1	Radiation Necrosis Affirmation by Analysis of Diffuse Axonal Injury Using Serial MR Imaging Angel Mironov Department of Neuroradiology Kantonsspital Aarau, Switzerland
2	P u r p o s e To explore the significance of existing diffuse axonal injury with secondary demyelination (Wallerian degeneration) of the corticofugal fibers at the level of midbrain on MR imaging, in differentiating radiation injury versus tumor recurrence in patients previously treated for brain neoplasm, who present with new contrast-enhancing mass recurrence at the site or vicinity of their primary tumor
3	Background Wallerian degeneration I Wallerian degeneration is the dissolution of the distal part of an axon and its myelin sheath that follows separation of the axon from the perikaryon In the PNS neurons may regenerate axons and reestablish synaptic connections Neurons in the CNS of humans do not regenerate axons
4	Background Wallerian degeneration II The process of Wallerian degeneration occurs in the distal stump and has four main events: Axolysis Myelinolysis Phagocytosis of the debris Proliferation of Schwann cells
5	Background Diffuse axonal injury I Diffuse axonal injury is diffuse degeneration of cerebral white matter Can be brought about: @ primary by the shearing of nerve fibers, @ secondary by hypoxic or ischemic damage, brain edema, or expanding lesion
6	Background Diffuse axonal injury II There are three distinctive pathological features: @ diffuse damage to axons @ focal lesion in the white matter or corpus callosum @ focal lesion in the rostral brain stem adjacent to the superior cerebellar peduncles
7	Background Diffuse axonal injury III A well-recognized feature of axonal injury is that of Wallerian degeneration The exact subcellular events and their time course in injured axons is not clear The Wallerian-type degeneration can be detected after 2-3 months in medial lemnisci, pyramidal tract, spinal cord, internal capsules
8	Model for exploration of Wallerian degeneration The tissue responses to definitive brain ischemia are characterized by selective neuronal injury with consequent cascade of encephalomalacia, coagulation necrosis, fluid-filled cavity The end phases of an ischemic infarct and a diffuse axonal injury resemble each other In large infarcts involving the cortex or its fiber, secondary degeneration of corticospinal fibers will occur with a consequent reduction in size (with asymmetry) of the cerebral peduncle, pons, and corticospinal tracts
9	Case 1: Wallerian degeneration 3 years after ischemia of right middle cerebral artery Signal alteration in the pyramidal tract
10	Case 2: Wallerian degeneration 8 months after ischemia of left middle cerebral artery Signal alteration of internal capsule and pyramidal tract with atrophy of cerebral peduncle
11	Case 3: Wallerian degeneration 7 months after ischemia of right middle cerebral artery There is signal alteration in the internal capsule and pyramidal tract with atrophy of cerebral peduncle
12	Case 4: Wallerian degeneration 5 years after ischemic stroke of middle cerebral artery There is atrophy of ipsilateral pedunculus cerebri
13	Hypothesis In the time of first diagnosis of brain tumor do not exist any diffuse axonal injury or Wallerian degeneration The Wallerian degeneration seem to be generated secondary after treatment of brain tumors by radiation The existence of Wallerian degeneration may be estimated as acting evidence of adverse effects after radiation therapy
14	Approach & Methods The follow up MR imaging of 20 patients have been analyzed for a period of 12 years All patients had been treated for brain mass by surgery and consequently underwent radiation therapy and chemotherapy Al patients developed radiation necrosis and underwent serial follow-up MR imaging over a maximum period of 12 years (6 to 15 follow-up)
15	Findings I In the time of surgery there were no signs of distant atrophy or distant signal abnormalities of corticofugal fibers and at the level of midbrain Intraparenchymal mass recurrence occurred in al patients, ranging from 5 to 120 months after the radiation therapy
16	Findings II The cerebral lesions became manifest as intensive bright peripheral and intra-focal enhancement and abnormal T2-weighted signal with remarkable discrepancy between the extension and the existing non-relevant mass effect There were a broadly based bright intensive enhancement with festoon-like or facet-like configuration It develops often centrifugal from the margin of the post-surgery brain defect and involves both the gyral surface and the subependymal periventricular space
17	Findings III Al cases showed an abnormal T2-weighted signal with different progressive atrophy of ipsilateral cerebral peduncle, which developed as late delayed feature, ranging from 5 to 120 months after the radiation This suggest a secondary neuroaxonal dystrophy, or demielination secondary to axon degeneration (Wallerian degeneration)
18	Radiation therapy for recurrence of meningioma
19	Fibrillary astrocytoma Gr 2 Surgery & radiation therapy
20	Oligodendroglioma Gr 2 Surgery & radiation therapy
21	Follow 15 months Radiation necrosis with discrete signal alteration of pyramidal tract
22	Follow up 34 m Progress of radiation necrosis with well demarked signal alteration of internal capsule and pyramidal tract
23	Follow 46 months Further progress of radiation necrosis with signal alteration in the internal capsule and pyramidal tract, and with remarkable atrophy of cerebral peduncle
24	Glioblastoma multiforme Surgery & radiation therapy Secondary appearance of radiation necrosis
25	Radiation treatment for metastasis with complete cure
26	Pleomorphic xanthoastrocytoma Surgery & radiation therapy
27	Follow up 25 months with progress of radiation necrosis Intensive signal alteration in the internal capsule and pyramidal tract with atrophy of cerebral peduncle
28	Low grade astrocytoma Surgery & Conventional radiotherapy
29	Follow 6 years Regress of radiation necrosis after steroid & antocoagulants treatment Signal alteration in the internal capsule, the pyramidal tract, and spinal cord with atrophy of cerebral peduncle
30	Low grade astrocytoma Surgery & Conventional radiation therapy
31	Follow up 30 months There is signal alteration in the internal capsule and pyramidal tract with atrophy of cerebral peduncle
32	Anaplastic astrocytoma Surgery & conventional radiotherapy Follow up 9 y 2 m with progressive radiation necrosis There is signal alteration in the internal capsule and pyramidal tract with atrophy of cerebral peduncle
33	Acustic neurinoma Treatment by Linac Radiosurgery
34	Anaplastic oligodendroglioma At the time of first diagnosis (above) and 4 years later without any treatment (below)
35	Follow up 10 years after surgery & radiation therapy & chemotherapy; Evidence of radiation necrosis
36	Follow up 12 years with appearance of radiation necrosis There is signal alteration in the internal capsule and pyramidal tract with atrophy of cerebral peduncle
37	Follow up 12 y 5 m with further progress of radiation necrosis Progress of signal alteration in the internal capsule and pyramidal tract with atrophy of cerebral peduncle
38	Conclusion I The influence of radiation can act on the natural history of brain tumors and neighborhood by causing different (direct or indirect) morphological and metabolic changes over an unlimited interval after radiation therapy The diffuse axonal injury is widely recognized as diffuse damage of white matter due to serious trauma or severe hypoxic alteration of brain tissue
39	Conclusion II The secondary diffuse axonal injury due to radiation-induced effects (direct radiation injury; indirect ischemic injury in radiation necrosis) can lead to distant demyelination and atrophy of corticofugal long fibers In cases with mass recurrence after radiation therapy associated with contrast enhancement, and consequently raised issues of indication for and choices of treatment, the sign of Wallerian degeneration at the level of midbrain indicate an existing radiation necrosis