Maxillofacial Osteonecrosis (NICO) A Review for Patients
ŠThe Maxillofacial Center for Diagnostics & Research
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Mandible of patient with chronic facial pain. Brown mush represents areas of necrotic marrow, with scattered cystic spaces or "cavitations."

The Maxillofacial Center, 165 Scott Avenue, Suite 100, Morgantown, WV 26508 USA
Phone: 304-292-4429   Fax: 304-291-5149    Email: MFC@aol.com

A note to patients with jawbone osteonecrosis (NICO)

A somewhat Less than Brief Review of NICO

Ischemic osteonecrosis (literally, "dead bone from poor blood flow") is as old as the dinosaurs but only recently has it gained enough recognition to be commonly diagnosed.  It is not so much a disease in its own right as it is the localized (in any bone) result of anything which significantly reduces the blood flow through the bone marrow.  Once called coronary disease of the hip because of the associated marrow ischemia (reduced blood flow) and infarction (complete blockage of a vessel) in cases involving the femoral head, the list of diseases and biological phenomena capable of producing this damage has grown to an impressive size during recent years, Table 1 provides an abbreviated summary.

This disease can affect any bone in the body but the hips, knees and jaws (or facial bones) are most often attacked. It can also attack at any age, with hip lesions being seen in adolescent and teenage boys (Perthes disease) and in pregnant women (transient ischemic osteoporosis, regional ischemic osteoporosis) and in middle aged men and women (avascular necrosis, bone marrow edema, ischemic osteonecrosis).  In the jaws, women aged 30-55 account for more than 80% of all cases, but they have been affected in teenagers and in persons more than 90 years of age.  Overall, this disease now is responsible for almost a third of all hip replacement surgeries performed each year, while 20 years ago it was a rare reason for hip replacement (we were calling them simply arthritis)

Osteonecrosis was once a common disease in the practice of dentistry because of the mercury, arsenic and bismuth in popular medicines, and also because some many people had to work around the fumes of phosphorus (safety matches), lead and other heavy metals.  These chemicals all interfere with the blood flow to and through the bones and settle in highest concentrations in regions of chronic infection, e.g. the gums.  Known variously as chemical osteomyelitis, bone caries (today tooth decay is called caries, i.e. destruction without pus), phossy jaw and argyria, jawbone cases, then, most likely represented a combination of osteonecrosis from these environmental toxins and osteomyelitis (infection of bone marrow) originating from abscessed teeth (periapical abscess) and gum disease (periodontitis). 

Even today the jaws are especially susceptible to reduced blood flow problems.  Trauma and infection are the primary triggering events for osteonecrosis and no other bones come close to the level of trauma and infection experienced by the jaws, e.g. tooth and gum infections, tooth extractions, trauma (a fist to the face, perhaps?), and oral or root canal (endodontic) or gum (periodontic) surgery.  To these potential causes we can add two more that are rather unique to dental procedures: local anesthetics used to numb to jaw for tooth procedures or oral surgery contain powerful chemicals (vasoconstrictors, e.g. epinephrine) for drastically reducing the blood flow in the area, thereby keeping the anesthetic in place longer and allowing more time to work.  This is wonderful for the procedure itself but can be disastrous for someone with an underlying, and usually undiagnosed, coagulation disorder.  As it turns out, 4 out of 5 osteonecrosis patients have such clotting disorders, and these disorders are of the type that are not picked up with routine blood studies.  

The most popular term in use today for jawbone cases is NICO (neuralgia-inducing cavitational osteonecrosis), but the term is usually reserved for those cases associated with chronic facial or jaw pain.  For those without pain, the more generic term, maxillofacial osteonecrosis (MFO) can be used, although some prefer the term silent NICO, in keeping with the orthopedic surgeons' use of silent hip for painless osteonecrosis of the hip.  Whether or not there is pain, however, it is extremely important to understand that osteonecrosis can produce major destruction or damage to bone marrow with minimal or no pain. In the hip, for example, it is not unusual for a patient's first sign of disease to be the collapse of the joint. In the jaws, many cases have presented with large, completely hollowed-out spaces in the marrow, with no history of pain.

Why the Jaws?

The jawbones appear to be common sites of osteonecrosis involvement and some have asked why this should be. A better question would be, why not the jaws? 

• the powerful vasoconstricting effects of dental anesthetic injections
• the release of tissue-damaging oxyradicals with each reperfusion of the bone after a local dental anesthetic
• the frequent direct application of heavy metals near bone
• the direct and indirect effects of nicotine (major reduction of blood flow to periodontal tissues/periosteum) (major reduction of blood flow to periodontal tissues/periosteum)
• the common practice of prescribing prednisone or prednisolone to prevent swelling after oral surgical procedures (corticosteroid use is the most common cause of non-traumatic osteonecrosis)
• recurring maxillary sinus infections with potential seeding of bacteria into alveolar bone

Numerous cases of maxillofacial osteonecrosis appear to occur spontaneously as neuralgia-like pain without a history of recent surgery or infection, but the majority of these "primary" or "idiopathic" cases will on close questioning and examination reveal an underlying medication, habit (especially alcohol and tobacco abuse), or systemic disease, as listed in Appendix A. The triggering event in these cases is presumably physiological, probably inflammation-enhanced clotting in bone with an already compromised blood flow.

The great intensity or unusual presentation of pain in some M-ON patients may be related to the fact that the jaws are the only bones in humans which contain large sensory nerves. In this light, it may be significant that facial or trigeminal neuralgias represent an extremely high proportion of all neuralgias, perhaps more than 85%. Could it be that branches of the trigeminal nerve are being stimulated or damaged by toxins, inflammatory mediators, focal ischemia, or increased tissue pressures from diseased marrow as they traverse the jaws?

Coagulation Disorders -- A Major Underlying Problem

Recent investigation has found that the majority of NICO patients who have not responded well to surgical treatment, i.e. serious cases, suffer from previously undiagnosed clotting disorders such as thrombophilia and hypofibrinolysis (Table 2). These coagulopathies typically are not picked up on routine clotting tests; the INR ratio may be helpful but is best used as a monitor for patients placed on anticoagulation therapy, not as a screening test. Table 3 puts this clotting dilemma in perspective, demonstrating that coagulopathies are much more prevalent in osteonecrosis than in the normal population, and are even more prevalent than in the disease previously thought to show the strongest association with coagulopathies, deep vein thrombosis of soft tissues.

Table 1: Diseases, events, etc. associated with osteonecrosis of any bone.

Table 2: Coagulation disorders found in patients with ischemic osteonecrosis of the hips, knees and jaws (NICO), compared to the proportions found in patients with deep vein thrombosis, a major clotting disorder, and with the normal population. Thrombophilia = increased tendency to develop clots inside vessels; hypofibrinolysis = reduced ability to breakdown the small clots always being formed and dissolved in blood vessels.

* usually autosomal dominant, i.e. it is not related to the gender of the child and each new baby has a 50% chance
   of inheriting the problem.

Table 3: Coagulation disorders found in NICO patients who failed to improve with decortication and surgical debridement.

                      * includes patients with multiple coagulopathies

There is also good evidence to suggest that as many as 11% of older individuals have major, even complete blockage of the arteries feeding the jaws.⁶³ Any process which diminishes blood inflow or outflow from the bone can produce this disease, but the mechanism may vary and may include one or more of the following: venous or arteriole blockage from thrombi, fat globules or necrotic debris; venous collapse from excess fluid or cellular pressures in tissues surrounding the vessels; vasculitis with inflammatory destruction of vessel walls; another mechanism as yet unknown. Adding a low-grade infection to the equation undoubtedly compounds the problem for jaw lesions, as inflammatory mediators and bacterial toxins are, in and of themselves, quite capable of diminishing local blood flow and causing local tissue death.^64-66

Who Is Affected and Where Are the Maxillofacial Lesions?

Maxillofacial osteonecrosis has been microscopically confirmed in patients as young as 14 years of age and as old as 94, and has been reported in both genders.^44,59 Typically, however, three-fourths of patients are 35-64 years of age and three-fourths are women. Outside of the jaws, the head of the femur is the most common site of involvement, but any bone may be affected (Appendix B). Alveolar bone sites most often involved, in decreasing order of frequency, are the mandibular molar/retromolar areas, the maxillary molar/tuberosity areas, and the maxillary cuspid/lateral incisor areas (Table 4). Third molar sites account for 45% of all jawbone involvement. Most M-ON sites are old extraction sites, but another common presentation is a radiographically successful endodontic procedure which continues to be painful after therapy, even after extraction.

Table 4: Location of 2,301 NICO lesions as reported on biopsy request forms from 1,333 patients with facial pain. Numbers represent the proportion (%) of all cases found at a specific site, first surgery only.

* includes tuberosity and retromolar areas

One-third of NICO patients have more than a single quadrant involved, not necessarily at the same time, and 10% have lesions in all four quadrants.^59-61 This is not unexpected, as it has long been known that 50-80% of hip cases eventually involve the opposite femoral head.^2-12 In our experience, the more generalized the condition, the more likely the jawbone patient is to suffer from multiple risk factors, including hyperthrombotic disorders.

The Clinical Presentation Of The Disease

Signs and symptoms. Maxillofacial osteonecrosis lesions produce only subtle, if any, inflammatory changes of overlying soft tissues, including transient erythema and edema, but histologic sections of overlying mucosa demonstrate mild to moderate subepithelial inflammatory cell infiltrates.³⁵ Most maxillary lesions, especially within the tuberosity, are tender to palpation or can be aggravated by pressure, perhaps even triggering a "jump sign" similar to that elicited when palpating myofascial trigger points (see Travell & Simons⁶⁶). Mandibular lesions are more difficult to identify with digital pressure, presumably because of the greater density of the cortical bone.

In this light, it may be significant that Friedman⁶⁷ found focal areas of alveolar tenderness within the quadrant of pain in 15 of 18 patients with atypical facial neuralgia/pain; 17 of the 18 patients demonstrated a focus of increased mucosal temperature in the quadrant of pain.

Sinus involvement. Recurrent sinusitis may involve the bony walls and floor of the maxillary sinus (Figure 16), allowing bacteria and/or inflammatory toxins into alveolar bone on a recurring basis and perpetuating osteomyelitis/osteonecrosis of multiple maxillary sites. Roberts et al ³² have suggested injecting a radiopaque dye into the maxillary sinus, with periapical radiographs taken at 20, 40, and 60 minutes, as a means by which to identify areas of sinus wall or floor perforation not otherwise apparent. Other walls are also affected, but less frequently. Some patients have shown considerable destruction of the infraorbital bone, and the lateral nasal wall appears to be especially susceptible, perhaps because of the popular use of corticosteroid nasal sprays.

Pain. When pain is associated with ischemic osteonecrosis of the jaws it is usually diagnosed as atypical facial neuralgia/pain (67% of all pain-associated cases) or trigeminal neuralgia (10%) until a jawbone lesion is discovered.⁶¹ An additional 23% are diagnosed with various headaches, sinusitis or phantom toothache/pain. The typical NICO patient has had his or her pain for approximately 6 years (range: 1 month to 32 years) before a jawbone biopsy confirms the presence of ischemic osteonecrosis or low-grade osteomyelitis.⁶¹ The pain, and presumably the ischemic process, appears to be very slowly progressive over time, with increasing pain, increasing frequency of pain and increasing areas of involvement. The pain is often intermittent and may vary in extent, location and character over time. It is often difficult for the patient to describe and localize.

Anesthetic confirmation. Pain response to local anesthetics is used as a diagnostic tool in M-ON (anesthetic confirmation, diagnostic local anesthesia). Box²⁶ appears to be the first to report the use of anesthetic confirmation, and recent authors have reaffirmed its usefulness,⁵⁷ but it was Ratner et al³³ and McMahon et al^57,59 who developed a specific protocol of diagnostic local anesthetic injections for localizing the lesion(s) and determining the association between the diseased bone and the pain dilemma. In sorting out pain-producing mandibular pathology, this anesthesia/hyperesthesia test depends on localizing small zones of unanesthetized gingiva in an area which would normally be expected to be anesthetized after inferior alveolar and long buccal nerve blocks. These tissues are then directly infiltrated in order to obtain complete analgesia and checked for "full terminus" anesthesia (complete, to the lip).

Pain-producing maxillary pathology, whether dental or osseous in origin, can be assessed by beginning anteriorly and selectively infiltrating buccally and palatally, proceeding posteriorly, until the pain has been extinguished. Because of the many snares of referred trigeminal pain phenomena, the reader is encouraged to review Ratner et al³³ and McMahon et al^57,59 for further details. The reader is especially reminded to use only anesthetic solutions without vasoconstrictors, in order to avoid further compromise of a marginally inadequate medullary blood flow.

Radiographic/Imaging Appearance

Dental x-rays. Simple periapical radiographs are readily available and are moderately successful (70-80% true positive rate) in identifying M-ON sites of involvement, but considerable diagnostic experience is required because changes are quite subtle and may mimic a number of other entities, including variations of normal anatomy (Figures 1-12). Many cases cannot be identified even by experienced diagnosticians, a fact that should not surprise us when we remember that osteonecrosis is primarily a disease of cancellous bone and that 30-50% of cancellous bone must be destroyed before changes become radiographically evident.^69-71 We emphasize, therefore, that dental radiographs without obvious abnormalities of cancellous bone cannot necessarily be interpreted as "normal," they too often turn out to be false negatives.

It is imperative that radiographs be viewed in a dark room with the use of magnification, and it is recommended that three periapical films be taken with the beam directed at different angles, one straight on and one each at 20-30 degrees distal and mesial to the site (triangulated periapicals). Pantographic films can certainly be used to identify osteonecrotic lesions in the jaws, but their lack of detail make them less acceptable.

When visible on radiographs, M-ON usually presents as a poorly-demarcated, non-expansile radiolucency (Figures 1-5), often with irregular vertical remnants of lamina dura (laminar rain, laminar lightning) associated with old extraction sites (Figure 6-9). Many cases will show a faint, diffuse, background haze, called ghost marrow (Figures 7 and 10), superimposed on the osteoporotic radiolucency. This presumably results from the combination of residual calcific necrotic debris and marrow fibrosis. In long bones, many cases show an irregular, globular radiopacity (smoke in the chimney), but this is seldom seen in the jaws (Figures 11 and 12) except in cases of florid cemento-osseous dysplasia. When it does occur in the jaws, the lesions may resemble target or bulls-eye lesions, with a central opacity surrounded by a thick radiolucent area, which in turn is surrounded by an thin, irregular radiopaque line (Figure 10).

It is important to know that the disease is characterized by radiographic variety. All of the following radiographic appearances listed below have, for example, been demonstrated in M-ON lesions, either as single features or in combination. They are listed in order of frequency:

• poorly-demarcated radiolucency

• moth-eaten radiolucency

• irregular vertical trabeculae in edentulous area (remnants of lamina dura; 'laminar rain,' 'laminar lightning')

• very mild ground-glass radiopacity ('ghost marrow')

• radiopaque flecks and streaks radiating outward from a central poorly defined radiolucency ('eagle's nest')

• focal destruction of bony wall of inferior alveolar canal

• soap-bubble radiolucency

• horizontal trabeculae in edentulous area (remnants of interradicular bone; 'Jacob's ladder' bone)

• focal destruction of wall of maxillary sinus

• focal destruction of cortical alveolar bone

• radiopaque flecks (cross points of thin trabeculae)

• cotton-wool or globular radiopacities

Imaging scans. MRI is the scan of choice for mild osteonecrosis of the ends of the long bones, but the irregular, flat bones of the face seem not to be conducive to this otherwise excellent test. In fact, in our experience M-ON is seldom visible on MRIs, routine CT scans, or any form of scintigraphy (radioisotope scan) except the ⁹⁹technetium-MDP bone scan. The thin-sliced (1.0-1.5mm) CT scan, however, is proving to be a valuable diagnostic tool, allowing detailed evaluation of the maxillofacial bones in three dimensions (Figures 13-16). When such scans are used, we recommend extension to include the infraorbital and ethmoid regions (sometimes called a NICO scan). Careful attention must be given to the evaluation of thin CT scans, as the number of available slices is large and interpretation of normal anatomic structures is difficult.

Slow cell turnover, poor microcirculation and few inflammatory cells in this disease appear to negate the efficacy of scintography scans which use isotopes attracted to inflammatory cells, such as the gallium and indium scans. If the circulation is reasonably intact, however, a ⁹⁹technetium bone scan can identify areas of osseous hyperemia or increased osteoblastic activity found at the periphery of many osteonecrosis lesions (Figures 19-22); the radioisotope attaches to new or ruptured apatite crystals exposed during bone formation or destruction. Early cases and some older lesions may show "cold spots" of decreased isotope uptake because of the complete shut down of local medullary blood flow, from infarction or excessive backup pressures in the vessels.

Scintography scans are positive in 50-75% of osteonecrosis cases, regardless of the bone involved, and the more computerized version, called a SPECT (Single Proton Emission Computed Tomography) scan, can be very helpful in localizing lesions in three dimensions (Figures 23, 24). Denucci et al⁷¹ used SPECT scans to determine that 75% of patients with atypical facial pain had an area of increased radioisotope uptake in the quadrant of pain, but they performed no exploratory surgery of the abnormal bone.

Regardless of the imaging technique used, it must always be remembered that negative tests do not necessarily mean a lack of disease. This is true for jaw cases as well as those from other skeletal sites, as exemplified by the fact that such a large proportion of hip lesions have been so completely negative to all forms of imaging procedures that a very unique Stage 0 has recently been included in the diagnostic classification scheme for osteonecrosis of the hip (Table 5).

Table 5: 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. (modified from reference #8)

Ultrasonic scans. An ultrasonic scanning device, called the Cavitat, has been designed to send sonic waves through the alveolar ridges from the facial side, to be picked up by a detection screen on the lingual or palatal side.⁷³ This instrument has recently received FDA approval and will soon be commercially available. It may prove remarkably effective in localizing and outlining cavitating lesions of the marrow spaces, but at the present time the resulting diagnostic diagram is a bit crude, with only 16 squares to a side, and requires a high level of expertise for proper interpretation (Figures 17, 18).

Electro-acupuncture diagnosis. A certain number of dentists submitting biopsied tissue samples for M-ON evaluation seem able to localize intramedullary disease through the identification of electrical disturbances of the mucosal surface. This is done through an electronic sensing device called a Computron. These practitioners may combine oral findings with diagnostic acupuncture techniques, a practice initiated by Voll⁷⁴ and often called EAV, or electro-acupuncture according to Voll. Much research needs yet to be performed to more substantially validate this technique, but an informal review of tissue submitted for microscopic interpretation has shown that M-ON is identified positively at the same level as that of practitioners using more conventional diagnostic techniques: somewhat more than 90% of samples submitted with a NICO or M-ON clinical diagnosis prove to be so on microscopic evaluation.

What the Surgeon Sees

At surgery, approximately one-third of lesions are completely hollow or partially blood-filled bony cavities (the ischemic cavitation phenomenon mentioned by Phemister,²³ Black²⁵ and Bouquot⁴⁹). These typically have irregular, discolored bony walls and range in size from a few mm. to several cm. (Figures 25-30). The bony walls are usually softened by disease (non-desiccated) or appear dry and chalky (desiccated), but sometimes have a smooth, marble-like appearance. Pain intensity and radiographic visibility are not necessarily related to lesional size.

Maxillofacial osteonecrosis lesions which are "solid" in appearance at surgery are variously seen and felt as soft, grayish-brown, mushy or spongy tissues with or without small embedded bone chips. They may show signs of being under increased marrow pressures, such as escaping foul odor or explosive discharge of necrotic debris through the surgical window in the cortex. Frequently, immiscible, iridescent, oily material oozes or flows from the degenerative bone with a stagnant-appearing bloody fluid, imparting the appearance of dirty motor oil. Yellowish spheres of liquid fat from fat necrosis, i.e. oil cysts, may be seen to give the appearance of hemorrhagic chicken soup. Obvious pus is only rarely present.

The maxillary cortex is often thin enough to puncture with a trocar, although this is not the case for the mandible. Occasional cases demonstrate cortical roughness, irregularity or perforation, although most have thinned but visibly normal cortical bone overlying them.

Small lesions may be hard to find and there may be interconnecting fistulae or worm holes between individual lesions. These unremodeled remnants of thrombosed vascular channels are perfectly round in cross-section and may be more than 2 cm. in length. The bony canal protecting the inferior alveolar neurovascular bundle may be partially or completely destroyed by the disease process. When the neurovascular bundle is exposed it may appear as a thin, brown, non-pulsatile, frayed, fibrotic cord, like an old frayed rope at dockside, with or without areas of extreme thinning (Figures 29, 30). These cases typically demonstrate atrophy and fibrous replacement of the vessels and nerves. We have seen completely hollow mandibles with no sign of a residual neurovascular bundle beyond a small frayed proximal stump extending from the ramus.

What the Pathologist Sees

Microscopic features of ischemic osteonecrosis are varied, are often subtle, and are so unique to this disease that a number of new names have been created to describe them: oil cysts, calcific/proteinaceous necrotic marrow detritus, calcific fat necrosis, eosinophilic reticular necrosis, reticular fatty degeneration, cavitation, ghost erythrocytes, worm holes, creeping fibrosis, creeping substitution, microcracking, gelatinous marrow, plasmostasis, and exploded trabecula, to name a few.^1-12 We intend no detailed discussion here, but it should be mentioned that ischemic changes differ considerably from the changes of infarction and necrosis.

Chronic ischemia is represented by fibrous replacement of marrow fat cells (reticular fatty degeneration, myelofibrosis), dilated marrow veins, defined as more than 5-7 erythrocyte diameters wide, and scattered chronic inflammatory cells (Figures 31-34). Chronically ischemic bone is often osteoporotic, with thin trabeculae containing two or more cement lines, often prominent cement lines, and perhaps with delamination or microcracking along cement lines (Figure 36). Some trabeculae will show a thickened osteoid rimming. Osteoblasts are seldom visible and osteoclasts are almost always absent, even in immature or newly forming bone. Osteocytes may or may not be missing or pyknotic. These changes essentially define bone marrow edema syndrome (transient ischemic osteoporosis).

Recent infarction may be seen as focal hemorrhage between fat cells, but liquefactive necrosis of fat is often present and occasionally the pathologist will be fortunate enough to see the responsible thrombosed and ruptured vessel. Liquified fat is seen as small fatty microvesicles, fat globules or large oil cysts, either in areas of infarction or in a background film of hemorrhage (Figure 35).

Older necrotic lesions may contain smudged aggregates or globules of calcific fat necrosis and dystrophic calcification, often with embedded slivers or shards of old, necrosed bone. The aggregates have been called NICO globules but they are only seen in 15-30% of biopsied tissue samples from the jaws. Two-thirds of jaw cases represent quiescent disease or bone marrow edema syndrome with only occasional evidence of past and present infarction.⁷⁴

Many tissue samples show tissue fragments coated by a film of fibrin and may show aggregates of this material, or of platelets, within areas of damaged fatty marrow. While such features are occasionally seen in routine intraosseous inflammation, they are much more common in M-ON lesions. Occasionally, aggregates of fibrin or platelets may be seen within the marrow sinusoids or other marrow vessels, sometimes causing complete blockage of the affected vessel; calcific debris may also be found within vessels, presumably from upstream lesions.

Death or necrosis of bone was once considered to be the hallmark feature of avascular necrosis, represented by a focal loss of osteocytes (Figure 36), as opposed to the scattered loss of individual cells seen as artifacts of laboratory decalcification. The surface resorption lacunae so common to the bony sequestra of osteomyelitis are almost never seen in ischemic osteonecrosis, but a layering of new bone may be seen immediately on top of the dead bone without evidence of remodeling (creeping substitution).

The desiccated cavitations of osteonecrosis may provide little or no tissue to evaluate microscopically. In this case the pathologist must take into account the hollow cancellous space noted at surgery in order to provide an appropriate diagnosis, i.e. the diagnosis from Table 1 which best fits the combined clinical and microscopic features. This is true also for those cases with only normal bone and marrow scraped from the cavitation walls.

Is There an Effective Treatment?

At the present time there is no completely effective treatment for osteonecrosis. The following therapies have been tried for M-ON with variable success.

Antibiotics. Antibiotics may temporarily diminish the associated pain of NICO in cases with superimposed low-grade infection, but they are unlikely to effect cure.

Curettage of bone lesion. The abnormal intrabony tissues usually must be surgically removed via decortication and curettage, as per Roberts et al.^29,32 or Ratner et al.^28,33 Once tactually and visually abnormal tissue is removed, the bony defect frequently heals and the intense facial pain subsides dramatically or disappears completely (Table 6). A third of NICO patients thus treated, however, experience minimal or no pain relief, and 3% experience increased pain.

Table 6. Long-term results of surgical curettage of NICO lesions of the jaws of 103 patients with facial neuralgias (atypical facial neuralgia or trigeminal neuralgia). Seventy-eight percent of individual lesions required only one surgery; 32% of patients had NICO in multiple quadrants. Patients were surveyed 1-18 years after last NICO surgery (average: 4.6 years). Only patients with follow-up ratings of 3 or 4 were considered cured. (Modified from ref. #61)

 * 2.9% experienced increased pain after surgery (long-term)
** patients consider themselves cured, are taking no prescription medications for pain, and describe their pain condition as "almost gone," "only an occasional problem," or "very livable."

Hyperbaric therapy. Combining surgery with antibiotic therapy, or surgery with hyperbaric chamber therapy, seems to have a slight positive effect on the outcome.

Anticoagulants. When systemic hypercoagulable states co-exist with other risk factors, the use of various anticlotting therapies (stanozolol, Coumadin, low molecular weight heparin, etc.) may prove to be of great benefit, as indicated by a recent study showing significant pain reduction with medication (no additional surgery) in at least 50% of patients who failed to improve with prior NICO surgery.⁶² Patients with homocystinemia associated with homozygosity for MTHFR can be treated with folic acid and pyridoxine. As a cost-effective follow-up measure, INR ratios can be determined and should remain in the 2.5-3.0 range for optimal coagulation function.

Recurrence of lesions. As we would expect in a disease which is often merely a sign of underlying systemic disorders, NICO has a strong tendency to recur and/or to develop in additional jawbone sites (1/3 of cases), often requiring multiple repetitions of the same surgical procedure. Thirty percent of affected patients who have subsequent post-surgical reduction of pain experience local recurrence of jaw or facial pain, often of a different type or location than the original pain. Nevertheless, despite a high rate of recurrence and of new primary lesions necessitating multiple surgeries, the long-term (average = 4.6 years) abatement of neuralgia pain is total or almost total in 73% and moderate in an additional 16% of cases (Table 6).⁶¹ Only 11% of patients consider the surgery to be without merit for the treatment of their maxillofacial pain. Appropriate pain management strategies with narcotic medications, psychological counseling and even temporary disability status with periodic family counseling should be considered in severe cases (70% of whom are disabled by pain). With future research, even this group of individuals may be helped by new therapeutic techniques, but until then we must be content with the suggestion by G. V. Black²⁵ to remove "every particle of softened bone" and expect that "generally, the case makes a good recovery."

How Common Is Maxillofacial Osteonecrosis?

Maxillofacial osteonecrosis does not appear to be a rare disease. In a preliminary population study of NICO cases in West Virginia the point prevalence rate for biopsy-proven cases, i.e. the number of new and old cases in the population at a specific point in time, was one of every 2,200-5,000 adults. For middle-aged females the rate was one in every1,009-2,500. This makes NICO the second most common form of osteonecrotic diseases, affecting more than 68,000 U.S. adults annually. If the majority of affected patients have no pain, which can be inferred from the work of Box,²⁶ then the prevalence of maxillofacial osteonecrosis must be considerably higher than the NICO rates.

A Note About Osteonecrosis, Nerves and Pain

Ischemic osteonecrosis is characterized by the pain it produces, even in cases with no radiographic evidence of disease (Stages 0 and 1).^1-12 Trigeminal axons have shown diminished or damaged myelin sheathing in some NICO patients,⁶¹ and others have demonstrated anti-peripheral myelin antibody titers which are almost as high as those of persons with Guillian-Barre syndrome, the classic disease of peripheral myelin degeneration.⁷⁶

While it is true that some authorities have suggested that a portion of facial neuralgia patients have persistent pain from trigeminal nerve damage at some distance from the brain, including nerves within inflamed jawbones,^77,78 nerve damage is not necessary to produce pain in osteonecrosis (Table 7). Ischemia itself is capable of causing a deep, painful aching or other paresthesia, even in soft tissues (ischemic neuropathy, such as in diabetics). Increased intramedullary pressures also produce pain. Intraosseous stasis and hypertension, first noted in osteoarthritis, is especially associated with a deep, aching pain at rest.^79-81

Table 7: Potential causes of "idiopathic" chronic jawbone pain, excluding temporomandibular disorders and dental infections.^,45

Nerve damage/degeneration:

• Traumatic/inflammatory neuritis 
• Traumatic neuroma
• Trigeminal neuralgia
• Atypical facial neuralgia/pain
• 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

Osteonecrotic pain has been shown to result from increased intramedullary pressure, which can be five times greater than normal and is routinely twice that of normal bone.^12,75,79-81 This has generally resulted from poor outflow from the bone and is unique to ischemic osteonecrosis. Certain authorities have advocated diagnostic injection of saline into the marrow of painful bones lacking obvious radiographic changes. The pain and medullary pressure increases in osteonecrosis patients but not in others.³

The pain of osteonecrosis may also be due to blood vessel distension, and the pain stimulus may originate in the vein wall.⁸¹ Additionally, it may be due to diminished blood flow from intravascular microthrombi, as recent clinical research has demonstrated major pain reduction in jawbone osteonecrosis patients with anticoagulants.⁶² NO-liberating organic nitrates, such as nitroglycerin, have been effective in controlling pain in localized ischemic conditions of other parts of the body, such as anal fissures.^82,83 However, these medications have not been administered for M-ON patients.

Other causes of deep bone pain are associated with osteonecrosis. Infarction resulting from the complete, abrupt blockage of marrow blood vessels creates an immediate and sharp pain. Toxins and inflammatory mediators, such as prostaglandin E₂ and other cytokines routinely released from necrotic tissues and local inflammatory responses, may result in a variety of different pain symptomatologies over an extended period. Additionally, infection of cancellous bone further compromises local blood flow and enhances coagulation. New microinfarctions can occur in adjacent marrow, only to repeat the entire process again.

A potential and troubling new cause of nerve pain or damage in cases of jawbone osteonecrosis is emerging from the work of Haley⁸⁴ at the University of Kentucky. Using standard and well established neurotoxicity assays, his evaluation of more than 50 NICO tissue samples has determined that there are unidentified but extremely neurotoxic components in each and every sample. It is not at this time known whether the toxins are being generated by microorganisms entrapped in osteonecrotic lesions, by the necrotic debris in the lesion, or by an inflammatory response to the debris or microorganisms.

References

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55. McMahon RE, Bouquot JE, Glueck CJ. Exogenous estrogen may exacerbate thrombophilia, impair bone healing and contribute to development of chronic facial pain. J Craniomand Pract 1998; 16:143-153.
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Additional/New References

84. Bouquot J, LaMarche M. Subpontic osteonecrosis: imaging and microscopic features in 38 patients with "idiopathic" chronic pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 86:209-210. (abstract)
85. McMahon R, Bouquot J, Mahan P, Saxen M. Elevated anti-myelin antibodies in patients with maxillofacial osteonecrosis (NICO). J Oral Pathol Med 1998; 27:345-346. (abstract)

Appendix A

Suggested Etiologic or Risk Factors for Ischemic Osteonecrosis Modified from Jones JP, Jr. In: Urbaniak JR, Jones JP Jr (editors). Osteonecrosis. 1997.13 Used with permission.

Familial Thrombophilia

• APC-resistance
• Protein C or S deficiency
• Antithrombin III deficiency

Hyperlipemia & Embolic Lipid
Alcoholism
Carbon tetrachloride poisoning
Diabetes mellitus
Fat emulsion therapy
Hypercortisolism
Hyperlipemia (types II & IV)
C-reactive protein increased
Obesity
Pregnancy
Disrupted adipocytes
Dysbaric phenomena
Hemoglobinopathies
Pancreatitis (lipase)
Severe burns
Fractures
Hypersensitivity Reactions

• Allograft organ rejection
• Kidney, heart, live, marrow
• Anaphylactic shock
• Antiphospholipid antibodies
• Immune complexes
• Immune globulin therapy
• Serum sickness
• Shwartzman reaction
  

Systemic lupus erythematosus

• Anticardiolipin antibodies
• Lupus anticoagulant

Hypofibrinolysis
Dysfibrinogenemia
Plasminogen deficiency
TPA decreased
PAI-1 increases
Infections

• Bacterial endotoxic reactions
• Bacterial lipopolysaccharides
• Bacterial mucopolysaccharides
• Corticosteroid suppression

Intravenous drug abuse
Septic abortion
Toxic shock (Staph. exotoxin)
Viruses

• Cytomegalovirus
• Hepatitis
• HIV
• Rubella
• Others

Proteolytic Enzymes
Pancreatitis (trypsin)
Snake venom
Tissue Factor Release
Inflammatory bowel disease

• Crohn's disease
• Ulcerative colitis

Malignancies

• Acute leukemia
• Hodgkin's disease
• Metastatic carcinoma
• Pancreatic carcinoma
• Others

Chemotherapy
Neurodamage

• Brain injury/surgery
• Spinal injury/surgery

Abnormal Pregnancy

• Abortion (hypertonic saline)
• Amniotic fluid embolism
• Fatty liver of pregnancy
• Retained fetus in utero
• Toxemia
• Preeclampsia
• Eclampsia
• Normal Pregnancy
• Shwartzman reaction?

Other Prethrombotic Conditions
Acidosis
Anorexia nervosa
Anovulatory agents (estrogen)
Cigarette smoking
Decompression sickness
Diabetic angiopathy
Gaucher crisis
Hemolytic-uremic syndrome
Hemolysis
Hepatic failure
Hyperfibrinogenemia
Hypertension
Hypertrophy of fatty marrow
Hyperviscosity
Hypotension (shock)
Immobilization
L-asparaginase therapy
Lipoprotein(a)
Nephrotic syndrome
Patent foramen ovale
Polycythemia
Postoperative states
Raynaud's phenomenon
Sickle-cell crisis
Storage diseases

• Fabry-Anderson disease
• Gaucher's disease
• Polyvinylpyrrolidone (PVP)
• Thrombocytosis

Thrombocytopenic purpura
Vasoconstriction
Vascular disorders

• Aneurysms
• Arteriosclerosis
• Coarctation
• Giant hemangioma

Vasculitis

Appendix B

Diagnostic terms used for osteonecrosis of the human skeleton. (ref. 2-12)

Links to NICO, Part I Handout Figures 1-32 (Composite pages)

Please note: These are composite pages with 6-12 photos on each.  It may take up to
6 minutes to download one page of figures at 24,000k.

Figures 1-12: Radiographs of NICO lesions
Figures13-18: CT & Ultrasonic scans (Cavitat)
Figures 19-24: Technitium-99 bone scans, including SPECT scans
Figures 25-30: Clinical and autopsy photos of maxillofacial osteonecrosis
Figures 31-36: Microscopic photos of maxillofacial osteonecrosis

Legends and Links to Individual Figures

Please note: These are gif files, each about 100K in size, and will take
50-90 seconds each to download at 24,000k.

Figure 1: Hollow tuberosity, right maxilla
Figure 2: "Normal" x-ray!?!
Figure 3: Multilocular radiolucency
Figure 4: Occlusal radiolucency
Figure 5: Irregular radiolucency
Figure 6: Laminar rain
Figure 7: Laminar rain & ghost marrow
Figure 8: Laminar rain
Figure 9: Calcified residual socket
Figure 10: Bulls-eye lesion
Figure 11: Focal osteosclerosis
Figure 12: Laminar rain, osteosclerosis
Figure 13: 1.5 mm. CT scan shows ghost marrow (red arrow) and several hollow cavitations (arrows)
Figure 14: 1.5 mm. CT scan show large cavitaiton (arrow) between incisors of anterior maxilla
Figure 15: Ghost marrow (arrow) posterior to left incisors of anterior maxilla
Figure 16: Three-diminesional CT scan shows moth-eaten destruction of the sinus floor (arrows)
Figure 17: Crude representation of ultrasound Cavitat scan of alveolar bone shows small cavitation (arrow). Scale: green = no bone loss; brown = much loss.
Figure 18: Cavitat scan of extensive destruction by osteonecrosis in alveolar bone
Figure 19: Technetium-99 MDP scintigraphy scan shows a black "hot spot" of increased uptake in areas of bone healing or destruction (new or damaged apatite crystals), seen here as a small area of MO
Figure 20: Tech-00 scan may show that other facial bones are involved.  Here the left zygoma and ethmoid region (arrows) are affected in addition to all four quadrants of the alveolar bone.
Figure 21: Tech-99 scan shows entire left maxilla and mandible with severe osteonecrosis.  Base of skull and cervical vertebrae (arrows) also affected.
Figure 22: Same patient as Figure 21.  Anterior veiw shows all four quadrants of jaws affected, although the right mandible is less involved.
Figure 23: The more computerized SPECT scan allows slices to be viewed in two dimensions to more accurately localize areas of involvement (arrows).
Figure 24: SPECT scans can show rotated three dimensional images to help localized lesions.
Figure 25: A hollow space or cavitation is seen beneath the cortex (here removed) in the first bicuspid region of the mandible.
Figure 26: A very large hollow space in the marrow extends from the mandibular left second molar deeply into the ramus.  The blood oozing from the cavity walls is darker than normal.
Figure 27: Mandibular retromolar area shows hollow intramedullary cavitation immediately after overlying cortex is removed.
Figure 28: An autopsy cases shows multiple dark, mushy areas of osteonecrosis.
Figure 29: Artist's rendition of medullary cavity with frayed, damaged nerve exposed within it.
Figure 30: Mirror image of lingual side of mandible shows large cavitation (c = microcavitations).
Figure 31: Normal fatty marrow shows few visible veins, no fibrosis, and small bony trabeculae (upper left). Fat cell walls are barely visible.
Figure 32: In osteonecrosis, backup pressure greatly dilates veins, causing release of red blood cells and fluids into marrow.  Fat is replaced by wispy fibers.
Figure 33: Chronic ischemia produces a streaming fibrosis between marrow fat cells, with scattered chronic inflammatory cells and foamy histiocytes.
Figure 34: Ischemia can lead to almost complete replacement of fat cells by fibrosis, here with a few scattered lymphocytes.  Dense fibrosis could also result from poor healing after surgery in such an ischemic environment.
Figure 35: When there has been recent and major infarction of fatty marrow, all that remains is blood with floating fatty microvesicles (small white spaces) and large oil cysts, evidence of fat necrosis.
Figure 36: The wall of a socket (tooth is in upper left corner) shows most osteocytes to be missing (white oval spaces), numerous cement lines and a microcrack along one line, all signs of chronic ischemia.