PENN RADIOLOGY THE ROOTS OF RADIOLOGICAL EXCELLENCE Wallerian Degeneration Beyond the ‘Corticospinal Tracts’ Conventional & Advanced MRI Findings S. Ali Nabavizadeh 1, Arastoo Vossough 2 Yin Jie Chen 1, Sunil Kumar 3 Laurie A Loevner 1, Suyash Mohan 1 1 Neuroradiology Division, Department of Radiology Perelman School of Medicine at University of Pennsylvania, 2 Children’s Hospital of Philadelphia, Philadelphia, PA 3 Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Presentation Title: eEdE-13

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Disclosure statement Neither the authors nor their immediate family members have a financial relationship with a commercial organization that may have a direct or indirect interest in the content.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Overview Wallerian degeneration: Overview First described in peripheral nerves by ‘Waller’ in rocess of progressive demyelination and disintegration of the distal axonal segment following axonal transection or damage to the neuron.Process of progressive demyelination and disintegration of the distal axonal segment following axonal transection or damage to the neuron. Imaging findings of Wallerian degeneration (WD) can be challenging, especially outside the corticospinal tracts. In this exhibit, we will elaborate imaging findings of different types of Wallerian degeneration secondary to various pathologies.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Content Organization A.Anatomy & pathophysiology of different types of WD 1.Corticospinal tract 2.Hypertrophic olivary degeneration 3.Pontocerebellar tract 4.Posterior column of the spinal cord 5.Corpus callosum 6.Mammillary body/fornix B.Imaging modalities reviewed 1.Conventional MRI 2.Diffusion weighted & diffusion tensor imaging 3.Susceptibility weighted imaging

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology The following temporal relationships between the MRI findings & the stages of WD are usually recognized. I.First stage: Characterized by the physical disintegration of the axons & myelin sheaths with little chemical changes. Usually no signal abnormality on conventional MR sequences. II.Second stage: Characterized by the rapid destruction of the myelin fragments observed in the first stage. Usually takes about 2-4 months. III.Third stage: Characterized by almost entire disappearance of myelin sheath, with gliosis occupying the area of the degenerated axons & myelin sheaths. Imaging findings of T2 hyperintensity develop in late stage 2 & stage 3 I.Fourth stage: Characterized by volume loss from atrophy in the brain stem as unilateral shrinkage following WD of the corticospinal tract. Generally happens after several years. Stages Wallerian degeneration: Stages

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Corticospinal tract Illustration of the corticospinal tract with fibers that project from the upper motor neurons in the cerebral cortex through the internal capsule & the cerebral peduncles before reaching the medulla, where the fibers mainly decussate to the contralateral side to form the lateral corticospinal tract, with small amount of fibers remaining on the ipsilateral side as the anterior corticospinal tract. Fibers of the upper motor neurons within the corticospinal tract ultimately project onto lower motor neurons within the anterior grey column of the spinal cord.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology 70 Y/F with slurred speech MRI demonsrates T2 prolongation & restricted diffusion consistent with acute infarction in left corona radiata 5 month follow up MRI demonstrates gliosis at the site of infarction & T2 prolongartion in left cerebral peduncle consistent with WD

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology WD: Diffusion weighted imaging DWI can identify acute white matter injury corresponding to stage I WD, which is not detectable on conventional sequences. DWI & DTI could serve as prognostic indicators in patients with infarction & intracranial hemorrhage. DTI is also sensitive to detect WD in corpus callosum in patients with brain tumors.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Axial DWI images demonstrate acute infarction in right middle cerebral artery territory in a neonate Notice: Acute WD with restricted diffusion in right cerebral peduncle WD: Diffusion weighted imaging

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Axial T2 images demonstrate encephalomalacia in left MCA territory & atrophy of left cerebral peduncle consistent with WD Color coded FA map & fiber tractography demonstrate marked attenuation of the left corticospinal tract WD: Diffusion tensor imaging

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Axial T2 images in a 15 year old with 3 rd ventricular tumor (T) (Path: WHO Grade 3 glioma) Bilateral encephalomacia in medial frontal lobes Axial color coded FA maps demonstrates decreased FA values in corticospinal tracts at the level of internal capsules & pons consistent with WD DTI as an early predictor of WD FA Values Right Left FA Values Right Left T

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Cortico-ponto-cerebellar fiber tract Illustration of cortico-ponto-cerebellar fiber tract, which extends from the cerebellar cortex to ipsilateral pontine nucleus (corticopontine tract), with second order neurons projecting to contralateral cerebellar hemisphere through middle cerebellar peduncle (pontocerebellar tract). SCP – superior cerebellar peduncle MCP – middle cerebellar peduncle ICP – inferior cerebellar peduncle PN – pontine nucleus

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology 3 month follow-up MRI demonstrates faint T2 hyperintensity without restricted diffusion in bilateral middle cerebellar peduncles ( ) without restricted diffusion consistent with WD of pontocerebellar tracts Axial FLAIR, axial trace diffusion & ADC maps demonstrate acute left paramedian pontine infarction

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Hypertrophic olivary degeneration (HOD) Unique neural degeneration caused by disruption of the dentato-rubro- olivary pathway, also known as the triangle of Guillain-Mollaret. Clinical manifestation: classical symptomatic palatal tremor (PT), also known as palatal myoclonus. Pathophysiology: loss of synaptic, afferent input to the olivary nucleus resulting in initial hypertrophy followed by atrophy. Typical MRI findings: Initial hypertrophy & T2 hyperintensity with subsequent atrophy & residual hyperintensity. Can develop secondary to a variety of pathologies: tumor, hemorrhage, vascular malformations, infarction, trauma, demyelination, & surgery.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Guillain-Mollaret triangle Illustration of Guillain-Mollaret triangle, consisting RN, ON, and contralateral DN as its three corners. RN – red nucleus ON – inferior olivary nucleus DN – dentate nucleus SCP – superior cerebellar peduncle MCP – middle cerebellar peduncle ICP – inferior cerebellar peduncle

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology 10 month F/U MRI demonstrates hyperintesity in bilateral medullary olives (arrow heads) consistent with olivary degeneration. Axial FLAIR & T1 images demonstrate a 4 th ventricular tumor (arrow head) in a 27 year old patient

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Axial FLAIR & T2 images demonstrate T2 hyperintensity in right medullary olive. Axial SWI images demonstrate susceptibility in left dentate nucleus consistent with prior hemorrhage. On axial SWI image, left red nucleus is less conspicuous compared to the right side consistent with red nucleus degeneration. HOD in a 70 year old with history of left cerebellar hemorrhage

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Axial T2 image in a pediatric patient with history of posterior fossa tumor surgery demonstrates HOD right olivary degeneration (arrow head, top image) Axial SWI image demonstrates decreased signal intensity in right red nucleus (arrowhead, bottom image) compared to right consistent with degeneration.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Posterior column of the spinal cord Illustration of the posterior column medial lemniscus fiber tracts, with sensory fibers from the lower body traveling within the gracile fasciculus and fibers from the upper body traveling within the cuneate fasciculus, which terminates in the ipsilateral cuneate / gracile nuclei in the medulla, where the second order neurons arise, whose fibers decussate in the medulla to travel in the contralateral medial lemniscus to terminate in the ventral posterolateral and ventral posteromedial nuclei of the thalamus, where the third order neuros arise and project to the sensory areas of the cerebral cortex.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Initial thoracic spine MRI in a pediatric patient demonstrated abnormal signal intensity in posterior column of mid thoracic cord. Cervical spine MRI was normal, and patient was diagnosed with transverse myelitis. Follow-Up MRI demonstrated linear abnormal signal in posterior column of upper thoracic and cervical cord consistent with WD of posterior column of the cord. Wallerian degeneration in posterior column of the spinal cord

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology 48 Y/M with history of recurrent ependymoma. MRI: Enhancing, mildly expansile lesion centered at C4-C5, with edema. F/U MRI 2 weeks after resection demonstrates the resection cavity. 3 month F/U MRI shows contraction of the resection cavity with new hyperintensity in the posterior column consistent with WD of the posterior column. WD in posterior column of the spinal cord

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Corpus callosum (CC) Largest commissural fiber that connects the cerebral hemispheres of the brain. Callosal axons exhibit a topographical distribution, with the different CC regions serving the different cortical regions. Genu and the rostrum of the CC have connections between the prefrontal brain regions. Most caudal region & splenium contain connections between the occipital, temporal & parietal regions. White matter tracts of CC are significantly influenced by cortical damage. Atrophy of the CC has been well described in patients with cerebral infarcts. DTI is more sensitive than the morphologic MR imaging in the evaluation of WD within the CC.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Axial diffusion image & ADC map demonstrate restricted diffusion in the splenium of CC consistent with acute WD. Axial T2 & FLAIR images in a pediatric patient following left occipital AVM resection. WD in CC

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Mammillary bodies & Fornix The hippocampus, fornix, & mamillary bodies are components of a single limbic circuit. The hippocampal fibers project to the mamillary body via the fornix. Neuronal damage of the hippocampus may cause atrophy of the ipsilateral fornix & mamillary body as a result of neuronal degeneration. Asymmetrically small fornix or mamillary body is a useful presurgical lateralizing sign of hippocampal sclerosis in patients with temporal lobe epilepsy.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology WD of mammillary body Coronal T2 & FLAIR images in a 43 Y/M with complex partial seizure demonstrate hyperintensity and volume loss in left hippocampus consistent with mesial temporal sclerosis. Axial T2 weighted image demonstrates atrophy of left mammillary body.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Conclusion WD occurs throughout various tracts in the central nervous system. Familiarity of radiologists with imaging findings of the different types of WD is essential to make the correct diagnosis & avoid unnecessary work-up. Given the more widespread use of advanced MRI sequences, early detection of WD can play an important role in prognostication of different brain pathologies.

Baltimore, Maryland Perelman School of Medicine at University of Pennsylvania Penn Radiology Selected References 1.Mazumdar A, Mukherjee P, Miller JH, Malde H, McKinstry RC. Diffusion-weighted imaging of acute corticospinal tract injury preceding Wallerian degeneration in the maturing human brain. Am J Neuroradiol Jun-Jul;24(6): Vossough A, Ziai P, Chatzkel JA. Red nucleus degeneration in hypertrophic olivary degeneration after pediatric posterior fossa tumor resection: use of susceptibility-weighted imaging (SWI). Pediatr Radiol Apr;42(4): Nabavizadeh SA, Mowla A, Mamourian AC. Wallerian degeneration of the bilateral middle cerebellar peduncles. J Neurol Sci Feb 15;349(1-2): Kashani H, Farb R, Kucharczyk W. Magnetic resonance imaging demonstration of a single lesion causing Wallerian degeneration in ascending and descending tracts in the spinal cord. J Comput Assist Tomogr Mar- Apr;34(2): Puig J, Pedraza S, Blasco G et al. Wallerian degeneration in the corticospinal tract evaluated by diffusion tensor imaging correlates with motor deficit 30 days after middle cerebral artery ischemic stroke. Am J Neuroradiol Aug;31(7): Thomalla G, Glauche V, Weiller C, Röther J. Time course of wallerian degeneration after ischaemic stroke revealed by diffusion tensor imaging. Neurol Neurosurg Psychiatry ;76(2): DeVetten G, Coutts SB, Hill MD, et al; MONITOR and VISION study groups. Acute corticospinal tract Wallerian degeneration is associated with stroke outcome. Stroke Apr;41(4): Kim JH, Tien RD, Felsberg GJ, Osumi AK, Lee N. Clinical significance of asymmetry of the fornix and mamillary body on MR in hippocampal sclerosis. Am J Neuroradiol Mar;16(3): Gu CN, Carr CM, Kaufmann TJ, Kotsenas AL et al. MRI Findings in Nonlesional Hypertrophic Olivary Degeneration. J Neuroimaging Sep-Oct;25(5):813-7.

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