Neurologic/Head and Neck Imaging

Cytotoxic Lesions of the Corpus Callosum That Show Restricted Diffusion: Mechanisms, Causes, and Manifestations

Published Online:https://doi.org/10.1148/rg.2017160085

This article describes the imaging spectrum and the causes of cytotoxic lesions of the corpus callosum.

Cytotoxic lesions of the corpus callosum (CLOCCs) are secondary lesions associated with various entities. CLOCCs have been found in association with drug therapy, malignancy, infection, subarachnoid hemorrhage, metabolic disorders, trauma, and other entities. In all of these conditions, cell-cytokine interactions lead to markedly increased levels of cytokines and extracellular glutamate. Ultimately, this cascade can lead to dysfunction of the callosal neurons and microglia. Cytotoxic edema develops as water becomes trapped in these cells. On diffusion-weighted magnetic resonance (MR) images, CLOCCs manifest as areas of low diffusion. CLOCCs lack enhancement on contrast material–enhanced images, tend to be midline, and are relatively symmetric. The involvement of the corpus callosum typically shows one of three patterns: (a) a small round or oval lesion located in the center of the splenium, (b) a lesion centered in the splenium but extending through the callosal fibers laterally into the adjacent white matter, or (c) a lesion centered posteriorly but extending into the anterior corpus callosum. CLOCCs are frequently but not invariably reversible. Their pathologic mechanisms are discussed, the typical MR imaging findings are described, and typical cases of CLOCCs are presented. Although CLOCCs are nonspecific with regard to the underlying cause, additional imaging findings and the clinical findings can aid in making a specific diagnosis. Radiologists should be familiar with the imaging appearance of CLOCCs to avoid a misdiagnosis of ischemia. When CLOCCs are found, the underlying cause of the lesion should be sought and addressed.

©RSNA, 2017

An earlier incorrect version of this article appeared online. This article was corrected on February 13, 2017.

References

  • 1. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 2013;30(4):297–306. Crossref, MedlineGoogle Scholar
  • 2. Phelps C, Korneva E, eds. Neuroimmune biology. Vol 6, Cytokines and the brain. Amsterdam, the Netherlands: Elsevier, 2008. Google Scholar
  • 3. Leonoudakis D, Braithwaite SP, Beattie MS, Beattie EC. TNFα-induced AMPA-receptor trafficking in CNS neurons: relevance to excitotoxicity? Neuron Glia Biol 2004;1(3): 263–273. Crossref, MedlineGoogle Scholar
  • 4. Kim YS, Honkaniemi J, Sharp FR, Täuber MG. Expression of proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the brain during experimental group B streptococcal meningitis. Brain Res Mol Brain Res 2004;128(1):95–102. Crossref, MedlineGoogle Scholar
  • 5. Kita T, Tanaka T, Tanaka N, Kinoshita Y. The role of tumor necrosis factor-α in diffuse axonal injury following fluid-percussive brain injury in rats. Int J Legal Med 2000;113(4):221–228. Crossref, MedlineGoogle Scholar
  • 6. Prow NA, Irani DN. The inflammatory cytokine, interleukin-1 beta, mediates loss of astroglial glutamate transport and drives excitotoxic motor neuron injury in the spinal cord during acute viral encephalomyelitis. J Neurochem 2008;105(4):1276–1286. Crossref, MedlineGoogle Scholar
  • 7. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012;76(1):16–32. Crossref, MedlineGoogle Scholar
  • 8. Matute C, Alberdi E, Domercq M, et al. Excitotoxic damage to white matter. J Anat 2007;210(6):693–702. Crossref, MedlineGoogle Scholar
  • 9. Hassel B, Boldingh KA, Narvesen C, Iversen EG, Skrede KK. Glutamate transport, glutamine synthetase and phosphate-activated glutaminase in rat CNS white matter: a quantitative study. J Neurochem 2003;87(1):230–237. Crossref, MedlineGoogle Scholar
  • 10. Domercq M, Matute C. Expression of glutamate transporters in the adult bovine corpus callosum. Brain Res Mol Brain Res 1999;67(2):296–302. Crossref, MedlineGoogle Scholar
  • 11. Goursaud S, Kozlova EN, Maloteaux JM, Hermans E. Cultured astrocytes derived from corpus callosum or cortical grey matter show distinct glutamate handling properties. J Neurochem 2009;108(6):1442–1452. Crossref, MedlineGoogle Scholar
  • 12. Moritani T, Smoker WR, Sato Y, Numaguchi Y, Westesson PL. Diffusion-weighted imaging of acute excitotoxic brain injury. AJNR Am J Neuroradiol 2005;26(2):216–228. MedlineGoogle Scholar
  • 13. Prilipko O, Delavelle J, Lazeyras F, Seeck M. Reversible cytotoxic edema in the splenium of the corpus callosum related to antiepileptic treatment: report of two cases and literature review. Epilepsia 2005;46(10):1633–1636. Crossref, MedlineGoogle Scholar
  • 14. Takayama H, Kobayashi M, Sugishita M, Mihara B. Diffusion-weighted imaging demonstrates transient cytotoxic edema involving the corpus callosum in a patient with diffuse brain injury. Clin Neurol Neurosurg 2000;102(3):135–139. Crossref, MedlineGoogle Scholar
  • 15. Conti M, Salis A, Urigo C, Canalis L, Frau S, Canalis GC. Transient focal lesion in the splenium of the corpus callosum: MR imaging with an attempt to clinical-physiopathological explanation and review of the literature. Radiol Med (Torino) 2007;112(6):921–935. Crossref, MedlineGoogle Scholar
  • 16. Kim TY, Park DW, Park CK, Lee YJ, Lee SR. Reversible splenial lesion in the corpus callosum on MRI after ingestion of a herbicide containing glufosinate ammonium: a case report. J Korean Soc Radiol 2014;70(6):399–402. https://doi.org/10.3348/jksr.2014.70.6.399. Published online June 3, 2014. CrossrefGoogle Scholar
  • 17. Fujiki Y, Nakajima H, Ito T, Kitaoka H, Takahashi Y. A case of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with anti-glutamate receptor antibody [in Japanese]. Rinsho Shinkeigaku 2011;51(7):510–513. Crossref, MedlineGoogle Scholar
  • 18. Takanashi J, Barkovich AJ, Shiihara T, et al. Widening spectrum of a reversible splenial lesion with transiently reduced diffusion. AJNR Am J Neuroradiol 2006;27(4):836–838. MedlineGoogle Scholar
  • 19. Bulakbasi N, Kocaoglu M, Tayfun C, Ucoz T. Transient splenial lesion of the corpus callosum in clinically mild influenza-associated encephalitis/encephalopathy. AJNR Am J Neuroradiol 2006;27(9):1983–1986. MedlineGoogle Scholar
  • 20. Maeda M, Tsukahara H, Terada H, et al. Reversible splenial lesion with restricted diffusion in a wide spectrum of diseases and conditions. J Neuroradiol 2006;33(4):229–236. Crossref, MedlineGoogle Scholar
  • 21. Takanashi J, Barkovich AJ, Yamaguchi K, Kohno Y. Influenza-associated encephalitis/encephalopathy with a reversible lesion in the splenium of the corpus callosum: a case report and literature review. AJNR Am J Neuroradiol 2004;25(5):798–802. MedlineGoogle Scholar
  • 22. Yokota S, Imagawa T, Miyamae T, et al. Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy. Pediatr Int 2000;42(2):197–203. Crossref, MedlineGoogle Scholar
  • 23. Tha KK, Terae S, Sugiura M, et al. Diffusion-weighted magnetic resonance imaging in early stage of 5-fluorouracil-induced leukoencephalopathy. Acta Neurol Scand 2002;106(6):379–386. Crossref, MedlineGoogle Scholar
  • 24. Tada H, Takanashi J, Barkovich AJ, et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004;63(10):1854–1858. Crossref, MedlineGoogle Scholar
  • 25. Takanashi J, Shiihara T, Hasegawa T, et al. Clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination. J Neurol Sci 2015;349(1-2):226–228. Crossref, MedlineGoogle Scholar
  • 26. Garcia-Monco JC, Cortina IE, Ferreira E, et al. Reversible splenial lesion syndrome (RESLES): what’s in a name? J Neuroimaging 2011;21(2):e1–e14. Crossref, MedlineGoogle Scholar
  • 27. Park MK, Hwang SH, Jung S, Hong SS, Kwon SB. Lesions in the splenium of the corpus callosum: clinical and radiological implications. Neurol Asia 2014;19(1):79–88. http://www.neurology-asia.org/articles/neuroasia-2014-19(1)-079.pdf. Google Scholar
  • 28. Doherty MJ, Jayadev S, Watson NF, Konchada RS, Hallam DK. Clinical implications of splenium magnetic resonance imaging signal changes. Arch Neurol 2005;62(3):433–437. Crossref, MedlineGoogle Scholar
  • 29. Kazi AZ, Joshi PC, Kelkar AB, Mahajan MS, Ghawate AS. MRI evaluation of pathologies affecting the corpus callosum: a pictorial essay. Indian J Radiol Imaging 2013;23(4):321–332. Crossref, MedlineGoogle Scholar
  • 30. Böttcher J, Kunze A, Kurrat C, et al. Localized reversible reduction of apparent diffusion coefficient in transient hypoglycemia-induced hemiparesis. Stroke 2005;36(3): e20–e22. Crossref, MedlineGoogle Scholar
  • 31. Kallenberg K, Bailey DM, Christ S, et al. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness. J Cereb Blood Flow Metab 2007;27(5):1064–1071. Crossref, MedlineGoogle Scholar
  • 32. Młodzikowska-Albrecht J, Steinborn B, Zarowski M. Cytokines, epilepsy and epileptic drugs: is there a mutual influence? Pharmacol Rep 2007;59(2):129–138. MedlineGoogle Scholar
  • 33. Kim SS, Chang KH, Kim ST, et al. Focal lesion in the splenium of the corpus callosum in epileptic patients: antiepileptic drug toxicity? AJNR Am J Neuroradiol 1999;20(1): 125–129. MedlineGoogle Scholar
  • 34. da Rocha AJ, Reis F, Gama HP, et al. Focal transient lesion in the splenium of the corpus callosum in three non-epileptic patients. Neuroradiology 2006;48(10):731–735. Crossref, MedlineGoogle Scholar
  • 35. Mirsattari SM, Lee DH, Jones MW, Blume WT. Transient lesion in the splenium of the corpus callosum in an epileptic patient. Neurology 2003;60(11):1838–1841. Crossref, MedlineGoogle Scholar
  • 36. Polster T, Hoppe M, Ebner A. Transient lesion in the splenium of the corpus callosum: three further cases in epileptic patients and a pathophysiological hypothesis. J Neurol Neurosurg Psychiatry 2001;70(4):459–463. Crossref, MedlineGoogle Scholar
  • 37. Anneken K, Evers S, Mohammadi S, Schwindt W, Deppe M. Transient lesion in the splenium related to antiepileptic drug: case report and new pathophysiological insights. Seizure 2008;17(7):654–657. Crossref, MedlineGoogle Scholar
  • 38. Cohen-Gadol AA, Britton JW, Jack CR Jr, Friedman JA, Marsh WR. Transient postictal magnetic resonance imaging abnormality of the corpus callosum in a patient with epilepsy: case report and review of the literature. J Neurosurg 2002;97(3):714–717. Crossref, MedlineGoogle Scholar
  • 39. Maeda M, Shiroyama T, Tsukahara H, Shimono T, Aoki S, Takeda K. Transient splenial lesion of the corpus callosum associated with antiepileptic drugs: evaluation by diffusion-weighted MR imaging. Eur Radiol 2003;13(8):1902–1906. Crossref, MedlineGoogle Scholar
  • 40. Verrotti A, Basciani F, Trotta D, Greco R, Morgese G, Chiarelli F. Effect of anticonvulsant drugs on interleukins-1, -2 and -6 and monocyte chemoattractant protein-1. Clin Exp Med 2001;1(3):133–136. Crossref, MedlineGoogle Scholar
  • 41. Renard D, Bonafe A, Heroum C. Transient lesion in the splenium of the corpus callosum after oral corticoid therapy. Eur J Neurol 2007;14(8):e19–e20. Crossref, MedlineGoogle Scholar
  • 42. Cecil KM, Halsted MJ, Schapiro M, Dinopoulos A, Jones BV. Reversible MR imaging and MR spectroscopy abnormalities in association with metronidazole therapy. J Comput Assist Tomogr 2002;26(6):948–951. Crossref, MedlineGoogle Scholar
  • 43. Kim E, Na DG, Kim EY, Kim JH, Son KR, Chang KH. MR imaging of metronidazole-induced encephalopathy: lesion distribution and diffusion-weighted imaging findings. AJNR Am J Neuroradiol 2007;28(9):1652–1658. Crossref, MedlineGoogle Scholar
  • 44. Hunt NH, Golenser J, Chan-Ling T, et al. Immunopathogenesis of cerebral malaria. Int J Parasitol 2006;36(5): 569–582. Crossref, MedlineGoogle Scholar
  • 45. Moritani T, Ekholm S, Westesson PL, eds. Diffusion-weighted MR imaging of the brain. 2nd ed. Berlin, Germany: Springer, 2009. CrossrefGoogle Scholar
  • 46. Starkey J, Moritani T, Kirby P. MRI of CNS fungal infections: review of aspergillosis to histoplasmosis and everything in between. Clin Neuroradiol 2014;24(3):217–230. Crossref, MedlineGoogle Scholar
  • 47. Combes V, Coltel N, Faille D, Wassmer SC, Grau GE. Cerebral malaria: role of microparticles and platelets in alterations of the blood-brain barrier. Int J Parasitol 2006;36(5):541–546. Crossref, MedlineGoogle Scholar
  • 48. Milner DA Jr, Whitten RO, Kamiza S, et al. The systemic pathology of cerebral malaria in African children. Front Cell Infect Microbiol 2014;4:104. doi:10.3389/fcimb.2014.00104. Published online August 21, 2014. Crossref, MedlineGoogle Scholar
  • 49. Kobata R, Tsukahara H, Nakai A, et al. Transient MR signal changes in the splenium of the corpus callosum in rotavirus encephalopathy: value of diffusion-weighted imaging. J Comput Assist Tomogr 2002;26(5):825–828. Crossref, MedlineGoogle Scholar
  • 50. Zhang S, Feng J, Shi Y. Transient widespread cortical and splenial lesions in acute encephalitis/encephalopathy associated with primary Epstein-Barr virus infection. Int J Infect Dis 2016;42:7–10. Crossref, MedlineGoogle Scholar
  • 51. Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol 2002;44(3):259–272. Crossref, MedlineGoogle Scholar
  • 52. Mathiesen T, Edner G, Ulfarsson E, Andersson B. Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor-α following subarachnoid hemorrhage. J Neurosurg 1997;87(2):215–220. Crossref, MedlineGoogle Scholar
  • 53. Gaetani P, Tartara F, Pignatti P, Tancioni F, Rodriguez y Baena R, De Benedetti F. Cisternal CSF levels of cytokines after subarachnoid hemorrhage. Neurol Res 1998;20(4):337–342. Crossref, MedlineGoogle Scholar
  • 54. Miller BA, Turan N, Chau M, Pradilla G. Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. Biomed Res Int 2014;(2014):384342. doi:10.1155/2014/384342. Published online July 3, 2014. Crossref, MedlineGoogle Scholar
  • 55. Butterworth RF, Giguère JF, Michaud J, Lavoie J, Layrargues GP. Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 1987;6(1-2):1–12. Crossref, MedlineGoogle Scholar
  • 56. Butterworth RF. Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure. J Clin Exp Hepatol 2015;5(suppl 1):S96–S103. Crossref, MedlineGoogle Scholar
  • 57. Matsusue E, Kinoshita T, Ohama E, Ogawa T. Cerebral cortical and white matter lesions in chronic hepatic encephalopathy: MR-pathologic correlations. AJNR Am J Neuroradiol 2005;26(2):347–351. MedlineGoogle Scholar
  • 58. Monfort P, Kosenko E, Erceg S, Canales JJ, Felipo V. Molecular mechanism of acute ammonia toxicity: role of NMDA receptors. Neurochem Int 2002;41(2-3):95–102. Crossref, MedlineGoogle Scholar
  • 59. Butterworth RF. Molecular neurobiology of acute liver failure. Semin Liver Dis 2003;23(3):251–258. Crossref, MedlineGoogle Scholar
  • 60. Jayakumar AR, Rama Rao KV, Norenberg MD. Neuroinflammation in hepatic encephalopathy: mechanistic aspects. J Clin Exp Hepatol 2015;5(suppl 1):S21–S28. Crossref, MedlineGoogle Scholar
  • 61. Rovira A, Alonso J, Córdoba J. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol 2008;29(9):1612–1621. Crossref, MedlineGoogle Scholar
  • 62. Albayram S, Ozer H, Gokdemir S, et al. Reversible reduction of apparent diffusion coefficient values in bilateral internal capsules in transient hypoglycemia-induced hemiparesis. AJNR Am J Neuroradiol 2006;27(8):1760–1762. MedlineGoogle Scholar
  • 63. Kim JH, Choi JY, Koh SB, Lee Y. Reversible splenial abnormality in hypoglycemic encephalopathy. Neuroradiology 2007;49(3):217–222. Crossref, MedlineGoogle Scholar
  • 64. Babanrao SA, Prahladan A, Kalidos K, Ramachandran K. Osmotic myelinolysis: does extrapontine myelinolysis precede central pontine myelinolysis? report of two cases and review of literature. Indian J Radiol Imaging 2015;25(2):177–183. Crossref, MedlineGoogle Scholar
  • 65. Takefuji S, Murase T, Sugimura Y, et al. Role of microglia in the pathogenesis of osmotic-induced demyelination. Exp Neurol 2007;204(1):88–94. Crossref, MedlineGoogle Scholar
  • 66. Hlaihel C, Gonnaud PM, Champin S, Rousset H, Tran-Minh VA, Cotton F. Diffusion-weighted magnetic resonance imaging in Marchiafava-Bignami disease: follow-up studies. Neuroradiology 2005;47(7):520–524. Crossref, MedlineGoogle Scholar
  • 67. Al Brashdi YH, Albayram MS. Reversible restricted-diffusion lesion representing transient intramyelinic cytotoxic edema in a patient with traumatic brain injury. Neuroradiol J 2015;28(4):409–412. Crossref, MedlineGoogle Scholar
  • 68. Kim JJ, Gean AD. Imaging for the diagnosis and management of traumatic brain injury. Neurotherapeutics 2011;8(1):39–53. Crossref, MedlineGoogle Scholar
  • 69. Wong SH, Turner N, Birchall D, Walls TJ, English P, Schmid ML. Reversible abnormalities of DWI in high-altitude cerebral edema. Neurology 2004;62(2):335–336. Crossref, MedlineGoogle Scholar
  • 70. Schommer K, Bärtsch P, Knauth M, Kallenberg K. Teaching neuroimages: reversible splenial cytotoxic edema in acute mountain sickness [comment]. Neurology 2012;78(12):932. Crossref, MedlineGoogle Scholar
  • 71. Sekine T, Ikeda K, Hirayama T, Suzuki A, Iwasaki Y. Transient splenial lesion after recovery of cerebral vasoconstriction and posterior reversible encephalopathy syndrome: a case report of eclampsia. Intern Med 2012;51(11):1407–1411. Crossref, MedlineGoogle Scholar
  • 72. Gilder TR, Hawley JS, Theeler BJ. Association of reversible splenial lesion syndrome (RESLES) with anti-VGKC autoantibody syndrome: a case report. Neurol Sci 2016;37(5):817–819. Crossref, MedlineGoogle Scholar
  • 73. Ogura H, Takaoka M, Kishi M, et al. Reversible MR findings of hemolytic uremic syndrome with mild encephalopathy. AJNR Am J Neuroradiol 1998;19(6):1144–1145. MedlineGoogle Scholar
  • 74. Takanashi J, Shirai K, Sugawara Y, Okamoto Y, Obonai T, Terada H. Kawasaki disease complicated by mild encephalopathy with a reversible splenial lesion (MERS). J Neurol Sci 2012;315(1-2):167–169. Crossref, MedlineGoogle Scholar
  • 75. Takahashi Y, Hashimoto N, Tokoroyama H, et al. Reversible splenial lesion in postpartum cerebral angiopathy: a case report. J Neuroimaging 2014;24(3):292–294. Crossref, MedlineGoogle Scholar
  • 76. Moritani T, Capizzano A, Kirby P, Policeni B . Viral infections and white matter lesions . Radiol Clin North Am 2014;52(2):355–382. Crossref, MedlineGoogle Scholar
  • 77. Ishikura R, Ando K, Hirota S, Okamoto N Fatterpekar G, Sacher M . Callosal and diffuse white matter lesions with restricted water diffusion in hemophagocytic syndrome . Magn Reson Med Sci 2010;9(2):91–94. Crossref, MedlineGoogle Scholar

Article History

Received: Apr 3 2016
Revision requested: Sept 1 2016
Revision received: Sept 22 2016
Accepted: Nov 1 2016
Published online: Feb 06 2017
Published in print: Mar 2017