Maxillofacial Osteonecrosis in a Patient with Multiple "Idiopathic Facial Pains
A published paper from The Maxillofacial Center for Diagnostics & Research
Other Links NICO Home Page Other Osteonecrosis Papers Dr. Bouquot's Work Home Page		This Topic Table of Contents Authors Journal Citation Summary for Nonscientists References Figures (Photos)
Section of mandible with multiple discolored, mushy regions of dead and damaged marrow, including gelatinous marrow along the inferior alveolar nerve. From: Adams WR, et al. J Oral Pathol Med 1999; 28:423-432; used with permission.

Table of Contents

Reference: Adams WR, Spolnik KJ, Bouquot JE. Maxillofacial osteonecrosis in a patient with multiple "idiopathic" facial pains. J Oral Pathol Med 1999; 28:423-432.

Authors

William R. Adams, D.D.S., M.S.D. Clinical Associate Professor of Endodontics, Indiana University School of Dentistry, Indianapolis, Indiana; Senior Clinical Investigator, The Maxillofacial Center, Morgantown, West Virginia.

Kenneth J. Spolnik, D.D.S., M.S.D. Former Clinical Assistant Professor of Endodontics, Indiana University School of Dentistry, Indianapolis, Indiana; Senior Clinical Investigator, The Maxillofacial Center, Morgantown, West Virginia.

Jerry E. Bouquot, D.D.S., M.S.D. Director of Research, The Maxillofacial Center for Diagnostics & Research, Morgantown, West Virginia; Former Chairman, Department of Oral & Maxillofacial Pathology, School of Dentistry, West Virginia University, Morgantown, West Virginia.

Abstract

Previous investigations have identified focal areas of alveolar bone tenderness, increased mucosal temperature, abnormal anesthetic response, radiographic abnormality, increased radioisotope uptake on bone scans, and abnormal marrow within the quadrant of pain in patients with chronic, idiopathic facial pain. The present case reports a 53 year old man with multiple debilitating, "idiopathic" chronic facial pains, including trigeminal neuralgia and atypical facial neuralgia, who was found at necropsy to have numerous separate and distinct areas of ischemic osteonecrosis on the side affected by the pains, one immediately beneath the major trigger point for the lancinating pain of the trigeminal neuralgia. This disease, called NICO (Neuralgia-Inducing Cavitational Osteonecrosis) when the jaws are involved, is a variation of the osteonecrosis which occurs in other bones, especially the femur. The underlying problem is vascular insufficiency with intramedullary hypertension and multiple intraosseous infarctions occurring over time. The present case report illustrates the extreme difficulties involved in the diagnosis and treatment of this disease.

Introduction

When a dental, temporomandibular joint or paranasal sinus cause cannot be found for chronic facial pain, subtle damage to the trigeminal nerve itself is usually assumed and diagnostic terms such as neuralgia, causalgia, phantom pain, deafferentation, hyperalgesia and anesthesia dolorosa are applied, depending on the presenting symptoms.(1,2) There is, however, another entire class of pain-producing conditions that require no nerve damage to explain chronic "idiopathic" pain. These have to do with a compromised flow of blood through the bone marrow or with inflammatory changes of medullary tissues (Table 1).(3-11) Many of these disease states produce no swelling or erythema of the overlying skin or mucosa, no alteration in routine lab values, and minimal or no alteration of radiographic images of the affected area. Radiographic and other imaging changes are, in fact, often so subtle that a very unique "Stage 0" classification has been created for those cases which are completely negative to all known forms of imaging technology (Table 2).(6,7,9)

Previous investigations have hinted at intramedullary jawbone disease in facial pain or neuralgia. Friedman(12) reported that 15 of 18 patients with chronic idiopathic facial pain had localized areas of alveolar tenderness in the painful quadrant; 17 of the 18 also had areas of elevated mucosal temperature in the painful quadrant. Denucci et al (13) took this a step further, evaluating a similar group of NIH patients with ⁹⁹technetium SPECT (Single Proton Emission Computed Tomography) scans. Such scans are primary diagnostic tools for bone infarcts and the claudication of marrow ischemia, generally demonstrating "hot spots" of increased vascularity or bone production in surrounding bone but occasionally showing ischemic "cold spots" of photopenia in lesions scanned during the initial phase of disease or during a quiescent period with no bone healing whatsoever.(14,15) After excluding areas of reactive periodontitis and periapical dental disease, Denucci et al reported that a remarkable 75% of the patients showed localized "hot spots" of increased isotope uptake within the quadrant of pain.

These investigators performed no biopsies, but in 46 patients with idiopathic facial pain McMahon et al (16) used local anesthetic injections to find reproducible sites of alveolar mucosal hyperesthesia or incomplete anesthesia in the quadrant of pain. Surgical exploration beneath these sites provided microscopic evidence of ischemic or inflammatory changes in all cases. Earlier reports had identified marrow fibrosis and chronic nonsuppurative osteomyelitis of the jaws in the quadrant of idiopathic facial pain, with several investigators commenting on a unique hollowing out of the affected cancellous bone.(17-20)

More recently, Bouquot et al (21-24) have clarified the histopathology as a form of ischemic osteonecrosis and applied the term NICO (Neuralgia-Inducing Cavitational Osteonecrosis) to cases associated with facial neuralgias and idiopathic pain. The majority of jaw cases fall into the diagnostic category of bone marrow edema syndrome (transient ischemic osteonecrosis), which is the histopathologically less severe form of osteonecrosis and is characterized by ischemic alterations rather than by extensive infarction and necrosis.(25) Follow-up studies have demonstrated that meticulous curettage of abnormal marrow is effective in eliminating or significantly diminishing the associated facial pain in at least two-thirds of affected patients.(19,20,22)

The new understanding of this as primarily an ischemic and infarctive process rather than an infection led Glueck et al (26-30) to evaluate for coagulopathies in large numbers of patients with osteonecrosis of the jaws, knees and hips, finding that the great majority were afflicted with one or more hereditary or acquired forms of hypofibrinolysis or thrombophilia (Table 3). This, in turn, has led to the recent use, with some success, of various anticoagulation medications in osteonecrosis patients identified with clotting dysfunctions.(31,32) It has also led to speculation as to the role of estrogen therapy as a co-factor in the onset of symptoms in persons otherwise susceptible to medullary ischemia because of underlying coagulopathies.(29,33) An impressive array of other etiologies and associations has been reported (Table 4).(11)

The present case report summarizes the clinical presentation and progression of disease in a patient with multiple idiopathic facial pains refractive to routine neurologic therapies but responsive to intraosseous curettage of damaged marrow. It evaluates the gross and microscopic features of affected alveolar bone and discusses emerging pathophysiologies.

Case Report: Presenting Signs and Symptoms. A 53 year old white male presented to the Indiana University Neurology Service with severe, lancinating pain of his left face. His pain was so intense that he could take no more than a few steps before a pain "attack" would force him to stoop over, grasping his face. Even while seated, episodes of excruciating, spasmodic pain would occur, frequently interrupting his neurologic evaluation. His grooming and demeanor reflected someone in first order chronic, severe pain. He had lost considerable weight because eating, drinking and the slightest motion of his head initiated or triggered paroxysms of "stabbing, shooting" pain, originating within his left upper lip and extending along the left side of his nose into the eye region on that side. The pain was accompanied by a strong burning sensation and lasted only for 15-20 seconds, but multiple attacks were characteristic, one immediately after the other for a period of several minutes. These attacks could be triggered by walking, talking, even by hitting road bumps while driving.

A second type of pain consisted of a constant, dull, throbbing, "gnawing" sensation of the left cheek and the molar areas of the mandible and the maxilla. This pain seemed to the patient to be more in the overlying soft tissues than in the bone. Every few seconds or minutes, a third and more intense or "hard," deep, bone pain (not the tic or lancinating pain described above) would alternate between the mid-portion of the mandible and the posterior maxilla on the left side.

The mucosa and skin overlying the areas of pain were normal in appearance. Pantographs showed only a poorly demarcated 0.5 cm. circular radiolucency of the left cuspid region of his edentulous mandible. Computer assisted tomography scans and extensive otolaryngology, neurology and neurosurgical examinations could find no apparent pathology. An MRI revealed an increased T2 signal in the pons which was interpreted as a focal area of ischemia, but no maxillofacial abnormalities were reported. A lumbar spinal tap for fluid analysis and lyme antibody titer showed no abnormalities. All available laboratory values were within normal limits.

Anesthetic nerve blocks to the infraorbital, inferior alveolar and mental nerves on the left side produced immediate and almost complete relief for an hour or more. Carbamazepine and phenytoin therapy were ineffective in altering any of the patient's pains and analgesics provided minimal relief. The Neurology Service diagnoses were atypical facial neuralgia of the third branch of the left trigeminal nerve and trigeminal neuralgia of the second branch of the left trigeminal nerve.

Case Report: Medical/Dental History. The patient had an unremarkable medical history except for several bouts of intractable hiccups during his fourth decade and hypertension treated since 46 years of age with a variety of medications, including acebutolol hydrochloride, terazosin hydrochloride and enalapril maleate. He was not a tobacco user or alcohol abuser and had no history of corticosteroid therapy prior to his facial pain. His only surgery, other than oral surgery, was a vasectomy. At 39 years of age the patient had his left anterior maxillary and mandibular teeth extracted because of a chainsaw injury to the area. During his 40s numerous additional teeth were extracted because of caries and periodontal disease.

The patient began experiencing "dental pain" of his left anterior maxillary and mandibular regions three years prior to presentation at the University Neurology Service. In consequence, all remaining teeth were extracted and an immediate denture was placed. The toothache-like pain, however, continued unabated and was diagnosed as phantom toothache after a negative sinus evaluation by an otolaryngologist. Additional specialists were enlisted, but no additional diagnoses or therapies were forthcoming, except for a tentative diagnosis of "focal nerve injury" and a course of baclofen, which proved ineffective and was not well tolerated.

Six months after onset, the patient's left jaw and face was "in constant pain" and he had occasional lancinating pains from his upper left lip to his left eye. The latter pains lasted 15-20 seconds and were occurring 2-3 times monthly. Within six more months the lancinating pains were occurring daily and were initiated by even slight facial movements.

During the second year after onset, the patient's non-lancinating pain altered to a generalized, constant, dull, throbbing, poorly-demarcated ache of both jaws on the left, and additional "hard pains" (deep bone pain) were occurring 20-30 times daily. The constant aching continued unabated but diminished temporarily with antibiotic therapy. Amitriptyline (25 mg qhs) helped the patient to sleep, but had no effect on his pain during his waking hours. Alcohol injected into the patient's infraorbital nerve partially diminished the deep, constant pain for several weeks, likewise a left infraorbital neurectomy relieved the paroxysmal, triggering pain, but only for a few weeks. Despite increasing the amitriptyline to 125 mg/day and adding capsaicin cream (0.025%) applications to the left face, the aching pain gradually became more severe and the paroxysmal pains became more frequent until the patient presented to the University Neurology Service as described above.

Case Report: Osteonecrosis Diagnosis and Therapy. Referral was made to the present authors, who identified several areas of alveolar hypersensitivity on the patient's left side using the diagnostic anesthesia/hyperesthesia test of Ratner-McMahon.(16,34) Mandibular left full terminus anesthesia (inferior alveolar, long buccal and mental blocks) provided approximately 70-80% relief of pain. Maxillary left infraorbital block, anterior superior alveolar infiltration and nasopalatine block eliminated all remaining pain. A ⁹⁹technetium-MDP scintigraphy scan demonstrated multiple areas of increased radioisotope uptake or "hot spots" in the maxillofacial bones (Figure 1).

Surgical exploration of the left cuspid regions found medullary bone which was soft, brownish and gritty, with areas of apparent fibrosis. After thorough curettage of all abnormal intramedullary tissues, the surgical defects where closed and weekly intra-lesional antibiotic injections of clindamycin phosphate (150 mg) and gentamicin sulfate (40 mg) were given for nine consecutive weeks.

Intramedullary tissue samples were microscopically characterized by replacement of mature fatty marrow by a loose fibrosis (reticular fatty degeneration, myelofibrosis), with severe dilation of marrow sinusoids and with a few scattered chronic inflammatory cells. Occasional areas showed focal necrosis of fatty marrow. An histopathologic diagnosis of ischemic osteonecrosis, Arlet Tissue Type I (transient ischemic osteoporosis, bone marrow edema syndrome), was made, with the left maxillary cuspid lesion additionally demonstrating overtones of chronic fibrosing osteomyelitis.

Within weeks the patient was having "really comfortable days" for the first time in years. There was noticeable improvement in his gait, grooming and general attitude. All Class II and III narcotics had been discontinued. Six months after curettage, however, he experienced a recurrence of his "hard" bone pain, this time reported as "bouncing" between the mandible and maxilla. Four additional weekly intralesional injections of antibiotics, combined with amoxicillin/clavulanate potassium therapy (500 mg/125 mg. t.i.d.), once again greatly diminished all pains. When the tic-like pain began occasionally recurring nine months after curettage, the left maxillary cuspid area was twice more injected with the same antibiotics, each time leading to considerable comfort for several months.

Fourteen months after bone curettage he began once again to experience all three pains, although none was as intense or as frequent as previous pains. The surgical sites were re-opened and curetted. Both bony defects were visibly smaller but neither was re-ossifying well and microscopic evaluation showed only dense fibrosis without new bone formation.

The lesions were injected weekly with the previously mentioned antibiotics for four consecutive weeks after surgery. After surgical healing the patient remained completely pain free for nine months, at which time he began experiencing a severe, deep, burning, aching pain in the posterior left mandible (a new pain). Surgical exploration of the third molar site demonstrated osteonecrotic bone clinically and microscopically, and after treatment the new pain decreased considerably, but not completely. Additional surgical exploration of a somewhat more anterior mandibular site was planned because of subtle radiographic changes in the area (it had been negative on ⁹⁹tech scans), but the patient died of sleep apnea/asphyxiation before the surgery could be performed.

Case Report: Gross Alterations at Necropsy.  Only the left maxillofacial bones were available for examination. After fixation in 10% formalin and slow decalcification in 3% nitric acid, the specimen was sectioned in various planes. On longitudinal sectioning the cancellous bone of the mandible was found to be grossly abnormal, demonstrating several distinct and separate sites of pathologic involvement with apparently normal marrow between sites (Figure 2). The most dramatic involvement was a 2.1 x 1.0 x 0.7 cm. subcortical area of spongy, discolored, poorly-demarcated, multi-cavitated necrosis and degeneration located in the mandibular first/second molar area (Figures 2B & 3A). The cortex above the lesion was completely missing, having been replaced by a dense fibrous tissue, and a cord of fibro-necrotic tissue extended distally into the ramus. Sites of previous surgery showed solid, brown-gray masses of dense intramedullary fibrosis with no apparent bone production (Figures 2A and 3C).

The bony wall of the inferior alveolar canal was destroyed along much of its length, leaving the neurovascular bundle exposed and often encased within a brown/gray semi-translucent material similar to the gelatinous marrow found in cachexia and chemotherapy (Figures 2 & 3A).(35) In one area a globular mass or concentration of this material had indented the exposed alveolar nerve. A tubular cavitation extended along much of the length of the inferior border (Figure 2A).

The maxilla was less severely involved but contained multiple areas of altered marrow and an area of dense fibrosis with the outline of a poorly-healed bicuspid extraction socket (Figure 4). The cancellous bone of the tuberosity had the appearance and consistency of gritty, blood-soaked sawdust, and the entire zygomatic buttress was essentially hollow and honeycombed with interconnected cavitations in the area of greatest radioisotope uptake (Figures 1 & 3B). Soft, discolored marrow also extended in narrow streaks from the maxillary alveolar bone into the hard palate, and a small, isolated area of desiccated necrosis and cavitation was found in the posterior wall of the left maxillary sinus, with perforation through the cortical bone of the antrum.

Case Report: Microscopic Features at Necropsy.  The histopathologic appearance of involved marrow varied from site to site, with normal fatty marrow separating areas of disease. Focal regions of fat necrosis were evident, especially in the mandible, with different areas demonstrating either liquefactive necrosis with oil cysts (globules of coalesced liquified fat), eosinophilic fat necrosis with pale granular cytoplasm in some dead adipocytes, calcific fat necrosis (adipocere, saponification) with precipitated hematoxylin-staining salts, or atrophic/desiccated necrosis with formation of intramedullary cavitations (Figure 5).

The cavitations typically showed smooth, undulating walls with minimal fibrosis, with occasional coating by serous fluids and with a few areas of exposed bone (Figure 5D). Some cavitations where almost completely lined by exposed bone. Presumably cavitations represent areas of previous necrosis from which necrotic detritus has slowly resorbed, leaving a hollow or "air-filled" space within cancellous bone. Osteonecrosis is one of only two diseases capable of producing such defects and was the first bone disease for which the terms cavitation and cavity were applied.(17,37)

Chronic inflammatory cells were found only occasionally and only in very small numbers, even in areas of fat necrosis and cavitation, and there was minimal evidence of attempted healing, even at the periphery of surgerized areas (Figures 5-8). Pus was not seen in any area of the marrow. This lack of strong inflammatory and reparative processes is unexplained in ischemic osteonecrosis but is a hallmark of fatty marrow in the "mild" variants of the disease, such as transient ischemic osteoporosis and bone marrow edema syndrome.(38,39)

Under chronic conditions of intramedullary ischemia, osteoclastic and osteoblastic activity is obviated, and a loose, wispy fibrosis is seen to "flow" between fat cells (Figure 6B).(36,38,39) Several areas of our case demonstrated this reticular fatty degeneration, while the gelatinous marrow showed the classic serous ooze or plasmostasis of bone marrow edema syndrome (Figure 6A). The residual socket of the maxillary bicuspid region was completely filled with very dense, almost avascular collagenic tissue.

In more than 85% of cases of extragnathic osteonecrosis, intramedullary pressures are twice that of normal bone and may be as much as five times higher.(11,36,38-41) This underlying pathophysiology usually results from poor outflow from the bone, with backup pressures dilating the marrow vessels and eventually causing the extravasation of proteinaceous plasma into the extravascular spaces, i.e. the plasmostasis previously mentioned. Our case also demonstrated dilated marrow veins, although none were extremely dilated. Significantly, one showed complete occlusion by aggregated fibrin and platelets (Figure 7).

The classic sign of osteonecrosis is a loss of osteocytes within cortical or trabecular bone, often with enlarged lacunae (osteocytic osteolysis).(7-9,36) This loss may be universal throughout large areas of bone or it may be localized. By definition, 50% of osteocytes in a focal area must be missing or pyknotic for a diagnosis of necrotic bone in this disease.(36) Since strong acids destroy osteocytes, only mild decalcifying solutions should be used if this feature is to be appropriately evaluated. In our case a weak acid was used and the bone still showed large expanses of bone with complete or partial loss of osteocytes, often with enlarged, rounded spaces indicative of the slow demise of the affected osteocytes (Figure 5).

Bone which has experienced long-term ischemia often has excessive numbers and prominence of cement lines, and there may be a rather unique delamination of bone layers along the lines, referred to as microcracks.(36) Our case demonstrated this phenomenon in only a few areas (Figure 8).

Numerous alveolar nerves were visible with routine staining, but only one area of the inferior alveolar nerve appeared damaged. This area showed poor demarcation of the nerve from the surrounding marrow tissues. The epineurium was not intact and individual fibers were splayed apart with edema between fibers. Luxol fast blue staining showed demyelination of only one nerve, the posterior superior alveolar nerve, which also demonstrated fibrosis, thickening and irregular orientation, reminiscent of traumatic neuroma.

Discussion

It has long been suggested that a certain proportion of facial neuralgia patients have persistent pain from trigeminal nerve damage or stimulation at some distance from the brain, including inflamed jawbones.(43,44) Our case tends to confirm this postulate and to add several additional causes of pain which require no nerve damage to explain the pain. We emphasize, however, that we have no idea how commonly this occurs in patients with "idiopathic" facial pain, although previous investigations have suggested that it is quite common.(13,16,18) Nor do we know what type or intensity of pain is attributable to damaged nerves as opposed to damaged marrow. By way of illustrating this point, Figure 9 demonstrates much more severe involvement of the mandibular marrow in another patient who had only experienced localized "phantom" pain of moderate intensity.

Clearly, recurring and multifocal medullary infarctions, thrombus-induced vessel distention, and the fluid dynamics of intramedullary hypertension go far to explaining the "wandering" facial pains in some patients with atypical facial neuralgia, or the sharp pains noted in the present case to "jump" between the mandible and maxilla. Another known phenomenon, the irregular perfusion characteristics of bone marrow, might explain the focal nature of the disease, wherein areas of necrosis are intermixed with areas of ischemic damage and areas of perfectly normal marrow.(39,40)

Bone marrow edema syndrome frequently produces a very ill-defined, intermittent, deep ache or sharp pain, as illustrated by one of its early names, medullary engorgement-pain syndrome.(30-35) Likewise, microinfarctions in bone marrow produce either an intense, sharp pain deep in the area of involvement or a more generalized dull ache, as is illustrated by the bone pains of sickle cell disease.(10,35) Such symptoms in the hip typically lead to a suspicion of bone disease, but when in the facial region the same symptoms are quickly categorized as part of a neurological disorder rather than a bone or vascular problem.

Several other aspects of the facial pain-osteonecrosis interrelationship are more difficult to explain. The very specific, triggering, lancinating pain of trigeminal neuralgia, for example, is dissimilar to other forms of facial pain and is perhaps more readily explained by true nerve damage than by simple marrow ischemia and infarction. Bouquot & Christian (22) found myelin degeneration in 13 of17 (77%) NICO patients, but there was no apparent correlation with the diagnosis of trigeminal neuralgia. Halley (University of Kentucky School of Pharmacy, personal communication) has found, using standard assay techniques, extremely high levels of neurotoxicity in 100% of a large sample of intramedullary curettings from NICO patients. This speaks for neural damage or stimulation from the altered intramedullary environment, but the exact toxins involved have not yet been identified and most of the tissue samples were derived from patients without trigeminal neuralgia.

In our patient, no neural tissue was found in biopsy samples of damaged marrow from the area of trigeminal neuralgia triggering, i.e. the origination point of the lancinating pain. In fact, the only demyelinated nerve found was several centimeters from the trigger point. To further compound the mystery, removal of the abnormal bone effectively eliminated the triggering phenomenon and no lancinating pain occurred for an extended time after surgery. When the triggering pains eventually recurred, a second and equally minor surgery had the same result. We do not know the underlying mechanisms involved in this phenomenon. We are well aware of the propensity of trigeminal neuralgia to have periods of spontaneous remission lasting up to six months, but this patient had experienced no such remission prior to osteonecrosis treatment and the pain loss seemed not to be spontaneous but to be obviously related to local therapy. Could it be that the relief of intramedullary pressures or the removal of local inflammatory or necrosis-related toxins affected the improvement, decreasing the stimulation of a chronically hypersensitized nerve?

Another aspect of this pain-disease interrelationship difficult be explain is the fact that some patients with extensive bone destruction have no history of pain while others have early and intense pain before any imaging techniques are capable of identifying damaged bone (Stage 0).(3-11) In our case, a biopsy from the right mandibular area of increased radioisotope uptake (Figure 1), not previously mentioned in the history, was consistent with ischemic osteonecrosis, and yet pain had never occurred on the right side. Again, we are unable to explain this phenomenon, but it is certainly common to the disease, regardless of the bone involved.(6,7,9)

On a final note, it should be emphasized that osteonecrosis is not a disease in the usual sense, but is rather an intramedullary response to a variety of local and systemic etiologic factors, all capable of interfering with blood flow through the marrow, usually by way of intravascular microthrombi, microinfarction, reduced outflow, or a combination thereof (Table 4). Identifiable etiologies, however, are not found in approximately one-fifth of cases.(19,23) No etiology was found in our patient, although odds are that he had a chronic hypercoagulation state. No laboratory evaluation was made for thrombophilia or hypofibrinolysis but he demonstrated intravascular in situ thrombus formation consistent with those diseases.(19-24) He also suffered from sleep apnea and had a history of major trauma to his left jawbones, which may have secondarily enhanced an underlying coagulopathy.

It would appear that, whatever the underlying cause, the problem had existed for quite some time prior to the onset of pain, as indicated by the lack of good healing after extractions more than 10 years earlier. The histopathology of his diseased bone, moreover, suggests an admixture of past and more recent ischemic and infarctive episodes.

We suspect that our patient would never have been completely and permanently free of facial pain. His marrow involvement was too extensive, with disease in many, many maxillofacial sites, some in areas negative to radiography and scintography at the time of examination. Presumably other bones of his skeleton were also involved or would eventually become involved. This case appears to be a rather extreme example of pain production in NICO, but it graphically illustrates the problems involved in the diagnosis and treatment of osteonecrosis of the maxillofacial region. We suggest that ischemic and infarctive disease of the bone marrow be ruled out before a true facial neuralgia is diagnosed.

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The authors wish to thank Dr. Susan Zunt of the Indiana University School of Dentistry, Division of Oral Pathology, for her kind assistance with tissue processing.

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Index of Tables

Note: Click on the Table number to go to that table.

Table 1: Causes of "idiopathic" chronic pain of the maxillofacial region, excluding temporomandibular disorders, dental infections and sinus infections.^2-11

Nerve damage/degeneration:

• Traumatic/inflammatory neuritis
• Traumatic neuroma
• Trigeminal neuralgia
• Atypical facial neuralgia/pain
• Anesthesia dolorosa
• Phantom toothache/odontalgia/causalgia
• Deafferentation
• Demyelination (multiple sclerosis, etc.)

Blood flow alterations:

• Intramedullary hypertension
• Intramedullary ischemia/claudication
  (from either poor inflow or poor outflow)

• Distention of marrow veins/capillaries
• Intravascular marrow thrombi
• Intramedullary microinfarction

Inflammation:

• Cytokines from intraosseous inflammation
• Bacterial toxins from intraosseous infections
• Neuropathic inflammation

Table 2: Radiographic staging for ischemic osteonecrosis (applies predominantly to hip lesions and ends of long bones); patients at all stages may or may not have pain.^6,7,9

Table 3: Coagulation disorders found in patients with ischemic osteonecrosis of the hips, knees and jaws. These are compared to the proportions found in patients with deep vein thrombosis of soft tissues and with the normal population. Resulting proportions do not total 100% because some patients had multiple disorders. Thrombophilia = increased tendency to develop thrombi; hypofibrinolysis = reduced ability to lyse thrombi. [Used with permission from Bouquot JE, LaMarche MG. J Prosthet Dent 1999; 81:148-158.]

   * usually autosomal dominant

Table 4: Suggested etiologies and triggering events for intramedullary ischemia and infarction.^3-11

Local Factors:

*** Trauma (mild or severe)
*** Radiation therapy for cancer
  ** Intraosseous inflammation/infection
  ** Rheumatoid arthritis
  ** Prosthetic obstruction of blood flow to marrow
  ** Intraosseous malignancy (especially lymphoma and metastatic carcinoma)
    * Intravascular coagulation ("localized DIC")
    * Intraosseous cryosurgery
    * Bone dysplasia

Systemic Factors:

*** Corticosteroid therapy (long- and short-term)/Cushing's syndrome
*** Variable atmospheric pressures in occupation (caisson's disease)
*** Alcoholism/pancreatitis
*** Systemic lupus erythematosus (with or without corticosteroids)
*** Familial hypofibrinolysis disease (plasminogen activator inhibitor deficiency)
*** Sickle cell disease
*** Thrombophilia (Protein C & Protein S deficiencies)
*** Gaucher's disease
*** Antiphospholipid antibody syndrome
 ** Pregnancy/high dose estrogen therapy
 ** Disseminated intravascular coagulation (DIC)
 ** Cigarette smoking
 ** Chemotherapy for cancer
   * Deficiency of thyroid hormone
   * Deficiency of growth hormone
   * Idiopathic thrombocytopenic purpura
   * Hyperlipidemia
   * Hemodialysis
   * Inactivity (bedridden, paraplegic, etc.)
   * Gout
____________________________________________________________________

  *** = very strong association; definite association
    ** = strong association; unproven
      * = weak association; unproven

Legends for Figures

	Click Image for Larger Image		Legend
		Return to Text	Figure 1: 99technetium-MDP bone scan demonstrated areas of increased isotope uptake in all four quadrants (arrows), especially the left zygoma area were disease extended from the alveolar bone to the ethmoid region.
		Return to Text	Figure 2A: Lingual half of the mandible demonstrated a large discolored area of soft, cystic necrosis (large arrows) in the first molar region, with destroyed crestal cortex. Also seen: semitranslucent globule of gelatinous marrow (GM), destroyed wall of the inferior alveolar canal, linear cavitation extending along the inferior cortex, area of discolored fibrosis in the cuspid area of previous surgery (small arrow).
		Return to Text	Figure 2B: Higher power view of largest area of damaged marrow.
		Return to Text	Figure 3A: Cross sections of lingual half of mandible in area of first molar (left) and third molar (right). Extensive marrow loss resulted in multiple intermeshing cavitations (C). Dense fibrous tissue (F) replaced the superior cortex and the bony canal around the neurovascular bundle was destroyed (O represents location of bundle, which fell out of the section during tissue processing). (magnification: 8x)
		Return to Text	Figure 3B: Left zygoma was essentially hollow, with multiple coalescing cavitations (C) and minimal remaining marrow. (magnification: 8x)
		Return to Text	Figure 3C: Mandibular cuspid region showed fibrous scar tissue (F) in the area of previous surgery, with several "air-filled" cavitations (C) above the inferior bony cortex. (magnification: 4x)
		Return to Text	Figure 4: Left maxilla showed a well-preserved post-extraction bicuspid socket (X) filled with dense fibrous tissue with no cortex on the antral or oral surfaces. Gelatinous marrow produced a slight discoloration and softening of cuspid region (arrows), extending toward the crest of the ridge where the cortex was also destroyed.
		Return to Text	Figure 5A: Fat necrosis was characterized by pale staining stroma with few residual nuclei. Some dead adipocytes contained a granular eosinophilic debris (eosinophilic necrosis). The bony trabeculae showed most osteocytes either missing or pyknotic in numerous areas. (magnification: 100x and 200x, respectively)
		Return to Text	Figure 5B: Fat necrosis was characterized by pale staining stroma with few residual nuclei. Some dead adipocytes contained a granular eosinophilic debris (eosinophilic necrosis). The bony trabeculae showed most osteocytes either missing or pyknotic in numerous areas. (magnification: 100x and 200x, respectively)
		Return to Text	Figure 5C: Some areas of calcific fat necrosis contained precipitated salts which imparted a somewhat dark, granular, smudged appearance. Fatty microvesicles were admixed with dead adipocytes and adjacent bone sometimes showed clustered loss of osteocytes. (magnification: 200x)
		Return to Text	Figure 5D: Cavitations (C) had smooth, undulating borders with minimal fibrosis separating the marrow from the "air-filled" space. Serous ooze sometimes coated the cavitational wall and some areas showed exposed bone. Inflammatory cells were seldom seen in the walls. (magnification: 40x)
		Return to Text	Figure 6A: Gelatinous marrow showed serous exudation or plasmostasis (arrows), interspersed with fat microvesicles, between adipocytes. Lipid globules (L) were seen within some sinusoids/veins. (magnification: 200x)
		Return to Text	Figure 6B: Reticular fatty degeneration (myelofibrosis, wispy marrow fibrosis) also contained fat microvesicles and was seen to flow around remaining adipocytes; occasional chronic inflammatory cells were present. (magnification: 200x)
		Return to Text	Figure 7: Marrow veins and sinusoids were often dilated and in one instance showed occlusion by aggregated fibrin and platelets (arrows). (magnification: 200x)
		Return to Text	Figure 8: Extensive delamination (microcracking) with prominent cement lines was occasionally noted, especially in areas with few missing osteocytes. (magnification: 40x)
		Return to Text	Figure 9A: A different patient showed extensive cavitation, toward the right, in the bicuspid region of the mandible, with area of white osteosclerosis in the first molar region, just posterior to the hollow space.
		Return to Text	Figure 9B: Radiograph shows the area of osteosclerosis with a poorly defined, multilocular radiolucency in area of cavitation. Oval radiolucency posterior to the osteosclerosis was another cavitation but is not well illustrated in 9A.