Long-term trends in total administered radiation dose from brain [¹⁸F]FDG-PET in children with drug-resistant epilepsy

By the age of 10, up to 46 in 100,000 children are diagnosed with epilepsy [1, 2]. Approximately one-third of these children do not respond to appropriately chosen and well-tolerated anti-seizure medications and are hence classified as having drug-resistant epilepsy (DRE) [3]. A significant predictor of DRE is the presence of a structural lesion, which refers to any brain abnormality known to increase the risk of epilepsy [4]. Epilepsy surgery is a safe and effective procedure in children whose focal onset DRE arises from a non-eloquent brain region [5, 6]. The mainstays of presurgical evaluation include video-electroencephalography (EEG), magnetic resonance (MR) imaging, and neuropsychological testing [7]. Children with a solitary, discrete lesion have higher chances of achieving postsurgical seizure freedom, provided that the lesion is completely removed [5, 8]. However, over the last two decades, surgical indications have expanded to include more complex cases of extensive or even bilateral lesions and MR-negative cases [5, 9], often necessitating auxiliary tests [7].

Nuclear medicine techniques, specifically interictal positron emission tomography (PET) and ictal single-photon emission tomography (SPECT), are crucial in complex cases, confirming the lateralization or lobar localization of the presumed epileptogenic zone (EZ), which can then be targeted for resection or further investigated by invasive EEG [7]. Past studies have indicated that 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG)-PET is instrumental in decision-making for nearly 50% of patients with incongruent findings between EEG and MR [10]. Most importantly, [¹⁸F]FDG-PET demonstrates lower rates of false negatives compared to SPECT [11] and helps in predicting surgical outcomes [10, 12‐14].

Despite its advantages, the use of hybrid imaging techniques, particularly [¹⁸F]FDG-PET/computed tomography (CT), in children undergoing presurgical evaluation for DRE raises safety concerns due to the dual sources of radiation involved [15, 16]. Given the significant number of children with DRE affected by this issue, there is a notable gap in research regarding radiation trends associated with hybrid imaging techniques like [¹⁸F]FDG-PET/CT and [¹⁸F]FDG-PET/MR. Thus, this study aimed to evaluate the trends in [¹⁸F]FDG doses administered and the radiation doses from CT over the study period in children with DRE who underwent hybrid [¹⁸F]FDG-PET scans. Additionally, we assessed how these changes impacted image quality.

In this retrospective, single-center study, we selected children with DRE who underwent hybrid brain [¹⁸F]FDG-PET scans at the Department of Nuclear Medicine, University Hospital of Zurich, for presurgical evaluation between January 1, 2005, and May 31, 2021. Inclusion criteria were: 1) DRE diagnosis, 2) hybrid [¹⁸F]FDG-PET brain scan, and 3) age ≤ 18 years at the time of the scan. Exclusion criteria were: 1) missing CT dose scan report, 2) congenital or acquired pathologies affecting the basal ganglia or thalamus that could interfere with image analysis (e.g., basal ganglia stroke, metabolic diseases), and 3) image artifacts that precluded evaluation.

We extracted epidemiological and epileptological data from medical records. A detailed description of these parameters is provided in the Supplementary Table 1. DRE structural etiology was classified according to Blümke et al. [17] (Table 1). For children who underwent epilepsy surgery, the structural etiology was determined based on histological analysis; those not operated were classified based on unequivocal imaging patterns on structural MR alone. Lateralization and lobar localization of the presumed EZ were determined based on seizure semiology, EEG, structural MR, PET findings, or surgical outcomes (Supplementary Table 2). Lesion lateralization was subdivided into right, left, bilateral, or negative; lobar localization was classified as frontal, temporal, posterior, deep, infratentorial, or bilateral (Supplementary Table 2) [18‐20]. In cases of unilateral lesions involving multiple lobes, the most affected lobe was identified for classification.

The local ethics committee approved the study (Number: 2020–03067). Written informed consent was waived for patients scanned before January 2016. After January 2016, only patients whose caretakers provided documented consent for the use of their medical data were included in the study.

Our study demonstrated that [¹⁸F]FDG-PET image quality improved annually by 9%, while CT-associated radiation dose decreased annually by 15–16%, and [¹⁸F]FDG administered activity per body weight remained stable over the last 15 years. Given that medical imaging is the most significant man-made source of ionizing radiation, our findings highlight the importance of the “As Low As Reasonably Achievable” principle [26, 27], particularly in children due to their long life expectancy and rapidly dividing cells [26, 27].

Compared to traditional radiological exams, [¹⁸F]FDG-PET/CT typically delivers higher radiation doses [28] due to its dual sources of radiation: radiopharmaceuticals and anatomical imaging [29]. Therefore, its use in children is approached with caution. Interestingly, our study detected a reduction in the injected [¹⁸F]FDG dose between 2005 and 2021. However, since we reported no variation in our injection protocol throughout the study period, we attribute this finding to the reduction in the age at scan, consistent with the idea of expedited epilepsy surgery in children with DRE [30]. During the study period, the European Association of Nuclear Medicine (EANM) issued several guidelines [31‐34], which formed the basis for international consensus documents [35]. While the study period spans almost two decades, our [¹⁸F]FDG injection strategy, as well as that suggested by international guidelines and consensus documents, did not vary. This proves the generalizability of our results even if our in-house protocol differed from the EANM one. Conversely, the higher administered activity per body weight in females was explainable with random patient-based deviation from the injection protocol. Of note, the radiation concerns differ between children with oncological diseases – who require multiple scans covering broad anatomical areas, including radiosensitive structures, such as the bone marrow, thyroid, and reproductive system [36] – and those with epilepsy, who typically need a single scan. This is reflected in our findings, where 93% of patients were scanned only once. Despite the global trend of shifting from PET/CT to PET/MR, PET/CT continues to be widely used in presurgical protocols of children with DRE [10, 11, 37‐39], hence, validating the ongoing tendency to reduce radiation CT-associated and/or FDG-associated doses observed in oncological scanning [21, 40] in these patients is of paramount importance.

The role of various ancillary diagnostic tools for children with DRE remains a subject of debate [7]. Different experts have favored distinct approaches based on the varying levels of confidence in these techniques. The need for an additional sedation session has been seen as a drawback, deterring pediatric neurologists and epileptologists from recommending [¹⁸F]FDG-PET scans for children with DRE. Nonetheless, [¹⁸F]FDG-PET is highly recommended for specific DRE cohorts, including those with extensive hemispheric lesions, inconclusive EEG or MR findings, or conflicting results from these modalities. These categories were well-represented in our study population, underlining the generalizability of our findings. Additionally, our results, which demonstrate substantial improvements in [¹⁸F]FDG-PET image quality, may bolster the credibility of this technique. Of note, literature shows that [¹⁸F]FDG-PET successfully localized the EZ in 72% of children deemed negative at 3T MR [41]. Further, a recent multicenter study demonstrated that short-term surgical outcomes were similar between MR-positive temporal lobe epilepsy patients with MR-EEG concordance and MR-negative patients with [¹⁸F]FDG-PET-EEG concordance (68% vs. 65%), underscoring the vital role of [¹⁸F]FDG-PET in presurgical evaluation of patients with DRE [10]. Additionally, the introduction of receptor radiotracers has proven to be more sensitive and accurate than [¹⁸F]FDG in localizing the EZ and is expected to yield additional improvements [36, 42].

Our study offers fresh insights into the perceived safety of hybrid scans, particularly [¹⁸F]FDG-PET/CT, among pediatric neurologists and epileptologists. Both standardized measures of radiation dose metrics, DLP and CTDIvol, have significantly decreased – a crucial finding for centers lacking PET/MR scanners. Notably, the CT-associated radiation doses in our study were much lower than those typically reported for traditional brain CT scans in the radiological literature [43, 44]. This reduction is increasingly relevant given the rising awareness of radiation's potential harm, making it an essential consideration for physicians and parents deciding on [¹⁸F]FDG-PET scans for children with DRE. In addition, ongoing technological advancements are expected to further enhance dose reduction, with newer and more efficient scanners [45].

Finally, the dissemination of PET/MR scanners could significantly reduce radiation concerns, providing a comprehensive “one-stop-shop” approach for children with DRE. The superior contrast resolution and the multiparametric capabilities of MR offer additional benefits. However, the widespread availability of such systems remains limited: currently, PET/MRs account for only ~ 1% [46] and 7% [47] of the hybrid scanners in the United States and Europe, respectively.

Over the past fifteen years, there has been a significant decrease in the overall radiation dose associated with hybrid [¹⁸F]FDG-PET/CT scans in children with DRE. This trend is expected to continue with technological advancements in PET/CT scanners and the increasing availability of PET/MR scanners. These developments are likely to promote more judicious use of this advanced and valuable imaging technique.