Clinical Utility of SPECT Neuroimaging in the Diagnosis and Treatment of Traumatic Brain Injury: A Systematic Review

Background: The most common assessment modalities to determine the level of injury following a traumatic brain injury (TBI) includes computerized tomography (CT) scans and/or magnetic resonance imaging (MRI). Evidence is mixed as to whether single photon emission computed tomography (SPECT) is specific and accurate in identifying TBI. Objectives: This study systematically assessed recent evidence of the clinical utility of SPECT in the diagnosis of TBI and examined the diagnostic accuracy of SPECT in TBI and its performance in comparison to other imaging modalities (e.g., CT and MRI). Methods: PubMed, MEDLINE, and Embase databases were systematically searched for published articles from December 2012 to July 2021. Randomized controlled trials (RCTs) and observational studies published in English that used SPECT to evaluate patients with all severity of TBIs were eligible for inclusion. Titles and abstracts were screened, and 109 selected full-text articles were independently screened based on predefined inclusion/exclusion criteria (guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PRISMA) and assessed for quality using the Newcastle-Ottawa Scale. Results: Fourteen eligible studies, all observational, reporting location of lesions on brain SPECT were included, reporting data from 21632 participants of which 20,746 participants were from one study; the remaining 886 participants were from the remaining13 studies. The heterogeneity of the data precludes a meta-analysis. There was no consensus among experts from the thirteen smaller studies; however, the largest study indicated that the specificity of visual readings was 54%. In particular, abnormalities and brain perfusions may lead to false positives. Quantitative analysis theoretically increases the reliability of findings for brain SPECT, but error rates are unknown and not published. Conclusion: There is a lack of evidence to support the clinical utility of brain SPECT for the diagnosis and treatment of TBI.

Introduction 48 1. A traumatic brain injury (TBI) results from trauma to the brain, and is a major cause of 49 disability and death (cite). Each, year it is estimated that approximately 69 million people 50 suffer from a TBI worldwide, of which the majority of cases are mild (81%) or moderate 51 (11%) [1]. Depending on the severity of the injury, those who sustain a TBI may face 52 health problems that can range from short to long-term in duration. Because prompt

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The copyright holder for this preprint this version posted July 17, 2022. This advanced neuroimaging modality is a nuclear scan created by American researchers 71 in 1963 that uses radioactive tracers to develop three-dimensional (D) images of blood flow [14]. 72 The brain SPECT has undergone critical updates over the decades and newer machines often 73 employs multi-headed cameras followed by quantitative analysis and attenuation to relay 74 metabolic changes and physiological data [11,14]. The spatial resolution of brain SPECT images 75 are lower compared to other similar scans such as positron emission tomography (PET) scan and 76 functional magnetic resonance imaging (fMRI) [15,16]. Brain SPECT has been utilized to study 77 neurological conditions and psychiatric disorders, which may include but not limited to: mood 78 disorders, post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD) [11,17].

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There are contradictory findings in the scientific literature on brain SPECT  reported poor results from the SPECT scan for TBI after a 3-month follow-up period, which is 90 when some signs and symptoms of minor head injury have already diminished. However, after a 91 12-month follow-up assessment, the sensitivity (100%), specificity (85%), negative predictive 92 value (100%), and positive predictive value (83%) of brain SPECT for TBI were remarkably . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 17, 2022. suggest post hoc ergo propter hoc ("after this, therefore because of this"), and thus, the clinical 104 history and evidence-based decision-making are necessary to investigate whether post-injury 105 findings are directly related to an event or accident. In order for the wider scientific community 106 and healthcare industry to endorse the use of brain SPECT for TBI, the generalizability of the 107 results of this medical imaging modality for different cohorts must be confirmed. Therefore, an 108 updated review of this study is necessary to determine if the findings from the previous review  CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 17, 2022. The purpose of this study was to update the systematic review by Raji and colleagues (2014) 116 [11] and to evaluate the clinical utility of SPECT in the diagnosis and treatment of TBI, ranging 117 from mild to severe The PICO statement and methods remained consistent from the prior study 118 so current findings could extrapolate from previous results. Thus, this updated review aims to 119 answer if abnormalities on brain SPECT could be utilize to diagnose and treat individuals with 120 TBI in clinical settings in comparison to other brain imaging modalities. A secondary analysis 121 was also conducted to identify possible associations between SPECT abnormalities and 122 neuropsychological and neurological outcomes.    rater reliability for the article selection process was calculated to be over 80%, which is 176 considered acceptable levels (κ = 0.87, p < .05). It should be noted that no RCT was found and 177 the heterogeneity of the data precludes conducting a meta-analysis. The combined sample size 178 for this study is 21,416 persons with TBI of all severity. 183 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted July 17, 2022.   There were 14 observational studies that examined brain SPECT and TBI (Table 2) PET scan is better at detecting lesions than brain SPECT for TBI [35]. However, brain . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted July 17, 2022.  values. In comparison to previously reported results, two studies reported lower sensitivity (≥ 248 67%) and most found similar specificity levels (≥ 54%) as illustrated in Table 3. The largest 249 cohort study (N = 20,746 participants) involving SPECT for TBI reported specificity was 54% at . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted July 17, 2022. The overall results of this study indicated that brain SPECT could still be considered an  Future studies must utilize larger sample size and scientifically rigorous methodology (i.e., 340 double-blind RCTs) to reduce risk of bias and enhance the strength of evidence available to 341 support clinical utility of SPECT for diagnosis of TBI. Lastly, a detailed report regarding brain 342 SPECT error rates is required before further inferences about its clinical utility are determined.

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The copyright holder for this preprint this version posted July 17, 2022. Recent findings on this topic helps provide clarity on whether SPECT is specific in 347 identifying TBI even without typical structural imaging such as CT and MRI. In conclusion, 348 there is no consensus among experts about the clinical utility of brain SPECT. This "advance" 349 medical imaging modality is currently not the gold standard diagnostic scan to investigate TBI. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.     . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 17, 2022. ; https://doi.org/10.1101/2022.07.15.22277668 doi: medRxiv preprint