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     The History of Maxillofacial Osteonecrosis (NICO)

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     Historical Overview
     1800-1930
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     Painful osteonecrosis/osteomyelitis, or "phossy jaw," of upper and
lower jaws sloughed out when dentist tried to
     extract several teeth because of "toothache."  Source: American
Journal of Dental Science, 1859.

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History of Maxillofacial Osteonecrosis (NICO)

First described in 1794 in a case of septic necrosis of the femoral head,
this enigmatic disease is as old as the dinosaurs but has been poorly
understood and has such subtle radiographic changes that until recently it
was seldom diagnosed prior to end-stage damage.[11-13]  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."

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.[9]  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.[1-5,9,14,15]

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.[2-9,14-16]  Histopathologically less severe or
nascent involvement has begun to be consolidated under a common diagnostic
term, bone marrow edema (Table 1), and the disease is now known primarily as
a vascular disorder readily influenced by a variety of risk factors or
trigger events ("hits") which promote thrombosis.[7,9,17-21]  Persons with
multifocal IO are more likely to suffer from systemic risk factors than
those with single site involvement and the great majority of patients have
inherited or acquired a systemic tendency toward fibrin generation (Table 2)
which predisposes them to microinfarction and ischemic marrow
damage.[8,9,15-22]

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 associated pain.[5,9] The
pain can take on a neuralgic character but its etiology is primarily a
function of intraosseous fluid dynamics and inflammatory mediators rather
than damaged nerves, as discussed later.[4,5,9,11,14-16]

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The Pre-Antibiotic Era: 1850-1930.

IO of the maxillofacial region is not new to dentistry. During the
pre-antibiotic 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.[23-29]  This disease was well established by 1867, did
not often occur in individuals with good gingival health, and appeared to
"attack" the mandible first.[25]  It was associated with localized or
generalized deep ache or pain, often of multiple jawbone sites.  The teeth
often appeared sound and suppuration was not present.  Even so, the dentist
often began extracting one tooth after another in the region of pain, often
with temporary relief but usually to no real effect.[24]  Occasionally,
large fragments of necrotic bone would come out with the tooth, sometimes
involving much of an entire quadrant, as depicted in the figure at the top
of this page.  Apparently, Lorinser of Vienna in 1845 was the first to call
attention to the problem.[25]

Less severe cases of maxillofacial osteonecrosis were discussed in the
classic 1898 oral pathology text by Barrett,[28] wherein he 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. He
had no suggested etiology for his cases.  Thirty years earlier and more than
a century ahead of his time, Noel[27] separated bone caries into two
distinct categories: "bone death" and the less intense "reduced vitality."
Even earlier, the 1848 text by Thomas Bond[23], which appears to be the
first true oral pathology text, was the first book to discuss bone necrosis
as such, emphasizing that this disease did not require abscessed teeth or
gums, could result in the complete death of bone.  Bond mentioned that
"necrosis may be caused by any means which destroys the nutrition of the
bone or any part of it"-- usually from "constitutional vitiations, or
defects of nutrition consequent upon general pravity."  His recommended
treatment: "when necrosis has taken place, the bone must be removed."

G. V. Black,[29] the father of modern dentistry, described in 1915 an
osteomyelitis look-alike disease which 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 proposed by Ferguson[24] in 1868 and by
Bond[23] in 1848.  Around the same time period osteonecrosis of the hip in
children was being recognized by the author's whose names would eventually
be affixed to that disease, i.e. the Legg-Calv?-Perthes disease.[31-33]

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The Forgotten Decades: 1930-1970.

For most of the twentieth century this disease was largely forgotten by the
dental profession, although a few investigators made significant
contributions to the advancement of our understanding.  Wilensky[24] and
Hankey[25] suggested that persistent regional necrosis in osteomyelitis of
the jaws was secondary to vascular insufficiency, while Brosch[26] described
the potential for hollow medullary spaces to enlarge and coalesce one with
another. Thoma[37,38] was likely the first to specifically correlate this
"residual infection" or "osteitis" with old extraction sites, many of which
demonstrated focal "necrotic exudates," fibrosis and "osteoclastic
resorption" of surrounding bone. His observations were affirmed in 1955 by
Box,[34] 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, by its multifocal nature, its localized tenderness
without inflammatory signs, and the neuralgia-like nature of accompanying
pain.

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The Over-Emphasis of Pain: 1970-1990.

The 1970s and 1980s saw a strong emphasis placed on the neuralgia-like pains
often accompanying osteonecrosis of the maxillofacial region, an influence
embodied in the currently popular diagnostic name NICO (neuralgia-inducing
cavitational osteonecrosis).[40-48] Significant or complete pain reduction
was achieved in chronic "idiopathic" facial pain by the simple expedient of
decortication and curettage of damaged alveolar bone (Table 3), supporting
the contention by neural researchers that persistent odontogenic and osseous
disease can be important contributing factors for such neuralgias.44-49 None
of these investigations included a control group, nor has any 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 in order to reduce potential
biases.[50]

Unfortunately, the major emphasis on the association with neuralgic pain
initiated significant controversy among professionals treating "idiopathic"
facial pain and kept involved researchers from focusing on other features of
the disease process, such as more appropriate diagnoses and diagnostic
techniques, and better understanding of the pathophysiology and
pathoetiology of the disease.  Early lesions were diagnosed by a number of
independent pathologists as chronic osteomyelitis, and microorganisms
cultured from many NICO lesions, combined with occasional facial pain relief
with antibiotic therapy, assured that these cases would be diagnosed and
treated as chronic osteomyelitis.  And yet, a significant number of patients
did not respond in a fashion appropriate to that diagnosis.  This led some
investigators to seek alternative interpretations for the biological
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.[56,57]

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[58]), 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.[5,7,9,14,15,59]

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.[60-62]  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.[63]

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Decade of Major Advances: 1990-2000.

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 in
NICO patients heritable disorders predisposing to adverse thrombotic events.
At least 72% proved to be afflicted with a variety of such disorders, as
compared to 70-87% for patients with IO of the hip and knee.[9,19-21,64-67
This was seen as a major breakthrough, eventuating in the use of
anticoagulants (without surgery or antibiotics) in persons with NICO and hip
osteonecrosis.[68-71]  Although not all affected individuals benefited, the
significant pain relief experienced by a large proportion of treated
patients confirms an association in those persons between the symptoms of IO
and the hypercoagulable disorders.[69,71]

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 99technetium-MDP (99mTc-MDP) scintigraphy and Single Proton Emission
Computed Tomography (SPECT) scans, instead of the indium and gallium scans
typically used for bone infections.[64,72-74]  The small number of chronic
inflammatory cells found in NICO lesions makes radioisotopes which attach to
leukocytes much less useful than those which 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 99mTc isotopes directed at fibrin "-chain peptide
may prove useful for patients actively forming microclots.[75]

A substantial proportion (25-35%) 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. We recommend,
therefore, that the surgeon review all films interpreted as negative.
Thin-sliced spiral CT scans and ultrasonic scans have also proven effective
in localizing NICO, although they require very careful evaluation.[76]  MRI
scans are valuable for the rounded ends of bones but in our experience are
of little benefit in alveolar cases.[77,78]

In a similar fashion the more contemporary histopathologic features of
ischemic osteonecrosis and bone marrow edema (its less severe counterpart)
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.[1-9,57]  Additionally, microscopic evaluation of maxillofacial
biopsy samples is made much 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.  Recent analyses have,
significantly, reported that almost 3/4 of jawbone biopsy samples of
ischemic osteonecrosis and NICO can be classified as the histologically more
subtle variants called bone marrow edema or regional ischemic
osteoporosis.[81,82]  This has helped to explain why some oral pathologists,
certainly not the majority, have difficulty distinguishing the classic
features from "normal" bone and bone marrow.

The first microscopic review of a large series of biopsied cases of NICO was
reported during the 1990s, as was the first necropsy example.[57,82]  These
papers strongly emphasized the multifocal nature of the disease, while
others reinforced the strong association between chronic facial pain and
inflammatory or ischemic marrow disease.[55,83]  In this light, one of the
most important advances was the refinement of the old
anesthesia/hyperesthesia and microanesthesia diagnostic tests to more
successfully localize areas of medullary disease in facial pain
patients.[84-86]

During the 1990s sophisticated assays were also applied, for the first time,
to maxillofacial osteonecrosis.  Haley and Pendergras[87] used a
well-established neurotoxicity assay on a very large number of tissue
samples, finding almost all to be extremely toxic -- often more toxic than
hydrogen sulfide, the chemical normally used to establish maximum level of
neurotoxicity.  The exact nature of the toxin is not yet known, but the
discovery of the neurotoxicity led some to question whether or not this
process damaged the peripheral nerve myelin of the alveolar nerves.  This
idea was further stimulated by the finding in a small number of NICO biopsy
samples of an unusual form of nonwallerian degeneration in the majority of
visible nerves.[55]  To this end the blood of another small sample of NICO
patients was evaluated by a newly-established assay which, for the first
time, allowed the determination of circulating antibodies against peripheral
nerve myelin.[88]  The sera of healthy humans normally show none of these
antibodies, as was true for a few of the NICO patients, but other NICO
patients had antibody levels as high as or higher than those found in the
classic demyelination disease, the Guillain-Barr? syndrome.[89,90]  This
suggests chronic exposure of the peripheral myelin to the immune system,
either as a primary attack (autoimmune) or secondary to myelin exposed or
partially destroyed by a local inflammatory/ischemic phenomenon.

While some patients had no such antibodies, others demonstrated Elevated
levels of circulating anti-peripheral nerve myelin (anti-PNM) antibodies
have been found in NICO patients, suggesting .120-122 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.123

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 78. Sano T, Westesson P-L, Larheim TA, Rubin SJ, et al. Osteoarthritis and
abnormal bone marrow of the mandibular condyle. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 1999; 87:243.

 80. Bouquot J, McMahon R. Bone marrow edema syndrome: new disease or early
presentation of ischemic osteonecrosis? J Oral Pathol Med 1998; 27:346.

 81. Bouquot J, McMahon R. Bone marrow edema syndrome, independent disease
or early presentation of ischemic osteonecrosis? Proceedings, Annual
Meeting, American Academy of Oral & Maxillofacial Pathology; Williamsburg,
Virginia; April, 2000.

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

 83. McMahon RE, Griep J, Marfurt CP, et al. Local anesthetic effects in
the presence of chronic osteomyelitis/necrosis of the mandible: implications
for localizing the etiologic sites of referred trigeminal pain. J Craniomand
Pract 1995; 13:212-226.

 84. Brown RS, Hinderstein B, Reynolds DC, et al. Using anesthetic
localization to diagnose oral and dental pain. J Amer Dent Assoc 1995; 126:
633-641.

 85. McMahon RE, Adams W, Spolnik K. Diagnostic anesthesia for referred
trigeminal pain, Part I. Compendium Cont Educ Dent 1992; 11:870-881.

 86.McMahon RE, Adams W, Spolnik K. Diagnostic anesthesia for referred
trigeminal pain, Part II. Compendium Cont Educ Dent 1992; 11:980-997.

 87. Haley BE, Pendergrass JC. http://www.altcorp.com. [Affinity Labeling
Technologies; University of Kentucky]

 88. Koski CL. Humoral mechanisms in immune neuropathies. Neurol Clin 1992,
10:629.

 89. McMahon R, Bouquot J, Mahan P, Gremillion H. Elevated serum peripheral
nerve anti-myelin antibody titers in atypical facial pain patients with
NICO. J Orofacial Pain 1994; 8:104.

 90. 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.

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Table 1: Alternative diagnostic names used for bone marrow
edema and ischemic osteonecrosis.1-9,14-16

     Bone Marrow Edema
    Ischemic Osteonecrosis

     Arlet Type I osteonecrosis
     Bone compartment disease
     Bone marrow edema syndrome
     Chronic traumatic edema
     Medullary engorgement-pain syndrome
     Migratory osteolysis
     Migratory osteoporosis
     NICO *
     Post-traumatic painful osteoporosis
     Post-traumatic reflex dystrophy
     Primary algodystrophy
     Regional ischemic osteoporosis
     Regional osteoporosis
     Roentgenologic transient osteoporosis
     Sudeck's disease (RSD) **
     Transient bone marrow edema syndrome
     Transient demineralization
     Transient ischemic osteoporosis
     Transient marrow edema
     Transient osteoporosis
     Transitory demineralization in pregnancy
    Aseptic necrosis
     Aseptic osteomyelitis
     Aseptic osteonecrosis
     Avascular necrosis
     Bone infarction
     Coronary disease of bone
     Ischemic necrosis
     NICO *
     Osteochondrosis desiccans
     Perthe's disease

* NICO: neuralgia-inducing cavitational osteonecrosis
   ** RSD: reflex sympathetic dystrophy

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Table 2: 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. Modified from Bouquot JE, LaMarche MG. J Pros Dent
1999; 81:148-158.

       Normal Population
    Deep Vein Thrombosis
    Osteonecrosis

     Thrombophilia

           Hereditary types*
    2-5%
    5-9%
    50-70%

           Acquired types
    3-7%
    20-50%
    33%

     Hypofibrinolysis:

           Hereditary types *
    <1%
    5-15%
    18-22%

           Acquired types
    <1%
    20-25%
    50%

     Total (includes multiple coagulopathies):
    5-9%
    20-50%
    65-87%

 * usually autosomal dominant

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Table 2: Results of surgical curettage of jawbone NICO (Neuralgia-Induced
Cavitational Osteonecrosis) lesions, an average of 4.5 years after last
surgery, in 103 patients with "idiopathic" chronic facial pain for an
average of 6 years (range: 2-18 years) prior to NICO surgery.

Reference: Bouquot JE, Christian J. Long-term effects of jawbone curettage
on the pain of facial neuralgia. J Oral Maxillofac Surg 1995; 53:387-397.

     Follow-up Rating Reduction % Pain Present Status of Pain % of Total
Cases
     0 0-10 % No improvement 8.8% *
     1 11-33 Minimal improvement 2.9
     2 34-75 Moderate improvement 15.5
     3 76-99 Considerable improvement ** 13.6
     4 100 No pain 59.2
     Total:
    100.0 %