New MRI findings of late delayed radiation injuries in long-term survivors after radiotherapy: punctate enhanced dot, oval, or rod-like lesions

New MRI findings of late delayed radiation injuries in long-term survivors after radiotherapy: punctate enhanced dot, oval, or rod-like lesions | 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 Research Article New MRI findings of late delayed radiation injuries in long-term survivors after radiotherapy: punctate enhanced dot, oval, or rod-like lesions Kenichiro Asano, Nozomi Fujiwara, Kosuke Katayama, Kiyohide Kakuta, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7283719/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Apr, 2026 Read the published version in Neuroradiology → Version 1 posted You are reading this latest preprint version Abstract Purpose In long-term survivors of central nervous system (CNS) tumors who have undergone radiotherapy, punctate enhancement within the radiation field is sometimes detected on contrast-enhanced (gadolinium) three-dimensional T1-weighted imaging (CE-3D T1WI). However, the clinical characteristics and significance of this finding remain unclear. The purpose of this study was to clarify the characteristics of this radiological finding. Methods Ninety patients who had received radiotherapy between January 2007 and June 2020 and were still alive 24 months later without recurrence were selected. Patients were classified into punctate enhancement (+) group and punctate enhancement (−) group, and their clinical courses were compared. Imaging examinations were performed using standard procedures, including CE-3D T1WI and gradient echo T2*-weighted imaging (T2*WI). Results Punctate enhancement within the radiation field was observed in 25.7% (19/74 cases). The median onset time of punctate enhanced lesions was 37 months. Lesion size remained stable, but in 21.1% of cases (4/19), enhancement resolved, appearing as low intensity on T2*WI. Significant differences were seen between the punctate enhancement (+) group and the punctate enhancement (−) group in the proportions of pathological diagnosis types (p = 0.001). Also, significant differences were seen between both groups in the proportions of radiotherapy techniques (p = 0.001). Higher radiation doses increased the likelihood of punctate enhancement. Conclusion Punctate enhancement is considered to be one of the late delayed radiation injuries occurring in patients with CNS tumors after high-dose radiotherapy. Some of these lesions showed loss of contrast enhancement and changed to low intensity on T2*WI. Late delayed radiation injury Long-term survivor MRI Punctate enhanced lesion Microvasculitis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Due to advances in surgical techniques and the development of radiation and chemotherapy, the treatment outcomes for glioblastoma a typically malignant central nervous system (CNS) tumor, are gradually improving; according to the Brain Tumor Registry of Japan, the 5-year survival rate is 16%, and if radiation and chemotherapy can be administered after complete removal of the tumor, the rate is 25.1%. Similarly, the 5-year survival rate for metastatic brain tumors and primary central nervous system lymphoma (PCNSL) have also improved, at 23.9% and 48.2%, respectively [ 1 ]. Therefore, the percentage of patients who survive longer than 2 years is increasing, and there are many opportunities for magnetic resonance imaging (MRI) follow-up of long-term survivors after radiotherapy. The primary purpose of follow-up MRI in patients with malignant CNS tumors is to detect recurrence early and initiate timely treatment. In recent years, the number of MRI sequences has increased, and they allow visualization of subtle findings. In particular, MRI using three-dimensional T1-weighted imaging (3D T1WI) is a widely used, high spatial resolution T1-weighted 3D sequence that improves the depiction of small enhancing lesions by contrast media compared with the two-dimensional (2D) conventional spin echo (SE) method [ 2 ]. Recently, our research group has noted that when contrast-enhanced (CE)-3D T1WI imaging is performed on patients undergoing long-term follow-up after radiation therapy in daily clinical practice, punctate enhanced lesions with a diameter of a few millimeters that do not change in size. Some of these lesions have also changed to gradient echo T2*-weighted imaging (T2*WI) low-signal intensity lesions. This is difficult to detect with the conventional SE method. Therefore, in this study, patients who had undergone radiation therapy for CNS tumors and had survived for more than 24 months were examined using serial CE-3D T1WI. Furthermore, the long-term changes in these lesions, the onset period, age, radiation dose, and other characteristics were clarified, and related factors were examined. Materials and methods The Institutional Review Board approved this retrospective observational study (No. 2022-017), and the requirement for informed consent was waived. Patient population Our university hospital has been conducting 3D T1WI imaging with MRI since January 2009. Therefore, all patients who had surgery or treatment led by our neurosurgery department, and who had no recurrence within 24 months and were alive for more than 24 months after the end of radiotherapy in January 2007 or later were included. The follow-up period was from the end of radiotherapy to July 2022. Follow-up MRI was performed at least every 3 months. The appearance date of the lesion was defined as the date of the previous follow up MRI scan if the lesion was a punctate enhanced lesion that appeared on the follow-up MRI scan and had not changed on the next follow-up MRI scan 1–3 months later, with the longest diameter being 10 mm or less. If the lesion showed an increasing trend on the next follow-up MRI scan 1–3 months later, it was considered to be a recurrence, and the date of the previous follow up MRI scan was defined as the recurrence date. If the lesion had disappeared, it was considered to be an artifact. Patients who developed punctate enhanced lesions on CE-3D T1-weighted imaging were defined as the punctate enhancement (+) group, whereas those without such lesions during follow-up were defined as the punctate enhancement (−) group. The following cases were excluded: 1) cases in which CE-3D T1WI was not performed in follow-up MRI; 2) cases in which the first lesion appeared more than 24 months and was considered to be a recurrence on the next follow-up MRI; 3) cases in which there were existing lesions, with progressive disease (PD) according to the response assessment in neuro-oncology (RANO) [ 3 ] criteria for target or non-target lesions; 4) cases for which the diagnosis was difficult to determine due to multiple lesions or other lesions; 5) cases with radiation necrosis diagnosed according to the diagnostic criteria in the guidelines [ 4 ]; 6) cases who had undergone stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) at another hospital and had been followed up at our hospital; 7) cases with a history of previous radiotherapy; 8) cases of metastatic brain tumors that have not involved neurosurgery and have received whole-brain radiation therapy (WBRT) or prophylactic cranial irradiation (PCI); and 9) total body irradiation (TBI) cases in which neurosurgery was not involved, such as bone marrow transplants. Patients who had undergone SRS and SRT were excluded because they were not treated at our hospital. Pathological diagnoses were made according to the World Health Organization (WHO) 2021 Classification of Brain Tumors (5th edition), and cases without a genetic diagnosis were defined according to the WHO 2007 Classification of Brain Tumors (4th edition). MRI equipment and imaging conditions The imaging machines used were the Signa Premier 3T (3-tesla) MRI scanner (GE Healthcare, Milwaukee, WI, USA), Signa Artist 1.5T MRI scanner (GE Healthcare), and MAGNETOM Vida 3T MRI scanner (Siemens, Berlin, Germany). The head coil was 8-channel with a 24x24 cm 2 field of view (FOV). Contrast medium was 0.2 ml/kg Gd via intravenous injection. Non-contrast-enhanced (NCE)-three-dimensional T1-weighted imaging (3D T1WI) and CE-3D T1WI were performed with a 0.8-mm gap and 1.6-mm-slice reconstructions (in the case of GE Healthcare, spoiled gradient recalled echo (SPGR); in the case of Siemens, magnetization prepared rapid acquisition with gradient echo (MPRAGE)). CE-three-dimensional magnetic resonance hydrography (3D MR hydrography) was performed with a 0.4-mm gap and 0.8-mm-slice reconstruction (In the case of GE Healthcare, fast imaging employing steady-state acquisition (FIESTA); in the case of Siemens, constructive interference in steady state (CISS)). CE-T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), 3D fluid attenuation inversion recovery (3D FLAIR), and T2*WI were performed with a 1.0-mm gap and 5.0-mm slices. Comprehensive summaries of the specifications and imaging protocols for each MRI device are provided in Supplemental Tables 1–3. Research study items All research was performed as retrospective analyses of data obtained from patient medical records and image servers. Imaging decisions were made by consensus of a board-certified neurosurgeon (KA) and a board-certified neuroradiologist (SK). The items evaluated were lesion appearance rate, visibility of lesions in each imaging sequence (e.g., NCE-3D T1WI, T2WI, T2*WI, 3D FLAIR, CE-3D T1WI, CE-3D MR hydrography, CE-T1WI), shape, age at the end of radiotherapy, sex, differences in appearance by tumor type, radiotherapy technique, and total radiation dose. For the punctate enhancement (+) group, the following information was collected: time to lesion appearance, age at appearance, total number of lesions at first appearance, median number of lesions in one case during follow-up, number of cases with increasing lesions during follow-up, total number of lesions during follow-up, median number of lesions in one case during follow-up, size of lesions appearing, site of origin (frontal, temporal, parietal, occipital, cerebellar, and other), anatomic site of origin (gray matter, white matter, corticomedullary borders, and ventricular walls), and whether they were inside or outside the T2WI or 3D FLAIR high-intensity area. Contrast-enhanced lesions were examined for disappearance, no change, enlargement, recurrence, and the timing of these changes. The number of cases with T2*WI low-signal intensity lesions, the time to the date of first lesion onset, and the total number of T2*WI low-signal intensity lesions during the follow-up period were also examined. The imaging evaluators compared the enlargement of the Virchow-Robin space around the lesion with the Virchow-Robin space on the contralateral side on T2WI. Enlargement was evaluated on a subjective grading scale of + 1 to -1 (+ 1: enlargement compared to the contralateral side, 0: no difference between the left and right sides, -1: shrinkage compared to the contralateral side). However, cases for which the radiation technique was WBRT, irradiation of the ventricular system including the cerebellum, and those with leukoencephalopathy were excluded. Lesion size was measured according to the Macdonald Criteria [ 5 ] by determining the shortest diameter orthogonal to the longest diameter. Partial volume was also included in the measurement. Punctate enhanced lesions were defined as “dots” when the ratio of the longest diameter to the orthogonal shortest diameter was less than 2.0, “oval” when the ratio was between 2.1 and 3.0, and “rod” when the ratio was 3.1 or greater. For convenience, the total dose of radiation was defined as the total dose for all irradiation to the central nervous system, including the spinal cord. Statistics The Chi-squared test was used to examine the significance of differences in sex, whereas Fisher's exact test was used to examine the significance of differences in the types of pathological diagnoses, in the types of radiotherapy techniques, and in laterality in Virchow-Robin space enlargement. The Mann-Whitney U test was performed for age at treatment, median observation period, and total radiation dose, and Pearson’s correlation coefficient was used for the correlation between age at treatment and time to presentation. The significance level of the statistical tests was 5%. The entire statistical analysis was performed on a Mac OSX 12.6.3 operating system, using JMP 15.2.0 (SAS Institute, Cary, NC, USA) statistical software. Results Differences between the punctate enhancement (+) group and the punctate enhancement (−) group. Ninety patients had received radiotherapy for more than 24 months earlier. Of these, 16 were excluded, including 4 cases of recurrence, 4 cases of multiple brain metastases, 1 case of radiation necrosis, and 7 cases that were not followed up with CE-3D T1WI, leaving 74 cases for analysis (Fig. 1 ). The 74 patients studied included 43 males and 31 females, with a median age at the end of radiotherapy of 49.5 years and a median observation period of 55.5 months. During follow-up, punctate enhanced lesions appeared in 19 (25.7%) patients. The median age at the end of radiotherapy was 39 years. Eight (42.1%) were male, and 11 (57.9%) were female. Overall, 13 (68.4%) of the patients had grade 3 glioma, 4 (21.1%) had grade 4 glioma, 1 (5.3%) had medulloblastoma, and 1 (5.3%) had another type of tumor (atypical meningioma). There was a significant difference between the punctate enhancement (+) group and the punctate enhancement (−) group in the proportions of pathological diagnosis types (p = 0.001). Radiotherapy with extended local irradiation was by far the most common type of radiation, accounting for 18 cases (94.7%), followed by craniospinal irradiation (CSI) + posterior fossa local boost radiation therapy (LBRT) for posterior fossa lesions in 1 case (5.3%). Significant differences were seen between the punctate enhancement (+) group and the punctate enhancement (−) group in the proportion of radiotherapy techniques (p = 0.001). There was no incidence of punctate enhanced lesions in patients with PCNSL or brain metastases irradiated with less than 54 gray (Gy) of WBRT or among those with germ cell tumors. However, there were cases of lesions in those with a total dose exceeding 54 Gy, such as grade 3 and 4 gliomas irradiated with 54 Gy or 60 Gy of extended local irradiation and medulloblastoma irradiated with CSI plus posterior fossa LBRT. The median total dose was 60 Gy in both the punctate enhancement (+) group and punctate enhancement (-) group, but there was a significant difference in total radiation dose between the punctate enhancement (+) group and punctate enhancement (-) group (p = 0.004) (Table 1 , Supplemental Table 4). Table 1 Patients’ clinical characteristics for all cases and by group Characteristic All cases (N = 74) Median (IQR), Range N (%)* Punctate enhancement (+) group (N = 19) Median (IQR), Range N (%)* Punctate enhancement (-) group (N = 55) Median (IQR), Range N (%)* p Age at the end of radiotherapy (years old) 49.5 (29.8, 64.3), 2–81 39.0 (33.0, 56.0), 5–64 51.0 (28.0, 67.0), 2–81 0.13 Median observation period (months) 55.5 (42.0, 88.5), 24–180 62.0 (49.0, 131.0), 32–180 52.0 (39.0, 81.0), 11–167 0.17 Sex Male 43 (58.1) 8 (42.1) 35 (63.6) 0.11 Female 31 (41.9) 11 (57.9) 20 (36.4) Pathological diagnosis Glioma grade 2** 1 (1.4) 0 (0) 1 (1.8) 0.001 Glioma grade 3** 27 (36.5) 13 (68.4) 14 (25.5) Glioma grade 4** 19 (26.4) 4 (21.1) 15 (27.3) Medulloblastoma 3 (4.1) 1 (5.3) 2 (3.6) PCNSL 15 (20.3) 0 (0) 15 (27.3) Germ cell tumor 4 (5.4) 0 (0) 4 (7.3) Brain metastases 2 (2.7) 0 (0) 2 (3.6) Others 3 (4.1) 1 (5.3) 2 (3.3) Radiotherapy technique ELRT 53 (71.6) 18 (94.7) 35 (63.6) 0.001 WBRT 9 (12.2) 0 (0) 9 (16.4) WBRT + LBRT 8 (10.8) 0 (0) 8 (14.5) CSI + posterior fossa LBRT 3 (4.1) 1 (5.3) 2 (3.6) LBRT 1 (1.4) 0 (0) 1 (1.8) Total radiation dose (Gy) 60.0 (39.4, 60.0), 23.4–90.0 60.0 (60.0, 60.0), 54.0–72.0 60.0 (36.0, 60.0), 23.4–90.0 0.004 Laterality in Virchow-Robin space enlargement (N = 37) + 1 12 (32.4) 10 (66.7) 2 (9.1) 0.001 0 25 (67.6) 5 (33.3) 20 (90.9) -1 0 (0) 0 (0) 0 (0) ** WHO 2021 Classification of Brain Tumors (5th edition) and WHO 2007 Classification of Brain Tumors (4th edition). IQR = Interquartile range; PCNSL = Primary central nervous system lymphoma; ELRT = Extended local radiotherapy; WBRT = Whole-brain radiotherapy; LBRT = Local brain radiotherapy; CSI = Craniospinal irradiation; +1: enlargement compared to the contralateral side; 0: no difference between the left and right sides; -1: shrinkage compared to the contralateral side Characteristics of punctate enhanced lesions In patients in the punctate enhancement (+) group, the median time to lesion onset was 37 months, and the interquartile range (IQR) varied widely from 31 to 59 months. The median age at onset was 44 years, with a negative correlation with time to onset (p = 0.008, r=-0.587) (Fig. 2 ). The total number of lesions at the time of onset was 24, and the median number of lesions per case was 1. The most common shape was dot type, followed by oval type and rod type (Fig. 3 ). Typical cases were dot-shaped on CE-3D T1WI and CE-3D MR hydrography, and they were difficult to detect on NCE-3D T1WI, 3D FLAIR, T2*WI, NCE-T1WI, CE-T1WI, and T2WI (Fig. 4 a-f). During follow-up, 7 cases (36.8%) showed an increase in the number of lesions. The total number of lesions was 62, with a median of 2 lesions per case. The 56 dot types had a mean orthogonal diameter (standard deviation (SD)) of 2.0 (0.5) mm x 1.5 (0.4) mm. The four oval shapes were 3.6 (0.4) mm x 1.6 (0.3) mm, and the two rod shapes were 6.9 (1.1) mm x 1.6 (0.6) mm. Sites of all punctate enhanced lesions were within the irradiated area, but the majority were in the frontal, parietal, and temporal lobes. They were not related to structural areas such as gray matter, white matter, corticomedullary borders, or ventricular walls. Of the punctate enhanced lesions, 29 (46.8%) appeared within radiation-induced high-intensity areas on T2WI/3D FLAIR, whereas 33 lesions (53.2%) were located outside these areas, indicating no clear spatial correlation. Three-monthly MRI follow-up showed a tendency toward an increase in the total number of lesions over time (Fig. 5 ). Of the total 62 lesions, 50 (80.6%) remained unchanged in size during the course of the disease, 12 (19.4%) disappeared, and there were no lesions that increased in size or recurred after disappearance. During follow-up, 12 punctate enhanced lesions in 4 cases (21.1%) exhibited low signal intensity on T2*WI. The median time to initial appearance of these lesions was 56.5 months, with a median of 1.5 lesions per case. Once a lesion became low-signal intensity on T2*WI, the contrast effect of CE-3D T1WI and CE-3D MR hydrography was lost (Fig. 6 ). All lesions that exhibited low signal intensity on T2*WI originated from punctate (dot type) enhancement; none of the lesions with oval or rod type morphology demonstrated low signal intensity on T2*WI (Table 2 ). Table 2 Characteristics and courses of the 19 cases with punctate enhanced lesions Characteristic Median (IQR), Range, N (%), Mean diameter (long (mm, SD) X short (mm, SD)) Time to first lesion appearance (months) 37 (31, 59), 25–100 Median age at first lesion appearance (years old) 44 (36, 59), 14–66 Total number of first lesion appearance 24 Median number of lesions in one case at first lesion appearance 1 (1, 1), 1–3 Number of cases with increasing lesions during follow-up 7 (36.8) Total number of lesions during follow-up 62 Median number of lesions in one case during follow-up 2 (1, 3), 1–21 Mean diameter at appearance during the course (n = 62) Dot type 56 (90.3), 2.0 (0.5) x 1.5 (0.4) Oval type 4 (6.5), 3.6 (0.4) x 1.6 (0.3) Rod type 2 (3.2), 6.9 (1.1) x 1.6 (0.6) Occurrence sites during the course of the disease (n = 62) Frontal 31 (50.0) Temporal 8 (12.9) Parietal 14 (22.6) Occipital 3 (4.8) Cerebellum 3 (4.8) Other 3 (4.8) Structural locations during the course of the disease (n = 62) Gray matter 20 (32.3) Border gray matter and white matter 17 (27.4) White matter 23 (37.1) Ventricle layer 2 (3.2) Lesion location relative to high-intensity areas on T2WI, FLAIR, or 3D FLAIR (n = 62) Inside 29 (46.8) Outside 33 (53.2) Changes of punctate enhanced lesions (n = 62) Disappearance 12 (19.4) No change 50 (80.6) Enlargement 0 (0.0) Recurrence 0 (0.0) Median time to disappearance of tiny enhanced lesions (months) (n = 12) 12.5 (6.5, 25.5), 3-107 Number of cases with T2*WI low-signal intensity lesions during the course 4 (21.1) Time to first lesion appearance of T2*WI lesions (months) 56.5 (15.75, 98,75), 8-107 Total number of T2*WI lesions during follow-up 12 Median number of T2*WI lesions in one case during follow-up 1.5 (1, 6.5), 1–8 IQR = Interquartile range; SD = Standard deviation; T2WI = T2-weighted imaging; FLAIR = Fluid attenuation inversion recovery; T2*WI = Gradient echo T2*-weighted imaging Laterality in Virchow-Robin space enlargement on T2WI Qualitative evaluation of Virchow-Robin space (VRS) enlargement on the irradiated side was performed using T2-weighted imaging (T2WI). In the punctate enhancement (+) group, 15 cases were analyzed after excluding one case with irradiation of the ventricular system including the cerebellum and three cases with leukoencephalopathy. Among these, VRS enlargement on the irradiated side was rated as + 1 in 10 cases (66.7%) and 0 in 5 cases (33.3%); no cases were rated as − 1. In the punctate enhancement (−) group, 22 cases were analyzed after excluding 18 cases with whole-brain radiotherapy (WBRT), 8 cases with irradiation including the cerebellum and ventricles, and 7 cases with leukoencephalopathy. In this group, VRS enlargement on the irradiated side was rated as + 1 in 2 cases (9.1%) and 0 in 20 cases (90.9%); again, no cases were rated as − 1. Comparison between the punctate enhancement (+) group and (−) group showed that VRS enlargement on the irradiated side was significantly more frequent in the punctate enhancement (+) group (p = 0.001) (Fig. 4 g, Table 1 ). Discussion Frequency of punctate enhanced lesions and clinical background characteristics. The frequency of punctate enhanced lesions of this study was 25.7% (19/74), and onset dates tended to be later in younger patients. There was no significant difference in the occurrence of punctate enhanced lesions by age or sex, but they were presumably affected by radiotherapy technique and dose. The most common techniques were extended local irradiation or whole-brain radiation plus boost, and the higher the total dose, the more likely the punctate enhanced lesions were to occur. The most common diseases were grade 3 or 4 high-grade gliomas and medulloblastomas. PCNSL and brain metastases treated with WBRT of about 30 Gy did not show punctate enhanced lesions. The reason for the negative correlation between age and the onset time from the last irradiation date is unknown. In the literature, it is generally thought that elderly persons are more likely to develop white matter encephalopathy after radiotherapy [ 6 , 7 ]. It is also thought that cerebrovascular disease is more likely to occur, and in particular, it is thought that independent risk factors are present in people aged 50 years and over, and it can be presumed that the damage to brain tissue and blood vessels from radiotherapy is greater [ 8 ]. Therefore, it may be inferred that older patients are more susceptible to brain damage, leading to earlier onset of punctate enhanced lesions, whereas younger patients may experience a delayed onset. Nature of punctate enhanced lesions Punctate enhanced lesions in this study showed permanent imaging changes and developed 2 years or more after radiotherapy, with some cases occurring up to 10 years later. In our preliminary study (unpublished data), patients with a history of radiation less than 2 years earlier did not show punctate enhanced lesions. Late delayed radiation injuries constitute irreversible changes such as radiation-induced brain necrosis, leukoencephalopathy, cerebrovascular disease, and radiation-induced tumors. Therefore, this finding of a small enhanced lesion can be considered one of the irreversible late delayed radiation injuries that has not been noted previously, based on the timing and imaging findings. Previously, routine imaging was performed using NCE-T1WI, T2WI, and CE-T1WI with a slice thickness of 5 mm. Therefore, the punctate enhanced lesions were too small to be detected due to poor spatial resolution, and their presence was only visible with the introduction of CE-3D T1WI. Microvasculitis as a possible pathological mechanism Ultimately, a total of 62 punctate enhanced lesions were identified, with a median of two lesions per patient. Although the pathological mechanisms could not be investigated in this study, the small enhanced lesions were estimated to be microvasculitis of small vessels, mainly represented by Virchow-Robin space vessels, based on their size and shape. In other words, they probably constituted one example of radiation-induced vasculopathy. Radiation-induced vasculopathy generally includes lacunar infarction, moyamoya disease, cavernoma, telangiectasia, aneurysm, and hemorrhage [ 9 ]. The degree of damage depends on the dose applied to normal blood vessels. In the case of low doses, telangiectasia and hemorrhagic infarction often appear after 1 to 2 years, although they are unlikely to occur in the early stages. In contrast, at high doses, vascular edema, thrombosis, and hemorrhage are likely to occur, and necrosis of the vascular wall resulting from the high dose may lead to bleeding and destruction of adjacent structures [ 10 ]. There has been a report comparing autopsy findings after radiation therapy with images taken before the autopsy. Essentially, radiation injury is less likely to occur in gray matter and more likely to occur in deep white matter [ 11 , 12 ]. White matter commonly shows demyelination, small infarcts, necrosis, tissue rarefaction and spongiosis, état criblé-like enlargement of the Virchow-Robin space, old and new microbleeds, and cavernous hemangioma-like changes [ 11 – 13 ]. In small vessels, blood-brain barrier (BBB) disruption, hyaline changes in the vessel wall, and fibrinoid necrosis are seen [ 11 , 13 ]. Rauch et al. [ 12 ] observed a transmural T-cell infiltrate in the vessels, suggesting the presence of microvasculitis. Therefore, the punctate enhanced lesions observed in this study may be indicative of radiation-induced microvasculitis and blood–brain barrier disruption in the Virchow–Robin space, with the underlying pathology characterized by inflammation, hyaline degeneration, and fibrinoid necrosis in the walls of small vessels. Taieb et al. [ 14 ] also considered punctate or curvilinear gadolinium-enhanced lesions as the cause of endothelial cell damage and BBB disruption after radiation therapy. As imaging evidence supporting the hypothesis of microvasculitis in the Virchow–Robin space, a review of 18 cases—including the four reported by Boutet et al.—has been published [ 15 ]. Among the 12 cases with clearly documented clinical courses, seven had a history of radiation therapy and demonstrated enlargement of the Virchow–Robin space surrounding the lesions [ 15 ]. Miyata et al. [ 16 ] also found an association between SLE disease activity and enlargement of the Virchow-Robin space due to microvasculitis in 130 SLE patients, suggesting that microvasculitis and the enlargement of the Virchow-Robin space are closely related. In the present cases, Virchow-Robin space enlargement was observed in the radiation field, which may support the hypothesis of microvasculitis primarily involving the Virchow-Robin space. Signal change of punctate enhanced lesions on T2*WI. In the current study, 21.1% (4/19) of patients demonstrated a change from punctate enhanced lesions on CE-3D T1WI to low intensity on T2*WI. In addition, a total of 12 punctate enhanced lesions showed disappearance of contrast enhancement at a median of 12.5 months. There have been reports of radiation-induced microbleeding [ 17 – 20 ]. In particular, Witzmann et al. [ 20 ] found no occurrence of microbleeding within 2 years, and Shen et al. [ 17 ] found microbleeding in 98.7% of patients with radiation necrosis and 42.9% of patients without radiation necrosis during radiation therapy for nasopharyngeal cancer. Morrison et al. [ 18 ] reported an annual increase in the number of microbleeds and a gradual decrease in the volume of individual hemorrhages over time in a susceptibility-weighted imaging (SWI) study using 7T MRI. Hemorrhages associated with radiation necrosis and hemorrhages in cavernous hemangioma-like lesions are well known [ 21 – 23 ]. Based on the size and temporal pattern of the hemorrhages, the underlying pathophysiology of the punctate enhanced lesions identified in our study appears to differ from that of the hemorrhages associated with radiation necrosis or cavernous hemangioma-like lesions reported in previous studies [ 17 – 23 ]. The observed conversion of punctate enhancing lesions to low signal intensity on T2*WI may indicate a precursor stage of radiation-induced microbleeds which were reported in the literature [ 17 – 20 ]. Furthermore, Bian W et al. [ 24 ] used a 7T multi-echo sequence to visualize arteries, veins, and microbleeds on a single image, concluding that most microbleeds originate from microvasculitis in the small arteries of the Virchow-Robin space. However, they also demonstrated that microbleeds are clearly present on the venous side in some cases. Although the MRI sequences we currently use routinely cannot accurately distinguish whether microbleeds are located in veins or arteries, it is generally believed that small and medium-sized arteries are more susceptible to damage from radiation therapy [ 25 ]. Therefore, we consider that most of the punctate enhanced lesions in the present study likely represented microvasculitis in the Virchow-Robin space, but some may also have been present on the venous side, and it is reasonable to consider microvasculitis within the brain as the underlying cause in a broader sense. Clinical implications and differential diagnosis of punctate enhanced lesions Clinically, the outcome of punctate enhanced lesions is unknown. At the very least, the lesion itself is a punctate lesion, and it is unlikely to be as problematic as leukoencephalopathy or radiation necrosis, regardless of sex, age, or other factors. However, Morrison et al. reported that increased microhemorrhage due to SWI may cause cognitive impairment even in young patients, and future studies are needed. The most important point of differentiation is the very early stage of tumor recurrence, but because of the minute size of the tumor, it is difficult to distinguish it by other sequences, and the lack of enlargement over time is the only point of differentiation. Limitations 1, This was a retrospective study, and the observation period varied from case to case. Therefore, the duration of punctate enhanced lesions and the T2*WI positivity rate may have varied because some patients may have had a short observation period. 2, This study did not include WBRT or prophylactic cranial irradiation cases in brain metastases not managed by neurosurgeons, or total body irradiation cases such as bone marrow transplantation. SRS and SRT cases for brain metastases were also not included, meaning our study population may not be representative of the real-word population of our local area. 3, This study used routine MRI results from 1.5T GE, 3.0T GE, and 3.0T Siemens MRI devices. Therefore, differences in scanner sensitivity may have led to variability in detecting the presence and onset timing of tiny punctate enhanced lesions. 4, All research involved retrospective analyses of data obtained from patient medical records and image servers. However, though all image servers are recorded, medical records are subject to a 5-year retention period under law. Therefore, some patient medical records are not retained. However, all patient summaries are retained, so the main treatment records are accurate. Nevertheless, there are cases for which detailed information such as medical history, complications, and concomitant diseases is not recorded, and so there is a possibility that the clinical course might not have been accurately understood. Conclusion Punctate enhanced lesions may not be clinically significant. However, they may be a result of advances in treatment that have led to the expectation of long-term survival for patients with brain tumors, as well as the increased accuracy of diagnostic equipment such as MRI. This MRI finding may be one type of late delayed radiation injury that tends to occur in patients with CNS tumors who have received high-dose radiation. It may also represent a precursor state of lesions previously considered to be microbleeds caused by radiation therapy. Abbreviations CNS, Central nervous system; PCNSL, Primary central nervous system lymphoma; MRI, Magnetic resonance imaging; 3D, Three-dimensional; 3D T1WI, Three-dimensional T1-weighted imaging; 2D, Two-dimensional; SE, Spin echo; CE, Contrast-enhanced; T2*WI, Gradient echo T2*-weighted imaging; Gd, Gadolinium; PD, Progressive disease; RANO, Response assessment in neuro-oncology; SRS, Stereotactic radiosurgery; SRT, Stereotactic radiotherapy; WBRT, Whole-brain radiation therapy; PCI, Prophylactic cranial irradiation; TBI, Total body irradiation; WHO, World Health Organization; T, Tesla; FOV, Field of view; NCE, Non-contrast-enhanced; SPGR, Spoiled gradient recalled echo; MPRAGE, Magnetization prepared rapid acquisition with gradient echo; 3D MR hydrography, Three-dimensional magnetic resonance hydrography; FIESTA, Fast imaging employing steady-state acquisition, CISS, Constructive interference in steady state; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging; 3D FLAIR, 3D fluid attenuation inversion recovery; CSI, Craniospinal irradiation; LBRT, Local boost radiation therapy; Gy, Gray; IQR, Interquartile range; SD, Standard deviation; BBB, Blood-brain barrier; SWI, Susceptibility-weighted imaging Declarations Funding Declaration: The authors have received no funding for this paper, and also have no personal, financial, or organizational interest in any of the drugs, materials, or equipment described. Disclosure of conflict of interest: All authors have no conflicts to report. Human Ethics and Consent to Participate declarations: This study was conducted with the approval of the ethics committees of Hirosaki University Graduate School of Medicine (2022-017). In addition, since this was a retrospective study, notifications to patients regarding an opt-out option were given on the homepage of Hirosaki University Hospital, and the requirement for informed consent was waived. Ethics declaration: This research was approved by the Hirosaki University Ethics Committee and was conducted in strict accordance with the ethical standards of the 1964 Declaration of Helsinki and its later revisions. Data Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request. Author Contribution KA and SK contributed to the concept and design of the study. SK contributed to support and supervision of the study. KA and SK contributed to acquisition and analysis of the data. KA and MM contributed to statistical analysis of the data. KA, KK1, KK2, NF, and ST, contributed to management of patients. All authors contributed to drafting the text and preparing the figure. References Narita Y (2017) Brain Tumor Registry of Japan (2005–2008). Neurol Med Chir (Tokyo) 57:9–102. https://doi.org/10.2176/nmc.sup.2017-0001 Kakeda S, Korogi Y, Hiai Y et al (2007) Detection of brain metastasis at 3T: comparison among SE, IR-FSE and 3D-GRE sequences. Eur Radiol 17:2345–2351. 10.1007/s00330-007-0599-9 Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972. 10.1200/JCO.2009.26.3541 Committee for the Development of Guidelines for Symptomatic Radiation-Induced Brain Necrosis (2017) Guidelines for the clinical management of symptomatic radiation-induced brain necrosis. 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Neuroradiology 58:221–235. 10.1007/s00234-015-1629-y Boutet A, Son HJ, Malik M et al (2024) Enlarging and shrinking focal perivascular spaces. Neuroradiol J:19714009241242642. 10.1177/19714009241242642 Miyata M, Kakeda S, Iwata S et al (2017) Enlarged perivascular spaces are associated with the disease activity in systemic lupus erythematosus. Sci Rep 7:12566. 10.1038/s41598-017-12966-4 Shen Q, Lin F, Rong X et al (2016) Temporal Cerebral Microbleeds Are Associated With Radiation Necrosis and Cognitive Dysfunction in Patients Treated for Nasopharyngeal Carcinoma. Int J Radiat Oncol Biol Phys 94:1113–1120. 10.1016/j.ijrobp.2015.11.037 Morrison MA, Hess CP, Clarke JL, Butowski N, Chang SM, Molinaro AM, Lupo JM (2019) Risk factors of radiotherapy-induced cerebral microbleeds and serial analysis of their size compared with white matter changes: A 7T MRI study in 113 adult patients with brain tumors. J Magn Reson Imaging 50:868–877. 10.1002/jmri.26651 Morrison MA, Mueller S, Felton E et al (2021) Rate of radiation-induced microbleed formation on 7T MRI relates to cognitive impairment in young patients treated with radiation therapy for a brain tumor. Radiother Oncol 154:145–153. 10.1016/j.radonc.2020.09.028 Witzmann K, Raschke F, Troost EGC (2021) MR Image Changes of Normal-Appearing Brain Tissue after Radiotherapy. Cancers (Basel) 13. 10.3390/cancers13071573 Yoshii Y (2008) Pathological review of late cerebral radionecrosis. Brain Tumor Pathol 25:51–58. 10.1007/s10014-008-0233-9 Jagannathan J, Bourne TD, Schlesinger D, Yen CP, Shaffrey ME, Laws ER Jr., Sheehan JP (2010) Clinical and pathological characteristics of brain metastasis resected after failed radiosurgery. Neurosurgery 66:208–217. 10.1227/01.Neu.0000359318.90478.69 Yamasaki F, Takayasu T, Nosaka R et al (2015) The postirradiation incidence of cavernous angioma is higher in patients with childhood pineoblastoma or primitive neuroectodermal tumors than medulloblastoma. Childs Nerv Syst 31:901–907. 10.1007/s00381-015-2626-5 Bian W, Banerjee S, Kelly DA et al (2015) Simultaneous imaging of radiation-induced cerebral microbleeds, arteries and veins, using a multiple gradient echo sequence at 7 Tesla. J Magn Reson Imaging 42:269–279. 10.1002/jmri.24802 Fajardo LF (2005) The pathology of ionizing radiation as defined by morphologic patterns. Acta Oncol 44:13–22. 10.1080/02841860510007440 Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1rev5.docx SupplementalTable2rev5.docx SupplementalTable3rev5.docx SupplementalTable4rev5.docx Cite Share Download PDF Status: Published Journal Publication published 14 Apr, 2026 Read the published version in Neuroradiology → Version 1 posted 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-7283719","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":501173591,"identity":"a5960ced-64e9-491d-b783-1fac91305b35","order_by":0,"name":"Kenichiro Asano","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIiWNgGAWjYNCCAwwM/BKMDSCmARtUjJmgFskZJGsxuAFhGhB0En//4WcPPpyxyTO+3dz24cMfO2M+Bh4Dhh81DOzmOLRI3EgzN5xxI63Y7M7B5pkz25LN2IBaGHuOMTBbNuDQc4PBTJrnw+HEbTcSm5l5G5ht2OTfGDDwNjAwGxzArkP+/PFvQC3/EzfPAGrh+VNvA7blLx4tBgdygLbcOJC4QQKkhe0w2GHM+GwxvJFTJjnjTHLiDKDDGGe2HTdmY2ArOCxzTAKnX+TOH98m8eGYXWL/jPTHDB/+VBvOb2De+PBNjU0yrhDDDoBOkkgmHEPowI50LaNgFIyCUTBMAQDEclcxBBr/UAAAAABJRU5ErkJggg==","orcid":"","institution":"Hirosaki University","correspondingAuthor":true,"prefix":"","firstName":"Kenichiro","middleName":"","lastName":"Asano","suffix":""},{"id":501173592,"identity":"970feaae-43fe-49bb-8d98-7ce472842283","order_by":1,"name":"Nozomi Fujiwara","email":"","orcid":"","institution":"Hirosaki University","correspondingAuthor":false,"prefix":"","firstName":"Nozomi","middleName":"","lastName":"Fujiwara","suffix":""},{"id":501173595,"identity":"75d35165-cffe-4e47-997b-5c944b927b4b","order_by":2,"name":"Kosuke Katayama","email":"","orcid":"","institution":"Hirosaki University","correspondingAuthor":false,"prefix":"","firstName":"Kosuke","middleName":"","lastName":"Katayama","suffix":""},{"id":501173597,"identity":"f6a198ed-ac21-4980-9f07-f99107991c1c","order_by":3,"name":"Kiyohide Kakuta","email":"","orcid":"","institution":"Hirosaki University","correspondingAuthor":false,"prefix":"","firstName":"Kiyohide","middleName":"","lastName":"Kakuta","suffix":""},{"id":501173599,"identity":"a82cc1f4-51a5-469c-bf16-0c05a2fbbdc3","order_by":4,"name":"Soichiro Tatsuo","email":"","orcid":"","institution":"Hirosaki University","correspondingAuthor":false,"prefix":"","firstName":"Soichiro","middleName":"","lastName":"Tatsuo","suffix":""},{"id":501173601,"identity":"6f5cf167-8541-4f33-aab8-44759e504b62","order_by":5,"name":"Masashi Matsuzaka","email":"","orcid":"","institution":"Hirosaki University","correspondingAuthor":false,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Matsuzaka","suffix":""},{"id":501173603,"identity":"049dc2a0-f3a1-49c2-bdb5-0878d11b5914","order_by":6,"name":"Shingo Kakeda","email":"","orcid":"","institution":"Hirosaki University","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Kakeda","suffix":""}],"badges":[],"createdAt":"2025-08-03 13:53:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7283719/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7283719/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00234-026-03994-x","type":"published","date":"2026-04-14T15:57:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89560500,"identity":"7e755c7d-36c5-4149-b62f-53e4885077fc","added_by":"auto","created_at":"2025-08-21 10:19:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":122427,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT-style flow diagram of the study. This study enrolled 90 long-term survivors from the end of radiotherapy, of which 74 patients were included in the study, excluding those with recurrence, multiple brain metastases, radiation necrosis that was difficult to differentiate, and those for whom CE-3D T1WI had not been obtained.\u003c/p\u003e","description":"","filename":"Fig.1rev5.png","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/6a7d78220ba6647f817a4ca3.png"},{"id":89560503,"identity":"e95ffa03-29e5-4fbe-a159-25515612e10b","added_by":"auto","created_at":"2025-08-21 10:19:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":164596,"visible":true,"origin":"","legend":"\u003cp\u003eAge at treatment correlates with lesion onset, with a negative correlation between time to onset of punctate enhanced lesions and age at onset (Pearson’s correlation coefficient, p=0.008, r=-0.587). The dashed line is the elliptic probability of 0.95 for the bivariate normal distribution.\u003c/p\u003e","description":"","filename":"Fig.2rev5.png","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/aa23c645c2cfe93daab76325.png"},{"id":89564433,"identity":"8998ab6c-2f3b-4a0f-bc3f-d40acd4cc113","added_by":"auto","created_at":"2025-08-21 10:35:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":302817,"visible":true,"origin":"","legend":"\u003cp\u003eTypical punctate enhanced lesion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea:\u003c/strong\u003e Dot type with the ratio of the shortest diameter to the longest diameter orthogonal to the longest diameter less than 2.0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb:\u003c/strong\u003e Oval type with a ratio of 2.1 to 3.0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec: \u003c/strong\u003eRod type with ratios greater than 3.1.\u003c/p\u003e","description":"","filename":"Fig.3rev5.png","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/aeeadb76d99bae879c04ecbe.png"},{"id":89560508,"identity":"a127f2f5-7bfa-4351-9e86-824b19289f7c","added_by":"auto","created_at":"2025-08-21 10:19:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":617987,"visible":true,"origin":"","legend":"\u003cp\u003eImages of punctate enhanced lesions in various MRI sequences in the same case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea: \u003c/strong\u003eNCE-3D T1WI shows a dot-like lesion in the white matter as an equivocal lesion, but it is difficult to determine whether it is the correct lesion (dashed white circle).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb:\u003c/strong\u003e A punctate enhanced lesion can be detected in the white matter by CE-3D T1WI (solid white circle).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec: \u003c/strong\u003eA punctate enhanced lesion can be detected in the white matter by CE-3D MR hydrography (solid white circle).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ed: \u003c/strong\u003e3D FLAIR shows a dot-like lesion in the white matter as an equivocal lesion, but it is difficult to determine whether it is the same lesion because the difference from other lesions is not clear (dashed white circle).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ee: \u003c/strong\u003eT2*WI cannot detect a punctate enhanced lesion at all (dashed white circle).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ef: \u003c/strong\u003eCE-T1WI also fails to detect a punctate enhanced lesion at all (dashed white circle).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eg:\u003c/strong\u003e T2WI shows marked enlargement of the Virchow-Robin space on the side of radiotherapy (large red dashed line).\u003c/p\u003e","description":"","filename":"Fig.4rev5.png","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/4418cfa8077f5adbbd1d8a39.png"},{"id":89562927,"identity":"49d66b66-0884-49d9-8cf7-0bd2b4cfd42f","added_by":"auto","created_at":"2025-08-21 10:27:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1031353,"visible":true,"origin":"","legend":"\u003cp\u003eTime course and lesion increase in the same case. All sequences are CE-3D T1WI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea–c:\u003c/strong\u003e 28 months after completion of treatment. One punctate enhanced lesion can be detected in the white matter only in A (white arrow). No lesions in B and C.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ed–f: \u003c/strong\u003e32 months after completion of treatment. A punctate enhanced lesion in D (white arrow) remains unchanged, and the contrast effect continues. However, a new punctate enhanced lesion appears in E (solid white circle). No lesions in F.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eg–i: \u003c/strong\u003e36 months after completion of treatment. Two lesions (white arrow in G and solid white circle in H) remain unchanged. A new punctate enhanced lesion appears in I (white arrowhead).\u003c/p\u003e","description":"","filename":"Fig.5rev5.png","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/85ce4e3cf6466c472e876e28.png"},{"id":89560515,"identity":"42ae8535-35f3-4844-a78a-1beb69d0130d","added_by":"auto","created_at":"2025-08-21 10:19:34","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":627635,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in a punctate enhanced lesion with time in the same patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea: \u003c/strong\u003eCE-3D T1WI at 127 months post-treatment, A punctate enhanced lesion is detectable in the white matter (solid white circle).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb: \u003c/strong\u003eCE-3D MR hydrography at 127 months post-treatment, A punctate enhanced lesion is detectable in the white matter (solid white circle).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec: \u003c/strong\u003eT2*WI at 127 months post-treatment. No lesions are detectable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ed: \u003c/strong\u003eCE-3D T1WI at 131 months post-treatment, with almost no contrast effect and a central dot-like low-intensity area (solid white circle). A new dot-like punctate enhanced lesion has appeared in another area (white arrow).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ee: \u003c/strong\u003eCE-3D MR hydrography at 131 months post-treatment, with almost no detectable contrast effect (solid white circle). A new dot-like punctate enhanced lesion of CE-3D T1WI is not detectable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ef: \u003c/strong\u003eT2*WI at 131 months post-treatment. There is a clear low-intensity dot-like lesion (solid red circle).\u003c/p\u003e","description":"","filename":"Fig.6rev5.png","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/32a7513f17fe6bb2e06d5014.png"},{"id":107350731,"identity":"c163aa95-fb3f-437b-bca0-a30b701cc2dc","added_by":"auto","created_at":"2026-04-20 16:01:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4960256,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/58dd3fe3-a04e-4c96-b935-2a38489ec59f.pdf"},{"id":89560501,"identity":"5c2268ee-ac24-4d51-bea2-911a1f2e1157","added_by":"auto","created_at":"2025-08-21 10:19:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20822,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1rev5.docx","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/a5a495a6e0f64059d604f2bf.docx"},{"id":89560505,"identity":"b1ff2995-689d-409c-b0a6-8db2bb841297","added_by":"auto","created_at":"2025-08-21 10:19:34","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18751,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable2rev5.docx","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/10110f08a214ad602beb4555.docx"},{"id":89565405,"identity":"b6991339-c6fb-40db-9782-acecca192c55","added_by":"auto","created_at":"2025-08-21 10:43:34","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":18104,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable3rev5.docx","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/0a285a9649a59edcab5d688e.docx"},{"id":89562926,"identity":"9942f7d7-eae2-4d58-aa40-f931081b71a1","added_by":"auto","created_at":"2025-08-21 10:27:34","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":27689,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable4rev5.docx","url":"https://assets-eu.researchsquare.com/files/rs-7283719/v1/c87520528973bb6a8195613e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"New MRI findings of late delayed radiation injuries in long-term survivors after radiotherapy: punctate enhanced dot, oval, or rod-like lesions","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDue to advances in surgical techniques and the development of radiation and chemotherapy, the treatment outcomes for glioblastoma a typically malignant central nervous system (CNS) tumor, are gradually improving; according to the Brain Tumor Registry of Japan, the 5-year survival rate is 16%, and if radiation and chemotherapy can be administered after complete removal of the tumor, the rate is 25.1%. Similarly, the 5-year survival rate for metastatic brain tumors and primary central nervous system lymphoma (PCNSL) have also improved, at 23.9% and 48.2%, respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Therefore, the percentage of patients who survive longer than 2 years is increasing, and there are many opportunities for magnetic resonance imaging (MRI) follow-up of long-term survivors after radiotherapy.\u003c/p\u003e\u003cp\u003eThe primary purpose of follow-up MRI in patients with malignant CNS tumors is to detect recurrence early and initiate timely treatment. In recent years, the number of MRI sequences has increased, and they allow visualization of subtle findings. In particular, MRI using three-dimensional T1-weighted imaging (3D T1WI) is a widely used, high spatial resolution T1-weighted 3D sequence that improves the depiction of small enhancing lesions by contrast media compared with the two-dimensional (2D) conventional spin echo (SE) method [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecently, our research group has noted that when contrast-enhanced (CE)-3D T1WI imaging is performed on patients undergoing long-term follow-up after radiation therapy in daily clinical practice, punctate enhanced lesions with a diameter of a few millimeters that do not change in size. Some of these lesions have also changed to gradient echo T2*-weighted imaging (T2*WI) low-signal intensity lesions. This is difficult to detect with the conventional SE method.\u003c/p\u003e\u003cp\u003eTherefore, in this study, patients who had undergone radiation therapy for CNS tumors and had survived for more than 24 months were examined using serial CE-3D T1WI. Furthermore, the long-term changes in these lesions, the onset period, age, radiation dose, and other characteristics were clarified, and related factors were examined.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThe Institutional Review Board approved this retrospective observational study (No. 2022-017), and the requirement for informed consent was waived.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePatient population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOur university hospital has been conducting 3D T1WI imaging with MRI since January 2009. Therefore, all patients who had surgery or treatment led by our neurosurgery department, and who had no recurrence within 24 months and were alive for more than 24 months after the end of radiotherapy in January 2007 or later were included. The follow-up period was from the end of radiotherapy to July 2022.\u003c/p\u003e\u003cp\u003eFollow-up MRI was performed at least every 3 months. The appearance date of the lesion was defined as the date of the previous follow up MRI scan if the lesion was a punctate enhanced lesion that appeared on the follow-up MRI scan and had not changed on the next follow-up MRI scan 1\u0026ndash;3 months later, with the longest diameter being 10 mm or less. If the lesion showed an increasing trend on the next follow-up MRI scan 1\u0026ndash;3 months later, it was considered to be a recurrence, and the date of the previous follow up MRI scan was defined as the recurrence date. If the lesion had disappeared, it was considered to be an artifact. Patients who developed punctate enhanced lesions on CE-3D T1-weighted imaging were defined as the punctate enhancement (+) group, whereas those without such lesions during follow-up were defined as the punctate enhancement (\u0026minus;) group.\u003c/p\u003e\u003cp\u003eThe following cases were excluded: 1) cases in which CE-3D T1WI was not performed in follow-up MRI; 2) cases in which the first lesion appeared more than 24 months and was considered to be a recurrence on the next follow-up MRI; 3) cases in which there were existing lesions, with progressive disease (PD) according to the response assessment in neuro-oncology (RANO) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] criteria for target or non-target lesions; 4) cases for which the diagnosis was difficult to determine due to multiple lesions or other lesions; 5) cases with radiation necrosis diagnosed according to the diagnostic criteria in the guidelines [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]; 6) cases who had undergone stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) at another hospital and had been followed up at our hospital; 7) cases with a history of previous radiotherapy; 8) cases of metastatic brain tumors that have not involved neurosurgery and have received whole-brain radiation therapy (WBRT) or prophylactic cranial irradiation (PCI); and 9) total body irradiation (TBI) cases in which neurosurgery was not involved, such as bone marrow transplants.\u003c/p\u003e\u003cp\u003ePatients who had undergone SRS and SRT were excluded because they were not treated at our hospital. Pathological diagnoses were made according to the World Health Organization (WHO) 2021 Classification of Brain Tumors (5th edition), and cases without a genetic diagnosis were defined according to the WHO 2007 Classification of Brain Tumors (4th edition).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMRI equipment and imaging conditions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe imaging machines used were the Signa Premier 3T (3-tesla) MRI scanner (GE Healthcare, Milwaukee, WI, USA), Signa Artist 1.5T MRI scanner (GE Healthcare), and MAGNETOM Vida 3T MRI scanner (Siemens, Berlin, Germany). The head coil was 8-channel with a 24x24 cm\u003csup\u003e2\u003c/sup\u003e field of view (FOV). Contrast medium was 0.2 ml/kg Gd via intravenous injection. Non-contrast-enhanced (NCE)-three-dimensional T1-weighted imaging (3D T1WI) and CE-3D T1WI were performed with a 0.8-mm gap and 1.6-mm-slice reconstructions (in the case of GE Healthcare, spoiled gradient recalled echo (SPGR); in the case of Siemens, magnetization prepared rapid acquisition with gradient echo (MPRAGE)). CE-three-dimensional magnetic resonance hydrography (3D MR hydrography) was performed with a 0.4-mm gap and 0.8-mm-slice reconstruction (In the case of GE Healthcare, fast imaging employing steady-state acquisition (FIESTA); in the case of Siemens, constructive interference in steady state (CISS)). CE-T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), 3D fluid attenuation inversion recovery (3D FLAIR), and T2*WI were performed with a 1.0-mm gap and 5.0-mm slices. Comprehensive summaries of the specifications and imaging protocols for each MRI device are provided in Supplemental Tables\u0026nbsp;1\u0026ndash;3.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResearch study items\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll research was performed as retrospective analyses of data obtained from patient medical records and image servers. Imaging decisions were made by consensus of a board-certified neurosurgeon (KA) and a board-certified neuroradiologist (SK).\u003c/p\u003e\u003cp\u003eThe items evaluated were lesion appearance rate, visibility of lesions in each imaging sequence (e.g., NCE-3D T1WI, T2WI, T2*WI, 3D FLAIR, CE-3D T1WI, CE-3D MR hydrography, CE-T1WI), shape, age at the end of radiotherapy, sex, differences in appearance by tumor type, radiotherapy technique, and total radiation dose.\u003c/p\u003e\u003cp\u003eFor the punctate enhancement (+) group, the following information was collected: time to lesion appearance, age at appearance, total number of lesions at first appearance, median number of lesions in one case during follow-up, number of cases with increasing lesions during follow-up, total number of lesions during follow-up, median number of lesions in one case during follow-up, size of lesions appearing, site of origin (frontal, temporal, parietal, occipital, cerebellar, and other), anatomic site of origin (gray matter, white matter, corticomedullary borders, and ventricular walls), and whether they were inside or outside the T2WI or 3D FLAIR high-intensity area. Contrast-enhanced lesions were examined for disappearance, no change, enlargement, recurrence, and the timing of these changes. The number of cases with T2*WI low-signal intensity lesions, the time to the date of first lesion onset, and the total number of T2*WI low-signal intensity lesions during the follow-up period were also examined.\u003c/p\u003e\u003cp\u003eThe imaging evaluators compared the enlargement of the Virchow-Robin space around the lesion with the Virchow-Robin space on the contralateral side on T2WI. Enlargement was evaluated on a subjective grading scale of +\u0026thinsp;1 to -1 (+\u0026thinsp;1: enlargement compared to the contralateral side, 0: no difference between the left and right sides, -1: shrinkage compared to the contralateral side). However, cases for which the radiation technique was WBRT, irradiation of the ventricular system including the cerebellum, and those with leukoencephalopathy were excluded.\u003c/p\u003e\u003cp\u003eLesion size was measured according to the Macdonald Criteria [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] by determining the shortest diameter orthogonal to the longest diameter. Partial volume was also included in the measurement. Punctate enhanced lesions were defined as \u0026ldquo;dots\u0026rdquo; when the ratio of the longest diameter to the orthogonal shortest diameter was less than 2.0, \u0026ldquo;oval\u0026rdquo; when the ratio was between 2.1 and 3.0, and \u0026ldquo;rod\u0026rdquo; when the ratio was 3.1 or greater. For convenience, the total dose of radiation was defined as the total dose for all irradiation to the central nervous system, including the spinal cord.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe Chi-squared test was used to examine the significance of differences in sex, whereas Fisher's exact test was used to examine the significance of differences in the types of pathological diagnoses, in the types of radiotherapy techniques, and in laterality in Virchow-Robin space enlargement. The Mann-Whitney U test was performed for age at treatment, median observation period, and total radiation dose, and Pearson\u0026rsquo;s correlation coefficient was used for the correlation between age at treatment and time to presentation. The significance level of the statistical tests was 5%.\u003c/p\u003e\u003cp\u003eThe entire statistical analysis was performed on a Mac OSX 12.6.3 operating system, using JMP 15.2.0 (SAS Institute, Cary, NC, USA) statistical software.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eDifferences between the punctate enhancement (+) group and the punctate enhancement (\u0026minus;) group.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNinety patients had received radiotherapy for more than 24 months earlier. Of these, 16 were excluded, including 4 cases of recurrence, 4 cases of multiple brain metastases, 1 case of radiation necrosis, and 7 cases that were not followed up with CE-3D T1WI, leaving 74 cases for analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe 74 patients studied included 43 males and 31 females, with a median age at the end of radiotherapy of 49.5 years and a median observation period of 55.5 months. During follow-up, punctate enhanced lesions appeared in 19 (25.7%) patients. The median age at the end of radiotherapy was 39 years. Eight (42.1%) were male, and 11 (57.9%) were female. Overall, 13 (68.4%) of the patients had grade 3 glioma, 4 (21.1%) had grade 4 glioma, 1 (5.3%) had medulloblastoma, and 1 (5.3%) had another type of tumor (atypical meningioma). There was a significant difference between the punctate enhancement (+) group and the punctate enhancement (\u0026minus;) group in the proportions of pathological diagnosis types (p\u0026thinsp;=\u0026thinsp;0.001). Radiotherapy with extended local irradiation was by far the most common type of radiation, accounting for 18 cases (94.7%), followed by craniospinal irradiation (CSI)\u0026thinsp;+\u0026thinsp;posterior fossa local boost radiation therapy (LBRT) for posterior fossa lesions in 1 case (5.3%). Significant differences were seen between the punctate enhancement (+) group and the punctate enhancement (\u0026minus;) group in the proportion of radiotherapy techniques (p\u0026thinsp;=\u0026thinsp;0.001). There was no incidence of punctate enhanced lesions in patients with PCNSL or brain metastases irradiated with less than 54 gray (Gy) of WBRT or among those with germ cell tumors. However, there were cases of lesions in those with a total dose exceeding 54 Gy, such as grade 3 and 4 gliomas irradiated with 54 Gy or 60 Gy of extended local irradiation and medulloblastoma irradiated with CSI plus posterior fossa LBRT. The median total dose was 60 Gy in both the punctate enhancement (+) group and punctate enhancement (-) group, but there was a significant difference in total radiation dose between the punctate enhancement (+) group and punctate enhancement (-) group (p\u0026thinsp;=\u0026thinsp;0.004) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Supplemental Table\u0026nbsp;4).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatients\u0026rsquo; clinical characteristics for all cases and by group\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll cases (N\u0026thinsp;=\u0026thinsp;74)\u003c/p\u003e\u003cp\u003eMedian (IQR), Range\u003c/p\u003e\u003cp\u003eN (%)*\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePunctate enhancement (+) group (N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e\u003cp\u003eMedian (IQR), Range\u003c/p\u003e\u003cp\u003eN (%)*\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePunctate enhancement (-) group (N\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e\u003cp\u003eMedian (IQR), Range\u003c/p\u003e\u003cp\u003eN (%)*\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eAge at the end of radiotherapy (years old)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e49.5 (29.8, 64.3), 2\u0026ndash;81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39.0 (33.0, 56.0), 5\u0026ndash;64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e51.0 (28.0, 67.0), 2\u0026ndash;81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eMedian observation period (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e55.5 (42.0, 88.5), 24\u0026ndash;180\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e62.0 (49.0, 131.0), 32\u0026ndash;180\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e52.0 (39.0, 81.0), 11\u0026ndash;167\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e43 (58.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (42.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35 (63.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31 (41.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11 (57.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20 (36.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e\u003cp\u003ePathological diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGlioma grade 2**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"7\" rowspan=\"8\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGlioma grade 3**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27 (36.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13 (68.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e14 (25.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGlioma grade 4**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19 (26.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (21.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15 (27.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eMedulloblastoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 (3.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003ePCNSL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15 (20.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15 (27.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGerm cell tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (5.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4 (7.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eBrain metastases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (2.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 (3.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 (3.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eRadiotherapy technique\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eELRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53 (71.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e18 (94.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35 (63.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eWBRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (12.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e9 (16.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eWBRT\u0026thinsp;+\u0026thinsp;LBRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 (10.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8 (14.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eCSI\u0026thinsp;+\u0026thinsp;posterior fossa LBRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 (3.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eLBRT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1 (1.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eTotal radiation dose (Gy)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60.0 (39.4, 60.0), 23.4\u0026ndash;90.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e60.0 (60.0, 60.0), 54.0\u0026ndash;72.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e60.0 (36.0, 60.0), 23.4\u0026ndash;90.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" morerows=\"2\" nameend=\"c2\" namest=\"c1\" rowspan=\"3\"\u003e\u003cp\u003eLaterality in Virchow-Robin space enlargement\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e+\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (66.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 (9.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25 (67.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (33.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20 (90.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e** WHO 2021 Classification of Brain Tumors (5th edition) and WHO 2007 Classification of Brain Tumors (4th edition).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eIQR\u0026thinsp;=\u0026thinsp;Interquartile range; PCNSL\u0026thinsp;=\u0026thinsp;Primary central nervous system lymphoma; ELRT\u0026thinsp;=\u0026thinsp;Extended local radiotherapy; WBRT\u0026thinsp;=\u0026thinsp;Whole-brain radiotherapy; LBRT\u0026thinsp;=\u0026thinsp;Local brain radiotherapy; CSI\u0026thinsp;=\u0026thinsp;Craniospinal irradiation; +1: enlargement compared to the contralateral side; 0: no difference between the left and right sides; -1: shrinkage compared to the contralateral side\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eCharacteristics of punctate enhanced lesions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn patients in the punctate enhancement (+) group, the median time to lesion onset was 37 months, and the interquartile range (IQR) varied widely from 31 to 59 months. The median age at onset was 44 years, with a negative correlation with time to onset (p\u0026thinsp;=\u0026thinsp;0.008, r=-0.587) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The total number of lesions at the time of onset was 24, and the median number of lesions per case was 1. The most common shape was dot type, followed by oval type and rod type (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Typical cases were dot-shaped on CE-3D T1WI and CE-3D MR hydrography, and they were difficult to detect on NCE-3D T1WI, 3D FLAIR, T2*WI, NCE-T1WI, CE-T1WI, and T2WI (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea-f).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eDuring follow-up, 7 cases (36.8%) showed an increase in the number of lesions. The total number of lesions was 62, with a median of 2 lesions per case. The 56 dot types had a mean orthogonal diameter (standard deviation (SD)) of 2.0 (0.5) mm x 1.5 (0.4) mm. The four oval shapes were 3.6 (0.4) mm x 1.6 (0.3) mm, and the two rod shapes were 6.9 (1.1) mm x 1.6 (0.6) mm. Sites of all punctate enhanced lesions were within the irradiated area, but the majority were in the frontal, parietal, and temporal lobes. They were not related to structural areas such as gray matter, white matter, corticomedullary borders, or ventricular walls. Of the punctate enhanced lesions, 29 (46.8%) appeared within radiation-induced high-intensity areas on T2WI/3D FLAIR, whereas 33 lesions (53.2%) were located outside these areas, indicating no clear spatial correlation. Three-monthly MRI follow-up showed a tendency toward an increase in the total number of lesions over time (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Of the total 62 lesions, 50 (80.6%) remained unchanged in size during the course of the disease, 12 (19.4%) disappeared, and there were no lesions that increased in size or recurred after disappearance.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eDuring follow-up, 12 punctate enhanced lesions in 4 cases (21.1%) exhibited low signal intensity on T2*WI. The median time to initial appearance of these lesions was 56.5 months, with a median of 1.5 lesions per case. Once a lesion became low-signal intensity on T2*WI, the contrast effect of CE-3D T1WI and CE-3D MR hydrography was lost (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). All lesions that exhibited low signal intensity on T2*WI originated from punctate (dot type) enhancement; none of the lesions with oval or rod type morphology demonstrated low signal intensity on T2*WI (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eCharacteristics and courses of the 19 cases with punctate enhanced lesions\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMedian (IQR), Range,\u003c/p\u003e\u003cp\u003eN (%),\u003c/p\u003e\u003cp\u003eMean diameter (long (mm, SD) X short (mm, SD))\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTime to first lesion appearance (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37 (31, 59), 25\u0026ndash;100\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eMedian age at first lesion appearance (years old)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44 (36, 59), 14\u0026ndash;66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTotal number of first lesion appearance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eMedian number of lesions in one case at first lesion appearance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1, 1), 1\u0026ndash;3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eNumber of cases with increasing lesions during follow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (36.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTotal number of lesions during follow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eMedian number of lesions in one case during follow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1, 3), 1\u0026ndash;21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eMean diameter at appearance during the course (n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDot type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56 (90.3), 2.0 (0.5) x 1.5 (0.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOval type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (6.5), 3.6 (0.4) x 1.6 (0.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRod type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (3.2), 6.9 (1.1) x 1.6 (0.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003eOccurrence sites during the course of the disease (n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFrontal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31 (50.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTemporal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (12.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParietal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (22.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOccipital\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (4.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCerebellum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (4.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (4.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eStructural locations during the course of the disease (n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGray matter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (32.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBorder gray matter and white matter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (27.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWhite matter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (37.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVentricle layer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (3.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eLesion location relative to high-intensity areas on T2WI, FLAIR, or 3D FLAIR (n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInside\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29 (46.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOutside\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33 (53.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eChanges of punctate enhanced lesions (n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDisappearance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (19.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50 (80.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEnlargement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRecurrence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eMedian time to disappearance of tiny enhanced lesions (months) (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.5 (6.5, 25.5), 3-107\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eNumber of cases with T2*WI low-signal intensity lesions during the course\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (21.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTime to first lesion appearance of T2*WI lesions (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56.5 (15.75, 98,75), 8-107\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTotal number of T2*WI lesions during follow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eMedian number of T2*WI lesions in one case during follow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.5 (1, 6.5), 1\u0026ndash;8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eIQR\u0026thinsp;=\u0026thinsp;Interquartile range; SD\u0026thinsp;=\u0026thinsp;Standard deviation; T2WI\u0026thinsp;=\u0026thinsp;T2-weighted imaging; FLAIR\u0026thinsp;=\u0026thinsp;Fluid attenuation inversion recovery; T2*WI\u0026thinsp;=\u0026thinsp;Gradient echo T2*-weighted imaging\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eLaterality in Virchow-Robin space enlargement on T2WI\u003c/b\u003e\u003c/p\u003e\u003cp\u003eQualitative evaluation of Virchow-Robin space (VRS) enlargement on the irradiated side was performed using T2-weighted imaging (T2WI). In the punctate enhancement (+) group, 15 cases were analyzed after excluding one case with irradiation of the ventricular system including the cerebellum and three cases with leukoencephalopathy. Among these, VRS enlargement on the irradiated side was rated as +\u0026thinsp;1 in 10 cases (66.7%) and 0 in 5 cases (33.3%); no cases were rated as \u0026minus;\u0026thinsp;1. In the punctate enhancement (\u0026minus;) group, 22 cases were analyzed after excluding 18 cases with whole-brain radiotherapy (WBRT), 8 cases with irradiation including the cerebellum and ventricles, and 7 cases with leukoencephalopathy. In this group, VRS enlargement on the irradiated side was rated as +\u0026thinsp;1 in 2 cases (9.1%) and 0 in 20 cases (90.9%); again, no cases were rated as \u0026minus;\u0026thinsp;1. Comparison between the punctate enhancement (+) group and (\u0026minus;) group showed that VRS enlargement on the irradiated side was significantly more frequent in the punctate enhancement (+) group (p\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eg, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cb\u003eFrequency of punctate enhanced lesions and clinical background characteristics.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe frequency of punctate enhanced lesions of this study was 25.7% (19/74), and onset dates tended to be later in younger patients. There was no significant difference in the occurrence of punctate enhanced lesions by age or sex, but they were presumably affected by radiotherapy technique and dose. The most common techniques were extended local irradiation or whole-brain radiation plus boost, and the higher the total dose, the more likely the punctate enhanced lesions were to occur. The most common diseases were grade 3 or 4 high-grade gliomas and medulloblastomas. PCNSL and brain metastases treated with WBRT of about 30 Gy did not show punctate enhanced lesions. The reason for the negative correlation between age and the onset time from the last irradiation date is unknown. In the literature, it is generally thought that elderly persons are more likely to develop white matter encephalopathy after radiotherapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It is also thought that cerebrovascular disease is more likely to occur, and in particular, it is thought that independent risk factors are present in people aged 50 years and over, and it can be presumed that the damage to brain tissue and blood vessels from radiotherapy is greater [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, it may be inferred that older patients are more susceptible to brain damage, leading to earlier onset of punctate enhanced lesions, whereas younger patients may experience a delayed onset.\u003c/p\u003e\u003cp\u003e\u003cb\u003eNature of punctate enhanced lesions\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePunctate enhanced lesions in this study showed permanent imaging changes and developed 2 years or more after radiotherapy, with some cases occurring up to 10 years later. In our preliminary study (unpublished data), patients with a history of radiation less than 2 years earlier did not show punctate enhanced lesions.\u003c/p\u003e\u003cp\u003eLate delayed radiation injuries constitute irreversible changes such as radiation-induced brain necrosis, leukoencephalopathy, cerebrovascular disease, and radiation-induced tumors. Therefore, this finding of a small enhanced lesion can be considered one of the irreversible late delayed radiation injuries that has not been noted previously, based on the timing and imaging findings. Previously, routine imaging was performed using NCE-T1WI, T2WI, and CE-T1WI with a slice thickness of 5 mm. Therefore, the punctate enhanced lesions were too small to be detected due to poor spatial resolution, and their presence was only visible with the introduction of CE-3D T1WI.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMicrovasculitis as a possible pathological mechanism\u003c/b\u003e\u003c/p\u003e\u003cp\u003eUltimately, a total of 62 punctate enhanced lesions were identified, with a median of two lesions per patient. Although the pathological mechanisms could not be investigated in this study, the small enhanced lesions were estimated to be microvasculitis of small vessels, mainly represented by Virchow-Robin space vessels, based on their size and shape. In other words, they probably constituted one example of radiation-induced vasculopathy. Radiation-induced vasculopathy generally includes lacunar infarction, moyamoya disease, cavernoma, telangiectasia, aneurysm, and hemorrhage [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The degree of damage depends on the dose applied to normal blood vessels. In the case of low doses, telangiectasia and hemorrhagic infarction often appear after 1 to 2 years, although they are unlikely to occur in the early stages. In contrast, at high doses, vascular edema, thrombosis, and hemorrhage are likely to occur, and necrosis of the vascular wall resulting from the high dose may lead to bleeding and destruction of adjacent structures [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. There has been a report comparing autopsy findings after radiation therapy with images taken before the autopsy. Essentially, radiation injury is less likely to occur in gray matter and more likely to occur in deep white matter [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. White matter commonly shows demyelination, small infarcts, necrosis, tissue rarefaction and spongiosis, \u0026eacute;tat cribl\u0026eacute;-like enlargement of the Virchow-Robin space, old and new microbleeds, and cavernous hemangioma-like changes [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In small vessels, blood-brain barrier (BBB) disruption, hyaline changes in the vessel wall, and fibrinoid necrosis are seen [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Rauch et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] observed a transmural T-cell infiltrate in the vessels, suggesting the presence of microvasculitis. Therefore, the punctate enhanced lesions observed in this study may be indicative of radiation-induced microvasculitis and blood\u0026ndash;brain barrier disruption in the Virchow\u0026ndash;Robin space, with the underlying pathology characterized by inflammation, hyaline degeneration, and fibrinoid necrosis in the walls of small vessels. Taieb et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] also considered punctate or curvilinear gadolinium-enhanced lesions as the cause of endothelial cell damage and BBB disruption after radiation therapy. As imaging evidence supporting the hypothesis of microvasculitis in the Virchow\u0026ndash;Robin space, a review of 18 cases\u0026mdash;including the four reported by Boutet et al.\u0026mdash;has been published [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Among the 12 cases with clearly documented clinical courses, seven had a history of radiation therapy and demonstrated enlargement of the Virchow\u0026ndash;Robin space surrounding the lesions [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Miyata et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] also found an association between SLE disease activity and enlargement of the Virchow-Robin space due to microvasculitis in 130 SLE patients, suggesting that microvasculitis and the enlargement of the Virchow-Robin space are closely related. In the present cases, Virchow-Robin space enlargement was observed in the radiation field, which may support the hypothesis of microvasculitis primarily involving the Virchow-Robin space.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSignal change of punctate enhanced lesions on T2*WI.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn the current study, 21.1% (4/19) of patients demonstrated a change from punctate enhanced lesions on CE-3D T1WI to low intensity on T2*WI. In addition, a total of 12 punctate enhanced lesions showed disappearance of contrast enhancement at a median of 12.5 months. There have been reports of radiation-induced microbleeding [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In particular, Witzmann et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] found no occurrence of microbleeding within 2 years, and Shen et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] found microbleeding in 98.7% of patients with radiation necrosis and 42.9% of patients without radiation necrosis during radiation therapy for nasopharyngeal cancer. Morrison et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] reported an annual increase in the number of microbleeds and a gradual decrease in the volume of individual hemorrhages over time in a susceptibility-weighted imaging (SWI) study using 7T MRI. Hemorrhages associated with radiation necrosis and hemorrhages in cavernous hemangioma-like lesions are well known [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Based on the size and temporal pattern of the hemorrhages, the underlying pathophysiology of the punctate enhanced lesions identified in our study appears to differ from that of the hemorrhages associated with radiation necrosis or cavernous hemangioma-like lesions reported in previous studies [\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The observed conversion of punctate enhancing lesions to low signal intensity on T2*WI may indicate a precursor stage of radiation-induced microbleeds which were reported in the literature [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Furthermore, Bian W et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] used a 7T multi-echo sequence to visualize arteries, veins, and microbleeds on a single image, concluding that most microbleeds originate from microvasculitis in the small arteries of the Virchow-Robin space. However, they also demonstrated that microbleeds are clearly present on the venous side in some cases. Although the MRI sequences we currently use routinely cannot accurately distinguish whether microbleeds are located in veins or arteries, it is generally believed that small and medium-sized arteries are more susceptible to damage from radiation therapy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Therefore, we consider that most of the punctate enhanced lesions in the present study likely represented microvasculitis in the Virchow-Robin space, but some may also have been present on the venous side, and it is reasonable to consider microvasculitis within the brain as the underlying cause in a broader sense.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical implications and differential diagnosis of punctate enhanced lesions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eClinically, the outcome of punctate enhanced lesions is unknown. At the very least, the lesion itself is a punctate lesion, and it is unlikely to be as problematic as leukoencephalopathy or radiation necrosis, regardless of sex, age, or other factors. However, Morrison et al. reported that increased microhemorrhage due to SWI may cause cognitive impairment even in young patients, and future studies are needed. The most important point of differentiation is the very early stage of tumor recurrence, but because of the minute size of the tumor, it is difficult to distinguish it by other sequences, and the lack of enlargement over time is the only point of differentiation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003e1, This was a retrospective study, and the observation period varied from case to case. Therefore, the duration of punctate enhanced lesions and the T2*WI positivity rate may have varied because some patients may have had a short observation period.\u003c/p\u003e\u003cp\u003e2, This study did not include WBRT or prophylactic cranial irradiation cases in brain metastases not managed by neurosurgeons, or total body irradiation cases such as bone marrow transplantation. SRS and SRT cases for brain metastases were also not included, meaning our study population may not be representative of the real-word population of our local area.\u003c/p\u003e\u003cp\u003e3, This study used routine MRI results from 1.5T GE, 3.0T GE, and 3.0T Siemens MRI devices. Therefore, differences in scanner sensitivity may have led to variability in detecting the presence and onset timing of tiny punctate enhanced lesions.\u003c/p\u003e\u003cp\u003e4, All research involved retrospective analyses of data obtained from patient medical records and image servers. However, though all image servers are recorded, medical records are subject to a 5-year retention period under law. Therefore, some patient medical records are not retained. However, all patient summaries are retained, so the main treatment records are accurate. Nevertheless, there are cases for which detailed information such as medical history, complications, and concomitant diseases is not recorded, and so there is a possibility that the clinical course might not have been accurately understood.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePunctate enhanced lesions may not be clinically significant. However, they may be a result of advances in treatment that have led to the expectation of long-term survival for patients with brain tumors, as well as the increased accuracy of diagnostic equipment such as MRI. This MRI finding may be one type of late delayed radiation injury that tends to occur in patients with CNS tumors who have received high-dose radiation. It may also represent a precursor state of lesions previously considered to be microbleeds caused by radiation therapy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCNS, Central nervous system; PCNSL, Primary central nervous system lymphoma; MRI, Magnetic resonance imaging; 3D, Three-dimensional; 3D T1WI, Three-dimensional T1-weighted imaging; 2D, Two-dimensional; SE, Spin echo; CE, Contrast-enhanced; T2*WI, Gradient echo T2*-weighted imaging; Gd, Gadolinium; PD, Progressive disease; RANO, Response assessment in neuro-oncology; SRS, Stereotactic radiosurgery; SRT, Stereotactic radiotherapy; WBRT, Whole-brain radiation therapy; PCI, Prophylactic cranial irradiation; TBI, Total body irradiation; WHO, World Health Organization; T, Tesla; FOV, Field of view; NCE, Non-contrast-enhanced; SPGR, Spoiled gradient recalled echo; MPRAGE, Magnetization prepared rapid acquisition with gradient echo; 3D MR hydrography, Three-dimensional magnetic resonance hydrography; FIESTA, Fast imaging employing steady-state acquisition, CISS, Constructive interference in steady state; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging; 3D FLAIR, 3D fluid attenuation inversion recovery; CSI, Craniospinal irradiation; LBRT, Local boost radiation therapy; Gy, Gray; IQR, Interquartile range; SD, Standard deviation; BBB, Blood-brain barrier; SWI, Susceptibility-weighted imaging\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Declaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have received no funding for this paper, and also have no personal, financial, or organizational interest in any of the drugs, materials, or equipment described.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of conflict of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have no conflicts to report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted with the approval of the ethics committees of Hirosaki University Graduate School of Medicine (2022-017). In addition, since this was a retrospective study, notifications to patients regarding an opt-out option were given on the homepage of Hirosaki University Hospital, and the requirement for informed consent was waived.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was approved by the Hirosaki University Ethics Committee and was conducted in strict accordance with the ethical standards of the 1964 Declaration of Helsinki and its later revisions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKA and SK contributed to the concept and design of the study. SK contributed to support and supervision of the study. KA and SK contributed to acquisition and analysis of the data. KA and MM contributed to statistical analysis of the data. KA, KK1, KK2, NF, and ST, contributed to management of patients. All authors contributed to drafting the text and preparing the figure.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNarita Y (2017) Brain Tumor Registry of Japan (2005\u0026ndash;2008). Neurol Med Chir (Tokyo) 57:9\u0026ndash;102. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2176/nmc.sup.2017-0001\u003c/span\u003e\u003cspan address=\"10.2176/nmc.sup.2017-0001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKakeda S, Korogi Y, Hiai Y et al (2007) Detection of brain metastasis at 3T: comparison among SE, IR-FSE and 3D-GRE sequences. 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Acta Oncol 44:13\u0026ndash;22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/02841860510007440\u003c/span\u003e\u003cspan address=\"10.1080/02841860510007440\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Late delayed radiation injury, Long-term survivor, MRI, Punctate enhanced lesion, Microvasculitis","lastPublishedDoi":"10.21203/rs.3.rs-7283719/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7283719/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn long-term survivors of central nervous system (CNS) tumors who have undergone radiotherapy, punctate enhancement within the radiation field is sometimes detected on contrast-enhanced (gadolinium) three-dimensional T1-weighted imaging (CE-3D T1WI). However, the clinical characteristics and significance of this finding remain unclear. The purpose of this study was to clarify the characteristics of this radiological finding.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNinety patients who had received radiotherapy between January 2007 and June 2020 and were still alive 24 months later without recurrence were selected. Patients were classified into punctate enhancement (+) group and punctate enhancement (\u0026minus;) group, and their clinical courses were compared. Imaging examinations were performed using standard procedures, including CE-3D T1WI and gradient echo T2*-weighted imaging (T2*WI).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePunctate enhancement within the radiation field was observed in 25.7% (19/74 cases). The median onset time of punctate enhanced lesions was 37 months. Lesion size remained stable, but in 21.1% of cases (4/19), enhancement resolved, appearing as low intensity on T2*WI. Significant differences were seen between the punctate enhancement (+) group and the punctate enhancement (\u0026minus;) group in the proportions of pathological diagnosis types (p\u0026thinsp;=\u0026thinsp;0.001). Also, significant differences were seen between both groups in the proportions of radiotherapy techniques (p\u0026thinsp;=\u0026thinsp;0.001). Higher radiation doses increased the likelihood of punctate enhancement.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePunctate enhancement is considered to be one of the late delayed radiation injuries occurring in patients with CNS tumors after high-dose radiotherapy. Some of these lesions showed loss of contrast enhancement and changed to low intensity on T2*WI.\u003c/p\u003e","manuscriptTitle":"New MRI findings of late delayed radiation injuries in long-term survivors after radiotherapy: punctate enhanced dot, oval, or rod-like lesions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-21 10:19:29","doi":"10.21203/rs.3.rs-7283719/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"189fb39e-28c7-43d1-9669-15f0b99943c7","owner":[],"postedDate":"August 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T16:00:34+00:00","versionOfRecord":{"articleIdentity":"rs-7283719","link":"https://doi.org/10.1007/s00234-026-03994-x","journal":{"identity":"neuroradiology","isVorOnly":false,"title":"Neuroradiology"},"publishedOn":"2026-04-14 15:57:35","publishedOnDateReadable":"April 14th, 2026"},"versionCreatedAt":"2025-08-21 10:19:29","video":"","vorDoi":"10.1007/s00234-026-03994-x","vorDoiUrl":"https://doi.org/10.1007/s00234-026-03994-x","workflowStages":[]},"version":"v1","identity":"rs-7283719","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7283719","identity":"rs-7283719","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}