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Trigeminal Nerve Anatomy in Neuropathic and Non-neuropathic
Orofacial Pain Patients
Sophie L. Wilcox,* Sylvia M. Gustin,* Elizabeth N. Eykman,* Gordon Fowler,*
Christopher C. Peck,
y
Greg M. Murray,
y
and Luke A. Henderson*
*Department of Anatomy and Histology, University of Sydney, Sydney, New South Wales, Australia.
y
JawFunction and Orofacial Pain Research Unit, Faculty of Dentistry, Westmead Hospital, University of Sydney, Sydney,
New South Wales, Australia.
Abstract: Trigeminal neuralgia, painful trigeminal neuropathy, and painful temporomandibular
disorders (TMDs) are chronic orofacial pain conditions that are thought to have fundamentally
different etiologies. Trigeminal neuralgia and neuropathy are thought to arise from damage to or
pressure on the trigeminal nerve, whereas TMD results primarily from peripheral nociceptor
activation. This study sought to assess the volume and microstructure of the trigeminal nerve in these
3 conditions. In 9 neuralgia, 18 neuropathy, 20 TMD, and 26 healthy controls, the trigeminal root
entry zone was selected on high-resolution T1-weighted magnetic resonance images and the volume
(mm
3
) calculated. Additionally, using diffusion-tensor images (DTIs), the mean diffusivity and frac-
tional anisotropy values of the trigeminal nerve root were calculated. Trigeminal neuralgia patients
displayed a signicant (47%) decrease in nerve volume but no change in DTI values. Conversely, tri-
geminal neuropathy subjects displayed a signicant (40%) increase in nerve volume but again no
change in DTI values. In contrast, TMD subjects displayed no change in volume or DTI values. The
data suggest that the changes occurring within the trigeminal nerve are not uniform in all orofacial
pain conditions. These structural and volume changes may have implications in diagnosis and man-
agement of different forms of chronic orofacial pain.
Perspective: This study reveals that neuropathic orofacial pain conditions are associated with
changes in trigeminal nerve volume, whereas non-neuropathic orofacial pain is not associated
with any change in nerve volume.
Crown Copyright 2013 Published by Elsevier Inc. on behalf of the American Pain Society
Key words: Volumetric MRI, trigeminal neuralgia, neuropathic pain, peripheral nerve, trigeminal
nerve.
T
he orofacial region represents one of the most
common sites of pain in the body.
23
In general,
chronic orofacial pain arises either from trigeminal
and/or central nervous system damage (neuropathic
pain) or from nociceptor activation (nociceptive pain).
These different orofacial pain conditions also
present differently. For example, trigeminal neuralgia
(an example of a neuropathic pain condition) is
characterized by sharp, shooting paroxysms of pain
that last seconds to minutes, whereas trigeminal neurop-
athy (neuropathic) is characterized by a lower intensity
and a more prolonged or continuous burning pain.
Evidence suggests that the most common cause of
trigeminal neuralgia is mechanical compression of the
trigeminal nerve at its root entry zone, commonly by
a blood vessel.
22
In contrast, although a small percentage
(20%) of trigeminal neuropathy patients also display
neurovascular compression,
16
it is suggested that the
majority of cases result from direct trauma to or inam-
mation of the trigeminal nerve.
14
Whereas trigeminal nerve root neurosurgery is a highly
effective treatment for patients with trigeminal neural-
gia, it is less successful and can even be detrimental
Received October 3, 2012; RevisedDecember 13, 2012; Accepted February
28, 2013.
This research was supported by the National Health and Medical
Research Council of Australia (Grant 1032072) and the Australian Dental
Research Foundation, Inc.
The authors have no conicts of interest, nancial or otherwise, related
to this study.
Supplementary data accompanying this article are available online at
www.jpain.org and www.sciencedirect.com.
Address reprint requests to Luke A. Henderson, PhD, Department of
Anatomy and Histology, F13, University of Sydney, Sydney, New South
Wales, Australia. E-mail: lukeh@anatomy.usyd.edu.au
1526-5900/$36.00
Crown Copyright 2013 Published by Elsevier Inc. on behalf of the
American Pain Society
http://dx.doi.org/10.1016/j.jpain.2013.02.014
The Journal of Pain, Vol 14, No 8 (August), 2013: pp 865-872
Available online at www.jpain.org and www.sciencedirect.com
865
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when attempted in patients with trigeminal neuropathy.
Because trigeminal nerve resection is often performed in
patients with trigeminal neuralgia, a number of studies
have investigated the anatomy of the trigeminal nerve
in these patients. For the main part, it has been revealed
that trigeminal neuralgia is associated with smaller
trigeminal nerves and decreased nerve ber numbers,
5
a situation that is thought to result in short episodes of
sharp, shooting pain. In contrast, the anatomy of the
trigeminal nerve in patients with trigeminal neuropathy
or temporomandibular disorder (TMD) has not been
explored. It is possible that changes also occur in the
trigeminal nerve in these patients and that targeting
the trigeminal nerve may provide a potential treatment
option. The aim of this case-controlled study is to use
structural magnetic resonance imaging (MRI) to deter-
mine the volume and diffusion tensor imaging (DTI) to
assess the microstructure of the trigeminal nerve in
patients with trigeminal neuralgia, trigeminal neuropa-
thy, and nociceptive TMD and compare these results to
healthy pain-free controls. We hypothesized that the
trigeminal nerve volumes would be reduced in both
neuropathic pain conditions and remain unchanged in
non-neuropathic orofacial pain.
Methods
Subjects
Nine patients with painful trigeminal neuralgia
(2 males, mean [6SEM] age: 64.9 6 2.6), 18 patients with
painful trigeminal neuropathy (3 males, mean [6SEM]
age: 48.0 6 1.7), 20 patients with painful TMD (4 males,
mean [6SEM] age: 45.7 6 2.9), and 26 healthy controls
without facial pain (mean [6SEM] age: 52.3 6 2.95, 5
males [ages: 55, 56, 60, 78, 87], 21 females [ages: 32, 32,
36, 37, 41, 41, 41, 42, 44, 48, 50, 53, 53, 56, 57, 58, 59, 64,
64, 68, 73]) were recruited at the Faculty of Dentistry,
University of Sydney, during a period from August 2006
to November 2012. Individual pain patient demographics
are shown in Supplementary Table 1. Trigeminal neurop-
athy and trigeminal neuralgia patients were diagnosed
according to the Liverpool criteria.
22
TMD patients were
diagnosed using the research diagnostic criteria for
TMD.
6
No chronic pain subject was diagnosed as having
more than 1 of these 3 pain conditions. Furthermore,
healthy controls were excluded only if they gave self-
report of chronic pain (pain lasting for more than
3 months, including migraine and headache), were
currently taking any form of analgesic medication, or
had any neurologic disorder. Informed written consent
was obtained for all procedures, and the study was
approved by the Institutional Human Research Ethics
Committees.
Pain Measures
Toassess the intensity of facial pain, eachpainsubject in-
dicated, with a vertical pencil stroke on a 10-cmhorizontal
line, the intensity of their pain (0 cm = no pain to
10 cm = maximum imaginable pain) in the morning,
noon, and at night. These 21 individual pain rating values
were averaged to provide an indication of each subjects
chronic pain rating (diary pain). Each subject also drew
a distribution map of their ongoing pain onto a standard
drawingof thefaceandcompletedaMcGill PainQuestion-
naire
20
in order to assess the nature of their pain. The
McGill questionnaire includes a series of graded adjectives
in categories related to the sensory component of pain.
MRI Acquisition
Subjects lay supine on the bed of a 3-T MRI scanner
(Achieva; Philips Medical Systems, Amsterdam, The
Netherlands) with their head immobilized in a tight-
tting head coil. In each subject, 3 high-resolution
3-dimensional T1-weighted anatomic image sets
covering the entire brain were collected (turbo eld
echo; echo time = 2.5 ms, repetition time = 5,600 ms,
ip angle = 8

, voxel size = .8 .8 .8 mm). Three


acquisitions were acquired to improve signal-to-noise
ratios. In addition, using a single-shot multisection
spin-echo echo-planar pulse sequence (repetition
time = 8,788 ms; ip angle = 90

, matrix
size = 112 112, eld of view = 224 224 mm, slice
thickness = 2.5 mm, 55 axial slices), 4 high-resolution
DTI image sets covering the entire brain were collected.
For each slice, diffusion gradients were applied along
32 independent orientations with b = 1,000 s/mm
2
after
the acquisition of b = 0 s/mm
2
(b
0
) images. Four acquisi-
tions were acquired to improve signal-to-noise ratios.
MRI Analysis
Trigeminal Nerve Volume Analysis. Using SPM8,
9
the
3 T1-weighted images from each subject were coregis-
tered, averaged, and resampled at .3 .3 .3 mm. Using
the resampled images, the left and right trigeminal
nerves within the root entry zone were isolated in all
subjects (Fig 1). All resampled images were coded with
a numerical identier and the assessor (S.L.W.) was blind
to patient group. The root entry zone encompasses the
trigeminal nerve within the pontine cistern, that is, from
the point at which the nerve emerges from the pons to
the point at which it exits the pontine cistern anteriorly.
All 3 orthogonal planes were used in dening the nerve,
with the axial plane being the rst plane used, followed
by coronal and sagittal views. The volume (mm
3
) within
the isolated nerve was then calculated. In addition, the
cross-sectional volume of the nerve in each coronal slice
was selected and from this the maximal coronal
cross-section value (mm
2
) was calculated. Additionally,
a second blinded assessor (G.F.) also isolated the nerve in
a subsample (n = 9) of control subjects in order to asses
interrater reliability; the total nerve volume of the
2 assessors was positively correlated (r = .66, P = .003).
Trigeminal Nerve Diffusion Analysis. Using SPM8 and
custom software, the 4 diffusion tensor image sets were
realigned and averaged. Using diffusion-weighted
images collected from 32 directions and b
0
images, the
diffusion tensor was calculated from the averaged
images using a linear model. Once the elements of
diffusion tensor were calculated, fractional anisotropy
(FA) and mean diffusivity (MD) maps were derived. The
866 The Journal of Pain Trigeminal Nerve Anatomy in Orofacial Pain
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images were then resampled at .3 .3 .3 mm. Using the
resampled images, the left and right trigeminal nerves
within the root entry zone were isolated as
aforementioned. Because of technical difculties, DTI
image sets were not obtained or could not be used for 2
of the control subjects. The FA and MD values within the
entire isolated nerve were then calculated. Furthermore,
using the coronal slice at which there was the maximum
cross-sectional area, the FA and MD values were calcu-
lated. In addition, because it has been previously sug-
gested that c-bers lie within the caudal portion of the
trigeminal root,
4
we divided this coronal section into
caudal, middle, and rostral thirds, and mean FA and MD
values were calculated and compared (Fig 1).
Statistical Analysis
In control subjects, the left and right trigeminal nerve
values were averaged. Within-group ipsilateral and
contralateral comparisons were determined using
dependent-samples t-tests. Between-group comparisons
were determined using independent-samples t-tests.
Volume and DTI values and pain characteristics were
correlated using 2-tailed Pearson correlations. Signi-
cance was set at P < .05.
Results
Pain Characteristics
Individual patient characteristics and analgesic
medication usage are shown in Supplementary Table 1.
In all 9 patients with trigeminal neuralgia, 9 of the
18 patients with trigeminal neuropathy, and 3 of the 20
TMD patients, ongoing pain was conned to one side
of the face. The remaining patients had pain on both
sides of the face. In 16 of the trigeminal neuropathy
and 17 of the TMD patients, their orofacial pain was
conned to areas of the face innervated by the maxillary
and mandibular divisions of the trigeminal nerve. The
average pain intensity during the week prior to the
scanning session was similar in all 3 pain groups
(P > .05, mean 6 SEM visual analog scale pain score;
trigeminal neuralgia: 3.2 6 .8; trigeminal neuropathy:
3.9 6.4; TMD: 3.7 6.5). In contrast, the average pain du-
ration was different between the 3 groups (mean 6SEM
years; trigeminal neuralgia: 14.6 6 4.3; trigeminal
neuropathy: 4.8 6 .8; TMD: 9.1 6 2.0).
Trigeminal neuralgia patients described their pain as
shooting (67%), stabbing (56%), and sharp (67%);
trigeminal neuropathy patients described their pain as
radiating (39%), shooting (33%), and sharp (33%);
whereas TMD patients described their pain as throbbing
(70%), tender (60%), and shooting (40%).
Trigeminal Nerve Root Volumes
Nerve volumes and maximum cross-sectional areas for
all subjects are shown in Table 1. The left and right
trigeminal nerve root volumes and maximal cross-
sectional areas in control subjects were not signicantly
different (P > .05). Because these values were not
signicantly different, they were averaged for the
remainder of the analysis (mean 6 SEM; total nerve:
58.70 6 3.2, maximal cross-sectional area: 2.53 6 .1).
Age was not signicantly correlated with nerve volume
(r = .14, P > .05) or maximal cross-sectional area
(r = .27, P > .05) in control subjects. Furthermore, there
was no effect of gender on nerve volume (total nerve:
males: 60.26 6 9.22, females: 58.33 6 2.94, P > .05) or
maximal cross-sectional area (males: 2.57 6 .26, females:
2.52 6 .12, P > .05).
In trigeminal neuralgia patients, comparison of the
ipsilateral (to side of pain) and contralateral nerves
revealed no signicant difference in volume or maximal
cross-sectional area. However, comparison of the nerve
ipsilateral to the pain to controls revealed a signicant
Figure 1. Axial, sagittal, and coronal T1-weighted anatomic images and corresponding DTIs showing the trigeminal nerve root entry
zone in a single subject. The DTI image is color coded for direction of greatest water movement. The outline of the trigeminal nerve
region used for total nerve analysis is also shown in red shading on the T1-weighted anatomic image and outlined in white on DTI
images. To the right is an example of the regions selected for the rostral (red), middle (yellow), and caudal (green) third of the nerve
at the maximal cross-sectional area.
Wilcox et al The Journal of Pain 867
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(P < .05), 47% decrease in total nerve volume and
a 32% decrease in the maximal cross-sectional area
(Table 1, Fig 2). In striking contrast to trigeminal
neuralgia patients, trigeminal neuropathy patients
displayed signicant nerve volume increases. Although
there were no signicant differences between the
ipsilateral and contralateral nerves in trigeminal
neuropathy patients with unilateral pain (n = 9), the
ipsilateral nerve volume of all trigeminal neuropathy
patients (n = 18) displayed a signicant (P < .05), 40%
increase in total nerve volume and a signicant
(P < .05), 26% increase in the maximal cross-sectional
area, compared with controls. Finally, total nerve
volume and maximal cross-sectional area of the
ipsilateral trigeminal nerve in patients with TMD
were not signicantly different from those of controls
(P > .05, Table 1, Fig 2).
In all 3 pain groups, ongoing pain intensity (pain diary)
values were not signicantly correlated to either nerve
volume or maximal cross-sectional area of the nerve on
the affected side: nerve volumetrigeminal neuralgia,
r = .551, P > .05; trigeminal neuropathy, r = .208,
P > .05; TMD, r = .130, P > .05; maximal cross-sectional
areatrigeminal neuralgia, r = .211, P > .05; trigeminal
neuropathy, r = .002, P > .05; TMD, r = .240, P > .05.
Similarly, in all 3 pain groups, pain durations were not
signicantly correlated to either nerve volume or
maximal cross-sectional area of the nerve on the affected
Table 1. Overall Volume and Maximal Cross-Sectional Area of the Trigeminal Root Entry Zone in
Pain-Free Controls, Trigeminal Neuralgia Patients, Painful Trigeminal Neuropathy Patients, and
Painful TMD Patients
CONTROLS TRIGEMINAL NEURALGIA TRIGEMINAL NEUROPATHY TMD
(N = 26) (UNILATERAL N = 9) (UNILATERAL N = 9)
(BILATERAL AND
UNILATERAL
N = 18)
(BILATERAL AND
UNILATERAL
N = 20)
LEFT RIGHT
PAIN
SIDE
NONPAIN
SIDE
PAIN
SIDE
NONPAIN
SIDE
MAXIMUM
PAIN SIDE
MAXIMUM
PAIN SIDE
Total nerve volume (mm
3
)
Mean (6SEM) 61.1 (3.6) 56.3 (2.8) 31.4 (5.7) 31.4 (4.5) 75.4 (11.7) 64.3 (4.9) 81.9 (7.2) 62.3 (7.4)
Maximal cross-sectional area (mm
2
)
Mean (6SEM) 2.6 (.1) 2.5 (.1) 1.7 (.2) 1.5 (.2) 3.1 (.2) 2.9 (.3) 3.2 (.2) 2.5 (.2)
Figure 2. Bar graphs showing mean (1SEM) total nerve volumes (upper panel) and maximal cross-sectional areas (lower panel) in
controls, trigeminal neuralgia, trigeminal neuropathy, and TMD patients. *P < .05.
868 The Journal of Pain Trigeminal Nerve Anatomy in Orofacial Pain
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side: nerve volumetrigeminal neuralgia, r = .205,
P > .05; trigeminal neuropathy, r = .047, P > .05; TMD,
r = .063, P > .05; maximal cross-sectional areatrigeminal
neuralgia, r = .109, P > .05; trigeminal neuropathy,
r = .084, P > .05; TMD, r = .091, P > .05.
Trigeminal Nerve Root Diffusion Values
MD and FA values for the entire nerve and for the
coronal sections at the maximum cross-sectional area
for all subjects are shown in Table 2. The left and right
trigeminal nerve root MD and FA values in control
subjects were not signicantly different and were
averaged for the remainder of the analysis. Age was
not signicantly correlated with overall MD (r = .01,
P > .05) or FA (r = .07, P > .05).
In trigeminal neuralgia patients, comparison of the
ipsilateral and contralateral nerves revealed no signif-
icant difference in overall MD or FA values or maximal
cross-sectional area MD or FA values (Table 2, Fig 3). In
trigeminal neuralgia patients, comparison of the
ipsilateral nerve to controls revealed no signicant
difference in any MD or FA value (ie, overall, total at
maximum cross-sectional area, or dorsal, middle, or
caudal nerve sections). Similarly, in trigeminal neurop-
athy patients, comparison of the ipsilateral and
contralateral nerves in unilateral neuropathy subjects
(n = 9) revealed no signicant differences in any MD
or FA value. Comparison of the ipsilateral nerve in all
trigeminal neuropathy patients compared to controls
also revealed no signicant difference in any MD or
FA value. Finally, in patients with TMD, comparison
of the ipsilateral nerve to controls revealed no
signicant difference in any MD or FA value (Table 2,
Fig 3).
Discussion
This study suggests that neuropathic orofacial pain
conditions are associated with changes in trigeminal
nerve volume, with the direction of change differing
between different types. Whereas trigeminal neuralgia
patients displayed a decrease in volume compared to
controls, neuropathy patients conversely displayed an
increase in volume. Surprisingly, these changes in nerve
volume were not coupled with any apparent change in
microstructure as assessed by DTI. In contrast to
neuropathic conditions, TMD was not associated with
any change in volume.
Although our sample size of trigeminal neuralgia
patients was relatively limited, thus restricting the
certainty of our results, there is mounting evidence
that this condition is associated with structural changes
in the trigeminal nerve. Similar to our ndings, it
has been shown that the volume, diameter, and cross-
sectional area of the nerve is smaller on the symptom-
atic side.
7,17
This overall nerve atrophy likely
corresponds to structural abnormalities reported in
pathologic ndings of nerve sampled from neuralgia
patients, which show evidence of axonal loss,
axonopathy, demyelination, and dysmyelination.
5,24
Furthermore, we found a signicant decrease in nerve
volume on the asymptomatic side, raising the
possibility of additional mechanisms. Trigeminal
neuralgia is thought to result from neurovascular
compression because neurovascular contact by an
artery or a vein at the trigeminal root entry zone is
typically seen in neuralgia patients.
27
However, innocu-
ous contact of the trigeminal nerve and vessels has also
been shown in cadaver and MRI such that the observa-
tion of contact is unreliable for diagnostic purposes.
12
Table 2. Fractional Anisotropy and Mean Diffusivity Values of the Trigeminal Root Entry Zone in
Pain-Free Controls, Trigeminal Neuralgia Patients, Painful Trigeminal Neuropathy Patients, and
Painful TMD Patients
CONTROLS TRIGEMINAL NEURALGIA TRIGEMINAL NEUROPATHY TMD
(N = 26) (UNILATERAL N = 9) (UNILATERAL N = 9)
(BILATERAL AND
UNILATERAL
N = 18)
(BILATERAL AND
UNILATERAL
N = 20)
LEFT RIGHT
AVERAGE
LEFT/RIGHT
PAIN
SIDE
NONPAIN
SIDE
PAIN
SIDE
NONPAIN
SIDE
MAXIMUM
PAIN SIDE
MAXIMUM
PAIN SIDE
Fractional anisotropy (mean [6SEM])
Total nerve .28 (.01) .27 (.01) .28 (.01) .26 (.02) .28 (.02) .26 (.02) .27 (.02) .26 (.01) .26 (.01)
Maximal cross-sectional area
Total .29 (.01) .27 (.01) .28 (.01) .27 (.02) .28 (.02) .26 (.02) .25 (.02) .25 (.01) .28 (.03)
Rostral third .35 (.01) .30 (.01) .33 (.01) .29 (.02) .30 (.03) .20 (.02) .28 (.02) .19 (.01) .30 (.03)
Middle third .22 (.01) .26 (.01) .24 (.01) .26 (.02) .23 (.03) .31 (.02) .27 (.02) .30 (.02) .25 (.03)
Caudal third .30 (.01) .25 (.01) .28 (.01) .28 (.01) .31 (.02) .27 (.02) .21 (.02) .26 (.01) .29 (.02)
Mean diffusivity (mean [6SEM] 10
3
)
Total nerve 2.49 (.07) 2.38 (.06) 2.44 (.07) 2.37 (.15) 2.43 (.06) 2.45 (.14) 2.33 (.10) 2.46 (.08) 2.50 (.08)
Maximal cross-sectional area
Total 2.52 (.09) 2.47 (.07) 2.50 (.08) 2.28 (.13) 2.51 (.11) 3.10 (.20) 2.90 (.30) 2.54 (.08) 2.43 (.12)
Rostral third 2.49 (.06) 2.51 (.08) 2.50 (.07) 2.23 (.12) 2.55 (.09) 3.06 (.15) 2.87 (.23) 2.46 (.10) 2.51 (.17)
Middle third 2.50 (.11) 2.40 (.09) 2.45 (.11) 2.41 (.21) 2.52 (.15) 3.21 (.22) 2.99 (.33) 2.60 (.06) 2.37 (.13)
Caudal third 2.54 (.07) 2.44 (.06) 2.49 (.06) 2.16 (.14) 2.41 (.11) 3.18 (.26) 2.85 (.36) 2.56 (.12) 2.44 (.12)
Wilcox et al The Journal of Pain 869
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Despite this, structural disarray and electrical instability
are thought to be caused by abnormal contact on
the trigeminal root, resulting in characteristic pain
paroxysms.
In striking contrast to the decreased volume in
neuralgia patients, trigeminal neuropathy was associ-
ated with a signicant increase in nerve volume. This
difference between nerve volumes in neuralgia and
neuropathy suggests that these 2 types of neuropathic
pain have different underlying pathomechanisms.
Although neuralgia patients present with intermittent
episodes of sharp, shooting pain, trigeminal neuropathy
is typically characterized by episodic sharp, shooting pain
combined with constant or long episodes of background
pain. Only 1 other study has examined trigeminal nerve
volumetry in neuropathy patients. Kress and
colleagues
15
examined nerve volume in trigeminal
neuropathy patientsdened as having a burning pain
condition with a duration of pain >10 minutes. Their
study found no signicant volume difference when
comparing the symptomatic to the asymptomatic
trigeminal nerve, nor when they compared the
symptomatic nerve with healthy controls. A possible
explanation for the discrepancy between these and our
results may be in the patient population used. Kress
and colleagues noted that a high percentage (84%) of
their neuropathy patients displayed a neurovascular
conict, possibly reecting a signicant inuence of
atypical (type 2) trigeminal neuralgia. In contrast, our
neuropathy patient population was almost exclusively
composed of individuals with posttraumatic neuropathy.
It remains unknown if, despite sharing a longer duration
of pain complaint, the pathogeneses of posttraumatic/
inammatory neuropathy is similar to atypical trigemi-
nal neuralgia.
Surprisingly, the changes in nerve volumes associ-
ated with trigeminal neuralgia and neuropathy
were not coupled with any changes in free water
movement, suggesting that the volumetric changes
are not coupled to changes in microstructure of the
nervous tissue itself. Diffusion-weighted parameters
are sensitive to microstructural changes because
processes including demyelination and axonal injury
can affect water anisotropy.
1
On the basis of the
volumetric changes and the previously reported path-
ologic ndings, it was hypothesized that these
structural abnormalities would be reected in
changes in the diffusion values. Previous studies
employing diffusion imaging to study the trigeminal
nerve in neuralgia patients have produced mixed
results varying from no apparent changes,
10
to
signicantly decreased FA with no change in MD,
19
to signicantly decreased FA coupled with an
increased MD.
17
Recently, Hodaie and colleagues
13
utilized DTI to study microstructural changes in the
trigeminal nerve after focal radiosurgery. Interest-
ingly, they reported that pain relief following
treatment was associated with a decrease in FA
values, possibly resulting from localized myelin
degeneration. In subjects with long-term follow-up,
Figure 3. Bar graphs showing mean (1SEM) mean diffusivity and fractional anisotropy of the entire trigeminal root (upper panel)
and at the maximal cross-sectional area (lower panel) in controls, trigeminal neuralgia, trigeminal neuropathy, and TMD patients. No
signicant differences (P < .05) were observed.
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recovery of FA valuessuggesting myelin regenera-
tionwas coupled with pain recurrence. Although
Hodaies study demonstrates the potential applica-
tion of diffusion imaging in assessing treatment and
longitudinal changes, the mixed results in baseline
studies remain at odds. Part of the discrepancy may
stem from variations in techniques, including the
location of data sampling. In order to potentially
alleviate this issue, we measured diffusion parameters
in a variety of positions; however, all measures
suggest that the nerve microstructure appears
unaltered in our neuralgia and neuropathy patients.
To our knowledge, only 1 case report has investi-
gated nerve histology in an individual with trigeminal
neuropathy. Watson and colleagues
26
reported, in
the case of a 14-year-old boy with severe posttrau-
matic trigeminal neuropathic pain, that although
the unmyelinated ber density remained normal
there was an increase in small, thinly myelinated
bers that they suggest represents regenerating
axons.
26
It is possible our observed increase in nerve
volume in neuropathy subjects reects an increase in
small, thinly myelinated bers. Although human
histologic evidence is limited, many investigators
have explored peripheral nerve anatomy in animal
models of neuropathic pain such as chronic constric-
tion injury model. Histologic studies indicate that
chronic constriction injury results in degeneration of
myelinated and unmyelinated axons distal to the
ligation; however, proximal to the ligation site
only minor or no pathologic changes occur.
3,18
Interestingly, Stanisz and colleagues
25
have shown
that although nerve transection results in long-term
pathologic changes, nerve crushing results in regener-
ation over time. Given that our neuropathy patients
developed pain following traumatic injuries that
did not result in nerve transaction, our results may
in fact reect adaptive changes in the nerve
in response to altered activity peripheral to the
trigeminal root.
The striking nding of the differing direction of
volumetric change between different types of neuro-
pathic orofacial pain is particularly interesting in light
of a potential new addition in the differential diagnosis
of trigeminal neuralgia versus neuropathy. Although
the current criteria distinguish the 2 primarily based
on sensory components (ie, pain quality and duration),
it has been noted that there is phenotypic overlap
between the 2 conditions.
2
Additionally, although MRI
has been used to optimally image the relationship of
the root entry zone of the nerve with blood vessels in
the vicinity, the accuracy of these ndings in differenti-
ating neuralgia from neuropathy remains uncertain.
22
The potential remains for this technique to be supple-
mented with the addition of volumetric assessment of
the nerve itself.
In comparison to both trigeminal neuralgia and
neuropathy, TMD patients were not associated with
any change in nerve volume or diffusion. Although
the etiology and pathology of TMD remains debated,
there is evidence for the role of peripheral nociceptive
afferent input combined with a more generalized
hyperexcitability in the central nervous system and/or
impairments of endogenous pain inhibitory systems.
8
The lack of trigeminal nerve anatomic change
suggests that the locus of aberrant input and/or
generalized hyperexcitability does not lie in the root
entry zone of the trigeminal nerve. Furthermore, we
have previously shown that in contrast to trigeminal
neuropathy, which is associated with signicant gray
matter volume changes in regions such as the
thalamus, TMD is not associated with any changes in
regional gray matter volume.
11
Younger and col-
leagues
28
did report volume increases in some brain
regions in TMD patients. However, given the differ-
ences in pain duration between studies (4.4 vs
11.5 years), the lack of change reported here may
reect adaptive changes that have subsided over
time. In contrast to our results, Moayedi et al
21
have
recently reported ndings of lower FA and higher
MD and radial diffusion in TMD subjects, in conjunc-
tion with alterations in cortical white mater tracts.
The authors suggest that these microstructural
changes may be caused by increased nociceptive
activity. This discrepancy in results may be due to
technique differences, as aforementioned. Equally,
the difference in ndings may be due to differing
patient populations, with Moayedis study focusing
on idiopathic TMD patients whereas ours included all
patients fullling the TMD research criteria.
6
The limitations of this study include that our diagnos-
tic criteria encompassed the broader populations of
TMD and trigeminal neuropathy as dened by the
TMD research diagnostic criteria and the Liverpool crite-
ria, respectively. Our sample numbers do not allow for
subgroup analysis and thus we cannot rule out that
these nerve changes are specic to certain subtypes.
Furthermore, although we assessed pain intensity and
duration and controlled for age and gender ratios,
there are further potential confounding variables that
may inuence nerve anatomy, such as the presence of
allodynia and hyperalgesia, tender points, previous
dental procedures, and others.
In conclusion, the present study has contributed to the
characterization of the root entry zone of the trigeminal
nerve in 3 distinct orofacial pain conditions. The data
suggest that the changes occurring within the trigemi-
nal nerve are not uniform in all orofacial neuro-
pathic pain conditions; rather, trigeminal neuralgia is
associated with decreased volume whereas trigeminal
neuropathy is associated with increased volume. In
contrast, TMD may not be associated with any nerve
changes.
Acknowledgments
We wish to thank the many volunteers in this study.
Supplementary Data
Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.jpain.2013.02.014.
Wilcox et al The Journal of Pain 871
29/07/2014
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872 The Journal of Pain Trigeminal Nerve Anatomy in Orofacial Pain
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