J Oral Maxillofac Surg67:576-581, 2009

licilaInogin, M

, PhD

lfred

mm

boneCH) b

Patients and Methods: This prospective study included 7 patients with UCH and a control group of6 volunteers. In addition to normal clinical investigations, labeled fluoride (18F) and oxygen 15-labeled

Uncoetithrca

*

lofa

and

and

Ne

sea

lofa

and

water (H215O) PET scans were performed.

Results: In control subjects the net rate of fluoride influx, representing bone metabolism, was similarfor left and right condylar sides. Interestingly, this was not significantly different from the affectedcondyles in UCH patients. Rather, the net rate of fluoride influx on the contralateral side of UCH patientswas reduced significantly compared with the affected side (P .02) and control subjects (P .004). Themean blood flow on the left and right condylar sides in control subjects was not significantly different.The same was true for the hyperactive and contralateral condyles of UCH patients. Blood flow in thecondylar region in UCH patients was similar to that in the control group.

Conclusions: There was no evidence of an abnormally high rate of bone growth in the affectedcondylar region in UCH patients. Instead, the rate of bone growth appeared to be reduced in thecontralateral condylar region. These PET results are in contrast to the characteristic clinical picture of UCHpatients and suggest the possibility of subgroups in patients with a mandibular asymmetry caused by UCH.Furthermore, no evidence of hypervascularization of the condylar region in UCH patients was found.2009 American Association of Oral and Maxillofacial SurgeonsJ Oral Maxillofac Surg 67:576-581, 2009

ilateral condylar hyperactivity (UCH) is a unilateralndition of the condylar head of the mandible. Itsology is unknown, but factors such as trauma, ar-itis, and hormonal disturbances have been impli-ted in its initiation.1,2 The condition equally affects

both genders3 and results in facial asymmetry andocclusal disturbance.4 Although most reported casesare documented histologically,5-7 in general, correla-tion of histologic aspects with age and clinical symp-toms is lacking. Before one considers a restoration of

Oral and Maxillofacial Surgeon, Department of Oral and Maxil-

cial Surgery and Oral Pathology, VU University Medical Center

Academic Center of Dentistry, Amsterdam, The Netherlands.

Nuclear Medicine Physician, Department of Nuclear Medicine

PET Research, VU University Medical Center, Amsterdam, The

therlands.

Research Assistant, Department of Nuclear Medicine and PET Re-

rch, VU University Medical Center, Amsterdam, The Netherlands.

Oral and Maxillofacial Surgeon, Department of Oral and Maxil-

cial Surgery and Oral Pathology, VU University Medical Center

Academic Center of Dentistry, Amsterdam, The Netherlands.

Oral and Maxillofacial Surgeon, Department of Oral and Max-

illofacial Surgery and Oral Pathology, VU University Medical

Center and Academic Center of Dentistry, Amsterdam, The Neth-

erlands.

Nuclear Medicine Physicist, Department of Nuclear Medicine

and PET Research, VU University Medical Center, Amsterdam, The

Netherlands.

Address correspondence and reprint requests to Dr Saridin: VU

University Medical Center, De Boelelaan 1117, PO Box 7057, 1007

MB Amsterdam, The Netherlands; e-mail: cp.saridin@vumc.nl

2009 American Association of Oral and Maxillofacial Surgeons

0278-2391/09/6703-0017$36.00/0

doi:10.1016/j.joms.2008.09.021

576No Signs of MetaboPatients With UnHyperactivity: An

Emission TomCarrol P. Sarid

Pieter G.H.M. Raijmakers, MD

Dirk B. Tuinzing, DMD, PhD, A

and Adriaan A. La

Purpose: The purpose of this study was to assessin patients with unilateral condylar hyperactivity (UHyperactivity interal CondylarVivo Positron

raphy StudyD, DDS,*

, Reina W. Kloet, MSc,

G. Becking, MD, DDS, PhD,ertsma, PhD

growth and blood flow in the condylar regiony use of positron emission tomography (PET).

factoacfurana htiocemiofelsbocotigrelpotitaQumehisThmiity

UCtiowenegrobloUCwagio

antiewiupsid

Pa

maofInlefadhismoPEstaac(us

cliscifordiapapahaMaAmralinc

wimaPEwaanbeantheica

forCTplaofmicotenofbitdascaing20artuomLInsmiitysio10usanwaa ra rvabripleusmi

SARIDIN ET AL 577ial symmetry by surgical intervention, it is essentialknow whether the condylar growth center is stilltive. In case of an active condylar growth center,ther progression of asymmetry can be expected,d in most cases the growth center is eliminated byigh (partial) condylectomy. Alternatively, interven-n may be postponed until pathologic growth hasased. Activity of the growth center can be deter-ned with several methods, ranging from evaluationgrowth by serial documentation with plaster mod-and conventional radiographs to radionuclide

ne scanning (planar and single photon emissionmputed tomography [SPECT] scans).8,9 Bone scin-raphy, however, only provides an assessment ofative (ie, left vs right) condylar activity. In contrast,sitron emission tomography (PET) allows for quan-tive in vivo measurements of biologic processes.antitative uptake of labeled fluoride (18F) in bone,asured by use of PET, is directly correlated withtomorphometric parameters of bone formation.10

erefore fluoride PET imaging of UCH patientsght improve identification of condylar hyperactiv-.As mentioned previously, the exact etiology ofH is not known. In an experimental study, forma-n of new bone (osteogenesis) and angiogenesisre found to be closely correlated.11 Furthermore,ovascularization plays an important role in condylarwth.12 At present, it is unclear whether condylarod flow is abnormally increased in patients withH. PET imaging with the tracer oxygen 15-labeledter (H2

15O) offers the possibility to quantify re-nal bone blood flow.13

The aim of this study was to assess bone growthd bone blood flow in the condylar region of pa-nts with suspected UCH by use of 18F and H2

15Oth PET. The main hypothesis was that net 18F

take was increased on the hyperactive condylare of UCH patients.

tients and Methods

PATIENT SELECTION

We prospectively included 7 UCH patients, 5 fe-le and 2 male patients, in the study. The mean ageall patients was 25.5 years (range, 17.1-43.2 years).4 patients condylar hyperactivity was noted on thet side, and in 3 patients it was noted on the right. Indition to normal clinical investigations (patientstory, clinical assessment, plain radiographs, plasterdels, and planar and SPECT scans), 18F and H2

15OT scans were performed. Because there is no goldndard for diagnosis of progressive condylar hyper-tivity, the diagnosis was based on patients historyually increasing facial deformity) and findings onnical examinations, with supportive radiologic andntigraphic evidence. In accordance with the 3ms of condylar hyperactivity,14 4 patients weregnosed with hemimandibular elongation (HE), 1tient had hemimandibular hyperplasia (HH), and 2tients had a hybrid form of HH and HE. All patientsd been referred to the Department of Oral andxillofacial Surgery, VU University Medical Center,sterdam, The Netherlands, which serves as a refer-center for complicated orthognathic problems,luding facial asymmetry.A control group of 6 patients, 3 women and 3 men,th normal facial symmetry and without temporo-ndibular jointrelated disease underwent the sameT scan protocol. The mean age of the control groups 22.4 years (range, 20.3-24.2 years). All patientsd control subjects provided written consent aftering fully informed about the purpose of the studyd any potential risks. The study was approved byMedical Ethics Committee of VU University Med-

l Center.

DATA ACQUISITION

Dynamic H215O and 18F PET scans were per-

med with an ECAT EXACT HR scanner (Siemens/I, Knoxville, TN), which records 63 continuousnes in an axial field of view of 15.7 cm. First, by userotating germanium-68 sources, a 10-minute trans-ssion scan of the condylar region was performed torrect the subsequent emission scans for tissue at-uation. A bolus injection (15 seconds, 10 mL/min)1,100 MBq H2

15O was administered in the antecu-al vein via an automated injector (Medrad, Warren-le, PA), followed by a 10-minute dynamic emissionn (in 2-dimensional acquisition mode). The follow-scanning protocol was used: 12 5, 12 10, 6

, and 10 30 seconds. During the H215O scan,

erial blood was withdrawn and monitored contin-usly from the distal radial artery at a rate of 5/min by use of an online blood sampler (Veenstratruments, Joure, The Netherlands). After a 10-nute period to allow for decay of oxygen 15 activ-, a second 60-minute 2-dimensional dynamic emis-n scan was started, after intravenous injection of0 MBq 18F. The following scanning protocol wased: 6 5, 6 10, 3 20, 5 30, 5 60, 8 150,d 6 300 seconds. During this scan, arterial bloods again withdrawn and monitored continuously atate of 5 mL/min during the first 10 minutes and atate of 2.5 mL/min thereafter. At 10-minute inter-ls, continuous blood withdrawal was interruptedefly to collect manual samples. These manual sam-s, counted in a cross-calibrated well counter, wereed to calibrate the online blood curve and to deter-ne plasmawhole blood ratios.

terrecprcyfac(Rtheofitelowbyianimcogrowaerawefratis

sinnowevoonvaratsta

2-tlarcoflurepplalowusanfou

lutvaWtoStawhflo

Re

prtioriaflu

vothe

bosigdy0.0

dy(0.mL

n righ

Sar Surg 2

578 UNILATERAL CONDYLAR HYPERACTIVITYDATA ANALYSIS

Dynamic scan data were corrected for decay, scat-, randoms, and (measured) photon attenuation andonstructed as 128 128 matrices via filtered backojection (FBP) with a Hanning filter (cutoff, 0.5cles/pixel). To enhance anatomic orientation andilitate correct positioning of the regions of interestOIs), the last 10 frames (20-60 min postinjection) of18F scan were summed and reconstructed by useordered subset expectation maximization with 2rations and 16 subsets (128 128 matrix), fol-ed by postsmoothing of the reconstructed imageuse of a 5-mm full widthathalf maximum Gauss-filter to obtain the same resolution as for the FBP

ages. ROIs of 1 1 cm were drawn around thendylar area in 4 axial planes. These ROIs were thenuped to form 1 single volume of interest, whichs also mirrored and positioned onto the contralat-l condyle (Fig 1). Finally, both volumes of interestre projected on all FBP-reconstructed dynamicmes of both 18F and H2

15O scans to generatesue time-activity curves.H2

15O tissue time-activity curves were fitted to agle-tissue compartment model15 by use of standardnlinear regression techniques. Time-activity curvesre fitted both with and without an arterial bloodlume (Va) component. Delay and dispersion of theline input function were individually fixed to thelues obtained from a similar fit of the total counte of the scanner, a curve with the best possibletistics.16

Similarly, 18F time-activity curves were fitted to aissue compartment model, including an extravascu-compartment and bone mineral,17 and with 4 ratenstants (K1, k2, k3, and k4) describing exchange oforide between compartments. The parameter Ki,resenting net rate of transfer of fluoride fromsma to bone mineral, was calculated with the fol-ing equation: Ki K1 k3/(k2 k3). Again, by

e of standard statistical criteria,18,19 the presence ofarterial blood volume (Va) and existence of therth kinetic parameter (k4) were evaluated. Abso-

FIGURE 1. 18F PET image of a patient with UCH o

idin et al. Unilateral Condylar Hyperactivity. J Oral Maxilloface values of blood flow and bone metabolism (Ki)lues were compared by use of Wilcoxon and Mann-hitney tests. A P value less than .05 was consideredbe significant. Results are expressed as mean SD.ndard linear regression was used for determiningether there was correlation between Ki and bloodw.

sults

In 96% of all calculations, a 3-parameter model waseferred over a 4-parameter model for the descrip-n of fluoride kinetics, according to standard crite-.18,19 Therefore k4 was not used for analysis oforide kinetics.For the analysis of blood flow, the arterial bloodlume (Va) was not included in the model, by use ofsame criteria as mentioned before.

PATIENTS

The net rate of fluoride influx (Ki), representingne metabolism, within the affected condyle wasnificantly higher than that in the contralateral con-le (0.018 0.004 mL min1 mL1 vs 0.012 04 mL min1 mL1, respectively; P .018).Mean blood flow in the affected hyperactive con-le was similar to that on the contralateral side100 0.012 mL min1 mL1 vs 0.090 0.022 min1 mL1, respectively; P .24).

CONTROL SUBJECTS

In control subjects Ki values on the left and rightndylar sides were not significantly different fromch other (P .92), with mean values of 0.021 07 and 0.022 0.004 mL min1 mL1, re-ectively.The mean blood flow values on the left and rightndylar sides were 0.128 0.529 and 0.119 0.026 min1 mL1, respectively, which were not

nificantly different from each other (P .92).

t side, showing higher uptake in right condyle.

009.coea0.0sp

comLsig

sidcocolowsh

affnogrothecodifthe

mabo0.0

Di

regcawaIneqthethaingrogrotio

bloorifacsidredsid

hyasyAccegroterpelacmebo

smalifirspaa dtracuoncacegro18Fclicoulapapa

FIGsubnotUC

Sarfac

FIGandsigtionthe

Sarfac

SARIDIN ET AL 579PATIENTS VERSUS CONTROL SUBJECTS

In UCH patients bone metabolism on the affectede was not significantly higher than that in thentrol group (P .317). In contrast, Ki on thentralateral side in UCH patients was significantlyer than that in the control group (P .004), as

own in Figure 2.As shown in Figure 3, blood flow on both theected and contralateral sides in UCH patients wast significantly different from that in the controlup (P .152 and P .063, respectively), althoughre was a trend for a lower blood flow for thentralateral side. The mean age was not significantlyferent in the patient group when compared withcontrol group (P .4).

Linear regression analysis across patients and nor-l control subjects showed no correlation betweenne metabolism and bone blood flow, with R2 07.

scussion

Although 18F uptake in the hyperactive condylarion of patients with suspected UCH was signifi-ntly higher than that on the contralateral side, theres no evidence of increased condylar bone growth.fact, net fluoride uptake on the suspected side wasual to that in normal control subjects, whereas incontralateral condyle it was significantly lower

n in control subjects. These findings suggest thatUCH patients, the affected condyle continues tow at a normal rate, together with a cessation ofwth in the contralateral condylar region. In addi-n, these differences were independent of regional

URE 2. Bone metabolism (Ki) in condylar region in patientscontrol subjects. Ki in the affected condyle in UCH patients was

nificantly higher than that in the contralateral condyle. In addi-, compared with control subjects, Ki was significantly lower incontralateral condyle of UCH patients.

idin et al. Unilateral Condylar Hyperactivity. J Oral Maxillo-Surg 2009.od flow, because no correlation between net flu-de uptake and bone blood flow was observed. Int, bone blood flow was normal on both condylares in UCH patients, although there was a trend foruced perfusion, especially on the contralaterale.These results do not support the hypothesis ofperactivity of the condylar region in patients withmmetric mandibular growth and suspected UCH.tually, mean levels of fluoride uptake suggest earlyssation of contralateral bone growth or a local bonewth defect in these patients. No uniform charac-istic histologic criteria have been reported in sus-cted hyperactive condyles of UCH patients. Thisk of characteristic histologic findings is in agree-nt with our observation of a normal bone meta-lic rate.Because this study was conducted in a relativelyall group of patients, the results cannot be gener-zed to the whole population of UCH patients. Theyt need to be confirmed in further studies in largertient groups. It should be noted that the finding ofistinctively lower rate of bone growth in the con-lateral condyle of UCH patients is in contrast torrent thinking. In general, disproportional growththe affected side is considered to be the major

use of mandibular asymmetry, not relative growthssation on the contralateral side with normalwth on the hyperactive side. In contrast to the PET results, all UCH patients included showednical evidence of persistent activity on the affectedndylar side. This included various types of (mandib-r) asymmetries such as HE (4 patients), HH (1tient), or a combination of both (hybrid form) (2tients). Obwegeser14 made a clear distinction in these

URE 3. Blood flow in condylar region in patients and controljects. Differences between patients and control subjects weresignificant, although there was a trend toward lower values inH patients, particularly on the contralateral side.

idin et al. Unilateral Condylar Hyperactivity. J Oral Maxillo-Surg 2009.

3 can

esiricOntiesuratcesuseccothegromimiabaninregex

hisasfluanlaranbobinincmepa

pradtertecatogePEstubowaridpa

nothabointhanestupr

unnifibothehaevcoizamebewaIntregcosigis pregiespa

resstiobthepobenoPEofinvasyiesga

Re1.

2.

3.

4.

5.

6.

7.

8.

9.

580 UNILATERAL CONDYLAR HYPERACTIVITYlassical variations of condylar growth hyperactivityd stated that HE is the most common variation.On the basis of our PET findings, it can be hypoth-zed that the population of patients with asymmet-mandibular growth consists of several subgroups.e subgroup of patients (some of the younger pa-nts) may have a normal bone growth rate on thespected UCH side but a relatively low bone growthe on the contralateral side. The cause of earlyssation of bone growth is unknown, but factorsch as an early local trauma might play a role. Aond subgroup of patients may have (abnormal)ntinuation of bone growth (at a normal rate) onUCH side, together with normal cessation of

wth on the contralateral side. This growth patternght be more specific in older patients. Finally, thereght be a third subgroup of UCH patients with annormally high rate of bone growth on the UCH sided normal growth on the contralateral side, resultingabnormal hyperactive bone growth in the condylarion, but in this study there was no evidence for theistence of this subgroup.Earlier studies showed a direct correlation withtomorphometric indices of bone formation, suchthe mineral apposition rate, and the 18F in-x.10,20 An alternative explanation for our results isabnormal endochondral ossification of the condy-regions in patients with asymmetric facial growthd suspected UCH. Obviously, further studies ofne growth in UCH patients are necessary. A com-ation of bone histomorphometry measurements,luding the mineral apposition rate, and 18F PETasurements might improve our insight into thethophysiology of asymmetric mandibular growth.PET provides reliable quantification of physiologicocesses, such as metabolism and flow.13,21,22 Indition, PET produces tomographic images with bet-spatial resolution than standard nuclear medicinehniques such as SPECT, resulting in improved an-mic precision.23 In the field of maxillofacial sur-ry, assessment of bone grafts by use of 18F andT was first investigated by Berding et al.24 In thisdy the incorporation of both pedicle and onlayne grafts was investigated. Fluoride influx in graftss considerably higher compared with the net fluo-e influx in the condylar region measured in ourtient group.In our study, in UCH patients 18F uptake showedcorrelation with bone blood flow, which suggestst there is no relation between bone formation andne blood flow in the condylar region. This result iscontrast to the finding of an experimental studyt showed a close correlation between formation ofw bone and angiogenesis.12,25 In addition, otherdies also have mentioned hypervascularization as aobable cause of UCH.7,26,27 Moreover, in patientsdergoing hip surgery, there appeared to be a sig-cant relation between fluoride uptake and localne blood flow.13 Therefore increased blood flow insuspected hyperactive condylar region could

ve been expected. However, in our study noidence of hypervascularization of the affectedndylar region was found. Therefore hypervascular-tion might be excluded as a major cause of asym-tric bone growth in patients with suspected UCH,cause blood flow in the suspected condylar regions the same as that in normal control subjects.erestingly, blood flow in the contralateral condylarion of UCH patients was lower than that in normalntrol subjects, although this difference did not reachnificance (P .06) in this small series of subjects. Itossible that blood flow in the contralateral condylarion is decreased in some UCH patients. Further stud-are needed to assess whether there are subgroups oftients with altered blood flow.Despite the somewhat unexpected findings withpect to bone metabolism, it seems that PET canll be used as a diagnostic tool for UCH, based on theserved differences in 18F uptake. Quantification ofrate of influx of 18F by use of PET offers the

ssibility to assess asymmetric bone growth and canused to differentiate a hyperactive condyle from armal or burned out condyle. More importantly,T may be useful in identifying possible subgroupspatients and especially in pathophysiologic studiesestigating hypotheses regarding the cause(s) ofmmetric mandibular growth. Clearly, further stud-are needed to assess the value of PET for investi-

ting UCH.

ferencesHarris SA, Quayle AA, Testa HJ: Radionuclide bone scanning inthe diagnosis and management of condylar hyperplasia. NuclMed Commun 5:373, 1984Eslami B, Behnia H, Javadi H, et al: Histopathologic comparisonof normal and hyperplastic condyles. Oral Surg Oral Med OralPathol Oral Radiol Endod 96:711, 2003Bruce RA, Hayward JR: Condylar hyperplasia and mandibularasymmetry: A review. J Oral Surg 26:281, 1968Iannetti G, Cascone P, Belli E, et al. Condylar hyperplasia:Cephalometric study, treatment planning, and surgical correc-tion (our experience). Oral Surg Oral Med Oral Pathol 68:673,1989Egyedi P: Hyperplasia of the mandibular condyle [in Dutch].Ned Tijdschr Geneeskd 118:1593, 1974Norman JE, Painter DM: Hyperplasia of the mandibular con-dyle. A historical review of important early cases with a pre-sentation and analysis of twelve patients. J Maxillofac Surg8:161, 1980Oberg T, Fajers CM, Lysell G, et al: Unilateral hyperplasia of themandibular condylar process. A histological, microradio-graphic, and autoradiographic examination of one case. ActaOdontol Scand 20:485, 1962Hodder SC, Rees JI, Oliver TB, et al: SPECT bone scintigraphyin the diagnosis and management of mandibular condylar hy-perplasia. Br J Oral Maxillofac Surg 38:87, 2000Saridin CP, Raijmakers P, Becking AG: Quantitative analysis ofplanar bone scintigraphy in patients with unilateral condylar

hyperplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod104:259, 2007

10. Piert M, Zittel TT, Becker GA, et al: Assessment of porcine bonemetabolism by dynamic [18F]fluoride ion PET: Correlationwith bone histomorphometry. J Nucl Med 42:1091, 2001

11. Shum L, Rabie AB, Hagg U: Vascular endothelial growth factorexpression and bone formation in posterior glenoid fossa dur-ing stepwise mandibular advancement. Am J Orthod Dentofa-cial Orthop 125:185, 2004

12. Rabie AB: Vascular endothelial growth pattern during demin-eralized bone matrix induced osteogenesis. Connect Tissue Res36:337, 1997

13. Temmerman OPP, Raijmakers PG, Heyligers IC, et al: Bonemetabolism after total hip revision surgery with impacted graft-ing: Evaluation using H215O, [18F]fluoride and positron emis-sion tomography: A pilot study. Mol Imaging Biol 10:288, 2008

14. Obwegeser HL: Mandibular Growth Anomalies. Heidelberg,Springer, 2001, pp 139-140

15. Lammertsma AA, Cunningham VJ, Deiber MP, et al: Combina-tion of dynamic and integral methods for generating reproduc-ible functional CBF images. J Cereb Blood Flow Metab 10:675,1990

16. Kety SS: The theory and applications of the exchange of inertgas at the lungs and tissues. Pharmacol Rev 3:1, 1951

17. Hawkins RA, Choi Y, Huang SC, et al: Evaluation of the skeletalkinetics of fluorine-18-fluoride ion with PET. J Nucl Med 33:633, 1992

18. Akaike H: New look at statistical-model identification. IEEETrans Automat Contr AC19:716, 1974

19. Schwarz G: Estimating dimensions of a model. Ann Stat 6:461,1978

20. Messa C, Goodman WG, Hoh CK, et al: Bone metabolic activitymeasured with positron emission tomography and [18F]fluo-ride ion in renal osteodystrophy: Correlation with bone histo-morphometry. J Clin Endocrinol Metab 77:949, 1993

21. Cook GJ, Fogelman I: The role of positron emission tomogra-phy in skeletal disease. Semin Nucl Med 31:50, 2001

22. Lammertsma AA: Positron emission tomography. Brain Topogr5:113, 1992

23. Hoh CK, Dahlbom M, Harris G, et al: Automated iterativethree-dimensional registration of positron emission tomogra-phy images. J Nucl Med 34:2009, 1993

24. Berding G, Burchert W, van den Hoff J, et al: Evaluation of theincorporation of bone grafts used in maxillofacial surgery with[18F]fluoride ion and dynamic positron emission tomography.Eur J Nucl Med 22:1133, 1995

25. Li QF, Rabie AB: A new approach to control condylar growthby regulating angiogenesis. Arch Oral Biol 52:1009, 2007

26. Egyedi P: Aetiology of condylar hyperplasia. Aust Dent J 14:12,1969

27. Wang-Norderud R, Ragab RR: Unilateral condylar hyperplasiaand the associated deformity of facial asymmetry. Case report.Scand J Plast Reconstr Surg 11:91, 1977

SARIDIN ET AL 581

No Signs of Metabolic Hyperactivity in Patients With Unilateral Condylar Hyperactivity: An In Vivo Positron Emission Tomography StudyPatients and MethodsPATIENT SELECTIONDATA ACQUISITIONDATA ANALYSIS

ResultsPATIENTSCONTROL SUBJECTSPATIENTS VERSUS CONTROL SUBJECTS

DiscussionReferences