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Neuralgia-inducing cavitational osteonecrosis (NICO). Osteomyelitis in 224

jawbone samples from patients with facial neuralgia

Article  in  Oral Surgery Oral Medicine Oral Pathology · April 1992

DOI: 10.1016/0030-4220(92)90127-C · Source: PubMed

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oral pathology
Editor:
LEWIS R. EVERISOLE, DDS, MSD, MA
Oral Diagnosis, Medicine & Pathology
School of Dentistry 53-058
UCLA Health Sciences Center
Los Angeles, California 90024

Controversies in oral pat hology

Neura,lgia-inducing cavitational osteonecrosis

(NICO)
Osteolmyelitis in 224 jawbone samples from patients with facial neuralgia

J. E. Bouquet, DDS, ~IKI?D,~A. M. Roberts, DDS,b P. Person, DDS, PhD,C

and J. Christian, DDS,d Morgantown, W.Va., Brooklyn, N.Y., and Detroit, Mich.

WEST VIRGINIA UNIVERSITY SCHOOL OF DENTISTRY AND SCHOOL OF MEDICINE, VETERANS

ADMINISTRATION MEDICAL CENTER, BROOKLYN, AND HENRY FORD HOSPITAL, DETROIT.

A somewhat obscure etiologic theory for facial neuralgias presumes a low-grade osteomyelitis of the jaws
that produces neural degeneration with subsequent production of inappropriate pain signals. Animal
investigations and treatment successes with human patients based on this theory lend it credence. The
present study examined 224 tissue samples removed from alveolar bone cavities in 135 patients with
trigeminal neuralgia or atypical facial neuralgia. All tissue samples demonstrated clear evidence of chronic
intraosseous IInflammation. The most common microscopic features included dense marrow fibrosis or
“scar” ,formai:ion, a sprinkling of lymphocytes in a relative absence of other inflammatory cells (especially
histiocytes), a.nd smudged, nonresorbing necrotic bone flakes. Very little healing or new bone formation
was visible. Tlhese lesions were able to burrow several centimeters to initiate distant cavities. The present
preliminary investigation cannot prove etiology, but the presence of intraosseous inflammation in every
single jalwbonte specimen in these patients and certain clinical and treatment aspects of these lesions (to
be reported Ialter) has led the authors to recommend the term neuralgia-inducing cavitational osteonecrosis
or N/CO for these lesions.
(ORAL SIJRC ORAL MED ORAL PATHOL 1992;73:307-19)

aProfessor and Chair, Department of Oral Pathology, West

Virginia University School of Dentistry; Professor and Section
Chief, Department of Pathology, West Virginia University School
of Medicine.
bClinical Assistant Professor, Departments of Oral Surgery and
Oral Pathology, West Virginia University School of Dentistry.
CResearch Laborat’ory for Oral Tissue Metabolism and Dental
Service, Veterans Administration Medical Center.
dSenior Staff Surgeon, Division of Oral & Maxillofacial Surgery,
Department of Surgery, Henry Ford Hospital.
7/14/34041
P ain, a normal and essential aspect of human phys-
iology, is the reason for approximately one half of all
patient visits to physicians each year’ and chronic
pain is a major part of the total pain spectrum.2 The
face, although the least likely of all major anatomic
sites to be affected with chronic pain, still carries a
33.8% risk of developing such pain by the age of 70
(24.3% by the age of 50).2 At any one time 15% and
8%, respectively, of men and women in the United
States suffer from chronic facial pain of various types
and intensities. Persons between 25 and 44 years of
307
308 Bouquot et al.

gable 1. Listing of NICO cases reported in the literature, by year of publication

Yl?W Number of Median pain Average duration
Author(s) ofpubl. patients reduction postop (%) of relief (yrs)

Ratner et a1.21 1976 26 (Wt 100(100) n/a

Ratner et a1.24 1978 1 (1) iO0 (100) 0.3
Ratner et a1.13* 1979 61 (38) 93 (95) 1.9(0.2-13.0)1]
Robertset a1.l4 1979 42 (18) 100(100) 1.2 (0.2-9.0)
Shaberet aLzs 1980 8 (8) 100(100) n/a
Mathis et a1.26 1981 8 (8) 100(100) 0.6
Ciao,Meng32 1981 37 (37) 100 (100) n/a
Wangeet a1.33* 1982 103(103) 100(100) n/a
Demeratb,Sistz7 1982 29 (?) 50 (?) 0.9
Munford7 1982 4 (?) 100(100) n/a
Robertset a1.28* 1984 208 (131) 95 (95) n/a (0.2-23.0)
Grechko,Puzin3’ 1984 65 (65) 100(100) n/a
Ratneret a1.29* 1986 1,300(?) 85 (?) n/a
Bouquet,Christian38* 1991 103(34) 90-lOO$ 4.6 (0.5-18.0)
TOTAL 1,995 95%(100)s 1.6 (0.2-23.0)s
*Includes unidentified number of patients from previously reported investigation, but considered a separate patient cohort for tabulation purposes.
tNumber in parenthesis refers only to trigeminal neuralgia patients.
$73% experienced total relief and 16% experienced moderate relief (still require aspirin, etc., but patients are satisfied and not seeking further treatment).
§Unweighted for size of individual patient cohorts.
/[Number in parenthesis refers to range in years.

age suffer most frequently.2 More than 16% of
persons with chronic facial pain consider it to be se-
vere in nature.2 Perhaps the most severe form of all
chronic facial pain is trigeminal neuralgia (TN), a
disease diagnosed in approximately 10,000 Ameri-
cans annually (4 in 100,000 persons).3 TN is one of
several conditions characterized by inappropriately
intense or spontaneously generated pain and usually
catagorized under the generic term neuropathicpain.
The pain intensity in TN is so great that formidable
intracranial procedures have become treatments of
choice and suicide is a well-known outcome of treat-
ment failure.4‘6
Appropriate therapy for TN has been hampered by
a lack of understanding of the etiology and patho-
physiology of the disease. The most accepted etiologic
theory postulates an epileptiform discharge of the
spinal trigeminalnucleus secondary to physical, chem-
ical, or inflammatory damage to the sensory roots or
intracranial nerve fibers of the fifth cranial nerve.“”
A number of medical and surgical therapies have been
based on this theory. 6-11 Varied surgical procedures
have all had fairly uniform success rates, which leads
some observers to conclude that the one common fea-
ture that resulted in successful short-term pain relief
was, in fact, nothing more than surgical trauma to
central portions of the fifth nerve.7pI2 Atypical facial
neuralgia (AFN), a more commonly diagnosed but
less distinct facial pain syndrome, has such a poor
surgical cure rate that neurosurgical procedures are
seldom employed.6
One etiologic theory presumes neural damage some
distance from the brain stem. This theory hypothe-
sizes a low-grade, chronic, intraosseous jawbone
infection that surrounds one or several branches of the
trigeminal nerve. 13,I4 This supposedly produces neu-
ral degeneration or demyelination with subsequent
inappropriate pain signals.
Such a theory was expounded in 1926 by British
neurosurgeon Sir Wilfred Harrisis, l6 and had been
accepted by dental surgeons in the US for a century
before that.17-20 It has gained partial acceptance in
the United States,8>21-29West Germany,30 Russia,31
and China.32‘34 It is partially substantiated by labo-
ratory evidence of gasserian ganglion demyelination
after damage as far away as a tooth pulp,35-37 and by
Ihe development of an animal model in which neural-
gia-like behavior is produced via myelin damage to
peripheral portions of the trigeminal nerve.35 It is also
somewhat corroborated by a remarkably high rate of
relatively long-term TN pain relief after simple but
meticulous curettage of jawbone “‘cavities” or foci of
diseased bone-even in patients who have failed to
respond to traditional medical and neurosurgical pro-
cedures (Table I).
Unfortunately, data presented in support. of this
theory tend to be anecdotal in nature, a situation that
has led to considerable, probably justified; skepticism
among oral surgeons and neurosurgeons alike. Re-
buttals likewise have been anecdotal and speculative.
No controlled prospective analysis of an unbiased
sample of facial neuralgia patients has been pub-
lished.
These jawbone lesions have been described vari-
ously as jawbone cavities, *3, 14:28,32,33osteocavitation
lesions,“7 pathologic bone cavities,22, 34 odontogenic
Volume 73
Number 3
trigeminal neuralgias, 31 alveolar cavitational osteo-
pathosis, trigger-lpoint bone cavities, Ratner bone
cavities, and Roberts bone cavities. No term, however,
has adequately addressed the salient and unique as-
pects of this disease. Hence we propose the use of the
term neuralgia-inducing cavitational osteonecrosis
(NICO), as it immediately identifies the major prob-
lem-possible induction of a chronic facial neural-
gia-and its two most unique local features: in-
traosseous cavity formation and long-standing bone
necrosis with minimal healing.
The purpose of the present investigation was to
provide a preliminary microscopic evaluation and
characterization of a large number of NICO lesions
and to differentiate them from other forms of osteo-
myelitis. Future papers will detail the clinical, thera-
peutic, and pathophysiologic aspects of this most in-
triguing disease. 38It is hoped that enough interest will
be generated to lead to controlled prospective studies
of the relationship between jawbone infections and
facial neuralgias.
METHOD AND MATERIAL
A total of 224 formalin-fix.ed, paraffin-embedded
tissue samples from 135 affected persons were re-
trieved from the archival files of three hospitals, along
with relevant surgical pathology reports, surgical re-
ports, and hospital admission records. Six-micron
sections were cut and stained with hemotoxylin and
eosin for routine microscopic interpretation. Selected
cases were a random sample of TN and AFN patients
in the care of four oral surgeons. These patients un-
derwent exploratory jaw surgery between Jan. 1,
1971, and Dec. 31, 1989.
All the patients had been previously diagnosed with
TN (n = 51) or AFN (n = 84). The accuracy and
criteria of these diagnoses could not, of course, be as-
certained from data gathered for the present analysis,
but review of hospital admission records indicated
that in 68.6% l(n = 35) of the patients with TN and
79.8% (n = 67) of those with AFN the conditions had
been previously diagnosed and/or treated by neurol-
ogists or neurosurgeons. The remaining conditions
were diagnosed by oral surgeons according to the cri-
teria of White and ISweet.39 Detailed clinical, radio-
graphic, and follow-up information was sought for
each case and ,will be subsequently reported,38 but it
should be stated here that 76.7% of the patients with
appropriate historical information (n = 92) were
edentulous in the site of at least one NICO lesion.
Extractions hald been performed several years or de-
cades earlier for all but four of the patients. Almost
all (n = 13 1) patients had NICO sites within the an-
atomic distribution of the trigeminal nerve branch(es)
affected by neuralgia.
Microscopic sections were examined by one of the
Neuralgia-inducing cavitational osteonecrosis 309
authors (J.E.B.), a pathologist with experience and
special training at the Mayo Clinic in bone pathology.
He evaluated 13 different parameters or characteris-
tics for each sample, subjectively rating the intensity
or density of each on a four-point scale as follows
(grading was relative to the total collection of tissue
samples as well as to normal bone):
0 = The parameter is completely missing,
0.5 = The parameter is present in only trace
amounts,
1 = Minimal amounts/numbers of the parameter
were noted,
2 = Moderate amounts/numbers of the parameter
were noted,
3 = Large amounts/numbers of the parameter
were noted,
4 = Excessive amounts/numbers of the parameter
were noted.
The parameters or characteristics canvased in-
cluded number of mature lymphocytes (with the ex-
ception of hematopoietic cells); number of mature
neutrophils (with the exception of hemorrhage);
number of obvious histiocytes; amount of necrotic
bone in marrow spaces; amount of necrotic marrow;
amount and density of marrow fibrosis (collageniza-
tion); amount of reactive or new bone; quantity of
foreign material in marrow spaces; number and size
of bacterial colonies; amount of hemosiderin in mar-
row spaces (indicative of presurgical hemorrhage);
number of normal nerve fibers or nerve “tumors”;
amount of squamous or other epithelium; amount of
normal bone marrow. Intensity was assessed in the
most severely involved areas from each curetted sam-
ple.
All tissue samples comprised curetted material
from cancellous bone of the maxilla or mandible, but
some contained only limited amounts of tissue, espe-
cially those from NICO cavities with surgically obvi-
ous “air-filled” spaces. Samples examined, however,
represented all tissue removed from NICO lesions; no
available tissue was ignored.
Six partially edentulous mandibles from autopsy
specimens of patients (41, 53, 59, 61, 70, 74 years of
age) without histories of chronic facial pain were de-
calcified, serially sectioned every 0.5 cm, and exam-
ined histologically. This number of cases is too small,
of course, to be considered true controls, and were
used only to reaffirm the appearance of normal bone
marrow as reported in the histology literature and to
determine that edentulous and dentulous alveolar
bone was similar.
RESULTS
The average patient age at the time of the NICO
diagnosis was 49.1 years, with a range from 24 to 84
years. Duration of TN or AFN before the NICO di-
340 Bouqwot et al.
Fig. 1. Alveolar bone iocations of primary NICO lesions in 135 TN and AFN patients; locations were sim-
ilar for each disease.
MARROW FIBROSIS
BONE NECROSIS
LYMPHOCYTE INFILTRATION
MARROW NECROSIS
NORMAL MARROW
HEMOSIDERIN DEPOSITS
NEUTROPHIL INFILTRATION
NEW (REACTIVE) BONE
NERVE FIBERS
HISTIOCYTE INFILTRATION
BACTERIAL COLONIES
0 10 20 30 40 50 60 70 80 90 100
%J SAMPLES WITH CHARAGTERISTIC
Fig. 2. Percentagesof various microscopic characteristics found in 224 NICO tissue samples, ranked by
frequency of occurrence.
agnosis averaged 6.2 years, with a range from 5
months to 32 years. Most patients were women
(66.6%), and the sites most frequently involved were
mandibular and maxillary molar areas and the max-
illary cuspid region (Fig. 1). All NICO sites were io-
cated within alveolar bone, 77% in edentulous areas.
The latter areas had been without teeth for 1 to 27
years (the mean was 11.8 years).
With the exceptions explained below, primary
lesions (without previous intraosseous surgery) and
recurrences were histologically identical and hence
were analyzed together. Similarly, NICO lesions in
TN patients were histologically identical to those in
AFN patients.
All surgically explored intraosseous sites demon-
strated gross changes variously described as “gritty,”
“like sawdust,” “hollow cavity,” “hemorrhagic,” and
“dry.” Occasional hard, “toothlike” bone was en-
countered. The overlying cortex was typically thinned
but not expanded and was occasionally perforated.
No surgical samples consisted entirely of normal
marrow, but several contained areas of either he-
matopoietic (n = 25) or fatty (n = 15) marrow. All
autopsy specimen controls consisted entirely of nor-
mal marrow with no evidence of inflammation, ne-
3K.C %IRG ORAL ?d/jw ORAL PATHOL
March 1992
crosis, or fibrosis. Edentulous and dentate areas were
histologically similar.
All NICO samples demonstrated marrow fibrosis,
lymphocytic infiltration, and/or necrotic bone chips.
While each of these features was almost universal
(Fig. 2), they varied greatly in their concentrations or
intensity levels (Fig. 3). Marrow fibrosis, most fre-
quently dense and avascular with minimal cellularity
(Fig. 4), demonstrated the highest average intensity
level of all parameters evaluated. Approximately two
thirds of the samples were graded at or above 3 on a
4-point scale (Table II).
Lymphocytic infiltration, a characteristic noted as
frequently as marrow fibrosis, was typically seen as
cells sprinkled throughout areas of fibrotic marrow
(Fig. 4). Only occasionally were higher concentra-
tions noted (Table II). Other chronic inflammatory
cells were seldom seen in areas with low concentra-
tions of lymphocytes. Histiocytes, in particular, were
rarely noted in large numbers; only 1.3% of the sam-
ples had intensity grades higher than 1 for histiocytic
infiltration (Table II).
Neutrophils, the sine qua non of acute inflamma-
tion, were seen in only one fourth of the NICO sam-
ples (Fig. 2), with an average intensity grade of only
Volume73
Number 3
MARROW FIBROSIS
HEMOSIDERIN DEPOSITS
BONE NECROSIS
MARROW NECROSIS
NORMAL MARROW
NEW (REACTIVE) BONE
NEUTROPHIL INFILTRATION
NERVE FIBERS
LYMPHOCYTE INFILTRATION
BACTERIAL COLONIES
HISTIOCYTE INFILTRATION
0 .5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
AVERAGE INTENSITY GRADE (4=MAXIMUM)
Fig. 3. Average intensity (severity) grades,relative to a four-point subjective scale,for various microscopic
characteristics in 224 NICO samples, ranked by intensity of characteristic.
1.6. Levels bellow 2 were considered too low to be
compatible with actual pus formation. Neutrophil
presence did not correlate well with the presence of
necrotic bone or marrow.
Foreign bodies, 93.2% of which consisted of glob-
ules that represented therapeutic ointments in recur-
rent lesions, did not typically elicit an inflammatory
response, but foreign-body giant cells were noted in 14
of 89 recurrent samples. No foreign body reactions
were noted in primary NICO lesions. Epithelial rem-
nants were seldom found except in recurrent lesions
that had been treated by placement of pedicle grafts.
Only two samples contained obvious remnants of cys-
tic squamous epithelium.
Perhaps the most interesting feature of NICO le-
sions was the almost constant presence (95.1%) of
small fragments, chips, or flakes of necrotic bone that
seldom appeareNdto have undergone resorption or in-
volucrum formation. These chips were similar to the
fresh fragments that often result from surgical curet-
tage of viable bone but had a “smudged” and rounded
microscopic appearamce (Fig. 5). They were fre-
quently embedded within a nonencapsulating collag-
enous or necrotic marrow and were usually noted in
moderate amounts (‘Table II). In two samples, new
reactive bone was seen to completely surround frag-
ments of necrotic bone. Osteoclasts were noted in only
three samples, and osteoblasts associated with reac-
tive new bone were noted in only 20.5% of the cases.
The typical NICO case demonstrated very little evi-
dence of histiocytic or osteoclastic activity, new bone
formation, or repair.
Soft tissue (marrow) necrosis was also frequently
found and was usually present in moderate amounts
(Figs. 2, 3, and 6). This necrosis was seldom accom-
Neuralgia-inducing cavitational osteonecrosis 3I I
panied by infiltration of neutrophils or histiocytes, al-
though a heightened lymphocytic intensity was fre-
quently associated with it. Marrow necrosis was not
necessarily required for bone necrosis, and many
samples demonstrated bone necrosis with absolutely
no evidence of marrow necrosis.
It was not unusual at surgery to find the alveolar
mandibular nerve within a NICO cavity, but because
every attempt was made to preserve such visible
nerves, few samples contained nerve fibers (Fig. 2);
when fibers were present, they usually appeared in
small quantities (Fig. 3). Gross evidence of demyeli-
nation or degeneration (frayed nerve fiber, brown or
yellow discoloration of nerve fiber, total focal destruc-
tion of nerve fiber, etc.) was frequently noted in sur-
gical reports. Special techniques were not employed to
demonstrate microscopic nerve damage, but most ap-
peared unremarkable except for occasional endoneu-
rial lymphocytes and edematous fibers. Seven samples
contained traumatic neuromas (five in recurrent
lesions), two contained neurofibromas, and three ad-
ditional casescontained abundant fibromyxoid stroma
similar to, but not diagnostic of, loose connective tis-
sues of neurofibromas.
While most NICO cavities appeared hemorrhagic
at surgery, fewer than one fourth of the samples con-
tained significant amounts of hemosiderin (Fig. 2).
Most of the hemorrhage, then, was new and related
to the surgery. As the center of these lesions was most
frequently avascular or “dry,” it appears that the
hemorrhage at surgery arose from a vascularized
“capsule” around an entire lesion or around multiple
lobules of collagenous tissue within the lesion itself,
Numerous air- or fluid-filled intraosseous cavities
were noted at surgery. Curetted samples from such
312 Bouquet et al.
Fig. 4. Typical marrow spacesfilled completely with a dense,minimally vascular collagenic fibrous tissue
scattered throughout with small numbers of mature lymphocytes. (Original magnification X 100.)
cavities were small and most frequently demonstrated
a thin layer of chronically inflamed collagenic tissues
overlying viable and sometimes reactive bone (Fig. 7).
The similarity to tissue removed from traumatic bone
cysts was remarkable.
Fig. 8 provides a composite illustration of the his-
tologic appearance of NICO cavities, as pieced to-
gether from our microscopic and surgical observa-
tions. When a hollow cavity is present, it is separated
from the surrounding bone by densely fibrotic con-
nective tissue, which in turn is frequently surrounded
by vascular tissue. Reactive new bone is usually seen
only in the vascular capsule. Fistulas, some as long as
2 cm at surgery, were noted in surgical reports to have
burrowed into surrounding normal bone marrow and
extended into a distant NICO site. The visible nerve
fibers within a NICO cavity were noted at surgery to
be typically brown, thinned, and frayed; the latter two
characteristics became more pronounced toward the
center of the cavity. Seven mandibular nerves were
reported to be completely severed at surgical exposure
(i.e., before curettage of the NICO cavity).
IS NICO HISTOLOGICALLY UNIQUE?
There can be no question that tissues removed from
NICO lesions are abnormal. Fibrosis sprinkled with
mature lymphocytes is not a feature of normal bone
marrow, to say nothing of the presence of necrotic
bone. The real question is whether NICO differs from
classic forms of acute or chronic osteomyelitis; we
contend that it does. While occasional polymorpho-
nuclear leukocytes are noted in NICO, they are sel-
dom present in large enough numbers to produce
ORAL SURG ORAL %‘iihD ORAL PATHOL
March 1992
suppuration or abundant tissue edema and/or necro-
sis. On the contrary, when necrosis is present in
NICO, as it usually is, neutrophils are almost never
associated with it. In acute osteomyelitis, pain inten-
sity is directly related to the presence of significant
suppuration and considerable relief is immediately
noted on cortical perforation and free egress of pus
from the medullary spaces. Such does not appear to
be the case with NICO lesions.
Also, the character of local pain differs between
these two diseases. Acute osteomyelitis produces
much more intense bone pain on palpation (tender-
ness) and is often very painful even without palpation,
whether it is located in the jaws4’, 4’ or in long bones,
as in Brodie’s abscesses4’ NICO cavities, while
known to trigger lancinating, paroxysmal attacks on
palpation, may be only mildly tender themselves and
seldom demonstrate sharp local pain without palpa-
tion. Neutrophils, edema, suppurative necrosis, and
extreme tenderness, the salient features of acute os-
teomyelitis, appear to be incidental and almost insig-
nificant findings in NICO.
Nor is NICO histologically similar to typical
lesions of chronic intramedullary osteomyelitis. Per-
haps the most unique aspect of NICO, other than its
production of intense pain without suppuration, is the
virtual absence of new bone formation or healing.
This is contrary to chronic osteomyelitis.43 In like
fashion there is a surprising lack of active resorption
of nonviable or necrotic bony flakes and spicules (Ta-
ble II). Although dense, avascular fibrosis of marrow
is a rather constant feature of NICO, there appears
to be no real attempt to “wall off’ fragments and
Volume 73 Neuralgia-inducing cavitational osteonecrosis 313
Number 3

Fig. 5. Typical aggregate of smudged and rounded ne-
crotic bone flakes (lar,ge arrow) within hematopoietic/fatty
marrow spaces.Notice lack of inflammatory cell infiltrate
or evidence of !resorption of necrotic bone. A peripheral
nerve fiber (small armw) is also present, but this was not a
usual occurrence. (Original magnification X250.)
Fig. 6. Hematopoietic/fatty marrow sprinkled through-
out with small foci of necrotic connective tissues (arrows).
Much larger areasof marrow necrosiswere often noted. Il-
lustrates the lack of acute inflammatory responseand the
multiple nature of such necrosis. (Original magnification
x250.)

Table II. Graded characteristics of 224 tissue samples of NICO

Low < < Intensity Grade* > > High
Number Percentage
Characteristic of cases of cases 0.0 0.5 1.0 2.0 3.0 4.0

Inflammatory cells
Lymphocyte infiltration 212 94.6 5.4% 21.9% 35.7% 24.6% 12.1% 0.4%
Neutrophil infiltration 59 26.3 73.7 5.8 10.3 5.4 2.2 2.7
Histiocytes (macrophages) 23 10.3 89.7 2.7 6.3 1.3 0.0 0.0
Marrow changes
Marrow fibrosis 219 97.8 2.2 2.7 15.2 17.9 25.9 35.1
Marrow necrosis 170 80.4 19.6 13.8 24.6 23.2 9.8 8.9
Foreign bodies? 74 33.0 67.0 3.6 8.0 8.9 6.7 5.8
Bacterial colonies 17 7.6 92.4 1.8 3.1 2.2 0.4 0.0
Hemosiderin 63 28.1 71.9 0.9 4.0 15.2 4.0 4.0
Epithelial remnants? 59 26.3 73.7 7.6 7.1 9.4 1.8 0.4
Peripheral nerves 35 15.6 84.4 3.6 7.6 1.3 2.2 0.9
Bone Changes
Necrotic bone chips 213 95.1 4.9 10.3 19.6 30.8 22.3 12.1
Reactive (new) bone 46 20.5 79.5 4.0 5.8 7.6 3.1 0.0
*Grading was subjective, with four representing the highest intensity or concentration of a particular cell type or histologic features.
iAlmost always ophthalmic ointment or epithelium placed at an earlier NICO surgery.

flakes of dead bone, hence, very little involucrum for-
mation is evident. Table III details other parameters
that separate WICO from chronic intramedullary os-
teomyelitis of the jaws.
Chronic osteomyelitis typically contains foci of
isolated suppuration (acute inflammation) and pre-
sents a course of acute exacerbations admixed with
periods of quie,scence. In reality this disease, then, is
an example of subacute, not chronic, inflammation of
bone. True chronic osteomyelitis encompasses a group
of diseases usually categorized under the common
term chronic nonsuppurative osteomyelitis (Table
IV). Each differs substantially from NICO: NICO
lacks the painless, well-defined radiopacity of con-
densing osteitis; NICO lacks the mildly painful, often
extensively radiopaque areas, the ability to expand the
cortex, and the racial predilection of diffuse scleros-
ing osteomyelitis; NICO is typically intramedullary,
and when it perforates the cortex it does not produce
onionskin or other cortical proliferations characteris-
tic of GarrC’s osteomyelitis, nor is it frequent in young
persons. NICO also lacks the low pain levels and the
histologic granulomas seen in granulomatous osteo-
myelitis (syphilitic, tubercular, mycotic, etc.).
NICO is somewhat similar to chronic nonsuppura-
tive apical periodontitis (periapical granuloma), and
many of the microorganisms cultured from NICO
cavities are those isolated from classic periapical pa-
314 Bouquot et al.
Mild lymphocytic infiltration of densely fibrotic connective tissues lining a hollow NICO cavity.
Notice new bone formation along bottom of fibrous tissues. (Original magnification X100.)
Fig. 8. Composite of suggested model for a typical NICO
lesion of the mandible. Degeneration and destruction of the
nerve are assumed to produce demyeiination rather than
wailerian changes; this is not yet proven.
thoses.t3* I4123,44,45 Periapical granulomas comprise
either collagenous or edematous granulation tissue,
typically with abundant neovascularity, numerous
mononuclear leukocytes and macrophages, occasional
foci of reactive (woven) bone formation, soft tissue
(marrow) necrosis, and peripheral (capsular) fibrosis.
URALSURG ORAL M~O~ALPATHOL
March 1992
The entity called “‘periapical scar” is the most NICO-
like of the periapical pathoses, although it lacks
smudged, necrotic bone, is limited in size, is obvious
radiographically, and is symptom free. True granula-
tion tissue is rare in NICO, as are macrophages. Ne-
ovascularity is seen, certainly, but typically as a “vas-
cular capsule” at the periphery. Conversely, fibrosis is
seen centrally, not as a fibrous capsule.
Also, pain is seldom, perhaps never, a prominent
feature of chronic nonsuppurative apical periodonti-
tis.40,44 Only during acute exacerbations with con-
comitam neutrophilic activity is pain produced. While
we presume that a great many NICO lesions begin as
periapical pathoses, we agree with Darling4” that such
pathoses require an additional local or systemic com-
plication if they are to progress to osteomyelitis and
that such progression is rare.
The skeletal lesion most similar microscopically to
this jaw disease appears to be aseptic ischemic
osteonecrosis (AIO). 42,46 AIO, a pressure-induced
medullary infarction or ischemia, is usually found in
stress-bearing areas of long bones in children and oc-
casionally results in considerable sclerosis, although a
poorly demarcated radiolucency is the typical radio-
graphic appearance. Such lesions produce local or re-
ferred pain, often intense, and may contain hematog-
enously or traumatically introduced microorganisms.
Volume 73
Number 3
They also tend not to heal without surgical curettage;
this minimal healing is considered to be secondary to
local hypoxic conditions. AI0 is rare in jaws, but has
been reported after trauma.47-49
The small necrotic bone flakes characteristic of
NICO are frequently seen in AIO, and involucrum
formation is rare in both. Fibrosis admixed with oc-
casional mononuclear leukocytes is also common to
both diseases,as is the paucity of granulation tissue-
even in areas of obvious marrow necrosis. The close
microscopic similarity to AI0 has convinced us that
the term osteonecrosis, rather than osteomyelitis, is
more appropriate to NICO, although we consider it
to be a subtype of osteomyelitis.
Another bolne d&order-the traumatic bone cyst
(TBC, solitary bone cyst, unicameral bone cyst)-
sharessimilar microscopic features with NICO. This
similarity has previously been noted.t3x22,29It is sig-
nificant that TBC is one of the very few nonepithelial,
nonneoplastic, cavitating lesions of bone and that its
location predilection is similar to those of AIO. TBCs,
furthermore, are thought to originate from abnormal
healing of infarcted or traumatized medullary bone.50
Other points of similarity include poorly defined bor-
ders and thinning of trabeculae within a predomi-
nantly radiolucent lesion, thinning of the overlying
cortex, the frequent discovery of a free (without its
bony canal) tri,geminal nerve branch coursing through
the cavity.
Points of dissimilarity between TBC and NICO
are, however, numerous: TBCs lack local or distant
pain; TBCs affect young persons,usually teenagersor
young adults; TBCs are able to produce cortical ex-
pansion; nerves traversing TBCs lack the “ragged
rope” appearance of those in NICO lesions; TBCs
heal readily after minimal surgical intervention; TBCs
lack evidence of odontogenic infection.
Nevertheless, it seemsappropriate, in spite of the
differences, to consider TBCs as pathophysiologically
similar to NICO. The major differences are perhaps
explained by the different patient ages(young, vascu-
lar bone versus old, relatively avascular bones’) and
by a lack of odontogenic infection in TBCs.
A final lesion with the unusual lack of resorption
and remodeling seenso routinely in NICO cavities is
a lesion that I<hinelander52 has called dormant os-
teonecrosis. Apparently nonhealing necrosis with fi-
brosis is seenoccasionally in cortical bone adjacent to
certain orthopedic prosthetic materials, acrylic ce-
ments in particular. It has been determined that the
osteonecrosis in these cases is due entirely to the
physical blockage of the medullary blood supply to the
cortex rather than to the chemical influences of these
materials. Dormant osteonecrosis does not seem to
occur in young, wel’l-vascularized bone. The similar-
Neuralgia-inducing cavitational osteonecrosis 315
ity between the two diseasesis only histologic, as dor-
mant osteonecrosisis not known to produce cavities or
unusual pain, although it is responsible for treatment
failures that result from the inability of affected bone
to remodel. It is interesting to speculate that this le-
sion might produce neuralgia if a peripheral nerve
were in the affected area, but sensory nerve fibers are
only rarely found in bone marrow and large in-
traosseousnerves are seen only in the jaw.51
WHAT CAUSES NICO?
Why do some persons with odontogenic and sinus
infections have NICO lesions and subsequentTN or
AFN while millions of others with the sameinfections
never have neuropathies of any type? Conversely, why
do TN and AFN patients appear to hold such a mo-
nopoly on NICO cavities? We can only speculate, of
course, but it is possible that one or several of the fol-
lowing hold true:
1. NICO patients have a localized or systemic im-
mune deficiency, probably of a specific type, that does
not allow bacterial destruction locally. (Altered im-
munity hasbeendemonstrated in patients with chronic
osteomyelitis as well as in patients with periapical
granulomas.45,53~54)
2. Unusual bacteria in NICO lesions induce fibro-
sis and avascularity (possibly infarction) with a
resultant inability to heal. (Numerous bacterialpatho-
gens have been isolated from NICO cavities, and
Ratner et a12’s23have found several that were previ-
ously unidentified.)
3. A reduced blood flow to affected jaws produces
medullary hypoxia or infarction as well as a dimin-
ished resistanceto odontogenic infections. (Maxillary
artery angiograms have demonstrated poor filling of
alveolar arteries in at least someNICO patients [per-
sonal communication with R. McMahon, oral sur-
geon, Merryville, Ind.]).
4. The relative lack of neutrophils and/or mac-
rophages, with a subsequent lack of chemotaxis,
phagocytosis, and proteolytic enzyme release (colla-
genase,elastase,etc.) does not allow the wound to be
cleaned and thus interferes with healing.43l55
5. NICO patients lack one or several intraosseous
growth factors required for new bone formation or
perhaps have an altered pH within the bone cavities,
with diminished osteoinductive effects (local bone in-
duction factors are essential to bone healing).55>56
6. NICO cavities are actually very common in the
older population, but are not diagnosed becausethey
produce pain only in personswith impaired inhibition
in the trigeminal nucleus or with a susceptibility to
neural demyelination. (One percent to 4% of TN and
NICO patients are afflicted with multiple sclero-
sis 6,28, 57, 58 >
316 Bouquoi et al. ORAL SURGORAL Mm ORAL PATHOL
March 1992

Table 111.Comparison of clinical and microscopic features of typical chronic intramedullary osteomyelitis
and NICO lesions
Feature Chronic Osteomyelitis40-43 NICO Cavity

Pain Mild, local Mild local, severe distant

Radiographic appearance Irregular radiolucency Irregular radiolucency
Poorly demarcated borders Poorly demarcated borders
Thinned, irregular trabeculae Thinned, irregular trabeculae
Occasional hazy opacity
Occasionally thick, short trabeculae
Cortical change F\lormal thickness Usually thinned
Often perforated Occasionally perforated
Fistula formation Typically to surface of bone Typically to other NICO cavities
Cavity formation Rare Routine
Duration Many months or years Many months or years
Exacerbations Routine Routine
Dead bone Nonviable trabeculae Nonviable small flakes and fragments
Moderate or large spicules
Internal suppuration common Suppuration is rare
Maybe somewhat radiopaque Maybe somewhat radiopaque
Reactive bone Routine Rare
Osteoclastic acitivity Routine Rare
Acute inflammation Routine Rare
Vascularity Routine Routine at periphery of lesion
Uniform throughout Rare in center of lesion
Pathologic fracture Frequent Never
Intraosseous fibrosis Minor amount in marrow Large amount in marrow
Abundant around involucrum Involucrum formation is rare
Surfaace celiulitis Frequent Rare
Macrophages Common Rare

Table IV. Comparison of clinical and microscopic features of the various types of chronic nonsuppurative
osteomyelitis and NICO cavities
Presentation NICO cavity

Focal sclerosing osteomyelitis Young adults affected Older adults affected

(condensing osteitis) Painless Mildly tender locally; trigger point
(bone scar)
Well-defined borders Poorly defined borders
No cortical change Thinning of cortex, minimal sclerosis
Radiopaque only
Diffuse sclerosing osteomyelitis Occasional mild local pain Mild local pain; trigger point
(florid osseous dysplasia)
Radiopaque/radiolucent Radiolucent usually
Expands cortex Thins or perforates cortex
Predilection for blacks No racial predilection
Garre’s osteomyelitis Cortical thickening (onion skinning) Cortical thinning
Young Patient Older patient
Short duration (weeks) Long duration (years)
Radiopaque Radiolucent
Granulomatous osteomyelitis* Mild pain Mild local pain
Trigger point
Microscopic granulomas No microscopic granulomas
Moth-eaten radiolucency Moth-eaten radiolucency
*Includingsyphilitic,tubercular,mycotic,etc

DOES NICO CAUSE FACIAL NEURALGIA?

with case-control investigations. After ah, the case for
The establishment of a definitive cause-and-effect a causal relationship between tobacco use and lung
relationship between NICO cavities and such neur- cancer, powerful as it is, falls short of definitive proof
opathies as TN and AFN is probably impossible, even because of limitations imposed by studies with human
Volume73
Number3
subjects over extended periods of time. Yet few seri-
ously doubt the existence of a strong link.
Etiologic evidencefor facial neuralgias is evenmore
difficult to evaluate in light of such well-known neu-
ralogic phenomena as temporal and spatial summa-
tion, spontaneousdischarges, interaxonal “crosstalk”
between demyelina.ted, damaged nerve fibers of var-
ious sizes and functions, psychogenic influences, pla-
cebo effects, .the common occurrence of periods of
spontaneous remissions in TN patients, pain reduc-
tion after any iminoirtrauma to central sensorytissues,
and the very real possibility that relief results from
simple surgical denervation.
We believe,, however, that there are enough data
available to justify lseriousconsideration of at least an
inductive or secondary relationship between NICO
and some cases of facial neuralgia. Animal studies
have established the feasibility of TN initiation and
trigeminal ganglion demyelination after damage to
pulpal nerves.36> 59 In human beings the presence of
discolored, frayed, evenseveredalveolar nerveswithin
NICO lesions strongly suggeststhat this remarkably
innocuous medullary “scar tissue” is capable of
inflicting damage on nerve fibers over time. Such vis-
ible changes were noted in the surgically exposed
jawbone nerves of TN patients 130 years ago,6oand
are also seen secondary to developmental vascular
compression of trigeminal roots.6’
Whether the damage noted in jawbone nerves is
demyelination remains to be proven. Analysis of my-
elin sheaths is of questionable value in formalin-fixed
tissues and was not performed in the present investi-
gation, but delmyelination with or without sprouting
similar to that found in traumatic neuromas is
assumed. Acceptance of the concept that peripheral
nerve damage in human beings can result in central
nervous system damage or hyperexcitability in the
trigeminal ganglion and nuclei with subsequent TN
development appears to be on the increase,1,s,9,11,62
and such authorities as Devor63 and Raskin64 have
recently suggested that we seriously reexamine this
phenomenon.
The presenceof chronic, nongranulomatous, nonos-
teogenic alveolar osteomyelitis in virtually all TN and
AFN patients surgically explored in the present study
certainly points to some type of strong relationship
between NICO and facial neuralgia, as does the dis-
covery of histdogically proven NICO recurrences
with each subsequent neuralgia recurrence among
146 patients followed by Bouquot and Christian.38
This unusual o,steomyelitis is simply too unique to be
ignored without the suggestion of a more logical ex-
planation for its presence. Referral bias should not
produce this strong a correlation (78% of patients
lived within a 3-hour drive of their NICO surgeon).38
Neuralgia-inducing
cavitationalosteonecrosis317
Likewise, it seemsunlikely that long-term (an aver-
age of 4.6 years), significant pain reduction in 91 of
103 neuralgia patients after NICO curettage would
result from a simple placebo effect or temporary
postsurgical trauma to nerves, especially in light of
the fact that in many NICO patients treatment with
neurosurgery and neurologic medications has failed.38
Many NICO sites in the anterior jaw were, moreover,
so close to the end of trigeminal nerve branches as to
greatly minimize the effect of denervation or surgical
trauma in the elimination of facial neuralogic pain
(Fig. 1).
CONCLUSION
We suggest that a correlation exists between this
unique form of chronic osteomyelitis of the jaw and
several types of facial neuralgia. We do not suggestit
as the only cause; nor can we detail the pathophysi-
ologic processesinvolved. On the other hand, no the-
ory has thus far explained the cause of facial neural-
gias, which perhaps accounts for the fact that most
surgical treatments for TN result in destruction of
pain pathways rather than cure of underlying defects.
The present analysis, of course, has several flaws
that stem from its uncontrolled, retrospective nature.
Neuralgia diagnoses were made by a variety of per-
sons without the tight definition required of a pro-
spective research protocol. The NICO surgical pro-
cedures, however, were fairly uniform, made up of
decortication and curettage of abnormal-appearing
bone. Also, histologic comparison with larger tissue
“plug” samplesremoved from NICO lesions in an in-
dependent project 65 has indicated that microscopic
features are not lost with the use of curetted samples.
The unique histologic features of NICO lesions
have been noted by one of us (J.E.B.) in four biopsy
samples from patients with radiographically demon-
strable NICO but no symptoms. Such histologic ap-
pearance was unusual enough for an oral pathology
biopsy service to invent diagnostic terms (“residual
periapical scar”) or to use simple descriptive terms
(“marrow fibrosis”). We now suspect that such
instanceswere examplesof early NICO lesionscaught
fortuitously before any pain began. We believe that
typically this condition takes years to produce symp-
toms, is most likely to be initiated in hypoxic jaw-
bones, cannot be adequately treated without surgical
removal of the diseasedbone, and has a tremendous
capacity for recurrence.38
Finally, we agree with Devo#j4 and Fromm et al8
that facial neuralgias have multiple, perhaps com-
bined causesthat involve both peripheral nerve fibers
and more central neural structures. We suggest that
all facial neuralgia patients be carefully examined for
alveolar osteomyelitis with the useof the radiographic
318 Boquol et&.
techniques of Roberts et al. 14X
l*, 66and the anesthe-
siaj’hyperesthesiatechniques of Ratner et al.,29Wang
et a1.,33,34or McMahon et a1.65
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INVITED COMMENTARY on
Neuralgia-inducing cavitational
osteonecrosis
William C. Do&on, DMD, MA,a Burlingame,
UNIVERSITY OF THE PACIFIC
T o gain acceptance for this new entity, “NICO,”
the authors ask us t’o discard our reliance on the sci-
entific method. They say: “The establishment of a de-
finitive cause-and-efyect relationship between NICO
cavities and such neuropathies as TN and AFN is
probably impolssible. . , . After all, the case for a
causal relation.ship between lobacco use and lung
cancer . . . falls sholrt of dejinitive proof. . . .” One
might also choose to point out that there are no stud-
ies that prove antiperspirants are effective! The con-
“Director, Facial Pain Research Center; Clinical Associate Profes-
sor, Diagnostic Sciences.
l/14/34042
View publication stats
Neuralgia-inducing
cavitationalosteonecrosis319
the face,Dolor FacieiCrucians”of Fothergill,with a newop-
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tions for localizing the etiologic site(s) of referred trigeminal
pain. [In press.]
Reprint requests:
J. E. Bouquet, DDS, MSD
Departmentof Oral Pathology
WVU Health Sciences Center-North
Morgantown, WV 24506
Calit
tent of this paper and its theories are equally nonsci-
entific.
They begin by assimilating data that have been
published in other papers and then use this material
in their study. No new cases are added. No attempt
is made to verify that each of the papers cited reports
only new cases; this may drastically inflate the
incidence of these findings.
Table I cites one paper with 1300 cases. They also
cite an epidemiologic study that reported an incidence
of trigerninal neuralgia of 4 cases per 100,000 persons.
To obtain 1300 cases, one would have to serve a pa-
tient population of 32,500,OOO.They tell us that 78%
of this surgeon’s patients lived within a 3-hour drive
of where they were treated. This means a patient base