J Neurosurg Pediatrics 13:408–413, 2014 ©AANS, 2014
Hypertrophic olivary degeneration in a child following midbrain tumor resection: longitudinal diffusion tensor imaging studies Case report Gunes Orman, M.D.,1 Thangamadhan Bosemani, M.D.,1 George I. Jallo, M.D., 2 Thierry A. G. M. Huisman, M.D.,1 and Andrea Poretti, M.D.1 Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science; and 2Division of Pediatric Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, Maryland
1
Hypertrophic olivary degeneration (HOD) is a dynamic process caused by disruptive lesions affecting components of the Guillain-Mollaret triangle (GMT). The authors applied diffusion tensor imaging (DTI) to investigate longitudinal changes of the GMT components in a child with HOD after neurosurgery for a midbrain tumor. Diffusion tensor imaging data were acquired on a 1.5-T MRI scanner using a balanced pair of diffusion gradients along 20 noncollinear directions 1 day and 3, 6, and 9 months after surgery. Measurements from regions of interest (ROIs) were sampled in the affected inferior olivary nucleus, ipsilateral red nucleus, and contralateral superior and inferior cerebellar peduncles and dentate nucleus. For each ROI, fractional anisotropy and the mean, axial, and radial diffusivities were calculated. In the affected inferior olivary nucleus, the authors found a decrease in fractional anisotropy and an increase in mean, axial, and radial diffusivities 3 months after surgery, while 3 months later fractional anisotropy increased and diffusivities decreased. For all other GMT components, changes in DTI scalars were less pronounced, and fractional anisotropy mildly decreased over time. A detailed analysis of longitudinal DTI scalars in the various GMT components may shed light on a better understanding of the dynamic complex histopathological processes occurring in pediatric HOD over time. (http://thejns.org/doi/abs/10.3171/2014.1.PEDS13490)
Key Words • diffusion tensor imaging • magnetic resonance imaging • children • hypertrophic olivary degeneration • inferior olivary nucleus • Guillain-Mollaret triangle
H
olivary degeneration (HOD) is a secondary transsynaptic deafferentation of the inferior olivary nucleus that occurs after disruption of the dentato-rubro-olivary pathway, or Guillain-Mollaret triangle (GMT).7 The GMT is defined by 3 gray matter nuclei: the dentate nucleus, the red nucleus, and the inferior olivary nucleus.8 These anatomical structures are connected by 3 pathways: 1) olivary-dentate fibers, or olivocerebellar fibers, arising from the hilum of the inferior olivary nucleus and crossing the midline through the inferior cerebellar peduncle to reach the contralateral dentate nucleus, 2) dentatorubral fibers arising from the contralateral dentate nucleus, entering their own superior cerebellar peduncle and decussating within the midbrain to reach the opposite
red nucleus, and 3) the ipsilateral central tegmental tract, or rubro-olivary tract, descending from the red nucleus to the original inferior olivary nucleus.8 Diffusion tensor imaging (DTI) is an advanced MRI technique that allows investigation of the organization, microstructure, and integrity of gray and white matter structures in vivo.5,13,15 Recent cross-sectional studies in children and adults with HOD showed that DTI can demonstrate and quantify the disruption of the GMT’s components.4,12,17 However, HOD is a dynamic process, and progressive changes have been shown by neuropathological examination and conventional MRI.6,7 The purpose of this study is to investigate longitudinal DTI changes of the GMT’s components in a child with HOD after neurosurgery for a midbrain tumor.
Abbreviations used in this paper: DTI = diffusion tensor imaging; GMT = Guillain-Mollaret triangle; HOD = hypertrophic olivary de generation; ROI = region of interest.
This article contains some figures that are displayed in color online but in black-and-white in the print edition.
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Diffusion tensor imaging in hypertrophic olivary degeneration Case Report Presentation. This 14-year-old boy presented with new-onset subtle intention tremor and dysdiadochokinesia of the left hand and bilateral horizontal gaze–evoked nystagmus 3 months after resection of a midbrain pilocytic astrocytoma. Additionally, neurological examination revealed truncal ataxia, dysarthria, and increased muscle tone in the right upper and lower extremities that became apparent shortly after neurosurgery. Palatal myoclonus was not present.
Conventional MRI and DTI. The MRI studies were acquired on a 1.5-T clinical MR scanner (Avanto, Siemens) using a standard 8-channel head coil. The standard departmental protocols included multiplanar T1- and T2weighted images, an axial FLAIR sequence, multiplanar T1-weighted images obtained after intravenous injection of a Gd-based contrast agent and a single-shot spin echo, and an echo planar axial DTI sequence with diffusion gradients along 20 noncollinear directions. An effective high b-value of 1000 sec/mm2 was used for each of the 20 diffusion-encoding directions. We performed an additional measurement without diffusion weighting (b = 0 sec/mm2). For the acquisition of the DTI data, the following parameters were used: TR 7100 msec, TE 84 msec, slice thickness 2.5 mm, FOV 240 × 240 mm, and matrix size 192 × 192. Parallel imaging iPAT factor 2 (Siemens) with GRAPPA (generalized auto-calibrating partial parallel acquisition reconstruction) was used. The acquisition was repeated twice to enhance the signal-to-noise ratio. Diffusion tensor imaging data were acquired 1 day and 3, 6, and 9 months after neurosurgery of a neoplasm affecting the left GMT.
Quantitative DTI Analysis. Diffusion tensor imaging data of the patient were transferred to an offline workstation for further postprocessing. DtiStudio, DiffeoMap, and RoiEditor software (available at www.MriStudio.org) were used. After correcting for eddy currents and motion artifacts, all images were coregistered to one another using a 12-mode affine transformation. Subsequently, the following maps were generated: fractional anisotropy, vector, color-coded fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. After rigid transformation for adjustment of position and rotation of images, regions of interest (ROIs) were drawn manually using the color-coded fractional anisotropy maps and the T2-weighted images, which have been coregistered to the DT images. Regions of interest were positioned within the inferior olivary nucleus, the ipsilateral red nucleus, contralateral inferior cerebellar peduncle, dentate nucleus, and superior cerebellar peduncle. For each ROI, fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity values were extracted. Imaging Findings. Conventional MRI showed a CSFfilled postsurgical defect involving the medial portion of the left midbrain with residual tumor that was stable in size over time (Fig. 1). A mild T2 hyperintense signal and enlargement of the left inferior olivary nucleus was first seen 3 months after surgery and suggested left HOD (Fig.
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Fig. 1. Axial T2- (A) and postcontrast T1- (B) weighted images showing a multilobulated, predominantly cystic tumor centered in the left midbrain extending superiorly into the left cerebral peduncle and inferiorly to the level of the pons. The solid, nodular component of the tumor demonstrates heterogeneous enhancement (arrow in B). Axial T2- (C) and postcontrast T1- (D) weighted images obtained 9 months after neurosurgery, demonstrating a postsurgical disruptive lesion involving the left midbrain with a T2-hyperintense lesion (arrow in C) that most likely represents residual tumor unchanged in size over time. Additionally, minimal linear enhancement along the resection cavity is noted (arrow in D).
2). T2 hyperintensity and enlargement of the left inferior olivary nucleus were noted 3 months later, confirming left HOD. The last follow-up MRI study obtained 9 months after surgery revealed no interval changes in T2 hyperintensity and degree of enlargement of the left inferior olivary nucleus. Contrast enhancement in the left inferior olivary nucleus was absent on all studies. Absolute values of DTI scalars derived from the GMT components are shown in Table 1, and their changes over time are illustrated in Fig. 3. In the inferior olivary nucleus, fractional anisotropy prominently decreased at 3 months postsurgery, increased without achieving the initial value 3 months later, and remained stable at 9 months after surgery. The mean diffusivity, axial diffusivity, and radial diffusivity had an opposite course from that of fractional anisotropy. Compared with the left inferior olivary nucleus, fractional anisotropy values in the other GMT components were less prominently altered.
Discussion
Hypertrophic olivary degeneration is an intriguing 409
G. Orman et al.
Fig. 2. Axial T2-weighted images (A–D) and color-coded fractional anisotropy maps (E–H) at the level of the medulla 1 day and 3, 6, and 9 months after surgery. Three months after surgery, the left inferior olivary nucleus appeared mildly enlarged and exhibited T2 hyperintensity (arrow in B). Enlargement and T2 hyperintensity of the left inferior olivary nucleus became more prominent 6 and 9 months after surgery (arrows in C and D). Retrocerebellar artifacts after midline suboccipital craniotomy are seen in panel A. Axial color-coded fractional anisotropy maps show a mild attenuation in signal of the left inferior olivary nucleus (arrows in E–H) at 3, 6, and 9 months after surgery compared with the right inferior olivary nucleus.
phenomenon affecting the inferior olivary nucleus. It is caused by disruptive lesions of the afferent GMT components (dentatorubral tract and central tegmental tract) resulting in a transsynaptic deafferentation of the inferior olivary nucleus.7 In children, disruptive lesions of the GMT may include low- and high-grade tumors and vascular malformations.10,12,14,16,21 Neurophysiologically,
this causes the removal of inhibition of the electrotonic gap junctions in the inferior olivary nucleus.3,18 On histopathology, disinhibition and deafferentation of the inferior olivary nucleus result in vacuolar degeneration and enlargement of neurons and an increase in glial cells and hypertrophy of astrocytes.6 Hypertrophic olivary degeneration is not static, but it is a reactive, dynamic,
TABLE 1: Diffusion tensor imaging scalars derived from the left GMT components on 4 postsurgical follow-up studies* GMT Component
Time Since Op
FA
MD†
AD†
RD†
ION
1 day 3 mos 6 mos 9 mos 1 day 3 mos 6 mos 9 mos 1 day 3 mos 6 mos 9 mos 1 day 3 mos 6 mos 9 mos 1 day 3 mos 6 mos 9 mos
0.253 0.111 0.202 0.201 0.634 0.577 0.538 0.532 0.188 0.175 0.182 0.172 0.711 0.712 0.709 0.671 0.293 0.245 0.236 0.234
1.154 1.325 0.929 1.034 0.936 0.975 1.016 1.025 1.051 1.117 1.013 1.009 0.880 0.973 0.986 0.978 0.984 1.004 1.436 1.464
1.459 1.483 1.124 1.220 1.725 1.677 1.708 1.714 1.262 1.309 1.317 1.330 1.763 2.037 1.941 1.893 1.306 1.343 1.766 1.812
1.001 1.246 0.831 0.941 0.541 0.624 0.670 0.680 0.945 1.021 0.861 0.848 0.439 0.442 0.508 0.521 0.824 0.834 1.271 1.291
ICP
DN
SCP
RN
* AD = axial diffusivity; DN = dentate nucleus; FA = fractional anisotropy; ICP = inferior cerebellar peduncle; ION = inferior olivary nucleus; MD = mean diffusivity; RD = radial diffusivity; RN = red nucleus; SCP = superior cerebellar peduncle. † Values are × 10−3 mm2/sec.
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Diffusion tensor imaging in hypertrophic olivary degeneration
Fig. 3. Longitudinal evolution of DTI scalars for the different components of the left GMT. AD = axial diffusivity; DN = dentate nucleus; FA = fractional anisotropy; ICP = inferior cerebellar peduncle; ION = inferior olivary nucleus; MD = mean diffusivity; RD = radial diffusivity; RN = red nucleus; SCP = superior cerebellar peduncle.
and evolving process that may take months to years to progress.1,7 Goto et al.6 classified the pathological changes in HOD into 6 phases: 1) no olivary changes, observed within 24 hours after onset; 2) degeneration of the olivary amiculum (the capsule of white matter composing the periphery of the oliva) at 2 to 7 days or more; 3) olivary hypertrophy (the stage of mild olivary enlargement with neuronal hypertrophy and no glial reaction) at about 3 weeks; 4) culminant olivary enlargement (the stage of hypertrophy of both neurons and astrocytes) at about 8.5 months; 5) olivary pseudohypertrophy (the stage of neuronal dissolution with gemistocytic astrocytes) at about 9.5 months and later; and 6) olivary atrophy (the stage of neuronal disappearance with olivary atrophy and prominent degeneration of the amiculum olivae) after a few years. Neuroimaging is necessary for diagnosis and confirmation of HOD and allows for study of the pathobiology of HOD in vivo. Conventional neuroimaging is mandatory for the diagnosis of HOD.2,7,11,16 Hypertrophic olivary degeneration is characterized by enlargement and increased T2 hyperintense signal of the inferior olivary nucleus.7,11,16 On postcontrast T1-weighted images, hypertrophic inferior olivary nuclei are typically not enhancing.19 Familiarity with HOD and its neuroimaging appearance in pediatric patients will help to avoid potential misdiagnosis of HOD as tumor recurrence, or, in highgrade primary tumors, for example, medulloblastomas, as metastatic lesions. Conventional neuroimaging allows only a limited understanding of the pathobiology of HOD. In our patient, a mild enlargement and T2 hyperintensity of the left inferior olivary nucleus was visible 3 months after surgery, which subsequently increased 6 months after surgery. On conventional MRI, 3 distinct stages with specific time intervals have been described: 1) T2 hyperintense signal of the inferior olivary nucleus without hypertroJ Neurosurg: Pediatrics / Volume 13 / April 2014
phy within the first 6 months after the disruptive event, 2) T2 hyperintense signal and hypertrophy of the inferior olivary nucleus up to 3–4 years after HOD onset, and 3) T2 hyperintense signal with progressive resolution of inferior olivary nucleus hypertrophy.7 These stages take into account the dynamic course of HOD and match macroscopic changes of the inferior olivary nucleus in HOD, such as increased content of water as part of vacuolar degeneration and gliosis (both are depicted by a hyperintense signal on T2-weighted images). Conventional MRI, however, does not provide detailed information about the microscopic structural change in the inferior olivary nucleus and involvement of the other GMT components. As in the studied patient, the other components of the GMT appear unremarkable on conventional MRI except for the component directly affected by the primary lesion or neurosurgical procedure. However, the involvement of the other GMT components plays an important role in the manifestation of HOD symptoms. Secondary damage of the olivary-dentate tract may cause over-excitation of the dentate nucleus and result in functional impairment of the patient’s ability to estimate the direction of gravity as recently demonstrated in a patient with HOD.20 Diffusion tensor imaging was shown to shed light on the pathobiology of HOD and microstructural changes occurring in the GMT components. At the mean postsurgical time of 20 months, Dinçer et al. demonstrated an increase in radial diffusivity, mean diffusivity, and axial diffusivity and a decrease in fractional anisotropy in all anatomical components of the GMT in 10 adults with HOD.4 A decrease in fractional anisotropy and an increase in radial diffusivity most likely represent demyelination in the late phase of HOD. Eight months after surgery, Meoded et al. found higher fractional anisotropy and axial diffusivity values of the inferior olivary nuclei and lower fractional anisotropy but higher radial diffusivity values of all other GMT components in a child with 411
G. Orman et al. bilateral HOD compared with age-matched controls.12 An increase in fractional anisotropy in the inferior olivary nuclei may reflect rearrangement of regenerating axons and shrunken neurons. Decreased fractional anisotropy and increased radial diffusivity in the other GMT components most likely reflect the demyelination process associated with axonal degeneration in accordance with histopathological studies. In this article, we applied DTI to investigate dynamic changes of the different GMT components in a child with HOD. In the left inferior olivary nucleus, fractional anisotropy had a variable course and decreased at 3 months after surgery. A decrease in fractional anisotropy, an increase in radial diffusivity and mean diffusivity, and an almost unchanged axial diffusivity may reflect transsynaptic deafferentation at an early stage of HOD with only mild olivary enlargement, which was depicted on conventional MRI. Six months after surgery, fractional anisotropy mildly increased and mean diffusivity, axial diffusivity, and radial diffusivity decreased. At this time, culminant olivary enlargement secondary to hypertrophy of both neurons and astrocytes was achieved.6 Olivary hypertrophy is expected to increase fractional anisotropy, while astrocytic proliferation or gliosis is expected to reduce it. Because fractional anisotropy increased in our patient 6 months after surgery, it is arguable that neuronal hypertrophy may play a preponderant role in comparison with gliosis. Nine months after surgery, fractional anisotropy remained stable, but mean diffusivity, axial diffusivity, and radial diffusivity increased. The lack of further increase in fractional anisotropy may represent a modified balance between neuronal hypertrophy and astrocytic proliferation. At about 9 months and later after surgery, neuronal dissolution and gemistocytic astrocytes represent the prominent histological findings.6 In the other GMT components, changes in DTI scalars are present but are less pronounced than in the inferior olivary nucleus. A decrease in fractional anisotropy and an increase in radial diffusivity (particularly in the inferior cerebellar peduncle and superior cerebellar peduncle) most likely reflect secondary demyelination associated with axonal degeneration, which occurs in transneuronal degeneration. This finding is in accordance with histopathological studies and previous DTI studies.4,12 In the red nucleus, however, changes in DTI scalars over time are more prominent, particularly the increase in mean diffusivity, axial diffusivity, and radial diffusivity. The marked, global increase of the diffusivity in the red nucleus is likely due to the primary lesion and postsurgical changes with resolution of necrotic tissue and formation of cystic spaces. Neurological symptoms in patients with HOD include palatal myoclonus, truncal and limb ataxia, and ocular movement disorders. These symptoms may be severe, have a major impact on activities of daily living, and consequently decrease the patient’s quality of life significantly. In adults with HOD, symptomatic therapeutic approaches using, for example, benzodiazepines or antiepileptic drugs have been attempted with varying results.9 A more detailed understanding of the pathobiology of HOD and its dynamic changes over time using noninvasive techniques such as DTI may allow the development 412
of more causative treatments. Additionally, longitudinal, quantitative DTI studies may monitor therapeutic results in patients with HOD. Preoperative DTI and fiber tractography allow the study of the integrity and course of the GMT as well as the study of the GMT’s anatomical relationship to the mass lesion, and these modalities determine children at risk for HOD. In a similar approach, DTI and fiber tractography are used to assess the risk of superior quadrantic visual field deficits by injury of the Meyer’s loop in temporal lobe resection.22,23 Integration of GMT fiber tractography into stereo-navigational systems together with T1-weighted anatomical images may reduce the risk of HOD due to GMT injury by neurosurgery. The feasibility of integration of GMT fiber tractography into stereonavigational systems for patients with brainstem lesions as well as its capability to prevent occurrence of HOD has to be addressed by future prospective studies. We are aware of some limitations in our report, including the study of only 1 child with HOD, the retrospective nature of the study and the ROI-based analysis, which is investigator dependent.
Conclusions
Our study shows that longitudinal detailed DTI analysis of the various components of GMT may shed light on the dynamic complex histopathological processes occurring in pediatric HOD over time. Future studies with a larger number of subjects and dedicated high angular DTI study of the brainstem may better address this issue. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Poretti, Huisman. Acquisition of data: all authors. Analysis and interpretation of data: Poretti, Orman, Bosemani. Drafting the article: Orman. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Poretti. Study supervision: Poretti. References 1. Birbamer G, Buchberger W, Felber S, Aichner F: MR appearance of hypertrophic olivary degeneration: temporal relationships. AJNR Am J Neuroradiol 13:1501–1503, 1992 2. Birbamer G, Gerstenbrand F, Aichner F, Buchberger W, Chemelli A, Langmayr J, et al: MR-imaging of post-traumatic olivary hypertrophy. Funct Neurol 9:183–187, 1994 3. De Zeeuw CI, Simpson JI, Hoogenraad CC, Galjart N, Koekkoek SK, Ruigrok TJ: Microcircuitry and function of the inferior olive. Trends Neurosci 21:391–400, 1998 4. Dinçer A, Özyurt O, Kaya D, Koşak E, Öztürk C, Erzen C, et al: Diffusion tensor imaging of Guillain-Mollaret triangle in patients with hypertrophic olivary degeneration. J Neuroimaging 21:145–151, 2011 5. Feldman HM, Yeatman JD, Lee ES, Barde LH, Gaman-Bean S: Diffusion tensor imaging: a review for pediatric researchers and clinicians. J Dev Behav Pediatr 31:346–356, 2010 6. Goto N, Kaneko M: Olivary enlargement: chronological and morphometric analyses. Acta Neuropathol 54:275–282, 1981
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Diffusion tensor imaging in hypertrophic olivary degeneration 7. Goyal M, Versnick E, Tuite P, Cyr JS, Kucharczyk W, Montanera W, et al: Hypertrophic olivary degeneration: metaanalysis of the temporal evolution of MR findings. AJNR Am J Neuroradiol 21:1073–1077, 2000 8. Habas C, Guillevin R, Abanou A: In vivo structural and functional imaging of the human rubral and inferior olivary nuclei: a mini-review. Cerebellum 9:167–173, 2010 9. Hornyak M, Osborn AG, Couldwell WT: Hypertrophic olivary degeneration after surgical removal of cavernous malformations of the brain stem: report of four cases and review of the literature. Acta Neurochir (Wien) 150:149–156, 2008 10. Jellinger K: Hypertrophy of the inferior olives. Report on 29 cases. Z Neurol 205:153–174, 1973 11. Kitajima M, Korogi Y, Shimomura O, Sakamoto Y, Hirai T, Miyayama H, et al: Hypertrophic olivary degeneration: MR imaging and pathologic findings. Radiology 192:539–543, 1994 12. Meoded A, Poretti A, Ilica AT, Perez R, Jallo G, Burger PC, et al: Diffusion tensor imaging in a child with hypertrophic olivary degeneration. Cerebellum 12:469–474, 2013 13. Pajevic S, Pierpaoli C: Color schemes to represent the orientation of anisotropic tissues from diffusion tensor data: application to white matter fiber tract mapping in the human brain. Magn Reson Med 42:526–540, 1999 14. Phatouros CC, McConachie NS: Hypertrophic olivary degeneration: case report in a child. Pediatr Radiol 28:830–831, 1998 15. Poretti A, Meoded A, Rossi A, Raybaud C, Huisman TA: Diffusion tensor imaging and fiber tractography in brain malformations. Pediatr Radiol 43:28–54, 2013 16. Sanverdi SE, Oguz KK, Haliloglu G: Hypertrophic olivary degeneration in children: four new cases and a review of the literature with an emphasis on the MRI findings. Br J Radiol 85:511–516, 2012 17. Shah R, Markert J, Bag AK, Curé JK: Diffusion tensor imaging in hypertrophic olivary degeneration. AJNR Am J Neuroradiol 31:1729–1731, 2010
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18. Shaikh AG, Hong S, Liao K, Tian J, Solomon D, Zee DS, et al: Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity. Brain 133:923–940, 2010 19. Shinohara Y, Kinoshita T, Kinoshita F, Kaminou T, Watanabe T, Ogawa T: Hypertrophic olivary degeneration after surgical resection of brain tumors. Acta Radiol [epub ahead of print], 2013 20. Tarnutzer AA, Palla A, Marti S, Schuknecht B, Straumann D: Hypertrophy of the inferior olivary nucleus impacts perception of gravity. Front Neurol 3:79, 2012 21. 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 42:481–485, 2012 22. Winston GP, Daga P, Stretton J, Modat M, Symms MR, Mc Evoy AW, et al: Optic radiation tractography and vision in anterior temporal lobe resection. Ann Neurol 71:334–341, 2012 23. Yogarajah M, Focke NK, Bonelli S, Cercignani M, Acheson J, Parker GJ, et al: Defining Meyer’s loop-temporal lobe resections, visual field deficits and diffusion tensor tractography. Brain 132:1656–1668, 2009
Manuscript submitted September 23, 2013. Accepted January 14, 2014. Please include this information when citing this paper: published online February 14, 2014; DOI: 10.3171/2014.1.PEDS13490. Address correspondence to: Andrea Poretti, M.D., Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, Charlotte R. Bloomberg Children’s Center, Sheikh Zayed Tower, Rm. 4174, 1800 Orleans St., Baltimore, MD 21287. email: aporett1 @jhmi.edu.
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Hypertrophic olivary degeneration in a child following midbrain tumor resection: longitudinal diffusion tensor imaging studies Case report Gunes Orman, M.D.,1 Thangamadhan Bosemani, M.D.,1 George I. Jallo, M.D., 2 Thierry A. G. M. Huisman, M.D.,1 and Andrea Poretti, M.D.1 Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science; and 2Division of Pediatric Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, Maryland
1
Hypertrophic olivary degeneration (HOD) is a dynamic process caused by disruptive lesions affecting components of the Guillain-Mollaret triangle (GMT). The authors applied diffusion tensor imaging (DTI) to investigate longitudinal changes of the GMT components in a child with HOD after neurosurgery for a midbrain tumor. Diffusion tensor imaging data were acquired on a 1.5-T MRI scanner using a balanced pair of diffusion gradients along 20 noncollinear directions 1 day and 3, 6, and 9 months after surgery. Measurements from regions of interest (ROIs) were sampled in the affected inferior olivary nucleus, ipsilateral red nucleus, and contralateral superior and inferior cerebellar peduncles and dentate nucleus. For each ROI, fractional anisotropy and the mean, axial, and radial diffusivities were calculated. In the affected inferior olivary nucleus, the authors found a decrease in fractional anisotropy and an increase in mean, axial, and radial diffusivities 3 months after surgery, while 3 months later fractional anisotropy increased and diffusivities decreased. For all other GMT components, changes in DTI scalars were less pronounced, and fractional anisotropy mildly decreased over time. A detailed analysis of longitudinal DTI scalars in the various GMT components may shed light on a better understanding of the dynamic complex histopathological processes occurring in pediatric HOD over time. (http://thejns.org/doi/abs/10.3171/2014.1.PEDS13490)
Key Words • diffusion tensor imaging • magnetic resonance imaging • children • hypertrophic olivary degeneration • inferior olivary nucleus • Guillain-Mollaret triangle
H
olivary degeneration (HOD) is a secondary transsynaptic deafferentation of the inferior olivary nucleus that occurs after disruption of the dentato-rubro-olivary pathway, or Guillain-Mollaret triangle (GMT).7 The GMT is defined by 3 gray matter nuclei: the dentate nucleus, the red nucleus, and the inferior olivary nucleus.8 These anatomical structures are connected by 3 pathways: 1) olivary-dentate fibers, or olivocerebellar fibers, arising from the hilum of the inferior olivary nucleus and crossing the midline through the inferior cerebellar peduncle to reach the contralateral dentate nucleus, 2) dentatorubral fibers arising from the contralateral dentate nucleus, entering their own superior cerebellar peduncle and decussating within the midbrain to reach the opposite
red nucleus, and 3) the ipsilateral central tegmental tract, or rubro-olivary tract, descending from the red nucleus to the original inferior olivary nucleus.8 Diffusion tensor imaging (DTI) is an advanced MRI technique that allows investigation of the organization, microstructure, and integrity of gray and white matter structures in vivo.5,13,15 Recent cross-sectional studies in children and adults with HOD showed that DTI can demonstrate and quantify the disruption of the GMT’s components.4,12,17 However, HOD is a dynamic process, and progressive changes have been shown by neuropathological examination and conventional MRI.6,7 The purpose of this study is to investigate longitudinal DTI changes of the GMT’s components in a child with HOD after neurosurgery for a midbrain tumor.
Abbreviations used in this paper: DTI = diffusion tensor imaging; GMT = Guillain-Mollaret triangle; HOD = hypertrophic olivary de generation; ROI = region of interest.
This article contains some figures that are displayed in color online but in black-and-white in the print edition.
ypertrophic
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Diffusion tensor imaging in hypertrophic olivary degeneration Case Report Presentation. This 14-year-old boy presented with new-onset subtle intention tremor and dysdiadochokinesia of the left hand and bilateral horizontal gaze–evoked nystagmus 3 months after resection of a midbrain pilocytic astrocytoma. Additionally, neurological examination revealed truncal ataxia, dysarthria, and increased muscle tone in the right upper and lower extremities that became apparent shortly after neurosurgery. Palatal myoclonus was not present.
Conventional MRI and DTI. The MRI studies were acquired on a 1.5-T clinical MR scanner (Avanto, Siemens) using a standard 8-channel head coil. The standard departmental protocols included multiplanar T1- and T2weighted images, an axial FLAIR sequence, multiplanar T1-weighted images obtained after intravenous injection of a Gd-based contrast agent and a single-shot spin echo, and an echo planar axial DTI sequence with diffusion gradients along 20 noncollinear directions. An effective high b-value of 1000 sec/mm2 was used for each of the 20 diffusion-encoding directions. We performed an additional measurement without diffusion weighting (b = 0 sec/mm2). For the acquisition of the DTI data, the following parameters were used: TR 7100 msec, TE 84 msec, slice thickness 2.5 mm, FOV 240 × 240 mm, and matrix size 192 × 192. Parallel imaging iPAT factor 2 (Siemens) with GRAPPA (generalized auto-calibrating partial parallel acquisition reconstruction) was used. The acquisition was repeated twice to enhance the signal-to-noise ratio. Diffusion tensor imaging data were acquired 1 day and 3, 6, and 9 months after neurosurgery of a neoplasm affecting the left GMT.
Quantitative DTI Analysis. Diffusion tensor imaging data of the patient were transferred to an offline workstation for further postprocessing. DtiStudio, DiffeoMap, and RoiEditor software (available at www.MriStudio.org) were used. After correcting for eddy currents and motion artifacts, all images were coregistered to one another using a 12-mode affine transformation. Subsequently, the following maps were generated: fractional anisotropy, vector, color-coded fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. After rigid transformation for adjustment of position and rotation of images, regions of interest (ROIs) were drawn manually using the color-coded fractional anisotropy maps and the T2-weighted images, which have been coregistered to the DT images. Regions of interest were positioned within the inferior olivary nucleus, the ipsilateral red nucleus, contralateral inferior cerebellar peduncle, dentate nucleus, and superior cerebellar peduncle. For each ROI, fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity values were extracted. Imaging Findings. Conventional MRI showed a CSFfilled postsurgical defect involving the medial portion of the left midbrain with residual tumor that was stable in size over time (Fig. 1). A mild T2 hyperintense signal and enlargement of the left inferior olivary nucleus was first seen 3 months after surgery and suggested left HOD (Fig.
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Fig. 1. Axial T2- (A) and postcontrast T1- (B) weighted images showing a multilobulated, predominantly cystic tumor centered in the left midbrain extending superiorly into the left cerebral peduncle and inferiorly to the level of the pons. The solid, nodular component of the tumor demonstrates heterogeneous enhancement (arrow in B). Axial T2- (C) and postcontrast T1- (D) weighted images obtained 9 months after neurosurgery, demonstrating a postsurgical disruptive lesion involving the left midbrain with a T2-hyperintense lesion (arrow in C) that most likely represents residual tumor unchanged in size over time. Additionally, minimal linear enhancement along the resection cavity is noted (arrow in D).
2). T2 hyperintensity and enlargement of the left inferior olivary nucleus were noted 3 months later, confirming left HOD. The last follow-up MRI study obtained 9 months after surgery revealed no interval changes in T2 hyperintensity and degree of enlargement of the left inferior olivary nucleus. Contrast enhancement in the left inferior olivary nucleus was absent on all studies. Absolute values of DTI scalars derived from the GMT components are shown in Table 1, and their changes over time are illustrated in Fig. 3. In the inferior olivary nucleus, fractional anisotropy prominently decreased at 3 months postsurgery, increased without achieving the initial value 3 months later, and remained stable at 9 months after surgery. The mean diffusivity, axial diffusivity, and radial diffusivity had an opposite course from that of fractional anisotropy. Compared with the left inferior olivary nucleus, fractional anisotropy values in the other GMT components were less prominently altered.
Discussion
Hypertrophic olivary degeneration is an intriguing 409
G. Orman et al.
Fig. 2. Axial T2-weighted images (A–D) and color-coded fractional anisotropy maps (E–H) at the level of the medulla 1 day and 3, 6, and 9 months after surgery. Three months after surgery, the left inferior olivary nucleus appeared mildly enlarged and exhibited T2 hyperintensity (arrow in B). Enlargement and T2 hyperintensity of the left inferior olivary nucleus became more prominent 6 and 9 months after surgery (arrows in C and D). Retrocerebellar artifacts after midline suboccipital craniotomy are seen in panel A. Axial color-coded fractional anisotropy maps show a mild attenuation in signal of the left inferior olivary nucleus (arrows in E–H) at 3, 6, and 9 months after surgery compared with the right inferior olivary nucleus.
phenomenon affecting the inferior olivary nucleus. It is caused by disruptive lesions of the afferent GMT components (dentatorubral tract and central tegmental tract) resulting in a transsynaptic deafferentation of the inferior olivary nucleus.7 In children, disruptive lesions of the GMT may include low- and high-grade tumors and vascular malformations.10,12,14,16,21 Neurophysiologically,
this causes the removal of inhibition of the electrotonic gap junctions in the inferior olivary nucleus.3,18 On histopathology, disinhibition and deafferentation of the inferior olivary nucleus result in vacuolar degeneration and enlargement of neurons and an increase in glial cells and hypertrophy of astrocytes.6 Hypertrophic olivary degeneration is not static, but it is a reactive, dynamic,
TABLE 1: Diffusion tensor imaging scalars derived from the left GMT components on 4 postsurgical follow-up studies* GMT Component
Time Since Op
FA
MD†
AD†
RD†
ION
1 day 3 mos 6 mos 9 mos 1 day 3 mos 6 mos 9 mos 1 day 3 mos 6 mos 9 mos 1 day 3 mos 6 mos 9 mos 1 day 3 mos 6 mos 9 mos
0.253 0.111 0.202 0.201 0.634 0.577 0.538 0.532 0.188 0.175 0.182 0.172 0.711 0.712 0.709 0.671 0.293 0.245 0.236 0.234
1.154 1.325 0.929 1.034 0.936 0.975 1.016 1.025 1.051 1.117 1.013 1.009 0.880 0.973 0.986 0.978 0.984 1.004 1.436 1.464
1.459 1.483 1.124 1.220 1.725 1.677 1.708 1.714 1.262 1.309 1.317 1.330 1.763 2.037 1.941 1.893 1.306 1.343 1.766 1.812
1.001 1.246 0.831 0.941 0.541 0.624 0.670 0.680 0.945 1.021 0.861 0.848 0.439 0.442 0.508 0.521 0.824 0.834 1.271 1.291
ICP
DN
SCP
RN
* AD = axial diffusivity; DN = dentate nucleus; FA = fractional anisotropy; ICP = inferior cerebellar peduncle; ION = inferior olivary nucleus; MD = mean diffusivity; RD = radial diffusivity; RN = red nucleus; SCP = superior cerebellar peduncle. † Values are × 10−3 mm2/sec.
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Diffusion tensor imaging in hypertrophic olivary degeneration
Fig. 3. Longitudinal evolution of DTI scalars for the different components of the left GMT. AD = axial diffusivity; DN = dentate nucleus; FA = fractional anisotropy; ICP = inferior cerebellar peduncle; ION = inferior olivary nucleus; MD = mean diffusivity; RD = radial diffusivity; RN = red nucleus; SCP = superior cerebellar peduncle.
and evolving process that may take months to years to progress.1,7 Goto et al.6 classified the pathological changes in HOD into 6 phases: 1) no olivary changes, observed within 24 hours after onset; 2) degeneration of the olivary amiculum (the capsule of white matter composing the periphery of the oliva) at 2 to 7 days or more; 3) olivary hypertrophy (the stage of mild olivary enlargement with neuronal hypertrophy and no glial reaction) at about 3 weeks; 4) culminant olivary enlargement (the stage of hypertrophy of both neurons and astrocytes) at about 8.5 months; 5) olivary pseudohypertrophy (the stage of neuronal dissolution with gemistocytic astrocytes) at about 9.5 months and later; and 6) olivary atrophy (the stage of neuronal disappearance with olivary atrophy and prominent degeneration of the amiculum olivae) after a few years. Neuroimaging is necessary for diagnosis and confirmation of HOD and allows for study of the pathobiology of HOD in vivo. Conventional neuroimaging is mandatory for the diagnosis of HOD.2,7,11,16 Hypertrophic olivary degeneration is characterized by enlargement and increased T2 hyperintense signal of the inferior olivary nucleus.7,11,16 On postcontrast T1-weighted images, hypertrophic inferior olivary nuclei are typically not enhancing.19 Familiarity with HOD and its neuroimaging appearance in pediatric patients will help to avoid potential misdiagnosis of HOD as tumor recurrence, or, in highgrade primary tumors, for example, medulloblastomas, as metastatic lesions. Conventional neuroimaging allows only a limited understanding of the pathobiology of HOD. In our patient, a mild enlargement and T2 hyperintensity of the left inferior olivary nucleus was visible 3 months after surgery, which subsequently increased 6 months after surgery. On conventional MRI, 3 distinct stages with specific time intervals have been described: 1) T2 hyperintense signal of the inferior olivary nucleus without hypertroJ Neurosurg: Pediatrics / Volume 13 / April 2014
phy within the first 6 months after the disruptive event, 2) T2 hyperintense signal and hypertrophy of the inferior olivary nucleus up to 3–4 years after HOD onset, and 3) T2 hyperintense signal with progressive resolution of inferior olivary nucleus hypertrophy.7 These stages take into account the dynamic course of HOD and match macroscopic changes of the inferior olivary nucleus in HOD, such as increased content of water as part of vacuolar degeneration and gliosis (both are depicted by a hyperintense signal on T2-weighted images). Conventional MRI, however, does not provide detailed information about the microscopic structural change in the inferior olivary nucleus and involvement of the other GMT components. As in the studied patient, the other components of the GMT appear unremarkable on conventional MRI except for the component directly affected by the primary lesion or neurosurgical procedure. However, the involvement of the other GMT components plays an important role in the manifestation of HOD symptoms. Secondary damage of the olivary-dentate tract may cause over-excitation of the dentate nucleus and result in functional impairment of the patient’s ability to estimate the direction of gravity as recently demonstrated in a patient with HOD.20 Diffusion tensor imaging was shown to shed light on the pathobiology of HOD and microstructural changes occurring in the GMT components. At the mean postsurgical time of 20 months, Dinçer et al. demonstrated an increase in radial diffusivity, mean diffusivity, and axial diffusivity and a decrease in fractional anisotropy in all anatomical components of the GMT in 10 adults with HOD.4 A decrease in fractional anisotropy and an increase in radial diffusivity most likely represent demyelination in the late phase of HOD. Eight months after surgery, Meoded et al. found higher fractional anisotropy and axial diffusivity values of the inferior olivary nuclei and lower fractional anisotropy but higher radial diffusivity values of all other GMT components in a child with 411
G. Orman et al. bilateral HOD compared with age-matched controls.12 An increase in fractional anisotropy in the inferior olivary nuclei may reflect rearrangement of regenerating axons and shrunken neurons. Decreased fractional anisotropy and increased radial diffusivity in the other GMT components most likely reflect the demyelination process associated with axonal degeneration in accordance with histopathological studies. In this article, we applied DTI to investigate dynamic changes of the different GMT components in a child with HOD. In the left inferior olivary nucleus, fractional anisotropy had a variable course and decreased at 3 months after surgery. A decrease in fractional anisotropy, an increase in radial diffusivity and mean diffusivity, and an almost unchanged axial diffusivity may reflect transsynaptic deafferentation at an early stage of HOD with only mild olivary enlargement, which was depicted on conventional MRI. Six months after surgery, fractional anisotropy mildly increased and mean diffusivity, axial diffusivity, and radial diffusivity decreased. At this time, culminant olivary enlargement secondary to hypertrophy of both neurons and astrocytes was achieved.6 Olivary hypertrophy is expected to increase fractional anisotropy, while astrocytic proliferation or gliosis is expected to reduce it. Because fractional anisotropy increased in our patient 6 months after surgery, it is arguable that neuronal hypertrophy may play a preponderant role in comparison with gliosis. Nine months after surgery, fractional anisotropy remained stable, but mean diffusivity, axial diffusivity, and radial diffusivity increased. The lack of further increase in fractional anisotropy may represent a modified balance between neuronal hypertrophy and astrocytic proliferation. At about 9 months and later after surgery, neuronal dissolution and gemistocytic astrocytes represent the prominent histological findings.6 In the other GMT components, changes in DTI scalars are present but are less pronounced than in the inferior olivary nucleus. A decrease in fractional anisotropy and an increase in radial diffusivity (particularly in the inferior cerebellar peduncle and superior cerebellar peduncle) most likely reflect secondary demyelination associated with axonal degeneration, which occurs in transneuronal degeneration. This finding is in accordance with histopathological studies and previous DTI studies.4,12 In the red nucleus, however, changes in DTI scalars over time are more prominent, particularly the increase in mean diffusivity, axial diffusivity, and radial diffusivity. The marked, global increase of the diffusivity in the red nucleus is likely due to the primary lesion and postsurgical changes with resolution of necrotic tissue and formation of cystic spaces. Neurological symptoms in patients with HOD include palatal myoclonus, truncal and limb ataxia, and ocular movement disorders. These symptoms may be severe, have a major impact on activities of daily living, and consequently decrease the patient’s quality of life significantly. In adults with HOD, symptomatic therapeutic approaches using, for example, benzodiazepines or antiepileptic drugs have been attempted with varying results.9 A more detailed understanding of the pathobiology of HOD and its dynamic changes over time using noninvasive techniques such as DTI may allow the development 412
of more causative treatments. Additionally, longitudinal, quantitative DTI studies may monitor therapeutic results in patients with HOD. Preoperative DTI and fiber tractography allow the study of the integrity and course of the GMT as well as the study of the GMT’s anatomical relationship to the mass lesion, and these modalities determine children at risk for HOD. In a similar approach, DTI and fiber tractography are used to assess the risk of superior quadrantic visual field deficits by injury of the Meyer’s loop in temporal lobe resection.22,23 Integration of GMT fiber tractography into stereo-navigational systems together with T1-weighted anatomical images may reduce the risk of HOD due to GMT injury by neurosurgery. The feasibility of integration of GMT fiber tractography into stereonavigational systems for patients with brainstem lesions as well as its capability to prevent occurrence of HOD has to be addressed by future prospective studies. We are aware of some limitations in our report, including the study of only 1 child with HOD, the retrospective nature of the study and the ROI-based analysis, which is investigator dependent.
Conclusions
Our study shows that longitudinal detailed DTI analysis of the various components of GMT may shed light on the dynamic complex histopathological processes occurring in pediatric HOD over time. Future studies with a larger number of subjects and dedicated high angular DTI study of the brainstem may better address this issue. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Poretti, Huisman. Acquisition of data: all authors. Analysis and interpretation of data: Poretti, Orman, Bosemani. Drafting the article: Orman. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Poretti. Study supervision: Poretti. References 1. Birbamer G, Buchberger W, Felber S, Aichner F: MR appearance of hypertrophic olivary degeneration: temporal relationships. AJNR Am J Neuroradiol 13:1501–1503, 1992 2. Birbamer G, Gerstenbrand F, Aichner F, Buchberger W, Chemelli A, Langmayr J, et al: MR-imaging of post-traumatic olivary hypertrophy. Funct Neurol 9:183–187, 1994 3. De Zeeuw CI, Simpson JI, Hoogenraad CC, Galjart N, Koekkoek SK, Ruigrok TJ: Microcircuitry and function of the inferior olive. Trends Neurosci 21:391–400, 1998 4. Dinçer A, Özyurt O, Kaya D, Koşak E, Öztürk C, Erzen C, et al: Diffusion tensor imaging of Guillain-Mollaret triangle in patients with hypertrophic olivary degeneration. J Neuroimaging 21:145–151, 2011 5. Feldman HM, Yeatman JD, Lee ES, Barde LH, Gaman-Bean S: Diffusion tensor imaging: a review for pediatric researchers and clinicians. J Dev Behav Pediatr 31:346–356, 2010 6. Goto N, Kaneko M: Olivary enlargement: chronological and morphometric analyses. Acta Neuropathol 54:275–282, 1981
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Diffusion tensor imaging in hypertrophic olivary degeneration 7. Goyal M, Versnick E, Tuite P, Cyr JS, Kucharczyk W, Montanera W, et al: Hypertrophic olivary degeneration: metaanalysis of the temporal evolution of MR findings. AJNR Am J Neuroradiol 21:1073–1077, 2000 8. Habas C, Guillevin R, Abanou A: In vivo structural and functional imaging of the human rubral and inferior olivary nuclei: a mini-review. Cerebellum 9:167–173, 2010 9. Hornyak M, Osborn AG, Couldwell WT: Hypertrophic olivary degeneration after surgical removal of cavernous malformations of the brain stem: report of four cases and review of the literature. Acta Neurochir (Wien) 150:149–156, 2008 10. Jellinger K: Hypertrophy of the inferior olives. Report on 29 cases. Z Neurol 205:153–174, 1973 11. Kitajima M, Korogi Y, Shimomura O, Sakamoto Y, Hirai T, Miyayama H, et al: Hypertrophic olivary degeneration: MR imaging and pathologic findings. Radiology 192:539–543, 1994 12. Meoded A, Poretti A, Ilica AT, Perez R, Jallo G, Burger PC, et al: Diffusion tensor imaging in a child with hypertrophic olivary degeneration. Cerebellum 12:469–474, 2013 13. Pajevic S, Pierpaoli C: Color schemes to represent the orientation of anisotropic tissues from diffusion tensor data: application to white matter fiber tract mapping in the human brain. Magn Reson Med 42:526–540, 1999 14. Phatouros CC, McConachie NS: Hypertrophic olivary degeneration: case report in a child. Pediatr Radiol 28:830–831, 1998 15. Poretti A, Meoded A, Rossi A, Raybaud C, Huisman TA: Diffusion tensor imaging and fiber tractography in brain malformations. Pediatr Radiol 43:28–54, 2013 16. Sanverdi SE, Oguz KK, Haliloglu G: Hypertrophic olivary degeneration in children: four new cases and a review of the literature with an emphasis on the MRI findings. Br J Radiol 85:511–516, 2012 17. Shah R, Markert J, Bag AK, Curé JK: Diffusion tensor imaging in hypertrophic olivary degeneration. AJNR Am J Neuroradiol 31:1729–1731, 2010
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18. Shaikh AG, Hong S, Liao K, Tian J, Solomon D, Zee DS, et al: Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity. Brain 133:923–940, 2010 19. Shinohara Y, Kinoshita T, Kinoshita F, Kaminou T, Watanabe T, Ogawa T: Hypertrophic olivary degeneration after surgical resection of brain tumors. Acta Radiol [epub ahead of print], 2013 20. Tarnutzer AA, Palla A, Marti S, Schuknecht B, Straumann D: Hypertrophy of the inferior olivary nucleus impacts perception of gravity. Front Neurol 3:79, 2012 21. 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 42:481–485, 2012 22. Winston GP, Daga P, Stretton J, Modat M, Symms MR, Mc Evoy AW, et al: Optic radiation tractography and vision in anterior temporal lobe resection. Ann Neurol 71:334–341, 2012 23. Yogarajah M, Focke NK, Bonelli S, Cercignani M, Acheson J, Parker GJ, et al: Defining Meyer’s loop-temporal lobe resections, visual field deficits and diffusion tensor tractography. Brain 132:1656–1668, 2009
Manuscript submitted September 23, 2013. Accepted January 14, 2014. Please include this information when citing this paper: published online February 14, 2014; DOI: 10.3171/2014.1.PEDS13490. Address correspondence to: Andrea Poretti, M.D., Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, Charlotte R. Bloomberg Children’s Center, Sheikh Zayed Tower, Rm. 4174, 1800 Orleans St., Baltimore, MD 21287. email: aporett1 @jhmi.edu.
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