Accepted Manuscript Calcifying pseudoneoplasm of the neuraxis (CAPNON): a case illustrating natural history over 17 years of radiological surveillance Sean M. Barber, Jacob Chen Ming Low, Paul Johns, Philip Rich, Bridget MacDonald, Timothy L. Jones PII: S1878-8750(18)30895-7 DOI: 10.1016/j.wneu.2018.04.175 Reference: WNEU 8011 To appear in: World Neurosurgery Received Date: 20 December 2017 Revised Date: 22 April 2018 Accepted Date: 23 April 2018 Please cite this article as: Barber SM, Ming Low JC, Johns P, Rich P, MacDonald B, Jones TL, Calcifying pseudoneoplasm of the neuraxis (CAPNON): a case illustrating natural history over 17 years of radiological surveillance, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.04.175. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Calcifying pseudoneoplasm of the neuraxis (CAPNON): a case illustrating natural history over 17 years of radiological surveillance Department of Neurosurgery, St George’s Hospital, London 2 Department of Neuropathology, St George’s Hospital, London 3 Department of Neuroradiology, St George’s Hospital, London 4 Department of Neurology, Croydon University Hospital SC 1 RI PT Sean M Barber1, Jacob Chen Ming Low1, Paul Johns2, Philip Rich3, Bridget MacDonald4, Timothy L Jones1 Abstract Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare central nervous system (CNS) lesion that can M AN U be found in both the brain and the spine. Although this entity is poorly understood, radiological and histological features have been identified. We describe a unique case of a 31-year-old patient who was managed with antiepileptic medication for 17 years before requiring neurosurgical intervention for tumour progression. T2weighted MRI revealed hyperintensity within the tumour with extensive associated vasogenic oedema, which is AC C EP TE D not normally associated with CAPNON. Resection was successful with no complications. ACCEPTED MANUSCRIPT Introduction Calcifying pseudoneoplasm of the neuraxis (CAPNON) was first described by Rhodes and Davis in 1978.1 This rare central nervous system (CNS) lesion is known to follow an indolent course, and can present as either an intracranial or spinal mass. These entities were initially thought to represent foci of atypical bony metaplasia,1 however it is now thought that these lesions may reflect a reactive proliferative process.2 Approximately 100 RI PT cases of CAPNON have been reported in the literature, and the associated radiological and histological features have been characterized.3 The radiological differential diagnosis includes meningioma, oligodendroglioma, and astrocytoma with calcifications, among others.4 SC Intracranial CAPNON can present with seizures, headaches, visual loss, weakness, or developmental delay.2,3,5,6 CAPNON of the spinal cord may present with back pain,7 sciatica,8 or less commonly, acute cauda equina M AN U syndrome.9 A small number of cases have also been discovered incidentally at autopsy.1 Once a radiological diagnosis of CAPNON has been made, treatment typically involves total surgical resection, which confers an excellent prognosis. Previous cases have described a 4-8 year monitoring period prior to progression warranting neurosurgical TE D intervention.4,10,11 To the best of our knowledge, this is the first case report to describe the natural history of CAPNON in a patient over an extended (17 year) period of frequent radiological surveillance prior to surgical intervention. We report a 31-year-old patient who was diagnosed as an adolescent with a perirolandic mass that EP was initially managed with anti-epileptic medication and regular monitoring by serial imaging. She AC C subsequently underwent total surgical resection after interval imaging demonstrated progression. Case Report A 14-year-old female with no significant past medical history presented with intermittent left facial numbness which was diagnosed retrospectively as simple partial epilepsy. She was found to have a mass in the right perirolandic area, initially thought to be a cavernoma, which was followed with serial imaging for several years. Her seizure frequency and severity continued to progress and intrusive complex partial seizures with occasional generalisation were treated with multiple anti-epileptic drugs without remitting. Imaging at the time of her most recent surgical presentation, at which time she had more than daily seizures despite triple therapy, revealed an intrinsic mass containing solid and cystic components with a surrounding area of diffuse T2 hyperintensity ACCEPTED MANUSCRIPT consistent with vasogenic oedema and/or infiltration. Although the lesion showed irregular contrast enhancement, it also contained several foci of susceptibility artefact consistent with calcification (Figure 1, Figure 2). Functional magnetic resonance imaging (fMRI) performed at the time of presentation confirmed superficial co-location with sensory cortex and involvement of motor pathways in deep white matter, where activation was seen with left finger tapping tasks. The location of the lesion was consistent with the patient’s RI PT seizure semiology, which typically involved left hemianesthesia, a distorted sense of sound and an altered perception in three-dimensional space, often progressing to generalized tonic-clonic activity. SC The patient was monitored with serial imaging (over a period of 17 years) prior to surgical intervention in view of the eloquent location of the mass, the presumed diagnosis of low-grade glioma, and the maintenance of relatively good seizure control. Follow-up magnetic resonance imaging (MRI) every 1-2 years demonstrated M AN U slow but progressive enlargement of the mass. In 2017, at the age of 31, further tumour enlargement and increase in extent of surrounding oedema was seen (Figure 1). Given this, together with worsening seizure control, the patient agreed to undergo right-sided awake craniotomy and resection of the mass. During the surgery, stimulation of the cortical surface overlying the tumour did not elicit motor activity, and TE D thus a corticectomy was made at this point to gain access to the mass. The lesion was found to be heavily calcified at the core necessitating piecemeal resection with pituitary rongeurs, microdissection and the use of an EP ultrasonic aspirating tool. Resection was carried out until normal-appearing brain was reached. Post-operatively, the patient complained of intermittent sensations of numbness and paraesthesiae in the left AC C forearm and hand, but was otherwise symptom free and had no neurological deficits. She recovered fully and was discharged home within several days. She has been monitored radiographically for 9 months without recurrence. Clinically she has experienced a greater than 50% reduction in her seizure frequency, but remains on anti-epileptics. Histologically, the tumour was characterized as a fibro-osseous lesion consisting of deposits of amorphous granular to fibrillary material and fibrous tissue, with variable calcification and foci of irregular osseous metaplasia. Numerous calcified foci of variable size were seen with central areas of dense mineralisation/ossification and radially arranged spicules at the peripheries. A population of cytologically bland ACCEPTED MANUSCRIPT and uniform (apparently meningothelial) cells was also noted, composed of cells with oval nuclei, indistinct nucleoli and little to no mitotic activity. A variable chronic, inflammatory infiltrate was also present, including a mixed population of small lymphocytes (CD20+ and CD3+), plasma cells, macrophages (CD68+) and occasional foreign-body-type giant cells. No necrosis, microvascular proliferation or mitotic activity was observed. The meningothelial-type cells expressed epithelial membrane antigen (EMA), but not pancytokeratin, RI PT and to a variable extent progesterone receptor (PR). The constituent cells were negative for neuronal and glial markers. The Ki67 proliferation index was low (5-10%), a proportion of which represented inflammatory cell infiltrates. This histological appearance (Figure 3) was felt to be consistent with a calcifying pseudoneoplasm of SC the neuraxis (CAPNON). Discussion M AN U CAPNON is a rare CNS lesion that is poorly understood. The aetiology is yet to be established, but the cellular element is postulated to be of arachnoid or fibroblastic origin. CAPNONs have been discovered in a variety of intra – and extra-axial locations within the CNS, including the foramen magnum,12 skull base,13 inferior colliculus,14 and spine,2 among others. Tables 1, 2 and 3 summarize over 100 cases of CAPNON that have been reported in the literature. Among these reported cases, the average age at presentation was 47 ± 17 years, and a TE D slight male predilection was seen (53.4% male, 44.7% female, 1.9% no data). 1,1015,1617,182,1920–2223,24253,264,13,14,27–356,7,36–435,44,45 211,20,4621,29,47–547,55–639,64,65 Seizures (31.1%) and headaches (31.1%) appear to be the primary clinical presentation of intracranial CAPNON (most likely due to EP localised mass effect), while spinal CAPNON most typically present with axial neck or back pain (57.1%) and radicular symptoms (35.7%). Kerr et al4 reported a case in which headaches were associated with enlargement AC C of a CAPNON at the right cerebellomedullary angle and hypothesised that headache occur due to growth of the mass itself or a reactive process in the surrounding brain tissue. Surgical resection is the treatment of choice, and due to the benign nature of the process, post-operative chemo-radiotherapy is not recommended. The radiological features of CAPNON documented in numerous case reports are relatively inconsistent. While a predominant hypointense signal intensity on both T1 & T2-weighted imaging is typically seen (corresponding to dense calcification on computed tomography [CT]), the enhancement and oedema patterns associated with CAPNON appear variable, as does the axial location of the mass. The majority of reported CAPNON cases display a minimal peripheral enhancement pattern,3,5,12,18 although in some cases a heterogenous or serpiginous ACCEPTED MANUSCRIPT internal enhancement pattern is seen.3,12,18 Mild surrounding T2 hyperintensity suggestive of oedema has been reported in several cases,5,18 but not in others.3,12 In the majority of reported cases, intracranial CAPNON is an intra-axial mass, but both Shrier et al.18 and Wiśniewski et al.12 have described cases in which CAPNON is seen as an extra-axial mass near the foramen magnum. Spinal CAPNON are most commonly extradural (Table 3). The imaging findings in our case are distinguished by a prominent T2 hyperintense component suggestive of progression (Figure 1G), which has not previously been described. RI PT cyst formation around the calcified nodule, as well as extensive surrounding oedema in the later stages of As in our case, these lesions are consistently immunopositive for vimentin and EMA, but negative for S100 SC protein and glial fibrillary acidic protein (GFAP).4,6,11,14,21 The typical histological characteristics of CAPNON have been summarised by Qian et al20 and include: (1) a chondromyxoid matrix in a nodular pattern; (2) M AN U palisading spindle to epithelioid cells; (3) fibrous stroma (4) osseous components containing birefringent lamellar bone, calcifications, and psammoma bodies; and (5) foreign-body reaction with giant cells. Not all features are present in every case. The rarity of this entity and the absence of any pathognomonic imaging features makes it difficult to diagnose TE D based on radiographic appearances alone. The radiological differential diagnosis includes intra-axial neoplasms which are also known to calcify (e.g. ganglioglioma and oligodendoglioma), vascular lesions (e.g. cavernomas), and infectious processes (e.g. tuberculomas). CAPNON may also develop extra-axially and mimic EP meningioma.21 Uniform T1 and T2 hypointensity without solid enhancement have been cited as key distinguishing features of CAPNON.3 However, as we have demonstrated CAPNON may produce a more AC C complex radiographic appearance and be associated with extensive surrounding vasogenic oedema. Conclusion CAPNON is a rare, non-neoplastic lesion of the central nervous system that, although benign, may nevertheless exert mass effect and may show a progressive increase in size, mimicking an intraaxial or extraaxial tumour. The present case illustrates the long-term natural history of CAPNON prior to resection and highlights the variations in radiological appearances that may be associated with this poorly understood entity. References ACCEPTED MANUSCRIPT 1. Rhodes RH, Davis RL. An unusual fibro-osseous component in intracranial lesions. Hum Pathol. 1978;9(3):309-319. 2. Bertoni F, Unni KK, Dahlin DC, Beabout JW, Onofrio BM. Calcifying pseudoneoplasms of the neural axis. J Neurosurg. 1990;72(1):42-48. doi:10.3171/jns.1990.72.1.0042 3. Aiken AH, Akgun H, Tihan T, Barbaro N, Glastonbury C. Calcifying pseudoneoplasms of the neuraxis: RI PT CT, MR imaging, and histologic features. Am J Neuroradiol. 2009;30(6):1256-1260. doi:10.3174/ajnr.A1505 4. Kerr EE, Borys E, Bobinski M, Shahlaie K. Posterior fossa calcifying pseudoneoplasm of the central 5. SC nervous system. J Neurosurg. 2013;118(4):896-902. doi:10.3171/2013.1.JNS121755 Higa N, Yokoo H, Hirano H, et al. Calcifying pseudoneoplasm of the neuraxis in direct continuity with doi:10.1111/neup.12384 6. M AN U a low-grade glioma: A case report and review of the literature. Neuropathology. 2017;37(5):446-451. Lyapichev K, Bregy A, Shah AH, et al. Occipital calcified pseudoneoplasms of the neuraxis (CAPNON): Understanding a rare pathology. BMJ Case Rep. 2014;2014:3-6. doi:10.1136/bcr-2014206855 7. Duque SG, Lopez DM, De Méndivil AO, Fernández JD. Calcifying pseudoneoplasms of the neuraxis: TE D Report on four cases and review of the literature. Clin Neurol Neurosurg. 2016;143:116-120. doi:10.1016/j.clineuro.2016.02.025 8. Chang H, Park JB, Kim KW. Intraosseous calcifying pseudotumor of the axis: a case report. Spine 9. EP (Phila Pa 1976). 2000;25(8):1036-1039. Lopes AM, Brock R, Martins T, et al. Intradural calcifying pseudoneoplasm of the neuraxis presenting 10. AC C as a cauda equina syndrome. Surg Neurol Int. 2016;7(43):1102. doi:10.4103/2152-7806.196771 Jun C, Burdick B. An unusual fibro-osseous lesion of the brain. Case report. J Neurosurg. 1984;60(6):1308-1311. doi:10.3171/jns.1984.60.6.1308 11. Smith DM, Berry AD. Unusual fibro-osseous lesion of the spinal cord with positive staining for glial fibrillary acidic protein and radiological progression: a case report. Hum Pathol. 1994;25(8):835-838. 12. Wiśniewski K, Janczar K, Tybor K, Papierz W, Jaskólski DJ. Calcifying pseudoneoplasm of the foramen magnum--Case report and review of the literature. Br J Neurosurg. 2015;29(6):891-893. doi:10.3109/02688697.2015.1039491 13. Hodges TR, Karikari IO, Nimjee SM, et al. Calcifying pseudoneoplasm of the cerebellopontine angle: ACCEPTED MANUSCRIPT Case report. Neurosurgery. 2011;69(SUPPL. 1):117-120. doi:10.1227/NEU.0b013e3182155511 14. Montibeller GR, Stan A-C, Krauss JK, Nakamura M. Calcifying Pseudoneoplasm of the Inferior Colliculus: an Unusual Location for a Rare Tumor: Case Report. Neurosurgery. 2009;65(5):E1005E1006. doi:10.1227/01.NEU.0000351770.69874.15 Maruki C, Nakajima K, Shimoji T, Ito K, Matsumoto M, Ishii S. [Brain stone. A case report]. No Shinkei Geka. 1984;12:1441-1445. 16. Hashimoto M, Tanaka T, Ohgami S, Yonemasu Y, Fujita M. A case of idiopathic brain stone presenting as psychomotor epilepsy. Neurol Surg. 1986;14(12):1457-1461. Nitta T, Ito M, Sato K, Ishii S. [Brain stone in the cerebellum. Case report]. Neurol Med Chir (Tokyo). SC 17. 1987;27(2):150-153. 18. RI PT 15. Garen PD, Powers JM, Stovall King J, Perot PL. Intracranial fibro-osseous lesion Case report. J 19. Tokunaga H, Iwanaga H, Imanishi M, et al. A huge idiopathic brain stone in the posterior fossa. Neurol Surg. 1995;23(8):711-716. 20. M AN U Neurosurg. 1989;70:475-477. doi:10.3171/jns.1989.70.3.0475 [doi] Qian J, Rubio A, Powers JM, et al. Fibro-osseous lesions of the central nervous system: report of four cases and literature review. Am J Surg Pathol. 1999;23(10):1270-1275. Shrier DA, Melville D, Qian J, et al. Fibro-osseous lesions involving the brain: MRI. Neuroradiology. TE D 21. 1999;41(1):18-21. doi:10.1007/s002340050697 22. Tsugu H, Fukushima T, Takeno Y. Calcifying pseudotumor of the neural axis--case report. Neurol Med 23. EP Chir (Tokyo). 1999;39(11):762-765. doi:10.2176/nmc.39.762 Albu G, Deak G, Mencser Z, Vajtai I. [Fibro-osseous lesion of the central nervous system]. Orv Hetil. 24. AC C 2001;142(22):1165-1167. Tatke M, Singh AK, Gupta V. Calcifying pseudoneoplasm of the CNS. Br J Neurosurg. 2001;15(6):521-523. 25. Ghosal N, Thakre D, Murthy G, Hegde A. Cerebral calculi in the temporal horn of the lateral ventricle: report of an unusual case. Histopathology. 2007;50:817-818. 26. Rodriguez FJ, Scheithauer BW, Fourney DR, Robinson CA. Ependymoma and intraparenchymal calcifying pseudoneoplasm of the neural axis: Incidental collision or unique reactive phenomenon? Acta Neuropathol. 2008;115(3):363-366. doi:10.1007/s00401-007-0286-6 27. Mohapatra I, Manish R, Mahadevan a, Prasad C, Sampath S, Shankar SK. Calcifying pseudoneoplasm ACCEPTED MANUSCRIPT (fibro osseous lesion) of neuraxis (CAPNON) - a case report. Clin Neuropathol. 2010;29(4):223-226. http://www.ncbi.nlm.nih.gov/pubmed/20569672. 28. Ghosal N, Furtado S V., Gupta K, Hegde AS. Fibro-osseous lesion of the pineal region resembling osteoblastoma: A case report. Neuropathology. 2011;31(2):158-161. doi:10.1111/j.14401789.2010.01140.x Rulseh A, Keller J, Klener J, et al. Calcifying Pseudoneoplasms of the Neural Axis . Report of Three Cases. Ces a Slov Neurol a Neurochir. 2011;107(5):584-589. 30. RI PT 29. Yan X, Marsh WR, Scheithauer BW. Dysembryoplastic neuroepithelial tumor and calcifying SC pseudoneoplasms of the neuraxis: a collision of two seizure-associated lesions. ClinNeuropathol. 2011;30(4):197-202. doi:8774 [pii] 31. Fletcher AM, Greenlee JJD, Chang KE, Smoker WR, Kirby PA, O’Brien EK. Endoscopic resection of M AN U calcifying pseudoneoplasm of the neuraxis (CAPNON) of the anterior skull base with sinonasal extension. J Clin Neurosci. 2012;19(7):1048-1049. doi:10.1016/j.jocn.2011.11.016 32. Nonaka Y, Aliabadi HR, Friedman AH, Odere FG, Fukushima T. Calcifying pseudoneoplasms of the skull base presenting with cranial neuropathies: case report and literature review. J Neurol Surg reports. 2012;73(1):41-47. doi:10.1055/s-0032-1321503 Salim AA, Wilson PJ, Cherukuri RK, McKenzie S, Buckland ME. An unusual association of calcifying TE D 33. pseudoneoplasm of the neuraxis with interhemispheric lipoma and agenesis of corpus callosum. Pathology. 2012;44(7):657-659. doi:10.1097/PAT.0b013e32835a00ef Grabowski M, Recinos P, Chen T, Prayson R, Vogelbaum M. Calcifying pseudoneoplasm of the EP 34. neuraxis overlying the corpus callosum: A case report and review of the literature. Clin Neuropathol. 35. AC C 2013;32(6):515-522. doi:10.5414/NP300640 Stienen MN, Abdulazim A, Gautschi OP, Schneiderhan TM, Hildebrandt G, Lücke S. Calcifying pseudoneoplasms of the neuraxis (CAPNON): Clinical features and therapeutic options. Acta Neurochir (Wien). 2013;155(1):9-17. doi:10.1007/s00701-012-1502-2 36. Shimony N, Aizic A, Cagnano E, et al. Supratentorial calcified pseudotumour: Experience of a single institution and review of the literature. Acta Neurochir (Wien). 2014;156(6):1115-1120. doi:10.1007/s00701-014-2066-0 37. Hubbard M, Qaiser R, Clark HB, Tummala R. Multiple calcifying pseudoneoplasms of the neuraxis. Neuropathology. 2015;35(5):452-455. doi:10.1111/neup.12198 ACCEPTED MANUSCRIPT 38. Krejčí T, Buzrla P, Večeřa Z, et al. Calcifying pseudoneoplasm of the neural axis - A case report. Ces a Slov Neurol a Neurochir. 2015;78(5):568-575. 39. Lu A, Nundkumar A, Greco C, Shen P. Calcified pseudoneoplasm of the neuraxis. Neurology. 2015;84:2289-2290. 40. Ghaemi J, Hons B, Wasimi M, Ed M, Siripurapu R. Calcifying pseudoneoplasm of the neuraxis ( 41. J M, A J. Calcified Pseudoneoplasm of the Neuraxis (CAPNON): A Lesson Learnt from a Rare Entity. J Neurol Neurosci. 2016;7(3):2-4. doi:10.21767/2171-6625.1000121 Tan L, Syed S, Arvanitis L, Munoz L. Calcifying pseudoneoplasm of the superior medullary velum: An SC 42. RI PT CaPNoN ): an unusual cause of third nerve palsy in a teenager. 2016;(December 2015):19-21. unusual location for a rare lesion. Neurol India. 2016;64:185-186. http://www.neurologyindia.com/text.asp?2016/64/1/185/173619. Zerehpoosh FB, Samadian M, Azhari VS, Maryam B, Himzadeh KE, Mahnaz H. A case report of M AN U 43. calcifying pseudoneoplasm of the neuraxis: an incidental finding after a car accident. Turkish J Pathol. 2016:98-101. doi:10.5146/tjpath.2015.01361 44. Brasiliense LB, Dickson DW, Nakhleh RE, Tawk RG, Wharen R. Multiple Calcifying Pseudoneoplasms of the Neuraxis. Cureus. 2017;9(2):e1044. doi:10.7759/cureus.1044 Nussbaum ES, Hilton C, Defillo A, et al. Extradural petromastoid calcifying pseudoneoplasm of the TE D 45. neuraxis (CAPNON): Case report and literature review. Clin Neurol Neurosurg. 2018;166(January):99106. doi:10.1016/j.clineuro.2018.01.010 Moser FG, Tourje EJ, Pressman BD, Blinderman EE. Calcifying pseudotumor of the cervical spine. Am EP 46. 47. Chang M, Park JB, Kim KW. Intraosseous calcifying pseudotumor of the axis: A case report. Spine 48. AC C J Neuroradiol. 1994;15(3):580. (Phila Pa 1976). 2000;25(8):1036-1039. doi:10.1097/00007632-200004150-00020 Mayr MT, Hunter S, Erwood SC, Haid RWJ. Calcifying pseudoneoplasms of the spine with myelopathy. Report of two cases. J Neurosurg. 2000;93(2 Suppl):291-293. http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med4&NEWS=N&AN=11012062. 49. Liccardo G, Lunardi P, Menniti A, Floris R, Pastore FS, Fraioli B. Calcifying pseudo-tumor of the spine: Description of a case and review of the literature. Eur Spine J. 2003;12(5):548-551. doi:10.1007/s00586-003-0546-7 50. Sharma M, Sinha R, Hussey K, Fouyas IP. Tumoral calcinosis of the filum terminale: Case report. ACCEPTED MANUSCRIPT Neurosurgery. 2005;57(3):596. doi:10.1227/01.NEU.0000170987.14821.6F 51. Park P, Schmidt LA, Shah G V., Tran NK, Gandhi D, Marca F La. Calcifying pseudoneoplasm of the spine. Clin Neurol Neurosurg. 2008;110(4):392-395. doi:10.1016/j.clineuro.2007.12.006 52. Apostolopoulos V, David KM, Malcolm A, King A. Intradural calcifying fibroblastic proliferation 1976). 2009;34(19):712-715. doi:10.1097/BRS.0b013e3181b2f7ee 53. RI PT associated with a nerve root: A reactive process mimicking a nerve sheath tumor. Spine (Phila Pa Tong D, Karunaratne N, Howe G, Spencer D, Manolios N. Clinical images: Calcifying pseudoneoplasm of the neuraxis. Arthritis Rheum. 2010;62(3):704. doi:10.1002/art.27293 Ozdemir M, Bozkurt M, Ozgural O, Erden E, Tuna H, Caglar YS. Unusual localization of an unusual SC 54. tumor: calcifying pseudoneoplasm of the foramen magnum. Clin Neuropathol. 2011;30(1):25-27. doi:10.5414/NPP30025 Jentoft ME, Scheithauer BW, Bertoni F, Abood C, Chang HT. Calcifying pseudoneoplasm of the M AN U 55. neuraxis with single nerve rootlet involvement. Can J Neurol Sci. 2012;39(6):840-842. doi:10.1017/S0317167100015730 56. Keong Kwan M, Abdelhai AM, Beng Saw L, Wei Chan CY. Symptomatic calcifying pseudotumor of the thoracic spine that resolved with the indomethacin treatment: A case report. Spine (Phila Pa 1976). 57. TE D 2012;37(26):1676-1679. doi:10.1097/BRS.0b013e318276b48c Muccio CF, Cerase A, Leone A, et al. Calcifying Pseudoneoplasm of the Neuraxis. Neuroradiol J. 2012;25(4):453-459. doi:10.1177/197140091202500407 Naidu PK, Patel SC. Calcifying Pseudoneoplasm of the Neural Axis Arising within the Lumbar Spine: EP 58. Implications of Unique Cross-Sectional Imaging Characteristics of a Rare Spinal Column Lesion. 59. AC C Neurographics. 2012;2(1):27-30. doi:10.3174/ng.1120021 Bartanusz V, Ziu M, Jimenez DF, Henry JM. Calcifying pseudoneoplasm of the atlantoaxial joint in a child. J Neurosurg Spine. 2013;18(4):367-371. doi:10.3171/2013.1.SPINE12810 60. Reinard K, Seyfried D, Gutierrez J, Rock J. A Rare Intradural Extramedullary Calcifying Pseudoneoplasm of the Spine Presenting with Radiculopathy. Br J Med Med Res. 2015;7(5):419-424. doi:10.9734/BJMMR/2015/16543 61. Song SY, Ahn SY, Rhee JJ, Lee JW, Hur JW, Lee HK. Three Cases of Calcifying Pseudoneoplasm which Involve the Epidural Space of the Spine. Korean J Spine. 2015;12(3):235-238. doi:10.14245/kjs.2015.12.3.235 ACCEPTED MANUSCRIPT 62. Wiśniewski K, Janczar K, Tybor K, Papierz W, Jaskólski DJ. Calcifying pseudoneoplasm of the foramen magnum—Case report and review of the literature. Br J Neurosurg. 2015;29(6):891-893. doi:10.3109/02688697.2015.1039491 63. Alshareef M, Vargas J, Welsh CT, Kalhorn SP. Calcifying Pseudoneoplasm of the Cervicomedullary Junction: Case Report and a Literature Review. World Neurosurg. 2016;85:364.E11-364.E18. Singh H, Zengou R, Moss IL. Intradural calcifying pseudoneoplasm. Spine J. 2016;16(1):e45-e46. doi:10.1016/j.spinee.2015.09.013 65. Wu HG, Yue L, Luo CJ, Wei ZH, Wang S, Zheng ND. Calcifying Pseudoneoplasm of the Neuraxis SC 64. RI PT doi:10.1016/j.wneu.2015.08.055 Arising From the Sacral Canal: Case Report and Review of the Literature. World Neurosurg. M AN U 2017;98:875.e9-875.e12. doi:10.1016/j.wneu.2016.11.107 TE D Figure 1. MRI images (2005, top row; 2017, bottom row). Images depict progression in tumour size and associated oedema over 12 years of radiographic follow-up. (A, F) axial T2, (B, G) axial T2 FLAIR, (C, H) coronal T1 pre-contrast, (D, I) coronal T1 post-contrast, (E, J) axial T1 post-contrast sequences. Figure 2. Axial susceptibility-weighted MRI demonstrating susceptibility artefact associated with the right frontoparietal mass, consistent with the dense calcification (later confirmed during surgery). AC C EP Figure 3. Histological appearance. (A) Low-power micrograph demonstrating areas of calcification (arrow) and metaplastic bone formation (arrowhead). (B) Medium-power image depicting increased cellularity and variable mineralisation/calcification. (C) Low power image. Radial spiculated arrangement around central mineralised area (arrow). (D) Immunohistochemistry for epithelial membrane antigen (EMA). EMA-positive cells are seen around the periphery of calcified nodules. ACCEPTED MANUSCRIPT Author Year 1 Rhodes and Davis 1 1978 27 Sex Presenting Symptoms F Headache Location Contrast Enhancement Oedema Right frontal (IA) ND ND 55 F Autopsy finding Cranial dura (EA) NA (autopsy) 3 60 M Autopsy finding Left cerebellum (EA) NA (autopsy) 4 74 F Autopsy finding Cranial dura (EA) NA (autopsy) NA (autopsy) NA (autopsy) 46 M Autopsy finding 6 62 M Autopsy finding Pineal region (EA) 83 M Autopsy finding Cranial dura (EA) 7 8 9 10 Jun et al. 10 Maruki et al. 15 Hashimoto et al. 16 NA (autopsy) 1984 55 M Headache, nausea Corpus callosum (EA) ND ND 1984 43 F Seizures Right temporal (IA) ND ND 1986 29 M Seizures Right temporal (IA) ND ND ND ND ND ND ND ND ND ND 1987 28 F Vertigo 12 Garen et al. 18 1989 44 M Facial pain 13 Bertoni et al. 2 1990 31 M Headache, jugular foramen syndrome 14 48 M Right cranial nerve 11 palsy Right cerebellum/dentate nucleus (IA) Right meckel’s cave (EA) Left jugular foramen, cerebellopontine angle (EA) Right cerebellar tonsil (IA) 15 32 M Seizures Frontal lobe (IA) EP TE D Nitta et al. 17 11 NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) M AN U 5 Choroid plexus, 4 th ventricle (EA) ND ND NA (autopsy) NA (autopsy) 45 F Autopsy finding; History of multiple cranial nerve palsies 17 58 M Hoarseness, hearing loss Jugular foramen (EA) ND ND 72 F Tinnitus, ataxia Cerebellum (IA) ND ND Developmental delay Left superior temporal gyrus (IA) ND ND Seizures Frontal lobe (IA) ND ND Left temporal (IA) Minimal, peripheral + 18 19 19 Qian et al. 20 1995 1999 20 33 F 47 F AC C 16 Right skull base (sphenoid, occipital bone, sella, foramen magnum) (EA) Tokunaga et al. 21 Shrier et al. 21 1999 32 F 22 Tsugu et al. 22 1999 22 F Seizures Right parietal (IA) ND None F Headache, visual loss Left fronto-parietal, right fronto-parietal (IA) ND ND 23 Albu et al. 23 2001 53 Incidental Clinical Outcome Recurrence Improved None NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) ND Stable None ND ND None ND Seizure free None ND ND ND 132 Pain resolved ND 156 ND Recurred at 3 years 228 ND None 360 ND None NA (autopsy) NA (autopsy) NA (autopsy) Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Lost to follow-up ND ND ND Improved ND 31 Stable None 36 ND None 12 Stable None ND Improved None ND ND ND ND Surgical resection NA (autopsy) NA (autopsy) NA (autopsy) SC 2 Treatment Postoperative Followup (months) RI PT Case Age (years) NA (autopsy) NA (autopsy) NA (autopsy) Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection NA (autopsy) 84 NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) NA (autopsy) ACCEPTED MANUSCRIPT 25 25 26 27 Ghosal et al. Rodriguez et al. 26 Aiken et al. 3 2001 F Seizures 2008 67 F Incidental 2009 16 M Incidental 29 49 30 32 59 27 Seizures 26 35 Montibeller et al. 14 Mohapatra et al. M 2007 28 31 6 M F M Seizures Left temporal (IA) ND Trigone/temporal horn (EA) Right cerebellar hemisphere (IA) Right temporal horn (EA) Minimal, irregular Minimal, peripheral Minimal, irregular Minimal, irregular Right temporal (IA) Seizures Left hippocampus (IA) Left arm numbness Right parietal (IA) ND ++ + None ND None Minimal Minimal, peripheral Strong, heterogenous Minimal, irregular None ND ND ND ND ND ND ND ND ND ND 18 Symptoms resolved None 6 Stable None None None None None Seizures Right temporal (IA) Strong, heterogenous ND Surgical resection 6 Stable None Surgical resection 7 Stable None 6 Improved None ND Improved ND 48 Seizure free None ND ND ND ND 2011 34 M Headaches, left cranial nerve 12 palsy Left cerebellopontine angle (EA) Moderate, irregular ND 35 Rulseh et al. 29 2011 46 M Headaches Right parietal (IA) Strong, heterogenous + 23 M Seizures M 38 Fletcher et al. 2012 19 M 39 Nonaka et al. 32 2012 56 M 35 M 2012 47 F 2013 49 F 40 43 Kerr et al. 4 2013 56 M 44 Stienen et al. 35 2013 46 M 55 F Seizures Frontal headache, nasal discharge Chronic right ear infections, right facial pain/numbness Occipital headaches, dizziness Headache, gait ataxia, cognitive decline None Minimal None ND Minimal, irregular ND Right infratemporal fossa (EA) Minimal, irregular None Surgical resection ND Stable ND Left clivus/posterior fossa (EA) Minimal, irregular Minimal Surgical resection 6 Stable None Right frontal, periventricular (IA) ND + Surgical resection ND Stable ND Corpus callosum (EA) Minimal, irregular + Surgical resection 21 Improved None None TE D 45 Left frontal (IA) EP 2011 31 Surgical resection Surgical resection Surgical resection Surgical resection Right mesial temporal (IA) Left ethmoid sinus, anterior skull base (EA) Headaches Suboccipital headache Right cerebellomedullary angle (EA) Minimal, peripheral Minimal Surgical resection 6 months Hoarseness, swallowing difficulty improving Seizures Right parietal (IA) Minimal, peripheral + Surgical resection 10 Seizure free ND Behavioral disorder Left frontoparietal (IA) Minimal, peripheral + Surgical resection 22 Temporary right brachiofacial hemiparesis, aphasia ND AC C 36 M AN U Hodges et al. 13 45 Recovered well M 34 34 ND 48 Headache, seizures Grabowski et al. None 2010 M 42 ND Episodic dizziness 50 Salim et al. 33 6 F 2011 41 None 67 Ghosal et al. 28 Yan et al. Improved 2009 33 37 6 Right inferior colliculus (EA) Posterior third ventricle/pineal region (EA) 30 Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection RI PT Tatke et al. 24 SC 24 ACCEPTED MANUSCRIPT 24 M Seizures, progressive visual loss Right temporo-occipital (IA) None Minimal 2014 33 M Headache, deteriorating vision Corpus callosum/parafalcine (EA) Minimal, peripheral ++ 48 54 M Incidental Corpus callosum/parafalcine (EA) Minimal, irregular Minimal 49 60 M Incidental Left frontal (IA) 46 F Headaches, left facial numbness Bilateral fronto-parietal (IA) 6 Shimony et al. 36 Surgical resection 1.5 Stable ND Surgical resection 10 Stable ND Surgical resection 2.5 Post-operative hemorrhage, left leg weakness, hydrocephalus ND 15 Stable ND 18 Headaches improved ND 17 Mild left arm weakness None ND ND ND 2015 38 F Seizures Right perirolandic (IA) 2015 No data No data Suboccipital headaches Right cerebellomedullary angle (EA) Minimal, peripheral Minimal, irregular Minimal, peripheral Minimal, irregular Duque et al. 7 2016 48 F Headaches Left atrium (EA) ND + Surgical resection 24 Stable ND 54 Ghaemi et al. 40 2016 18 ND Headache, left oculomotor nerve palsy Left interpeducular cistern (EA) Minimal, peripheral None Surgical resection No data ND ND 55 Merola et al. 41 2016 39 F Seizures Left perisylvian (IA) Minimal, peripheral ++ Surgical resection 1 Left frontoparietal infarct, right hemiparesis ND 56 Tan et al. 42 2016 45 M Headaches, diplopia, left cranial nerve 6 palsy Superior medullary velum (EA) Irregular/rim Minimal Surgical resection 3 Improved ND 57 Zerehpoosh et al. 43 2016 25 M Incidental TE D 47 Lyapichev et al. RI PT 2014 46 Left temporal (IA) Minimal, irregular Minimal Surgical resection 36 Stable ND (1) None, (2) minimal, irregular (1) None, (2) Minimal Surgical resection (left frontal) 4 Stable None 51 Krejči et al. 52 Lu et al. 39 53 38 2015 Minimal + Minimal Brasiliense et al. 44 2017 67 F Seizures 59 Higa et al. 5 2017 62 M Headaches Left cingulate gyrus (IA) Minimal, peripheral + Surgical resection 14 Improved Recurred at 14 months 45 2018 39 F Right-sided hearing loss/tinnitus Right jugular foramen (EA) Minimal, irregular None Surgical resection ND Right-sided complete hearing loss ND Barber et al. 2018 14 F Seizures Right perirolandic (IA) Minimal, irregular +++ Surgical resection 9 Improved seizure frequency None AC C 61 Nussbaum et al. EP 58 60 (1) Ventral midbrain (IA), (2) left frontal (IA) Surgical resection Surgical resection Surgical resection Surgical resection SC Hubbard et al. 37 M AN U 50 Minimal Table 1. Summary of reported cases of intracranial CAPNON in the literature. M, male; F, female; ND, no data; NA, not applicable; IA, intra-axial; EA, extra-axial ACCEPTED MANUSCRIPT Author Year 1 Bertoni et al. 2 1990 50 Sex Presenting Symptoms M Right neck pain, occipital headache Location Contrast Enhancement Oedema Right foramen magnum, extradural ND ND 23 M Back pain T10, extradural ND ND 3 58 M Incidental C2/3, extradural ND ND 4 12 M Neck pain C6, extradural ND ND 5 32 M Back pain L4/5, extradural ND 33 F Back pain T9, extradural 7 68 F Right hip pain L4/5, extradural 9 Moser et al. 11 Smith and Berry 11 12 Qian et al. 20 1994 14 15 16 Shrier et al. Chang et al. Mayr et al. 8 48 19 Liccardo et al. 49 Sharma et al. 50 68 M M 1999 49 M 59 M Shuffling gait M Neck pain, shuffling gait 1999 2000 2000 2003 2005 59 60 M 58 M 63 M 40 M 55 M 20 Park et al. 51 21 Apostolopoulos et al. 52 2009 53 M 22 Tong et al. 53 2010 67 F 23 Ozdemir et al. 54 24 Rulseh et al. 29 Back pain Left arm radicular pain Left leg radicular pain 48 17 18 F C2, extradural 1994 13 21 56 Incidental 2008 2011 59 F 53 M 43 F Weakness Neck pain Back pain, myelopathy Bilateral upper extremity numbness, myelopathy Thoracic radicular pain, myelopathy Low back pain, bilateral leg pain Neck pain, left C8 radicular pain Low back pain, left leg pain ND ND ND ND ND L4/5, extradural ND ND Left C7/T1, extradural Minimal, peripheral None None ND ND ND C1/2, extradural ND ND Left foramen magnum, extradural C2 odontoid process, intraosseous Solid, heterogenous + L2/3, intradural/extramedullary C1/clivus/foramen magnum, extradural Heterogenous None T10-12, extradural Minimal, peripheral None C3/4, extradural ND None T8/9, extradural None ND None None EP 10 F AC C 46 20 TE D 8 ND ND M AN U 6 L3, intradural/filum terminale Conus, Intradural/extramedullary Minimal, peripheral Strong, heterogenous Lower back pain Left L4/5, extradural No data ND Left facial pain, left leg weakness Low back pain, bilateral leg pain Left foramen magnum, intradural/extramedullary Strong, heterogenous + L3, extradural ND None Left C7-T1, extradural Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection SC 2 Treatment Postoperative Followup (months) RI PT Case Age (years) Minimal ND Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Clinical Outcome Recurrence 42 ND None Lost to follow-up ND ND 112 ND None 39 ND None 84 ND None Lost to follow-up ND ND 16 ND ND ND ND ND ND ND Improved ND ND Improved ND 90 ND None 46 ND None 24 Stable None 24 Improved Local recurrence at 24 months 48 Improved None 60 Improved None 36 Improved ND ND Improved ND ND Improved radicular pain ND ND Improved ND ND ND ND ND ND 10 Stable None Lost to follow-up Lost to follow-up ACCEPTED MANUSCRIPT 26 56 27 Kwan et al. Muccio et al. 57 2012 2012 2012 28 29 30 26 48 55 57 Naidu and Patel 58 Bartanusz et al. 59 60 Reinard et al. 32 61 2013 43 2 None Surgical resection ND Improved back pain ND Left thoracic radicular pain T9/10, extradural None None Indomethacin 3 Improved Complete resolution Neck pain Right foramen magnum, intradural/extramedullary M F M M F 2015 44 M 2015 77 F 33 67 F 34 78 2015 2016 Back pain, paraparesis Low back pain, left leg pain None None T10/11, dorsal extradural None Left L4, intradural/extramedullary Strong, heterogenous Minimal, peripheral Minimal, irregular Neck pain, torticollis Left C1/2, extradural Lower back pain, left leg pain Lower back pain, bilateral leg pain L4, extradural Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection Surgical resection 14 Stable None Improved paraparesis None None None ND ND ND 12 Improved neck pain and torticollis None None at 8 months None 48 Improved ND 5 Pain resolved None ND Pain resolved ND ND Pain resolved ND ND Right leg pain L2/3, extradural ND F Lower back pain L1, extradural ND 29 M Headaches, impaired head rotation Right foramen magnum, intradural/extramedullary Minimal, peripheral Minimal Surgical resection 24 Stable ND 59 F Incidental Right cerebellomedullary angle/foramen magnum, intradural/extramedullary Strong + Surgical resection 12 Stable None 51 F Lower back pain, bilateral leg pain L2, dorsal extradural ND None Surgical resection 12 Improved pain None 38 46 F Neck pain C3, intraosseous ND None Surgical resection 27 Improved pain None 39 73 F Paraparesis T2, intradural/extramedullary ND ND Surgical resection 12 Improved None L2, intradural None None Surgical resection No data Improving paraparesis ND C7/T1, intradural/extramedullary ND Minimal 2 Improved ND S2, intradural Strong, irregular None 36 Improved None 37 Alshareef et al. 63 Duque et al. 7 Lopes et al. 9 2016 72 F Cauda equina syndrome 41 Singh et al. 64 2016 90 F Myelopathy Wu et al. 2017 39 F Sacrococcyeal pain AC C 42 65 EP 40 ND ND M AN U 36 Wiṥniewski et al. 62 ND 2 T12, extradural 35 Song et al. Strong Left low back pain TE D 31 2012 L1/2, intradural F RI PT Jentoft et al. 55 SC 25 Surgical resection Surgical resection Table 2. Summary of reported cases of spinal CAPNON in the literature. M, male; F, female; ND, no data ACCEPTED MANUSCRIPT N Male Female No data Age 103 55 (53.4%) 46 (44.7%) 2 (1.9%) 47 ± 17 years Cranial Spinal 61 (59.2%) N Supratentorial Infratentorial Pineal region No data Infratemporal fossa 38 (62.3%) 15 (24.6%) 4 (6.6%) 3 (4.9%) 1 (1.6%) Lumbar Cervical Thoracic Foramen magnum Sacral 15 (35.7%) 11 (26.2%) 8 (19%) 7 (16.7%) 1 (2.4%) Intraaxial Extraaxial 33 (54.1%) 28 (45.9%) Extradural Intradural/extramedullary Intraosseous 27 (64.3%) 13 (31%) 2 (4.7%) M AN U Presenting Symptoms Axial pain (e.g. back, 19 (31.3%) neck) 19 (31.1%) Radicular symptoms 7 (11.5%) Myelopathy/weakness 6 (9.8%) Incidental 6 (9.8%) Cauda equina syndrome 3 (4.9%) 3 (4.9%) 3 (4.9%) 2 (3.3%) 2 (3.3%) TE D Headache Seizures Autopsy finding Incidental Cranial nerve palsy Dizziness/vertigo Facial pain Visual loss Hearing loss Ataxia SC Location 42 (40.8%) RI PT N 24 (57.1%) 15 (35.7%) 9 (21.4%) 3 (7.1%) 1 (2.4%) AC C EP Table 3. Characteristics of patient demographics, presenting symptoms and lesion location for all intracranial and spinal CAPNON reports in the literature. M, male; F, female; ND, no data AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare central nervous system (CNS) lesion that can be found in both the brain and the spinal cord. - Several consistent radiographic features have been previously described, such as T1 and T2 hypointensity, and calcification on CT, although the axial location of the mass and the degree of enhancement/oedema are variable. - Histologically, CAPNON consist of a variable combination of nodular chondromyxoid matrices with palisading spindle to epithelioid cells, a fibrous stroma, osseous components, and foreign-body reactions with giant cells. - We describe a case of a CAPNON in a 31-year-old patient monitored with serial imaging for 17 years prior to surgical resection and definitive diagnosis. Over this time period a progressive and extensive surrounding oedema developed, a radiographic finding which has not been described previously. AC C EP TE D M AN U SC RI PT - ACCEPTED MANUSCRIPT CAPNON, calcifying pseudoneoplasm of the neuraxis CNS, Central nervous system MRI, magnetic resonance imaging RI PT fMRI, functional magnetic resonance imaging EMA, epithelial membrane antigen PR, progesterone receptor CT, computed tomography AC C EP TE D M AN U SC GFAP, glial fibrillary acidic protein ACCEPTED MANUSCRIPT Declaration of Interests AC C EP TE D M AN U SC RI PT The authors of the enclosed manuscript have no conflicts of interest – financial or otherwise - to disclose.