufts (axonal sprouting) after extraction or infection, and modulation by higher brain centers.
<ce:cross-refs refid="bib50 bib69 bib92 bib101 bib102">
<ce:sup>50,69,92,101,102</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0145">The symptoms of the maxillofacial lesions do not usually differ from those of lesions in other bones except that a certain proportion (up to 7%, in our experience) of NICO patients have sharp, severe bursts of lancinating pain that mimic or induce the attacks of so-called idiopathic trigeminal neuralgia of central or intracranial origin. Likewise, NICO patients often have pain initiated or precipitated by routine crown preparations, endodontic therapy, extractions, even periodontal scaling. Normal inflammatory mediators released into a preconditioned “terrain,” along with vasoconstrictor-induced ischemia at the time of the procedure, undoubtedly play a role in the seemingly exaggerated postsurgical pain responses so frequently experienced by these individuals.</ce:para>
<ce:para id="p0150">Regardless of the bone involved, symptomatic patients often have trouble describing and localizing the pain, which can be intermittent or constant, deep or superficial, aching or sharp, mild or intense.
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib14 bib15 bib35 bib36 bib37 bib38 bib39 bib40 bib41 bib42 bib43 bib50">
<ce:sup>1-9,14,15,35-43,50</ce:sup>
</ce:cross-refs>
Most often the pain is described as a deep ache or sharp bone pain. It typically begins as quite mild and vague, increasing slowly in frequency and intensity over months and years, but it also may have a sudden onset. It may roam in the general anatomic area or be referred some distance from the affected bone.
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib43 bib50 bib93">
<ce:sup>1-9,43,50,93</ce:sup>
</ce:cross-refs>
Pressure and deep burning sensations are described by many, and the cortex is regularly tender to careful palpation, although the tenderness is often quite mild. It is not unusual for the pain to prevent sleep or to awaken the patient, and it is often remarkably resistant to routine analgesics.</ce:para>
<ce:para id="p0155">Many patients experience heightened pain with gingival or periapical inflammation, exercise, stress, smoking, changes in atmospheric or blood pressure, dependence of the affected part (lying down, for maxillofacial bones), the use of certain medications such as estrogen or corticosteroids (pain associated with medications often does not present for months after the onset of use), and dental procedures.
<ce:cross-refs refid="bib1 bib2 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib14 bib15">
<ce:sup>1-9,14,15</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0160">For the patient with superimposed infection, antibiotic therapy will reduce or even eliminate the pain, but only while the antibiotic is in use. The pain returns shortly thereafter. In these cases, the inflammatory mediators and toxins of infection are driving much of the medullary ischemia and increased pressures and, of course, medullary blood flow must be at least adequate to bring the antibiotic into the affected bone, although probably not at levels capable of completely eliminating the infection. With more compromised vascular flow, antibiotics will have very little effect unless decortication and curettage initiates fresh hemorrhage and angiogenesis. We have seen bone at surgery so desiccated that no hemorrhage could be induced, an appearance especially likely with corticosteroid-induced osteonecrosis.</ce:para>
<ce:para id="p0165">In the hip, the symptoms typically “progress relentlessly” until there is collapse of the femoral head, usually after 3 to 5 years, but many cases stabilize and never go on to complete collapse.
<ce:cross-refs refid="bib1 bib9 bib15 bib103">
<ce:sup>1,9,15,103</ce:sup>
</ce:cross-refs>
A significant minority of patients, in fact, undergo self-healing without treatment (Table 4).
<ce:float-anchor refid="tab4"></ce:float-anchor>
Stabilized lesions without progressively increasing pain occur in the jaws as well but are at constant risk of inflammatory events capable of exacerbating the compromised marrow flow and pushing the disease over a threshold into increased pain (osteoradionecrosis is a good model for this concept).</ce:para>
</ce:section>
<ce:section id="s0035">
<ce:section-title>Nerve damage</ce:section-title>
<ce:para id="p0170">Although nerve damage is not required to explain the pain of osteonecrosis, it is to be expected that alveolar nerves traversing ischemically damaged or inflamed marrow will be affected by the toxins, immunoglobulins, and inflammatory mediators enveloping them (Fig 9A), or by the substantial release of free radicals during reperfusion after vasoconstrictor use.
<ce:cross-ref refid="bib104">
<ce:sup>104</ce:sup>
</ce:cross-ref>
<ce:display>
<ce:figure id="fig9">
<ce:label>Fig. 9</ce:label>
<ce:caption>
<ce:simple-para id="sp0105">Nerve changes in NICO.
<ce:italic>A,</ce:italic>
Maxillary alveolar nerve coated by lymphocytes;
<ce:italic>B,</ce:italic>
Cross-section of fibrosed neurovascular bundle with no residual veins or nerves and a degenerated artery;
<ce:italic>C,</ce:italic>
Normal middle maxillary alveolar nerve with abundant myelin and no fibrosis;
<ce:italic>D,</ce:italic>
Considerable loss of myelin (demyelination) and fibrosis of alveolar nerve (C & D = luxol fast blue stain, myelin-stained blue/green).</ce:simple-para>
</ce:caption>
<ce:link locator="gr9"></ce:link>
</ce:figure>
</ce:display>
These nerves and their internal vessels, the vasa nervorum, are affected by the same increased pressures and thrombosis-driven ischemia as the enveloping marrow, engendering a form of necrotizing angiopathic neuropathy similar to that described by Dyck et al
<ce:cross-ref refid="bib105">
<ce:sup>105</ce:sup>
</ce:cross-ref>
as a painful consequence of peripheral vascular disease in diabetics.
<ce:cross-refs refid="bib106 bib107">
<ce:sup>106,107</ce:sup>
</ce:cross-refs>
Progressive sensitization and degeneration of alveolar nerves and specialized dental sensory presso- and mechanoreceptors, even deafferentation and brainstem neuroplastic alterations after tooth-pulp removal, can explain why the regions innervated by these nerves account for the majority of neuralgias in humans.
<ce:cross-refs refid="bib108 bib109 bib110 bib111 bib112 bib113 bib114">
<ce:sup>108-114</ce:sup>
</ce:cross-refs>
Remyelinization of damaged nerves also may contribute to a neuropathy by producing internodes of varying lengths with subsequently altered conduction velocities, and toxins from damaged marrow may be transported centrally as far as the nucleus caudalis, potentially causing degenerative changes at more distant sites.
<ce:cross-refs refid="bib90 bib115 bib116 bib117 bib118">
<ce:sup>90,115-118</ce:sup>
</ce:cross-refs>
The latter phenomenon may explain the minor lymphocytic infiltration, fibrosis, and myelin sheath abnormalities common to gasserian ganglia and associated sensory roots in postmortem examinations.
<ce:cross-ref refid="bib119">
<ce:sup>119</ce:sup>
</ce:cross-ref>
Other ganglia do not show these signs of inflammatory damage.</ce:para>
<ce:para id="p0175">Although the marrow disease influences the alveolar nerves, the nerves themselves can adversely influence the marrow disease through neurogenic inflammation. Neuropeptide release, especially substance P and calcitonin-gene-related peptide, and neural control of vasoactivity occur in inflamed tissues, and sensory nerves have the ability to develop local mitogenic and trophic effects at their peripheral endings in injured and healing tissues.
<ce:cross-refs refid="bib111 bib112 bib113">
<ce:sup>111-113</ce:sup>
</ce:cross-refs>
When severe and prolonged nerve stimulation occurs, the inflammatory responses evoked locally may produce additional tissue injury instead of helping to maintain tissue integrity and strengthening the repair process.
<ce:cross-refs refid="bib94 bib95 bib96 bib97 bib98 bib108 bib109 bib110 bib111 bib112 bib113 bib114">
<ce:sup>94-98,108,109-114</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0180">The scarcity of nerves in NICO tissue samples has made it difficult to provide direct evidence of damage to dental and alveolar nerves. Most curettage procedures are conservative and avoid clinically visible neural tissue, and damaged axons frequently undergo wallerian degeneration and die back to their cell bodies. However, we have seen degenerative fibrosis of the entire inferior alveolar neurovascular bundle with no residual neural tissue (
<ce:cross-refs refid="fig1 fig8">Figs 1C, 8B</ce:cross-refs>
), as well as cortex-to-cortex marrow loss with no evidence of the neurovascular bundle except a small, frayed stump swinging from the proximal wall (
<ce:cross-ref refid="fig1">Fig 1D</ce:cross-ref>
). Also, nonwallerian myelin degeneration has been reported in 13 of 17 nerves from NICO tissue samples (
<ce:cross-refs refid="fig9 fig9">Figs 9C, D</ce:cross-refs>
), and direct inflammatory or immune attacks against nerves are occasionally obvious at the microscopic level (
<ce:cross-ref refid="fig9">Fig 9A</ce:cross-ref>
).
<ce:cross-ref refid="bib50">
<ce:sup>50</ce:sup>
</ce:cross-ref>
</ce:para>
<ce:para id="p0185">Elevated levels of circulating anti-peripheral nerve myelin antibodies have been found in NICO patients, which suggests chronic exposure of the peripheral myelin to the immune system.
<ce:cross-refs refid="bib120 bib121 bib122">
<ce:sup>120-122</ce:sup>
</ce:cross-refs>
The sera of healthy humans normally show none of these antibodies, but some NICO patients have had levels as high as or higher than those found in the Guillain-Barré syndrome. Chronic nerve damage is likely enhanced by the very high levels of neurotoxicity found by bioassay in virtually all tissue samples of maxillofacial osteonecrosis, although the responsible neurotoxins have not yet been identified.
<ce:cross-ref refid="bib123">
<ce:sup>123</ce:sup>
</ce:cross-ref>
</ce:para>
<ce:para id="p0190">Additional indirect evidence of alveolar nerve hypersensitization (neuritis) in patients with ischemic and inflammatory marrow disease includes the extremely high proportion of neuralgias occurring in the mandibular and maxillary regions (implying that
<ce:italic>something</ce:italic>
is different about the maxillofacial/trigeminal nerve environment), as well as the results of the hyperesthesia/anesthesia test.
<ce:cross-refs refid="bib43 bib92 bib124 bib125">
<ce:sup>43,92,124,125</ce:sup>
</ce:cross-refs>
This test is predicated on the presence of anesthetic-resistant intraosseous nerves sensitized by chronic ischemia or inflammation. The ends of these nerves perforate the cortex to innervate extraosseous target tissues or receptor fields in surface mucosa. Anesthetizing the supraperiosteal innervation, through the use of inferior alveolar, lingual, and long buccal nerve blocks in mandibular cases may affect the pain somewhat, but additional infiltration of local anesthetic directly into the hyperesthetic site will eliminate or dramatically reduce the pain. When pain abatement occurs, the test is considered positive, and the underlying bone or the adjacent tooth should be suspect.</ce:para>
</ce:section>
<ce:section id="s0040">
<ce:section-title>A heightened level of clinical suspicion</ce:section-title>
<ce:para id="p0195">The symptoms of IO typically lead to a diagnosis of medullary disease when the femoral head or another long bone is affected, but when they occur in the face, appropriate evaluation for bone marrow disease seldom occurs. This is in part because marrow disease is interpreted by clinician and patient alike as a toothache, and in part because the teeth on the side of pain often do become painful—they are, after all, involved in the same ischemic process. One of the great frustrations of dealing with NICO is separating dental disease from marrow disease and recognizing when comorbidity exists.</ce:para>
<ce:para id="p0200">Although dental parameters must always be considered, all too often unnecessary root canal therapy is initiated in NICO patients, sometimes involving whole quadrants of teeth. This therapy only serves to compound the nerve injury and to perpetuate the pain dilemma. Eventually, the patient will be referred to a neurologist, who will invariably make a diagnosis of “idiopathic” neuralgia, causalgia, phantom pain, deafferentation, hyperalgesia, allodynia, or anesthesia dolorosa.
<ce:cross-refs refid="bib126 bib127">
<ce:sup>126,127</ce:sup>
</ce:cross-refs>
This is understandable, given the difficulty of diagnosing IO and occult alveolar osteomyelitis, and the obvious existence of truly idiopathic neuralgias, but it need not be the case. A heightened level of clinical suspicion allows a bone diagnosis to be made when appropriate, even without the use of expensive imaging techniques.
<ce:cross-refs refid="bib50 bib69 bib92 bib124 bib128 bib129 bib130 bib131 bib132 bib133 bib134">
<ce:sup>50,69,92,124,128-134</ce:sup>
</ce:cross-refs>
</ce:para>
<ce:para id="p0205">The frequent lack of obvious soft tissue and radiographic change in this disease is so well understood in medicine that staging protocols include a very unique stage 0, representing lesions completely negative to all available imaging techniques and capable of diagnosis only through microscopic evaluation of intraosseous tissue (
<ce:cross-ref refid="tab4">Table 4</ce:cross-ref>
).
<ce:cross-refs refid="bib5 bib6 bib9">
<ce:sup>5,6,9</ce:sup>
</ce:cross-refs>
To the best of our knowledge, no other orthopedic disease has a stage 0, and some authorities have suggested that the lack of imaging evidence of disease makes IO the diagnosis of choice for the painful hip.
<ce:cross-ref refid="bib6">
<ce:sup>6</ce:sup>
</ce:cross-ref>
Unfortunately, the same level of understanding appears to be wanting in the dental profession. The “normal” dental radiograph is commonly equated with “no disease,” despite the fact that the profession has repeatedly been warned that considerable medullary destruction can occur without appreciable alteration of the radiographic image (
<ce:cross-ref refid="fig8">Fig 8</ce:cross-ref>
).
<ce:cross-refs refid="bib135 bib136 bib137">
<ce:sup>135-137</ce:sup>
</ce:cross-refs>
This problem is accentuated by the relative unfamiliarity of dentists with the use of the hyperesthesia/anesthesia test for the confirmation of subtle radiographic changes and with the use of IO imaging techniques other than radiographs.
<ce:cross-ref refid="bib125">
<ce:sup>125</ce:sup>
</ce:cross-ref>
</ce:para>
<ce:para id="p0210">A low level of clinical suspicion for bone marrow disease in the chronic “idiopathic” facial pain setting is surprising in light of the long history behind the concept. More than a century and a half ago, James Ware,
<ce:cross-ref refid="bib138">
<ce:sup>138</ce:sup>
</ce:cross-ref>
founding editor of the
<ce:italic>New York Dental Recorder</ce:italic>
(precursor to
<ce:italic>Dental Cosmos</ce:italic>
), stated that “we can safely say that... most of the cases of Neuralgia Facialis have their origin in irritation about the fangs of the teeth.” The 1898 Barrett
<ce:cross-ref refid="bib29">
<ce:sup>29</ce:sup>
</ce:cross-ref>
text suggested “local irritation” as merely one of several potential causes. This more realistic concept was echoed by leaders of early American dentistry, including Chapin Harris,
<ce:cross-ref refid="bib139">
<ce:sup>139</ce:sup>
</ce:cross-ref>
co-founder of the first dental school, and Simon P. Hullihen,
<ce:cross-ref refid="bib140">
<ce:sup>140</ce:sup>
</ce:cross-ref>
the father of oral surgery, and continued to be espoused by internationally recognized neuropathic pain authorities throughout the 20th century.
<ce:cross-refs refid="bib45 bib46 bib47 bib48 bib49 bib50">
<ce:sup>45-50</ce:sup>
</ce:cross-refs>
Likewise, the first English-language textbook of peripheral neuropathology published in the 21st century has concluded that “spontaneous or induced electrical discharges from damaged nerves play an important role in the genesis of neuropathic pain.”
<ce:cross-ref refid="bib90">
<ce:sup>90</ce:sup>
</ce:cross-ref>
This view is especially compelling when we understand that the only animal model thus far developed for trigeminal neuralgia creates pain through suppurative pulpal/periapical infection of multiple teeth in a single quadrant.
<ce:cross-refs refid="bib141 bib142 bib143">
<ce:sup>141-143</ce:sup>
</ce:cross-refs>
</ce:para>
</ce:section>
<ce:section id="s0045">
<ce:section-title>The clot/infection connection</ce:section-title>
<ce:para id="p0215">It has already been mentioned that maxillofacial osteonecrosis lesions, similar in so many ways to those of long bones, differ significantly in having a much greater involvement of infection and trauma. Chronic dentoalveolar infections diminish blood flow and enhance coagulation in surrounding marrow, a serious concern for persons who are already dealing with systemic prothrombotic tendencies.
<ce:cross-refs refid="bib86 bib87 bib88 bib144">
<ce:sup>86-88,144</ce:sup>
</ce:cross-refs>
In that cohort, the infection may lead to complete stasis, with progressive infarction of large zones of marrow and little, if any, chance for resolution or healing.</ce:para>
<ce:para id="p0220">However, it should be emphasized that chronic or recurring infections, including localized infections of the mouth and sinuses, also increase the risk of profound systemic sequelae. There are strong correlations, mentioned even in the popular press, between focal infections such as chronic periodontitis and periapical or sinus infections, and cardiovascular disease and stroke.
<ce:cross-refs refid="bib145 bib146 bib147 bib148 bib149 bib150 bib151">
<ce:sup>145-151</ce:sup>
</ce:cross-refs>
In fact, focal infection has been shown to be one of the most significant pathoetiologic factors for stroke, and persons with excessive prothrombotic tendencies are at considerably heightened risk.</ce:para>
<ce:para id="p0225">Several processes are involved in the creation of a systemic hypercoagulable state by chronic or recurring infections, not the least of which is the activation of the complement cascade. C4a-binding proteins (C4a-BP) produced during inflammation bind to free protein S, a natural circulating anticoagulant, to produce a deficiency of free protein S so that protein C (another anticoagulant) in circulation is less effective in inhibiting factors VIIIa and Va, thereby creating a prothrombotic environment.
<ce:cross-refs refid="bib152 bib153">
<ce:sup>152,153</ce:sup>
</ce:cross-refs>
Excessive fibrin in the blood stream creates microthrombi and can coat endothelial walls, producing microinfarctions in small vessels and interfering with perfusion through the endothelium. Moreover, it must be dissolved by activation of the fibrinolytic system, a process hampered by low levels of activated protein C.</ce:para>
<ce:para id="p0230">The longer an infection or inflammatory condition is allowed to persist, the greater will be the binding of protein S, the greater the procoagulant (prothrombotic) activity, and the greater the difficulty of maintaining homeostasis in coagulation. Of course, this process is a more significant problem for persons with heritable deficiencies of protein S and protein C, or those with activated protein C resistence influenced by exogenous factors such as estrogen.
<ce:cross-ref refid="bib62">
<ce:sup>62</ce:sup>
</ce:cross-ref>
Thus, a recurrent infection or persistent inflammatory condition becomes a systemic risk factor (an independent “hit”) for the development of thromboembolic phenomena, while amplifying the intramedullary thrombosis of the affected jawbone sites. Additionally, it provides yet another argument for not taking the heart or stroke patient off coumadin in preparation for removal of infected teeth.
<ce:cross-refs refid="bib154 bib155">
<ce:sup>154,155</ce:sup>
</ce:cross-refs>
If and when the infection/inflammation is eliminated and an excess of thrombin is no longer being generated, the process of clearing vessels and “thinning” the blood may take several weeks, extending the period at risk.</ce:para>
<ce:para id="p0235">Intravascular thrombi, fibrin-coating of capillaries and small veins, vessels dilated by back-up pressures and fluid slowdown, extravasation and stagnation of serous fluids between fat cells, and ischemic myelofibrosis all compromise marrow nutrition and all are common microscopic features of NICO specimens.
<ce:cross-refs refid="bib45 bib52 bib69 bib125">
<ce:sup>45,52,69,125</ce:sup>
</ce:cross-refs>
Heritable and acquired prothrombotic disorders also have been tentatively associated with various other diseases found with frequency in NICO patients, including chronic fatigue syndrome, fibromyalgia, myofascial pain syndrome, and migraine headache.
<ce:cross-refs refid="bib156 bib157 bib158">
<ce:sup>156-158</ce:sup>
</ce:cross-refs>
As yet the strength and causality of the associations are not known, but hypercoagulation may prove to be the common denominator explaining the intermingling of these disparate diseases in numerous patients. Likewise, in addition to deep bone pain, we have seen very severe thrombophilias produce overlying infarctive destruction of soft tissues (Fig 10) in a manner reminiscent of thromboangiitis obliterans (Buerger disease) or the less severe ulceration of Behcet disease.
<ce:cross-refs refid="bib159 bib160">
<ce:sup>159,160</ce:sup>
</ce:cross-refs>
<ce:display>
<ce:figure id="f0035">
<ce:label>Fig. 10</ce:label>
<ce:caption>
<ce:simple-para id="sp0110">Skin necrosis 3 months postneurectomies (bilateral inferior alveolar nerve and left infraorbital nerve) in patient with antiphospholipid syndrome and other major hematologic “hits”: hyperhomocystinemia (MTHFR homozygosity), elevated lipoprotein (a) and hyperlipidemia.</ce:simple-para>
</ce:caption>
<ce:link locator="gr10"></ce:link>
</ce:figure>
</ce:display>
</ce:para>
</ce:section>
<ce:section id="s0050">
<ce:section-title>In the name of controversy</ce:section-title>
<ce:para id="p0240">Few diseases represent such a subtle microscopic reflection of long-standing physiologic phenomena as IO, and few maxillofacial diseases are so difficult to diagnose and separate from odontogenic inflammatory conditions. Almost no others show such an intimate intermingling of unique environment (intramedullary tissues), interaction with strong and typically undiagnosed systemic problems (coagulation tendencies influencing and being influenced by local disease), and interaction with neuropathic processes (again, influencing and being influenced by local disease).</ce:para>
<ce:para id="p0245">The future role of dentistry is this disease is exciting. After more than 150 years of clinical awareness of and controversy over the relationship between alveolar inflammatory disease and certain facial neuralgias, we are finally progressing toward a real understanding. The controversy has greatly diminished, although there are a few who remain proudly “standing in the middle of their own preconceptions with the stolid air of one who is quite prepared to wait until continental drift budges him from his position.”
<ce:cross-refs refid="bib161 bib162">
<ce:sup>161,162</ce:sup>
</ce:cross-refs>
Every emerging disease concept has its critics, and this criticism is important to the processes of improved awareness.</ce:para>
<ce:para id="p0250">More than most other diseases, the very names used for maxillofacial osteonecrosis over the years have acquired a certain amount of notoriety, not excluding the current term, NICO. And yet the latter name was created merely to emphasize 2 of the most obvious and unique features of a well-established systemic disease: 1) the disintegration of marrow, that is, “dry rot,” with formation of hollow spaces and; 2) the neuropathic character of the accompanying pain. It was deliberately intended to remind the clinician to consider ischemic medullary disease when generating a differential diagnosis for chronic facial pain.</ce:para>
<ce:para id="p0255">The current name seems a good one and has succeeded more than any other diagnostic term in awakening a new consciousness in this regard, but it is after all just a name. For those who believe that IO “produces” or “accompanies” rather than “induces” the facial neuralgia and for those who believe the associated pain is “neuritis” rather than “neuralgia,” we suggest the use of the histopathologic terms
<ce:italic>ischemic osteonecrosis</ce:italic>
and
<ce:italic>bone marrow edema.</ce:italic>
For those who persist in the belief that there can be no neuralgia-like pain with IO or who believe that the jaws are miraculously and completely immune to ischemic damage, we suggest a review of the pathophysiology of osteonecrosis and chronic osteomyelitis.</ce:para>
<ce:para id="p0260">With time, a better understanding will be achieved and, as more health professionals become aware of the subtleties surrounding the diagnosis and treatment of maxillofacial osteonecrosis, affected patients will less often be viewed as narcotic-dependent “head cases,” and clinicians will provide appropriate evaluation for medullary disease. NICO will then be viewed as just another oral sign of systemic disease. Along the way, we will become more aware of the frightening potential for prothrombotic events in our patients, will learn to extend our evaluations to include imaging techniques other than radiographs, and will become more concerned about the systemic effects of local alveolar infections and necrotic processes.
<ce:cross-refs refid="bib144 bib145 bib146 bib147 bib148 bib149 bib150 bib151 bib152 bib153 bib163">
<ce:sup>144-153,163</ce:sup>
</ce:cross-refs>
</ce:para>
</ce:section>
</ce:sections>
</body>
<tail>
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<title>Neuropathic pain in maxillofacial osteonecrosis</title>
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<title>Neuropathic pain in maxillofacial osteonecrosis</title>
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<namePart type="given">Jerry E.</namePart>
<namePart type="family">Bouquot</namePart>
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<namePart type="given">Robert E.</namePart>
<namePart type="family">McMahon</namePart>
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<note>*Director of Research, The Maxillofacial Center for Diagnostics & Research, Morgantown, WV; Consultant, New York Eye and Ear Infirmary, New York, NY.</note>
<note>†Private Practice, Oral Surgery Group, Valparaiso, IN; Clinical Investigator, The Maxillofacial Center for Diagnostics & Research, Morgantown, WV; Clinical Investigator, Residual Infection in Bone (RIIB) Project, Indiana University Medical Center, Indianapolis, IN.</note>
<note>Address correspondence and reprint requests to Dr Bouquot: The Maxillofacial Center, 165 Scott Ave, Suite 100, Morgantown, WV 26508; e-mail: bouquot@@aol.com</note>
<note type="content">Section title: Clinical Controversies in Oral and Maxillofacial Surgery: Part One</note>
<note type="content">Table 1: LOCALIZED AND SYSTEMIC DISEASES AND PATHOPHYSIOLOGIC PROCESSES ASSOCIATED WITH ISCHEMIC OSTEONECROSIS</note>
<note type="content">Table 3: COAGULATION DISORDERS FOUND IN PATIENTS WITH ISCHEMIC OSTEONECROSIS OF THE HIPS, KNEES, AND JAWS</note>
<note type="content">Table 4: INTERNATIONAL CLASSIFICATION FOR THE STAGING OF ISCHEMIC OSTEONECROSIS (APPLIES PREDOMINANTLY TO HIP LESIONS AND ENDS OF LONG BONES); PATIENTS AT ALL STAGES MAY OR MAY NOT HAVE PAIN</note>
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