SUBMITTED 29 APR 22 1 REVISION REQ. 2 AUG 22; REVISION RECD. 14 AUG 22 2 ACCEPTED 7 SEP 22 3 ONLINE-FIRST: September 2022 4 DOI: https://doi.org/10.18295/squmj.9.2022.058 5 6 Physiological Intracranial Calcifications in Children 7 A computed tomography-based study 8 Faiza Al Hajri,1 Srinivasa Rao Sirasanagandla,2 Ammar Boudaka,3,4 9 Humoud Al Dhuhli,5 *Eiman Al Ajmi5 10 11 1Radiology Residency Program, Oman Medical Specialty Board, Muscat, Oman; 12 Departments of 2Human & Clinical Anatomy, 4Physiology and 5Radiology & Molecular 13 Imaging, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman; 14 3Department of Basic Medical Sciences, College of Medicine, Qatar University, Doha, Qatar. 15 *Corresponding Author’s e-mail: ealajmi@squ.edu.om 16 17 Abstract 18 Objectives: Physiological intracranial calcifications (PICs) are benign in nature and related to 19 aging. We aimed to study the frequency of physiological intracranial calcifications (PICs) in 20 pediatric population using computed tomography (CT). Methods: The brain CT scans of 21 consecutive patients (age range, 0-15 years) who had visited Sultan Qaboos University 22 Hospital from January 2017 to December 2020 were retrospectively assessed for the presence 23 of PICs. The presence of calcifications was identified using 3 mm thick axial images, and 24 coronal and sagittal reformats. Results: A total of 460 patients were examined and the mean 25 age was 6.54 ± 4.94 years. The frequency of PIC in boys and girls was 35.1% and 35.4%, 26 respectively. PICs were most common in choroid plexus with 35.21% (age range 0.4 -15 27 years; median, 12 years), followed by the pineal gland in 21.08% (age range 0.5 -15 years; 28 median, 12 years) and the habenular nucleus in 13.04% of subjects (2.9 -15 years; median, 12 29 years). PICs were less common in falx cerebri with 5.86% (age range 2.8-15 years; median, 30 13 years) and tentorium cerebelli in 3.04% (age range 7-15 years; median, 14 years) of 31 subjects. PICs increased significantly with increasing age (p<0.001). Conclusion: Choroid 32 plexus is the most frequent site of calcification. Choroid plexus and pineal gland 33 mailto:ealajmi@squ.edu.om calcifications may be present at less than 1 year of age. Recognizing PICs is clinically 34 important for radiologists as they can be mistaken for hemorrhage or pathological entities like 35 neoplasms or metabolic diseases. 36 Keywords: Calcification; Pineal gland; Dura Mater; Brain; Computed Tomography 37 38 Advances in Knowledge 39  This is the first study to evaluate physiological intracranial calcifications in Omani 40 children. 41  The choroid plexus is the most frequent site of physiological intracranial calcification. 42  Choroid plexus and pineal gland calcifications may be present at less than 1 year of 43 age. 44 45 Application to Patient Care 46  The baseline data of PICs are clinically important for neuroradiologists and 47 neurosurgeons as they can be mistaken for hemorrhage or pathological entities 48 like neoplasms or metabolic diseases. 49 50 Introduction 51 Physiological intracranial calcifications (PICs) are benign in nature and typically occur with 52 aging.1 PICs are well known to occur in pineal gland, choroid plexus, habenula, dural folds: 53 falx cerebri, and tentorium cerebelli, sagittal sinus, and petroclinoid ligaments.2 Structurally, 54 they are deposits of calcium and/or iron in the brain parenchyma or vasculature. PICs are not 55 associated with any disease and/or underlying pathology.1,2 PICs are incidental findings in 56 neuroimaging. PICs occurrence at all ages of life has been reported. PICs prevalence 57 increases with age, and its prevalence varies between 50% and 70% in subjects older than 30 58 years.1 However, their prevalence is low in preadolescents3 and children4. They can be 59 detected in both genders and any race or ethnic group.5 They can be detected by plain 60 radiography, sonography, computed tomography (CT), and magnetic resonance imaging. 61 However, CT is often preferred due to the hyperdense appearance of calcium deposits in this 62 imaging.6,7 63 64 In general, PICs are smaller in size, and larger size (>1cm) calcifications should be suspected 65 of having an underlying pathological cause.2 Intracranial calcifications may be pathological 66 due to a wide range of infectious, metabolic, neoplastic, and vascular etiologies or because of 67 prior brain insult.8 It has been reported that environmental factors such as altitude and 68 sunlight exposure influence the pineal gland calcification (PGC) process.9 Till date, very few 69 studies exist on the prevalence of PICs in the pediatric population, particularly choroid and 70 dural calcifications.4,10 In children PICs are most commonly found in the choroid plexus and 71 less commonly found in dural folds.4 Baseline data of PICs are clinically important for 72 neuroradiologists and neurosurgeons as they can be mistaken for hemorrhage or pathological 73 entities like neoplasms or metabolic diseases. Furthermore, the reported prevalence of PICs in 74 children is varied among different studies. Despite having tremendous clinical significance, 75 very few studies have been conducted on the prevalence of PICs in children. Hence, we 76 aimed to study the frequency of PICs in Omani children using CT. 77 78 Materials and Methods 79 Study population 80 In this retrospective cross-sectional study, brain CT scans of consecutive Omani children 81 aged ≤15 years who had visited Sultan Qaboos University Hospital (SQUH) during the 82 period from January 2017 to December 2020 were assessed. Each patient's demographic 83 information and diagnostic findings were obtained from the electronic medical records of 84 SQUH. After applying inclusion and exclusion criteria, we included a total of 460 patients. 85 Relevant patients’ clinical information was obtained. The most common clinical indications 86 for CT examinations in our cohort were trauma, seizures, and headache. On the other hand, 87 the exclusion criteria considered patients with known neuronal diseases, which were 88 associated with calcifications, excessive motion artifacts, epithalamic masses, and cerebral 89 hemorrhages. Patients with incomplete details and non-Omanis were also excluded from the 90 study. 91 92 Acquisition protocol and data acquisition 93 All brain CT examinations were performed using 64-slice multidetector CT scanner (Siemens 94 Sensation 64) with a slice collimation of 30 x 0.6 mm and a 512 x 512 matrix. The Picture 95 Archiving and Communication System (PACS) (Synapse PACS, FUJIFILM Worldwide, 96 version 5.7.102) was used for screening the images. The studies were reviewed by a single 97 observer. In each case, presence of calcifications in the falx cerebri, tentorium cerebelli, 98 epithalamus, and choroid plexus were analyzed using 3 mm thick axial images and coronal 99 and sagittal reformats. Based on their distinct locations, epithalamic calcifications were 100 identified separately as pineal or habenular calcifications. Falcine and tentorial calcifications 101 were identified along the dural folds. The side of choroid plexus calcification was noted 102 whether unilateral or bilateral. Positive intracranial calcification in any of the areas 103 mentioned above was defined by being of higher attenuation compared to the gray matter.4 104 The morphology of calcifications in the choroid plexus and the pineal gland was classified to 105 single or punctate versus large or multiple.4 The Medical Research Ethics Committee, Sultan 106 Qaboos University, Muscat approved the study and waived the requirement for written 107 consent. 108 109 Statistical analysis 110 Statistical Package for the Social Sciences (SPSS, version 23.0, IBM Corporation, NY, USA) 111 for Windows was used to present the data. The data was presented as mean and standard 112 deviation. Chi-square test was used to determine the gender and age influence on frequency 113 of PICs in different regions of the brain. The differences were considered significant at p 114 value <0.05. 115 116 Results 117 In the present study, PICs were examined in the CT scans of 460 children. The mean age of 118 the subjects was 6.54 ± 4.94 years. The study subjects were categorised into five age groups: 119 0-3 years (179); 3.1-6 years (71); 6.1–9 years (69); 9.1-12 years (48); >12 years (93). PICs 120 increased significantly with increasing age (p<0.001; [Figure 1]). Among the study subjects, 121 265 (57.6%) were boys, and 195 (42.4%) were girls. The frequency of PICs in boys and girls 122 was 35.1% (93/265) and 35.4% (69/195), respectively. The gender influence on PICs 123 frequency was not significant (p = 0.311). In Figure 2, the frequency of PICs in different 124 regions of the brain (choroid plexus, pineal gland, habenular nucleus, falx cerebri, and 125 tentorium cerebelli) in each year, is presented. Additionally, Table 1 depicts the age range of 126 PIC occurrence in different regions of the brain. The highest frequency of PICs was observed 127 in the choroid plexus with 35.21% (162/460). The age range of choroid plexus calcification 128 was 0.4 -15 years (median, 12 years). Majority of choroid calcification morphology was 129 either punctate or single, accounting for 90.7% (147/162) of the total, with large or multiple 130 accounting for 9.3% (15/162). Choroid calcifications were found bilaterally in 84.57% 131 (137/162) of subjects and in 11.1% (18/162) on the right side of cerebrum and 4.32% (7/162) 132 on the left side. The overall epithalamic calcification frequency was 34.13% (157/460). 133 Pineal gland calcification (PGC) was identified in 21.08% (97/460) of subjects with an age 134 range of 0.5 to 15 years (median, 12 years). Majority of PGC morphology was punctate or 135 single with 83.51%, (81/97), followed by large or multiple with 16.49% (16/97). Habenular 136 calcification was observed in 13.04% (60/470) of subjects with an age range of 2.9 -15 years 137 (median, 12 years). Dural calcifications were observed most frequently in the falx cerebri 138 with 5.86% (27/460), followed by those in the tentorium cerebelli with 3.04% (14/460). The 139 age range of falx cerebri and tentorium cerebelli calcifications was 2.8-15 years (median, 13 140 years) and 7-15 years (median, 14 years), respectively. Figure 3 and Figure 4 are the 141 representative CT images showing PICs in different regions of the brain. 142 143 Discussion 144 Knowing the detectable age of PICs on imaging is crucial clinically, especially in the early 145 years of life. The current study demonstrated that PICs are found in the pediatric population 146 across all age groups with varying frequency. 147 148 The pineal gland is a part of the epithalamus located in the midline at the quadrigeminal 149 cistern, close to the posterior end of the roof of the third ventricle. It secretes melatonin, 150 serotonin, and N, N-dimethyl-tryptamine hormones and plays an important role in circadian 151 rhythm regulation.11,12 Light stimuli regulate its secretory activity and are highly active during 152 darkness.11,12 Histologically, PGC or corpora arenacea consist of by-products of pineal 153 neuronal and glial polypeptide exocytosis, the exophytic membrane debris with surrounding 154 calcification.13 These calcified concentrations are mainly composed of calcium and 155 magnesium salts.14 PGC is known to appear early in life and increase gradually with 156 advancing age. A histopathology study has documented the presence of PGC even in fetal 157 life.15 Although the prevalence rate of PGC is high in adults, it is less prevalent in children.9 158 In a study by Helmke and Winkler, the reported frequency of PGC was 3% in the first year of 159 life, and then it increased gradually to 7.1% in the first decade of life.16 In the same study, the 160 frequency of PGC increased to 33% in 10-18 year age group.16 In a study by Doyle and 161 Anderson, PGC was observed in 1% and 8% of subjects younger than 6 and 10 years old, 162 respectively, and 39% in 8-14 years old subjects.10 In this study, the youngest patient with 163 PGC was 3 years.10 Similarly, in a study by Whitehead et al., the youngest patient with PGC 164 was 3 years old.4 In this study PGC was observed only in 5% of children with an age range of 165 3.2 to 8.9 years.4 In a recent study by Caliskan and Ozturk, a high frequency of 35.8% PGC 166 was observed in the 7-12 year age group, and it increased to 67% in the 13-17 year age 167 group.3 In the present study, PGC was observed in 21.08% of subjects younger than 15 years. 168 169 Similar to previous studies, in our study, PGC frequency increased gradually with increasing 170 age, with 7% in the 3-6 year age group and 51.6% in the 12-15 year age group, respectively. 171 In our study, the youngest patient with PGC was 5 months old. PGC was observed only in 172 four subjects younger than 3 years. To the best of our knowledge, this is the first time we 173 observed PGC at a very young age using contemporary CT technology. In the previous study, 174 in the majority of patients, PGC morphology was single or punctate (71%).4 Similarly, in our 175 study, single or punctate PGC were the most common morphology pattern, with a frequency 176 of 83.51%. The habenula is a bilaterally paired epithalamic nuclear complex situated close to 177 the dorsomedial surface of the thalamus. It plays an important role in the limbic system and 178 acts as a relay and processing center between the midbrain and the limbic system.17 Its 179 calcifications generally appear as a curvilinear pattern with a prevalence rate of 15% in 180 adults.1 The composition of these calcifications is found to be similar to that of the pineal 181 gland with salts of calcium and magnesium.14 In a previous study, habenular calcifications 182 were noted in 10% of subjects younger than 9 years old, and they were the most frequent site 183 of calcification in the epithalamus.4 In contrast, we observed habenular calcifications only in 184 4.1% of the patients younger than 9 years of age. However, it increased to 8.9% in subjects 185 aged 9-15 years. An association between habenular calcification and pathophysiology has 186 been postulated as habenular calcifications are observed in schizophrenia patients.18-20 Hence, 187 baseline data of habenular calcifications are clinically important. 188 189 The choroid plexus produces cerebrospinal fluid and helps in the removal of brain metabolic 190 waste and xenobiotics.21 It is the major source of transferrin protein in the brain.22 The atria 191 of the lateral ventricles are the most commonly affected sites of calcification, followed by the 192 third or fourth ventricles.1 Similar to previous studies,23,24 in our study, choroid plexus 193 calcification increased significantly with age. In a study by Kendall and Cavanagh, choroid 194 plexus calcification was found in only 2% of subjects younger than 8 years.24 Modic et al. 195 have noted choroid calcification in 0.5% of subjects younger than 10 years old.25 In a study 196 by Doyle and Anderson, it was noted in 7% and 16% of subjects younger than 10 and 16 197 years, respectively.10 Whitehead et al. have noted the calcification in 12% of children 198 younger than 9 years of age, and the youngest subject was less than 1 month old.4 In our 199 study, choroid plexus calcification was the most common intracranial calcification, with a 200 frequency of 35.21%. In subjects less than 9 years of age, it was noted in 35.1% of subjects. 201 The youngest patient with choroid calcification was 4 months old. In the previous study by 202 Whitehead et al., the majority of choroid plexus calcifications were single or punctate 203 (93.1%).4 Similarly, in our study, single or punctate choroid plexus calcifications were 204 observed in majority of the subjects (83.51%). Furthermore, choroid calcifications were 205 found bilaterally in majority of the subjects. Various pathological conditions such as 206 intraventricular infection, inflammation, hemorrhage, chronic calcium and phosphate 207 imbalance are known to be associated with premature choroid plexus mineralization. Hence, 208 age thresholds of normally expected choroid plexus calcification are clinically important to 209 distinguish physiology from pathology.4 210 211 In children, PICs in falx cerebri and tentorium cerebelli are rare, and is often identified as an 212 incidental finding during routine brain CT examination.26 In the skull radiographs of adults, 213 calcification of falx cerebri was observed in 7% of subjects.27,28 In two different CT studies of 214 adults, dural calcifications were observed in 7.3% and 12.5% of subjects,5,29 with a male 215 dominance.5 To the best of our knowledge, physiological calcifications in the dural folds in 216 children have been reported only in two studies. In a study by Kendall and Cavanagh, dural 217 calcifications were observed in 0.8% of subjects less than 15 years of age.24 In another study 218 by Whitehead et al., it was observed in 1% of subjects less than 9 years of age.4 In this study, 219 dural calcifications were most prevalent in tentorium cerebelli followed by falx cerebri.4 220 221 In contrast, we observed 5.86% in falx cerebi and 3.04% in tentorium cerebelli. Furthermore, 222 falx cerebri and tentorium cerebelli calcifications are not present in less than 2 and 7 years, 223 respectively. As falx cerebri is formed from pluripotent embryonic mesenchymal stem cells, 224 any external stimuli including, irritation, trauma, and haemorrhage would predispose these 225 mesenchymal cells to transform into osteogenic cells, resulting in falcine ossification.30,31 The 226 extensive dural calcifications are known to be associated with a few pathological conditions, 227 particularly basal cell nevus syndrome.32 There is inconsistency in the existing literature 228 regarding gender influence on the occurrence of PICs in the paediatric population. In a study 229 by Whitehead et al., no significant gender difference (p=0.41) was observed.4 Two other 230 studies by Doyle & Anderson10 and Caliskan and Ozturk3, found no evidence of a gender 231 effect on PGC calcification. Similarly, in the present study, gender influence on intracranial 232 calcification was not observed. In contrast, two studies have reported a significant gender 233 influence with male dominance.5,29 Further research needs to be conducted to draw a 234 conclusive result in this regard. The prior knowledge of reference values of PICs in children 235 is clinically important as this may frequently interfere with the differential diagnosis of 236 metabolic mineralization, intracranial hemorrhage, and tumours. The following are some of 237 the limitations of this study. The volume, or CT density of PIC could not be performed. The 238 study sample may not be representative of the Omani population because it is a single-239 centered study. A multi-centered study involving subjects from various parts of Oman and 240 analysis of calcification quantification would be interesting. 241 242 Conclusion 243 The study provides the reference values for PICs in the Omani paediatric population. PICs 244 are detected in all age groups of the paediatric population. The choroid plexus is the most 245 frequent site of calcification, and it is bilateral. Choroid plexus and pineal gland calcifications 246 may be present at less than one year of age. Calcifications in dural folds are relatively less 247 common and are not present at less than 2 years of age. The baseline data of PICs are 248 clinically important for neuroradiologists as they can be mistaken for hemorrhage or 249 pathological entities like neoplasms or metabolic diseases. 250 251 Conflicts of interest 252 The authors declare that they have no conflict of interest 253 254 Funding 255 No funding was received for this study. 256 257 Author Contributions 258 Conceptualization and methodology was done by SRS and EA. Validation was done by EA 259 and HA. Formal analysis was performed by SRS and AB and investigation was done by FA. 260 FA and EA curated the data. The original manuscript draft preparation was done by SRS and 261 the revision and editing were done by EA, HA and AB. Visualization was done by FA, SRS 262 and EA and supervised by EA. The project administration was handled by EA, SRS and HA. 263 All authors approved the final version of the manuscript. 264 265 Acknowledgment 266 We would like to thank Dr Sadhana Roychoudhury for her assistance in English editing. The 267 present study has been presented at the 20th Congress of the International Federation of 268 Associations of Anatomists, held in Istanbul, Turkey. 269 270 References 271 1. Kıroğlu Y, Callı C, Karabulut N, Oncel C. Intracranial calcifications on CT. Diagn 272 Interv Radiol 2010;16(4):263-9. DOI:10.4261/1305-3825.DIR.2626-09.1. 273 2. Deepak S, Jayakumar B, Shanavas. Extensive intracranial calcification. J Assoc 274 Physicians India 2005;53:948. 275 3. Caliskan E, Ozturk M. Evaluation of Physiologic Pineal Gland Calcification via 276 Computed Tomography in the Pediatric Population. Ann Med Res 2019;26:2391-2396. 277 DOI:10.5455/annalsmedres.2019.06.338. 278 4. 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Saldino RM, Di Chiro G. Tentorial calcification. Radiology. 1974 Apr;111(1):207-10. 344 DOI:10.1148/111.1.207. 345 29. Daghighi MH, Rezaei V, Zarrintan S, Pourfathi H. Intracranial physiological 346 calcifications in adults on computed tomography in Tabriz, Iran. Folia Morphol (Warsz). 347 2007;66(2):115-9. 348 30. Tubbs RS, Kelly DR, Lott R, Salter EG, Oakes WJ. Complete ossification of the human 349 falx cerebri. Clin Anat 2006;19(2):147-50. DOI:10.1002/ca.20162. 350 31. Rao SR, Rao TR, Ovchinnikov N, McRAE A, Rao AVC. Unusual Isolated Ossification 351 of Falx Cerebri: A Case Report. Neuroanatomy 2007;6:54-55. 352 32. Makariou E, Patsalides AD. Intracranial Calcifications. Appl Radiol 2009;38:48. 353 354 355 Figure 1. The frequency of physiological intracranial calcification in different age groups. The 356 total number of patients analyzed was 460.Note calcification increased with increasing age 357 (Chi square test; p<00.1). 358 359 360 Figure 2: The frequency of physiological intracranial calcifications among the 460 patients 361 across different ages. 362 363 364 A B 365 Figure 3. Examples of intracranial calcifications from the study. Axial CT images of the brain 366 show (A) focal calcification in the falx (arrow), (B) bilateral calcifications of the choroid plexus 367 in the trigones of the lateral ventricles (arrows), (C) habenular calcification (small arrow), and 368 large pineal calcification (large arrow). (D) Reformatted coronal CT image of the brain shows 369 right tentorial calcification (arrow). 370 371 372 Figure 4: Punctate calcifications versus large calcifications in the choroid plexus. (A) Axial 373 CT image of the brain shows punctate calcifications in the choroid plexuses (arrows). (B) CT 374 image in another patient demonstrates large choroid plexus calcifications (arrows). 375 376 C D A B Table 1. The age ranges of physiological intracranial calcifications at different regions of brain. 377 378 Location of Calcification No. of Patients Age Range (years) Falx cerebri 27/460 2.8-15 (median, 13) Tentorium 14/460 7-15 (median, 14) Choroid Plexus 162/460 0.4 -15 (median, 12) Pineal Gland 97/460 0.5 -15 (median, 12) Habenula 60/460 2.9 -15 (median, 12)