Failure Of Gallium-68 Citrate Scan To Detect Large, Enhancing Central Nervous System Tuberculomas: A Cautionary Tale

Failure Of Gallium-68 Citrate Scan To Detect Large, Enhancing Central Nervous System Tuberculomas: A Cautionary Tale | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Failure Of Gallium-68 Citrate Scan To Detect Large, Enhancing Central Nervous System Tuberculomas: A Cautionary Tale Selwyn Selva Kumar, Adrian Keith Noronha, Julie Hephzibah, Harshad Arvind Vanjare, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4610855/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Background Gallium-68 citrate is an emerging diagnostic tool for the evaluation of infections. Its performance in brain infections, specifically central nervous system (CNS) tuberculosis, is unknown. The available diagnostics for CNS tuberculosis are imprecise. Case Presentation We report a patient with large, active, enhancing, microbiologically confirmed tuberculomas in the right frontal lobe who underwent Gallium-68 PET CT. It did not show any tracer uptake in the tuberculous lesions. Conclusions We report caution in the use of Gallium-68 PET CT for CNS TB, especially with concomitant steroid use. Gallium-68 PET CT Central nervous system tuberculosis Brain infections Figures Figure 1 Background Tuberculosis (TB) of the central nervous system (CNS) is the most severe form of disease with high rates of disability and mortality. Imaging plays a key role in supporting the diagnosis of CNS TB and in the evaluation of extrapulmonary involvement. The available microbiological diagnostics are poorly sensitive. Magnetic Resonance Imaging (MRI) brain is the preferred modality for detecting meningeal and parenchymal disease. Nuclear imaging with various radioactive probes has shown mixed results. 18F-fluorodeoxyglucose positron emission tomography (FDG PET) is poorly sensitive to intracranial and intraspinal lesions in relation to the MRI in view of high metabolic uptake throughout the brain. However, it is useful for evaluating extra neural involvement [ 1 , 2 ]. Though Gallium-67 (Ga-67) citrate has been used to detect cranial and cerebral pathologies, evidence for the utility of Gallium-68 (Ga-68) citrate for brain infections is scarce [ 3 ]. In vivo animal studies have shown an appreciable tumour-to-brain ratio to the Ga- 68 isotype [ 4 ]. Compared with FDG-PET, it showed a better definition for intracerebral lesions [ 5 ]. Ga-68 could be a useful adjunct in the diagnosis and follow-up of CNS TB patients. However, currently, no data exists in the literature. Here, we present a case where a Ga-68 citrate scan showed no avidity in the active intracranial tuberculous lesions. Case Presentation A 47-year-old gentleman from North India with no comorbid illnesses presented with intermittent low-grade fever and holocranial headache for 3 months and altered sensorium for a week with no neurological deficit. He was evaluated at a local medical facility and was diagnosed to have rifampicin-susceptible tuberculous meningitis based on TrueNat MTB/Rif (Molbio Diagnostics, Verna, India) in the cerebrospinal fluid. He was initiated on anti-tuberculous therapy (ATT) with rifampicin, streptomycin, levofloxacin and ethambutol since his liver enzymes were elevated at baseline. After 2 months of therapy, he developed unsteadiness while walking, progressive over the next 4 months. He then presented to our centre with the above complaints. Magnetic Resonance Imaging (MRI) of the Brain and Spine with Gadolinium contrast revealed multiple ring-enhancing lesions with perilesional edema in the right supratentorial and infra-tentorial compartments with basal cistern lesions (Fig. 1 a and 1 b). In addition, spine imaging revealed extramedullary compressive tuberculomas at the thoracic spinal level (T1 to T12 levels). He was then initiated on appropriate weight-based anti-mycobacterial therapy with isoniazid, rifampicin, pyrazinamide, ethambutol and pyridoxine along with dexamethasone at 0.4mg per kg per day. After 45 days of appropriate anti-TB therapy and steroids, he had a worsening imbalance and was given infliximab (5 mg per kg) for a severe paradoxical reaction. Around 45 days of infliximab, he developed worsening left-sided spastic hemiparesis and was readmitted. Neurological examination revealed significant gait ataxia, with cerebellar findings predominantly involving the lower limbs and trunk and impaired dorsal column sensations. The baseline laboratory investigations were normal. The C-reactive protein was 4.76 mg/L (Reference normal: < 6 mg/L). Given the subacute development of a new onset hemiparesis, a repeat contrast-enhanced MRI brain and spine was done. There was a significant increase in the enhancement as well as the perilesional edema with new lesions in the right frontal, parietal, temporal, and occipital lobe lesions, with some of the lesions compressing the brainstem and causing uncal herniation (Fig. 2a and 2b). The spine imaging did not show any progression or regression of prior lesions. At this time, he was on tapering dexamethasone of 4 mg per day. A Gallium-68 citrate scan of the brain was performed at this point to evaluate activity in the lesions. However, this did not reveal any uptake in the brain (Fig. 2c and 2d). He was then restarted on high-dose dexamethasone at 0.4 mg per kg per day, which is being tapered over 12 weeks. Anti-TB therapy was continued. At a follow-up visit 10 weeks later, his weakness has improved, and he is functionally independent for all activities of daily living. Discussion and Conclusions In our patient, the Gallium-68 citrate scan failed to show uptake in the active cerebral tuberculomas. This is the first report of performance of Ga-68 citrate PET CT for CNS tuberculoma. FDG PET has been useful in assessing extra neural disease and response of the inflammatory granulomatous lesions to treatment. However, it is of limited value in CNS tuberculosis perse in view of high physiologic uptake in the brain. Ga-68 citrate PET CT could be a useful adjunct for evaluating activity in the CNS TB lesions, in the place of FDG PET. However, in our patient it did not show any uptake despite the presence of large enhancing granulomatous lesions in the MRI. Whether this reflects the performance of Ga-68 scan in CNS TB lesions or modified by the concomitant use of high dose steroids is unclear. The effect of steroids on Ga-67 citrate uptake was demonstrated by Alan D Waxman et al. [ 6 ] in intracerebral tumours. Steroids when given above replacement doses, reduced the sensitivity of Ga -67 in detecting primary and metastatic brain tumours than technetium glucoheptonate. Uptake of Ga -67 in the brain is due to a non-transferrin-mediated mechanism [ 7 ]. Poor uptake of Gallium isotopes on steroid therapy could be due to its interaction with the blood-brain barrier (BBB) in two ways. Firstly, by reducing the permeability of tight junctions. Secondly, as a strong inducer of P-glycoprotein expression in BBB [ 8 ]. But this may not explain the discordant results where Gadolinium enhanced the lesions whereas Ga68 citrate failed to do so. The exact mechanism of differential uptakes in various radiopharmaceuticals needs to be studied further. Ga-67 citrate has been in clinical use since the 1970s and shown to be more sensitive than routine chest radiography for the detection of both lung parenchymal involvement and adenopathy in tuberculosis. It also facilitates the choice of biopsy sites [ 9 ]. Recently developed Ga-68 citrate, unlike Ga-67 citrate, has a shorter half-life (66 hours), leading to a dosimetric advantage and early procedure completion [ 10 ]. It has shown excellent performance in the diagnosis of bone and prosthetic joint infections and endovascular infections [ 11 , 12 ]. Ga-68 citrate may perform better than FDG PET in specific settings such as small lesions with low glycolytic activity and pathologies nearby or within the organs with high physiologic uptake sites like the brain, heart, liver, and kidney [ 13 ]. Ga-68 citrate scan is a potential alternative modality to FDG PET to measure intracranial disease activity; however, clinicians should practice caution while interpreting results in patients on concurrent steroids. Since ours is a case report, we emphasise cautious interpretation of our findings. This report will spur further research in this important area. As we await further evidence, we suggest against routine use of Gallium − 68 citrate PET CT scan in CNS tuberculosis for clinical purposes. Abbreviations CNS- Central Nervous System TB- Tuberculosis MRI- Magnetic Resonance Imaging FDG PET -18F Fluoro Deoxy Glucose Positron Emission Tomography (FDG PET) Ga- Gallium ATT- Anti Tuberculous Therapy BBB- Blood Brain Barrier Declarations Ethical approval and consent to participate The patient provided written informed consent to participation. Consent for publication The patient provided written consent for publication of the case Availability of data and materials All relevant data has been presented in the manuscript, and further inquiries can be made to the corresponding author. Competing Interests The authors have no competing interests to declare. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author contributions AMconceptualised the study. SSK and AKN wrote the original draft. HAV and JH provided the radiological assessment and images. JH provided the critical review. All authors reviewed and approved the final manuscript and agreed to the submission for publication. Acknowledgement The authors also thank Dr. Minnu Ann Mohan, Dr. Mithun Mohan George, and Dr. Nishi Somarkutty for their technical assistance and proof reading the article. References FDG-Positron Emission Tomography in patients with Tuberculous Meningitis: A Prospective Evaluation - PMC [Internet]. [cited 2024 Jun 8]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592133/ Bomanji J, Sharma R, Mittal BR, Gambhir S, Qureshy A, Begum SMF, et al. PET/CT features of extrapulmonary tuberculosis at first clinical presentation: a cross-sectional observational 18F-FDG imaging study across six countries. Eur Respir J [Internet]. 2020 Feb 1 [cited 2024 Jun 8];55(2). Available from: https://erj.ersjournals.com/content/55/2/1901959 Wong VC, Yung G, Russo R, Reddel SW, Mansberg R. Pachymeningitis Demonstrated on Gallium SPECT/CT Scan. Clin Nucl Med. 2019 Apr;44(4):305. Rezazadeh F, Kilcline AP, Viola NT, Laschinsky C, Theurer S, Herold T, et al. FOCUS ON MOLECULAR IMAGING. Ankrah AO, Lawal IO, Boshomane TMG, Klein HC, Ebenhan T, Dierckx RAJO, et al. Comparison of Fluorine(18)-fluorodeoxyglucose and Gallium(68)-citrate PET/CT in patients with tuberculosis. Nukl Nucl Med. 2019 Sep;58(5):371–8. Waxman AD, Beldon JR, RichIl W, Tanasescu DE, Siemsen JK. Steroid-Induced Suppression of Gallium Uptake in Tumors of the Central Nervous System: Radunovic A, Habgood MD, Bradbury MWB. Uptake of Ga-67 into rat cerebral hemisphere and cerebellum. Comparison with Fe-59. Biometals. 1997 Dec 1;10(4):343–9. Witt KA, Sandoval KE. Steroids and the blood-brain barrier: therapeutic implications. Adv Pharmacol San Diego Calif. 2014;71:361–90. Goldfarb CR, Colp C, Ongseng F, Finestone H, Havas J. Gallium scanning in the “new” tuberculosis. Clin Nucl Med. 1997 Jul;22(7):470–4. Shealy CN, Aronow S, Brownell GL. GALLIUM-68 AS A SCANNING AGENT FOR INTRACRANIAL LESIONS. J Nucl Med Off Publ Soc Nucl Med. 1964 Mar;5:161–7. Nanni C, Errani C, Boriani L, Fantini L, Ambrosini V, Boschi S, et al. 68Ga-Citrate PET/CT for Evaluating Patients with Infections of the Bone: Preliminary Results. J Nucl Med. 2010 Dec 1;51(12):1932–6. Diagnosis of Prosthetic Aortic Valve Endocarditis With Gallium-67 Citrate Single-Photon Emission Computed Tomography/Computed Tomography Hybrid Imaging Using Software Registration | Circulation: Cardiovascular Imaging [Internet]. [cited 2024 Jun 8]. Available from: https://www.ahajournals.org/doi/10.1161/CIRCIMAGING.109.854661 Chang JM, Lee HJ, Goo JM, Lee HY, Lee JJ, Chung JK, et al. False positive and false negative FDG-PET scans in various thoracic diseases. Korean J Radiol. 2006;7(1):57–69. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editor assigned by journal 28 Jun, 2024 Submission checks completed at journal 27 Jun, 2024 First submitted to journal 20 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4610855","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":320132064,"identity":"70e56fb4-3124-416f-bb5a-3d5081614e67","order_by":0,"name":"Selwyn Selva Kumar","email":"","orcid":"","institution":"Christian Medical College","correspondingAuthor":false,"prefix":"","firstName":"Selwyn","middleName":"Selva","lastName":"Kumar","suffix":""},{"id":320132069,"identity":"33e7a353-2b16-4087-9c77-924c2c204ec8","order_by":1,"name":"Adrian Keith Noronha","email":"","orcid":"","institution":"Christian Medical College","correspondingAuthor":false,"prefix":"","firstName":"Adrian","middleName":"Keith","lastName":"Noronha","suffix":""},{"id":320132073,"identity":"67ff0aac-5ac4-4a60-b582-793b3e9b7e99","order_by":2,"name":"Julie Hephzibah","email":"","orcid":"","institution":"Christian Medical College","correspondingAuthor":false,"prefix":"","firstName":"Julie","middleName":"","lastName":"Hephzibah","suffix":""},{"id":320132076,"identity":"8029e935-69bc-481b-ad52-40fec6b53859","order_by":3,"name":"Harshad Arvind Vanjare","email":"","orcid":"","institution":"Christian Medical College","correspondingAuthor":false,"prefix":"","firstName":"Harshad","middleName":"Arvind","lastName":"Vanjare","suffix":""},{"id":320132077,"identity":"66a81c9a-11a8-470a-aae1-d90d62a33503","order_by":4,"name":"Abi Manesh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYDACCcYGMG3ADqINLEjRwnMAREoQowVKG0gkIHPxAP7Zza0bfu6wsTeXfH51w48CCQb+9u4E/JbcOdh2s/dMWuLO2TllN3uADpM4c3YDfmtuJLbd4G07nGBwOyftBg9Qi4FELn4t8kAtN/+2/bc3uHkm7eYfYrQYALXc5m07wLjhBvux20TZYgj0y23ZtuTEDWdy2G7LGEjwEPSL3O32ZzffttnZGxw//uzmmz82cvztvQS8jwA8BmCSWOUgwP6AFNWjYBSMglEwggAAj/FPSKkhtBIAAAAASUVORK5CYII=","orcid":"","institution":"Christian Medical College","correspondingAuthor":true,"prefix":"","firstName":"Abi","middleName":"","lastName":"Manesh","suffix":""}],"badges":[],"createdAt":"2024-06-20 09:48:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4610855/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4610855/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60707099,"identity":"ff26e0bf-5a18-46c6-a8c5-d8fffc31b649","added_by":"auto","created_at":"2024-07-19 19:31:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":440279,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFirst study: 1a (T2W axial) \u003c/strong\u003edemonstrating a necrotic tuberculoma involving the right frontal lobe with minimal surrounding oedema and \u003cstrong\u003e1b(post-contrast T1W) \u003c/strong\u003eshowing ring enhancement. \u003cstrong\u003eFollow-up second study\u003c/strong\u003e: \u003cstrong\u003e2a (T2W axial)\u003c/strong\u003e demonstrating an increase in the size of the necrotic tuberculoma with worsening of the surrounding oedema. Another tuberculoma is partially visualised in the right parietal lobe. \u003cstrong\u003e2b (post-contrast T1W) \u003c/strong\u003eshowing ring enhancement. \u003cstrong\u003e2c (Gallium-68 citrate fused PET CT image) \u003c/strong\u003edid not demonstrate tracer uptake in the region of the tuberculoma. \u003cstrong\u003e2d (corresponding CT only image) \u003c/strong\u003edemonstrating the tuberculoma.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4610855/v1/92747290e1deaa67f14f6101.png"},{"id":60707133,"identity":"46268a0c-f9cf-42ca-8f94-8daeab76885c","added_by":"auto","created_at":"2024-07-19 19:31:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":890710,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4610855/v1/fba13252-0335-40eb-abf2-504d203de71d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Failure Of Gallium-68 Citrate Scan To Detect Large, Enhancing Central Nervous System Tuberculomas: A Cautionary Tale","fulltext":[{"header":"Background","content":"\u003cp\u003eTuberculosis (TB) of the central nervous system (CNS) is the most severe form of disease with high rates of disability and mortality. Imaging plays a key role in supporting the diagnosis of CNS TB and in the evaluation of extrapulmonary involvement. The available microbiological diagnostics are poorly sensitive. Magnetic Resonance Imaging (MRI) brain is the preferred modality for detecting meningeal and parenchymal disease. Nuclear imaging with various radioactive probes has shown mixed results. 18F-fluorodeoxyglucose positron emission tomography (FDG PET) is poorly sensitive to intracranial and intraspinal lesions in relation to the MRI in view of high metabolic uptake throughout the brain. However, it is useful for evaluating extra neural involvement [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThough Gallium-67 (Ga-67) citrate has been used to detect cranial and cerebral pathologies, evidence for the utility of Gallium-68 (Ga-68) citrate for brain infections is scarce [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In vivo animal studies have shown an appreciable tumour-to-brain ratio to the Ga- 68 isotype [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Compared with FDG-PET, it showed a better definition for intracerebral lesions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Ga-68 could be a useful adjunct in the diagnosis and follow-up of CNS TB patients. However, currently, no data exists in the literature. Here, we present a case where a Ga-68 citrate scan showed no avidity in the active intracranial tuberculous lesions.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 47-year-old gentleman from North India with no comorbid illnesses presented with intermittent low-grade fever and holocranial headache for 3 months and altered sensorium for a week with no neurological deficit. He was evaluated at a local medical facility and was diagnosed to have rifampicin-susceptible tuberculous meningitis based on TrueNat MTB/Rif (Molbio Diagnostics, Verna, India) in the cerebrospinal fluid. He was initiated on anti-tuberculous therapy (ATT) with rifampicin, streptomycin, levofloxacin and ethambutol since his liver enzymes were elevated at baseline. After 2 months of therapy, he developed unsteadiness while walking, progressive over the next 4 months. He then presented to our centre with the above complaints. Magnetic Resonance Imaging (MRI) of the Brain and Spine with Gadolinium contrast revealed multiple ring-enhancing lesions with perilesional edema in the right supratentorial and infra-tentorial compartments with basal cistern lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). In addition, spine imaging revealed extramedullary compressive tuberculomas at the thoracic spinal level (T1 to T12 levels). He was then initiated on appropriate weight-based anti-mycobacterial therapy with isoniazid, rifampicin, pyrazinamide, ethambutol and pyridoxine along with dexamethasone at 0.4mg per kg per day. After 45 days of appropriate anti-TB therapy and steroids, he had a worsening imbalance and was given infliximab (5 mg per kg) for a severe paradoxical reaction. Around 45 days of infliximab, he developed worsening left-sided spastic hemiparesis and was readmitted. Neurological examination revealed significant gait ataxia, with cerebellar findings predominantly involving the lower limbs and trunk and impaired dorsal column sensations.\u003c/p\u003e \u003cp\u003eThe baseline laboratory investigations were normal. The C-reactive protein was 4.76 mg/L (Reference normal: \u0026lt; 6 mg/L). Given the subacute development of a new onset hemiparesis, a repeat contrast-enhanced MRI brain and spine was done. There was a significant increase in the enhancement as well as the perilesional edema with new lesions in the right frontal, parietal, temporal, and occipital lobe lesions, with some of the lesions compressing the brainstem and causing uncal herniation (Fig.\u0026nbsp;2a and 2b). The spine imaging did not show any progression or regression of prior lesions. At this time, he was on tapering dexamethasone of 4 mg per day. A Gallium-68 citrate scan of the brain was performed at this point to evaluate activity in the lesions. However, this did not reveal any uptake in the brain (Fig.\u0026nbsp;2c and 2d).\u003c/p\u003e \u003cp\u003eHe was then restarted on high-dose dexamethasone at 0.4 mg per kg per day, which is being tapered over 12 weeks. Anti-TB therapy was continued. At a follow-up visit 10 weeks later, his weakness has improved, and he is functionally independent for all activities of daily living.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eIn our patient, the Gallium-68 citrate scan failed to show uptake in the active cerebral tuberculomas. This is the first report of performance of Ga-68 citrate PET CT for CNS tuberculoma. FDG PET has been useful in assessing extra neural disease and response of the inflammatory granulomatous lesions to treatment. However, it is of limited value in CNS tuberculosis perse in view of high physiologic uptake in the brain. Ga-68 citrate PET CT could be a useful adjunct for evaluating activity in the CNS TB lesions, in the place of FDG PET. However, in our patient it did not show any uptake despite the presence of large enhancing granulomatous lesions in the MRI. Whether this reflects the performance of Ga-68 scan in CNS TB lesions or modified by the concomitant use of high dose steroids is unclear.\u003c/p\u003e \u003cp\u003eThe effect of steroids on Ga-67 citrate uptake was demonstrated by Alan D Waxman et al. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] in intracerebral tumours. Steroids when given above replacement doses, reduced the sensitivity of Ga -67 in detecting primary and metastatic brain tumours than technetium glucoheptonate. Uptake of Ga -67 in the brain is due to a non-transferrin-mediated mechanism [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Poor uptake of Gallium isotopes on steroid therapy could be due to its interaction with the blood-brain barrier (BBB) in two ways. Firstly, by reducing the permeability of tight junctions. Secondly, as a strong inducer of P-glycoprotein expression in BBB [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. But this may not explain the discordant results where Gadolinium enhanced the lesions whereas Ga68 citrate failed to do so. The exact mechanism of differential uptakes in various radiopharmaceuticals needs to be studied further.\u003c/p\u003e \u003cp\u003eGa-67 citrate has been in clinical use since the 1970s and shown to be more sensitive than routine chest radiography for the detection of both lung parenchymal involvement and adenopathy in tuberculosis. It also facilitates the choice of biopsy sites [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Recently developed Ga-68 citrate, unlike Ga-67 citrate, has a shorter half-life (66 hours), leading to a dosimetric advantage and early procedure completion [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. It has shown excellent performance in the diagnosis of bone and prosthetic joint infections and endovascular infections [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGa-68 citrate may perform better than FDG PET in specific settings such as small lesions with low glycolytic activity and pathologies nearby or within the organs with high physiologic uptake sites like the brain, heart, liver, and kidney [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Ga-68 citrate scan is a potential alternative modality to FDG PET to measure intracranial disease activity; however, clinicians should practice caution while interpreting results in patients on concurrent steroids.\u003c/p\u003e \u003cp\u003eSince ours is a case report, we emphasise cautious interpretation of our findings. This report will spur further research in this important area. As we await further evidence, we suggest against routine use of Gallium \u0026minus;\u0026thinsp;68 citrate PET CT scan in CNS tuberculosis for clinical purposes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCNS- Central Nervous System\u003c/p\u003e\n\u003cp\u003eTB- Tuberculosis\u003c/p\u003e\n\u003cp\u003eMRI- Magnetic Resonance Imaging\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFDG PET -18F Fluoro Deoxy Glucose Positron Emission Tomography (FDG PET)\u003c/p\u003e\n\u003cp\u003eGa- Gallium\u003c/p\u003e\n\u003cp\u003eATT- Anti Tuberculous Therapy\u003c/p\u003e\n\u003cp\u003eBBB- Blood Brain Barrier\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient provided written informed consent to participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient provided written consent for publication of the case\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant data has been presented in the manuscript, and further inquiries can be made to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAMconceptualised the study. SSK and AKN wrote the original draft. HAV and JH provided the radiological assessment and images. JH provided the critical review. All authors reviewed and approved the final manuscript and agreed to the submission for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors also thank Dr. Minnu Ann Mohan, Dr. Mithun Mohan George, and Dr. Nishi Somarkutty for their technical assistance and proof reading the article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFDG-Positron Emission Tomography in patients with Tuberculous Meningitis: A Prospective Evaluation - PMC [Internet]. [cited 2024 Jun 8]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592133/\u003c/li\u003e\n\u003cli\u003eBomanji J, Sharma R, Mittal BR, Gambhir S, Qureshy A, Begum SMF, et al. PET/CT features of extrapulmonary tuberculosis at first clinical presentation: a cross-sectional observational 18F-FDG imaging study across six countries. Eur Respir J [Internet]. 2020 Feb 1 [cited 2024 Jun 8];55(2). Available from: https://erj.ersjournals.com/content/55/2/1901959\u003c/li\u003e\n\u003cli\u003eWong VC, Yung G, Russo R, Reddel SW, Mansberg R. Pachymeningitis Demonstrated on Gallium SPECT/CT Scan. Clin Nucl Med. 2019 Apr;44(4):305.\u003c/li\u003e\n\u003cli\u003eRezazadeh F, Kilcline AP, Viola NT, Laschinsky C, Theurer S, Herold T, et al. FOCUS ON MOLECULAR IMAGING.\u003c/li\u003e\n\u003cli\u003eAnkrah AO, Lawal IO, Boshomane TMG, Klein HC, Ebenhan T, Dierckx RAJO, et al. Comparison of Fluorine(18)-fluorodeoxyglucose and Gallium(68)-citrate PET/CT in patients with tuberculosis. Nukl Nucl Med. 2019 Sep;58(5):371\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eWaxman AD, Beldon JR, RichIl W, Tanasescu DE, Siemsen JK. Steroid-Induced Suppression of Gallium Uptake in Tumors of the Central Nervous System:\u003c/li\u003e\n\u003cli\u003eRadunovic A, Habgood MD, Bradbury MWB. Uptake of Ga-67 into rat cerebral hemisphere and cerebellum. Comparison with Fe-59. Biometals. 1997 Dec 1;10(4):343\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eWitt KA, Sandoval KE. Steroids and the blood-brain barrier: therapeutic implications. Adv Pharmacol San Diego Calif. 2014;71:361\u0026ndash;90.\u003c/li\u003e\n\u003cli\u003eGoldfarb CR, Colp C, Ongseng F, Finestone H, Havas J. Gallium scanning in the \u0026ldquo;new\u0026rdquo; tuberculosis. Clin Nucl Med. 1997 Jul;22(7):470\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eShealy CN, Aronow S, Brownell GL. GALLIUM-68 AS A SCANNING AGENT FOR INTRACRANIAL LESIONS. J Nucl Med Off Publ Soc Nucl Med. 1964 Mar;5:161\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eNanni C, Errani C, Boriani L, Fantini L, Ambrosini V, Boschi S, et al. 68Ga-Citrate PET/CT for Evaluating Patients with Infections of the Bone: Preliminary Results. J Nucl Med. 2010 Dec 1;51(12):1932\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eDiagnosis of Prosthetic Aortic Valve Endocarditis With Gallium-67 Citrate Single-Photon Emission Computed Tomography/Computed Tomography Hybrid Imaging Using Software Registration | Circulation: Cardiovascular Imaging [Internet]. [cited 2024 Jun 8]. Available from: https://www.ahajournals.org/doi/10.1161/CIRCIMAGING.109.854661\u003c/li\u003e\n\u003cli\u003eChang JM, Lee HJ, Goo JM, Lee HY, Lee JJ, Chung JK, et al. False positive and false negative FDG-PET scans in various thoracic diseases. Korean J Radiol. 2006;7(1):57\u0026ndash;69.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-clinical-microbiology-and-antimicrobials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmam","sideBox":"Learn more about [Annals of Clinical Microbiology and Antimicrobials](http://ann-clinmicrob.biomedcentral.com/)","snPcode":"12941","submissionUrl":"https://submission.nature.com/new-submission/12941/3","title":"Annals of Clinical Microbiology and Antimicrobials","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gallium-68 PET CT, Central nervous system tuberculosis, Brain infections","lastPublishedDoi":"10.21203/rs.3.rs-4610855/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4610855/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eGallium-68 citrate is an emerging diagnostic tool for the evaluation of infections. Its performance in brain infections, specifically central nervous system (CNS) tuberculosis, is unknown. The available diagnostics for CNS tuberculosis are imprecise.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCase Presentation\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe report a patient with large, active, enhancing, microbiologically confirmed tuberculomas in the right frontal lobe who underwent Gallium-68 PET CT. It did not show any tracer uptake in the tuberculous lesions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe report caution in the use of Gallium-68 PET CT for CNS TB, especially with concomitant steroid use.\u003c/p\u003e","manuscriptTitle":"Failure Of Gallium-68 Citrate Scan To Detect Large, Enhancing Central Nervous System Tuberculomas: A Cautionary Tale","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-19 19:31:17","doi":"10.21203/rs.3.rs-4610855/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2024-06-28T08:24:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-27T07:03:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Clinical Microbiology and Antimicrobials","date":"2024-06-20T09:46:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-clinical-microbiology-and-antimicrobials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmam","sideBox":"Learn more about [Annals of Clinical Microbiology and Antimicrobials](http://ann-clinmicrob.biomedcentral.com/)","snPcode":"12941","submissionUrl":"https://submission.nature.com/new-submission/12941/3","title":"Annals of Clinical Microbiology and Antimicrobials","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3cd2edb5-1436-4b15-83b7-c1228a1e4e70","owner":[],"postedDate":"July 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-07-19T19:31:17+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-19 19:31:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4610855","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4610855","identity":"rs-4610855","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}