Radionucide Diagnosis of Vertebral Osteomyelitis: Indium-i 11-Leukocyte and Technetium-99m-Methylene Diphosphonate Bone Scintigraphy

Christopher J. Palestro, Chun K. Kim, Alfred J. Swyer, Shankar Vallabhajosula, and Stanley J. Goldsmith

Department ofPhysics-Nuclear Medicine, Mt. Sinai School ofMedicine, Mt. Sinai Medical Center, One GustaveL. Levy PL, New York, New York 10029

reviewed leukocyte images performed on 7 1 patients with Seventy-six 111ln-labeledleukocyte images performed on 71 possible vertebralosteomyelitis in order to more precisely patientswith possiblevertebralosteomyelitiswere reviewed. characterize the appearance of this entity on leukocyte Twenty-eight cases of vertebral osteomyelitis were diag imaging, as well as to assess the utility of this modality for nosed.Vertebrallabeledleukocyteactivitywas normalin 2, the diagnosis of osteomyelitis of the spine. increasedin 11, and decreasedin 15 casesof osteomyelitis. The median duration of symptoms was significantly longer in patients with osteomyelitis and decreased vertebral activity MATERIALSAND METhODS than in patients with osteomyelitis and increased activity (3 PatientPopulation mo versus 2 wk; p = 0.019). No significantrelationship Seventy-one patients, 42 males and 29 females, with a mean between the duration of antibiotic therapy and the appearance age of 59 yr (range: 2—90yr) who underwent a total of 83 of vertebralosteomyelitison Ieukocyteimageswas identified leukocyte studies, were included in this review. Seventy-six stud (p = 0.62). Increasedvertebral activitywas highlyspecific ies were performed as part of an initial diagnostic evaluation in (98%)forosteomyelitisbut relativelyinsensitive(39%).De the seventy-one patients. Seven patientswith vertebralosteomye creased activity was nefther sensitive (54%) nor specific litis were restudied between 2 and 18 mo after initial imaging. In (52%).Sevenpatientswithclinicallyresolvedinfectionunder addition to labeled leukocyte imaging, 57 @mTc.methylenedi went follow-up imaging. Of four patients who initially pre phosphonate (MDP) bone scans (including 31 two-phase studies) sentedwithincreasedactivity,onehadnormalandthreehad were performed as part of the initial diagnostic evaluation. The decreasedvertebralactivity on follow up studies.All three seventy-six spinal regions of concern included 9 cervical, 19, patients with decreased activity initially had decreased activity thoracic, 47 lumbar,and 1 sacral. Final diagnoses were based on on follow-up.Usingincreasedor decreasedactivityas criteria laboratory studies including microbiologic and histologic data, forinfection,theaccuracyofleukocyteimagingfordiagnosing radiographic findings, and clinical course. vertebral osteomyelitis was 66%, similar to that of @‘Tcbone imaging (63%) in our population. Leukocyte imaging did how Scintigraphy ever provide important information about extraosseous infec Leukocyte imaging was performed 24 hr after injection of tion in 12 of the patients studied. approximately 18.5 MBq (500 @zCi)of mixed autologous leuko cytes labeled with ‘‘‘Inaccording to the method of Thakur et al. J NucIMed 1991;32:1861—1865 (12). Imaging was performed on a large field of view gamma camera equipped with a medium-energyparallel-holecollimator using 20% windows centered over the 174 keY and 247 keY photopeaks of ‘‘‘In.Six-minute anterior and posterior static ndium-l 11-labeled leukocyte scintigraphy is a useful images ofthe region ofinterest were obtained in all cases. Whole procedure for diagnosing osteomyelitis (1—5).Although body imaging was performed when clinically indicated. typically manifest as an area ofincreased accumulation of Two-phase bone scintigraphywas performedafterinjection of approximately 740 MBq (20 mCi) of 99mTc@MDP.(Although labeled white cells relative to some reference point, osteo three-phasebone scintigraphywas usually performedwhen eval myelitis presenting as a zone of photopenia, especially in uating the cervical or lumbosacral spines, dynamic imaging of the spine, has been described (4—11).We retrospectively the thoracic spine was unsatisfactorydue to activity in the heart and great vessels; therefore for the purposes of this study only blood-pool and delayed images were evaluated.) Imaging was ReceivedDec. 28, 1990; revision accepted Apr. 23, 1991. performed on a large field of view gamma camera equipped with For reprintscontact:ChristopherJ. Palestro,MD, Box 1141, Physics Nuclear Medicane,Mount Sin@Medical Center, 1 Gustave L. Levy P1, New a low-energyhigh-resolutionparallel-holecollimator usinga 20% York, NY 10029. window centered over the 140 keY photopeak of 99mTc.Five

DiagnosisofVertebralOsteomyelitis•Palestroet al 1861 hundred thousand count anterior and posterior blood-pool im TABLE I ages ofthe region ofinterest were obtained. Delayed bone images Leukocyte Imaging in 28 Patients with Vertebral performed 2—3hr after injection were acquired using this same Osteomyelitis technique. When bone scintigraphywas performedfirst(n = 26), Pt.*SexAgeLocationDurationImageOrganism1M41Lumbar2 at least 48 hr elapsed before leukocyte imaging was performed. strep2M70Thoracic3 daysIB. hemOlytiC When leukocyte imaging was performed first (n = 31), bone aureus3M81Lumbar3 daysIS. scintigraphy was generally performed immediately afterwards. fecails4M72Thoracic3 daysIS. Regardless of the order in which they were performed, however, aureust5M77Thoracic1 daysIS. both studies were always performed within five days of each aureust6F73Lumbar2 wkIS. other. aureus7F57Lumbar3 wkIS. wkDPurulence8M4Lumbar3 ImageInterpretation wkDPurulence9F59Lumbar4 Radiotraceruptake on both leukocyte and bone images was aureus1 wkIS. comparedto adjacentand presumablynormal, vertebralactivity, aureust10M72Cervical4 wkIS. and classified as normal (equal to), increased, or decreased. For aureus11M50Lumbar4 wkDS. purposesof analysis, three different criteriafor a positive leuko wkDPurulence12F85Lumbar4 cyte image were evaluated:(1) increased activity only, (2) de viridans14M72Cervical63M20Cervical4 wkNS. creased activity only, and (3) increased or decreased activity. epidermidis1 wkNS. Two-phase bone images were considered positive for infection cloacae15M67Lumbar2 moIEnterobacter strept16F56Thoracic2 moDB. hemolytic when discrete hyperemiain the region of interestwas present on aureus17M66Lumbar3 moDS. blood-pool images, and diffusely increased activity in the verte moDPurulence18M58Lumbar3 bra(e)in question was presenton delayed bone images. Diffusely moDPurulence20M52Thoracic59F52Sacrum3 increased activity in the vertebra(e) in question was considered aureus21M42Lumbar5 moIS. positive for infection when delayed images only were interpreted. aureus22M70Lumbar6 moDS. aureus23M60Thoracic6 moIS. mo0Purulence24M57Thoracic6 RESULTS moDPurulence25F87Thoracic8 Twenty-eight cases of vertebral osteomyelitis were iden moDPurulence26F31Thoracic12 tuberculosis27M83Thoracic12moDM. tified. Twenty-four cases were confirmed by biopsy and moD aureus;P.mirabi fourcases were classifiedas osteomyelitis by positive blood ils cultures plus radiographic changes consistent with osteo 28 F 62 Cervical l8mo DS. M. tuberculosis myelitis plus clinical improvement following appropriate antibiotic therapy. Final diagnoses in the remaining 48 I = increased,D = decreased,and N = normal. cases were: metastasis (8), Paget's disease (5), arthritis (5), * Patients are listed in order of increasing duration of symptoms. disc herniation (5), compression fracture (4), meningitis t Positive blood culture, no tissue specimen Obtained. (2), neuritis (2), radiculopathy (1), and extraosseous infec tion (16). (Four patients with vertebral osteomyelitis also had extraosseous sites of infection.) difference between the two median durations (2 wk versus Normal vertebral activity was present on 26 leukocyte 3 mo) was statistically significant (p = 0.019 by the median images, including two cases of osteomyelitis. Increased test with the Fischer exact test). Sixteen patients were vertebral activity was present on 12of76 leukocyte images, including 11 cases ofosteomyelitis. One patient with acute A., pyelonephritis also demonstrated increased uptake in the 3rd lumbar vertebra;however there was no other evidence to support the diagnosis of vertebralosteomyelitis and the study was classified as false-positive. Decreased vertebral activity was present on 38 leukocyte images including 15 cases of osteomyelitis (Table 1, Fig. 1). Noninfectious :t@ B conditions associated with decreased vertebral activity are listed in Table 2. The duration of symptoms was longer than 2 mo in only 2 of 11 patients with osteomyelitis and increased activity on leukocyte images, as compared to 10 of 15 patients with osteomyelitis and decreasedactivity on leukocyte images. The median duration of symptoms in patients with osteomyeiitis and increased activity was 2 FIGURE I. (A)Intenselyincreasedleukocyteactivityispresent wk, while the median duration of symptoms in patients in L5 in an 81-yr-oldmalewith vertebralosteomyelitis.The causativeorganismwas S. fecalis.(B)A well-definedphotopenic with osteomyelitis and decreased activity was 3 mo. The defect involvingapproximatelyT8 and T9 is present in a 31-yr median test was performed using the grand median dura oldfemalewhohadbeensymptomaticfor 12 mo.Thecausative tion (=2 mo) in all 26 cases as the cutoff value. The organismwasM. tuberculosis.

1862 The Journalof NuclearMedicine•Vol. 32 •No. 10 •October1991 TABLE 2 TABLE 4 Noninfectious Conditions Associated with Decreased Follow-upLeukocyteImagingin Seven Patientswith VertebralActivityon LeukocyteImages Vertebral Osteomyelitis ConditionnMetastasis8Paget's Pt.InitialFollow-upno. Location imageimage lnterval* disease5Degenerative 1LumbarID6mo4ThoracicIN3mo6LumbarID3mo12Lumbar0D3mo18LumbarDD3mo20ThoracicID2 arthritis5Compression fracture3Idiopathic2Total23

mo21Lumbar00l8mo

receiving antibiotic therapy at the time of leukocyte im aging. There was no significant difference in duration of * Time interval between initial leukocyte imaging and follow-up imaging. antibiotic therapy between six patients with increased up take (median duration = 10 days) and ten patients with decreased uptake (median duration = 8 days) (p = 0.62 DISCUSSION by the median test with the Fisher exact test). Twelve of 3 1 two-phase bone studies were interpreted While leukocyte images are usually interpretedas posi as positive for infection, including eight cases of osteo tive for infection when the area of interest demonstrates myelitis. Thirty-seven of 57 (delayed) bone scans were increased activity relative to some reference point, osteo interpreted as positive for infection, including 19 cases of myelitis presenting as an area of photopenia, especially in osteomyelitis. Among the criteria evaluated, increased up the spine, hasbeen described(4—11).It hasbeen postulated take on leukocyte imaging had the highest positive predic that this photopenia results from occlusion of the micro tive value (92%), while a normal leukocyte image yielded circulation of the involved bone resulting in acute inflam the highest negative predictive value (92%). Table 3 com mation and necrosis (6). Infection-induced death of retic pares sensitivity, specificity, accuracy and predictive values uloendothelial cells that normally accumulate labeled leu ofleukocyte and bone imaging. kocytes may also play a role (4). While recent work by Seven patients with vertebral osteomyelitis underwent Whalen et al. (11) suggests that the photopenic appearance follow-up leukocyte imaging between two and 18 months of vertebral osteomyelitis may be related to previous an after the initial study. All seven were clinically judged to tibiotic therapy, we found no significant relation between have been adequatelytreated.Four initially presentedwith the duration of antibiotic therapy and the appearance of increased activity and three initially presented with de this entity on leukocyte imaging. We did, however, find creased activity. One patient, who initially presented with that the median duration of symptoms was significantly increased uptake, demonstrated normal vertebralactivity longer in individuals presenting with photopenia than in on a follow-up study performed3 mo later.The remaining individuals presentingwith increasedactivity on leukocyte six patients, including three who initially presented with images (3 mo versus 2 wk, p = 0.019), and we speculate

. increased uptake, all demonstrated decreased uptake on that the appearanceofvertebral osteomyelitis on leukocyte follow-up studies (Table 4). imaging may be dependent, at least in part, on the patho physiology of the disease itself as well as the predominant TABLE 3 cellular immune response at the time of imaging. Comparison of Leukocyte and Bone Scintigraphy for Vertebral osteomyelitis presumably originates as a septic DiagnosisofVertebralOsteomyelitis embolism that lodges in the metaphyseal artery, an end Criterion Sen Spc Ace +PV —PV arteriole in the vertebralbody metaphysis. This embolus Leukocyte(I) 39% 98% 76% 92% 73% propagates retrograde into the metaphyseal anastomosis, (n= 76) and circumferentially around the vertebral body sequen Leukocyte(D) 54% 52% 53% 39% 66% tially occluding other metaphyseal arteries. The regions of (n= 76) the vertebralmetaphysis supplied by each of these meta Leukocyte(Ior D) 93% 50% 66% 52% 92% physealarteries undergo sequential septic infarction pro (n= 76) Two-Phasebone 47% 71% 58% 67% 53% ducing osteomyelitis(13). (n= 31) Acutely, an infection is characterized by a neutrophilic Delayedbone 86% 49% 63% 51% 85% response.This responsesubsidesover time and is replaced (n= 57) by a monocyte/macrophage response. Because we label a mixed population ofleukocytes, approximately 60%—80% Sen = sensitivity; Spc = specificity;Acc = accuracy; +PV = of the cells reinjected are neutrophils, while only 2%—8% positivepredictivevalue;—PV= negativepredictivevalue;I = in aremonocytes, probablytoo few to be successfullyimaged. creased;andD = decreased. Consequently increased activity on leukocyte images will

Diagnosis of Vertebral Osteomyelitis •Palestro et al 1863 @ c@

A B C D i@4: .@

FIGURE 2. Theprincipallimitationtolabeledleukocyteimaginginvertebrasosteomyelitisisthenonspecificityofskeletalphotopenia, presentin54% of the casesof osteomyelitisinourseries.We were unableto distinguishthe skeletalphotopeniaseenininfection fromothercausesof skeletalphotopenia.(A)Thoracicvertebralosteomyelitisina 57-yr-oldmalesymptomaticfor 6 mo(purulence onlywaspresentinbiopsyspecimen—noorganismswerecultured).(B)Prostatecarcinomametastasesto the lowerthoracicspine ina 73-yr-oldmale(photopeniainvolvinga rightlowerposteriorribis alsoevident).(C) Lumbarspinecompressionfracturesina 66- yr-old female.(D)Paget's diseaseinvolvingL5 in a 61-yr-oldmale.

be present only as long as a sufficiently intense neutrophilic In summary, the presentation of vertebral osteomyelitis response exists. As the neutrophilic response (and hence on leukocyte imaging is variable, with more than half labeled cell activity) subsides, the only evidence that a (54%) ofthe patients in our series presenting with skeletal pathologic process exists will be the photopenic defect photopenia. Although increased vertebral activity was produced by the initial insult. highly specific for infection (98% specificity, 92% positive Two patientswith vertebralosteomyelitis presentedwith predictive value), decreased activity was associated with normal leukocyte images. One individual had been symp several other conditions and was nondiagnostic for osteo tomatic for 4 wk, the other for 6 wk. It is possible that myelitis (52% specificity, 39% positive predictive value). these “normal―images represented a transitional, isoin The nonspecificity of decreased activity also limited the tense phase of an entity whose presentation varies with usefulness of the study for monitoring patient response to time, from increased to decreased activity. therapy. While the overall accuracy of leukocyte imaging Leukocyte images are typically interpreted as positive (when decreased activity was included as a criterion for for infection when uptake in the region of interest exceeds infection) was 66%, only slightly higher than that of bone uptake in some reference point. In the absence of infection, imaging (63%) in our population, this procedure did pro leukocytes are generally not incorporated into areas of vide important information about extraosseous infection increased bone mineral turnover, and therefore leukocyte in 12 patients. imaging is highly specific for diagnosing osteomyelitis (1— 3). This testis especiallyusefulin the settingof underlying REFERENCES osseous pathology such as trauma, tumor, and other con I. Propst-ProctorSL, DillinghamMF, McDougallIR, GoodwinD. The white ditions that limit the usefulness of routine bone scintigra blood cell scanin orthopedics. C/in Orihop Re/Res 1982;l68:l57—165. phy (1—5,14—17). This point is well illustrated in our 2. SchauweckerDS, Park HM, Mock BH, et al. Evaluation of complicating patient population where the specificity of leukocyte im osteomyelitiswith Tc-99m-MDP, In-i 11-granulocytes,and Ga-67-citrate. J NuciMed 1984;25:849—853. aging, when only increased activity was considered positive 3. Maurer AH, Miilmond SH, Knight LC, et al. Infection in diabetic osteo for infection, was 98% versus 71%for two-phase bone and arthropathy: use of indium-labeled leukocytes for diagnosis. Radiology 49% for delayed bone imaging. The sensitivity of this 1986:161:221—225. 4. Wukich DK, Abreu SH, CallaghanJi, et al. Diagnosisof infectionby criterion, however, was only 39%. More than half (54%) preoperativescintigraphywith indium-labeledleukocytes.J Bone Joint of the cases of vertebral osteomyelitis in our population Surg (A) 1987:69:1353—1360. presentedas photopenia. Skeletalphotopenia on leukocyte 5. Schauwecker DS. Osteomyelitis: diagnosis with In-l 11-labeled leukocytes. Radiology1989:171:I4l—146. images is nonspecific and has also been observed in tumor, 6. MokYP,CarneyWH, Fernandez-UlloaM. Skeletalphotopeniclesionsin previous radiation therapy, fracture, avascular necrosis, In-I 1l-WBCimaging.J NuciMed 1984:25:1322—1326. myeloflbrosis, Paget's disease, and fibrous dysplasia. 7. Brown ML, Hauser MF, Aznarez A, Fitzgerald RH. Indium-lil-leukocyte imaglng the skeletalphotopenic lesion. C/in Nuc/Med 1985:11:611—613. Therefore it is nondiagnostic for osteomyelitis (5—10,18— 8. Datz FL, Thorne DA. Causeand significanceof cold bone defectson 22). When we included decreased activity as a criterion indium-I I 1-labeledleukocyteimaging.J NucI Med 1987;28:820—823. for a positive study, the specificity was only 50%. 9. Wukich DK, Van Dam B, Abreu SH. Preoperative indium-labeled white blood cell scintigraphy in suspectedosteomyelitis of the axial skeleton. Using increased or decreased activity as criteria for Spine1988;13:I168—i170. infection, the overall accuracy of leukocyte imaging for 10. WhaleniL, BrownML,McCleodR, FitzgeraldRH. Limitationsofindium diagnosing vertebral osteomyelitis was 66%, similar to the leukocyteimaging for the diagnosisofspine infections. Spine 199l;16:193— 197. 63% accuracy of bone imaging. Unfortunately, the same 11. EisenbergB, PowerJE,Alavi A. Colddefectsin In-i 11-labeledIeukocyte conditions that adversely affect the specificity of bone imaging ofosteomyelitis in the axial skeleton.C/in NuclMed 1991:16:103— scintigraphy such as tumor, trauma, and Paget's disease 106. 12. Thakur ML, Lavender JP, Arnot RN, Silverstein Di, SegalAW. Indium also had an adverse effect on the specificity of leukocyte I 1i-labeled autologousleukocytesin man. J Nuc/ Med 1977;I8:1014— imaging in our patients (Fig. 2). 1021.

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Diagnosisof VertebralOsteomyelitis•Palestroet al 1865