1. Hypertrophic Olivary Degeneration: Lesions and Lessons eEdE-05
Sepand Salehian1, Lon Hoang1, Justin Tran1,
Navid Mahabadi2, Mohammad Toliyat1, Marco Pinho1
1. UT Southwestern, Dallas, TX
2. A.T. Still University School of Medicine, Mesa, AZ
Hypertrophic Olivary Degeneration: Lesions and Lessons
Abstract No:
eEdE-05 
Submission Number:
1502 
Authors:
S Salehian

2. The authors have no financial disclosures.
Sepand Salehian1, Lon Hoang1, Justin Tran1,
Navid Mahabadi2, Mohammad Toliyat1, Marco Pinho1
1. UT Southwestern, Dallas, TX.
2. A.T. Still University School of Medicine, Mesa, AZ

3. History
The triangle of Guillain and Mollaret is a dentato-rubro-olivary pathway, described in 1931.
Oppenheim was the first to provide evidence of inferior olivary enlargement in post-mortem studies1.

4. Introduction
The triangle of Guillain and Mollaret is a pathway comprised of three anatomic structures2
1) dentate nucleus
2) contralateral red nucleus in the midbrain
3) contralateral inferior olivary nucleus in the medulla

5. Introduction
The triangle of Guillain and Mollaret is an anatomical, trans-synaptic apparatus; it is a neuronal pathway which helps control fine voluntary movements.3

6. Clinical features Clinical symptomology include:
Palatal myoclonus (cyclic tremors of the soft palate)
Ocular myoclonus
Dentato-rubral tremor
The symptom profile typically evolves 10 months after primary lesion.

7. Anatomy
Hypertrophic olivary degeneration(HOD) is caused by a lesion which insults the integrity of the triangle of Guillain and Mollaret.
HOD occurs where there is disruption of the afferent components of this triangle; specifically, within the dentato-rubral tract and central tegmental tract.

8. Anatomy Red nucleus Dentate nucleus Inferior olivary nucleus
Superior cerebellar peduncle
Dentate
nucleus
Central
tegmental
tract
Inferior cerebellar peduncle
Inferior olivary nucleus

9. Anatomy

10. Pitfall
Recognition of hypertrophic olivary degeneration is important to avoid an erroneous diagnosis of tumor, mass, or other space-occupying lesion.

11. Histopathology
Corruption of the tracts of the Guillain-Mollaret triangle results in a trans-synaptic deafferentation of the inferior olivary nucleus.
Neurophysiologically: results in removal of inhibition of the electrotonic gap junctions in the inferior olivary nucleus.
Histopathologically: disinhibition and deafferentation of the inferior olivary nucleus results in vacuolar degeneration and enlargement of neurons, with a concomitant increase in glial cells and associated hypertrophy of astrocytes.

12. Ultrastructural/Metabolic/Perfusion Changes
Ultrastructural electron microscopic studies have shown that increased neuronal size may be due to neurofilamentous proliferation and cytoplasmic vacuolization to the formation of rough endocytoplasmic reticulum4.
Mitochondrial proliferation in glial cells may be related to the increased metabolic activity noted in PET in the early stages of HOD5.
SPECT-ECD studies revealed hyperfusion of the affected inferior olivary nucleus in a patient who had posterior fossa surgery for removal of a tumor, and thereafter clinically experienced a palatal tremor 2 months after surgery6,7.

13. Evolution and Time Course
HOD is a dynamic reactive process, progressing over the course of months.
The pathological changes in HOD occur in 6 phases8,9 with varying changes in cellular organization on a microscopic level
Within 24 hours: No olivary changes
2-7 days: Degeneration of the olivary amiculum at 2-7 days
3 weeks: Olivary hypertrophy (neuronal hypertrophy)
8.5 months: Culminant olivary enlargement (neuronal and astrocytic hypertrophy)
9.5 months: Olivary pseudohypetrophy (neuronal dissolution and gemistocytic astrocytes)
>1 year(s): Olivary atrophy (neuronal disappearance with olivary atrophy)

14. Logic of HOD -- If A, then B --
Disruption of the afferent fibers of the dentato-rubro-olivary pathway results in varying appearances on imaging.
-- If A, then B --
If lesion is in the red nucleus, then there is ipsilateral HOD
If the lesion is in the pons or involves the central tegmental tract, then there is ipsilateral HOD
If the lesion is in the upper midbrain (which only possesses SCP fibers from the contralateral dentate nucleus), then there is ipsilateral HOD
If the lesion is in the dentate nucleus or the superior cerebellar peduncle, then there is contralateral HOD
If the lesion is in the lower midbrain (which contains bilateral SCP fibers), this will cause bilateral HOD
Lesions of the olivary efferent pathway, coursing through the inferior cerebellar peduncle, do not typically cause HOD. However, some patients with HOD demonstrate contralateral cerebellar atrophy which may be presumably mediated by the olivo-dentate fibers10

15. Causes Infarct Hemorrhage Demyelination Traumatic brain injury Tumor
Post-surgical resection of tumor
Subependymal spread of metastatic disease along the periaqueductal region
Vascular lesions (i.e. capillary telangiectasias, AVM, etc.)
Infection (neurosyphillis, pontine neuro-Behcet11)
Surgery for vascular lesions have been reported as causes of HOD
Idiopathic
Nonlesional Hypertrophic Olivary Degeneration18
Nonlesional HOD is characterized by no identifiable lesion in the brain to account for the findings in the inferior olivary nucleus

16. HOD and posterior fossa syndrome
Posterior fossa syndrome is characterized by a variety of signs and symptoms including mutism or speech disturbances, dysphagia, decreased motor movement, cranial nerve palsies, and emotional lability.
Cerebellar mutism is a core element of the diagnosis
Cerebellar mutism is a form of speech apraxia
Posterior fossa syndrome has been described as a complication of posterior fossa surgery.
Damage to the dentate nuclei has been repeatedly cited as a cause of cerebellar mutism.

17. HOD and posterior fossa syndrome
Damage to the bilateral proximal efferent cerebellar pathways may cause posterior fossa syndrome.
Interestingly, bilateral hypertrophic olivary degeneration has been described in association with posterior fossa syndrome and cerebellar mutism12.

18. HOD: diffusion tensor imaging
Diffusion tensor imaging allows for the investigation of the organization, microstructure, and integrity of white matter tracts in vivo.
Studies have demonstrated and have quantified the dynamic longitudinal changes seen with HOD.
The deafferentation of the inferior olivary nucleus produces varying and shifting quantifiable DTI scalar value changes (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], radial diffusivity [RD]).

19. HOD: diffusion tensor imaging
Diffusion tensor imaging reveals:
Diminished white matter volume in the central tegmental tract12
Axonal diffusivity, mean diffusivity, radial diffusivity, fractional anisotropy values typically reflect an interplay between the forces of neuronal hypertrophy and demyelination and their effect on these measurements
For instance, increases in the radial and axial diffusivity in the inferior olives reflect demyelination and neuronal hypertrophy, respectively14
Decreasing FA would reflect increasing disruption and disorganization of the central tegmental tract15,16

20. Imaging
MRI
T2 prolongation in the inferior olivary nucleus with or without hypertrophy
Lack of contrast enhancement or restricted diffusion
Insult or evidence of corruption to the ipsilateral brainstem or contralateral cerebellum (generally speaking)

21. Differential Diagnosis
Wallerian degeneration
Amyotrophic lateral sclerosis
Adrenoleukodystrophy
Although these demonstrate high T2 signal abnormality in the anterior medulla, the aforementioned entities are limited in the corticospinal tract and not the inferior olivary nucleus.
General differential diagnosis:
Infarct
Demyelination
Astrocytoma
Metastases
Lymphoma
Tuberculosis

22. MR Imaging: Example Case
41 year old female with history of primary CNS lymphoma

23. MR Imaging: Example Case
Axial T2 FLAIR image demonstrates T2FLAIR signal hyperintensity predominantly located in the left aspect of the midbrain, extending anteriorly to involve the expected region of the left central tegmental tract, inferior to the red nucleus.
Axial T2 image demonstrates T2 signal hyperintensity predominantly located in the left aspect of the midbrain, extending from the left inferior colliculus anteriorly to involve the expected region of the left central tegmental tract.
Contrast enhanced T1 image demonstrates punctate focus of enhancement in the lesion occupying the left midbrain.

24. MR Imaging: Example Case
Axial T2FLAIR image demonstrates T2 prolongation in the left inferior olivary nucleus. The initial insult was in close approximation to the left central tegmental tract, just inferior to the red nucleus; this lesion was compatible with HOD.

25. Chronology of MRI findings
Three distinct MRI appearances of the inferior olivary nucleus which evolve over time (as described in the literature)3:
1st month: T2 FLAIR hyperintensity
~6 months: T2 FLAIR hyperintensity and hypertrophy
3-4 years: T2 FLAIR hyperintensity and atrophy in perpetuity

26. Chronology of MRI findings: Example Case
39 year old male with pineoblastoma with initial imaging conducted on 3/2/2015
Contrast enhanced T1 weighted SPGR image demonstrates a large mass in the pineal gland with mass effect upon the superior cerebellar peduncles and dorsal midbrain.

27. Chronology of MRI findings: Example Case
Within 24 hours: No olivary changes,
2-7 Days: Degeneration of the olivary amiculum at 2-7 days
3 weeks: olivary hypertrophy (neuronal hypertrophy)
8.5 months: culminant olivary enlargement (neuronal and astrocytic hypertrophy)
9.5 months: olivary pseudohypetrophy (neuronal dissolution and gemistocytic astrocytes)
>1 year(s): olivary atrophy (neuronal disappearance with olivary atrophy)
3/2/ /20/ /13/ /28/2015
Initially, there is scantly seen T2 FLAIR signal hyperintensity in the inferior olivary nucleus
Emerging Olivary Hypertrophy (1st 6 months)
Multiple axial FLAIR images

28. Chronology of MRI findings: Example Case
Within 24 hours: No olivary changes,
2-7 Days: Degeneration of the olivary amiculum at 2-7 days
3 weeks: olivary hypertrophy (neuronal hypertrophy)
8.5 months: culminant olivary enlargement (neuronal and astrocytic hypertrophy)
9.5 months: olivary pseudohypetrophy (neuronal dissolution and gemistocytic astrocytes)
>1 year(s): olivary atrophy (neuronal disappearance with olivary atrophy)
10/29/ /30/ /29/ /15/2016
Culminant Olivary Hypertrophy
(latter 6 months)
Olivary atrophy: in this case, the atrophic phase occurred at a more accelerated pace than what is typically explicated in the literature.
Multiple axial FLAIR images

29. More Examples Cases

30. Case 1
30 year old with AIDS and neurotoxoplasmosis presents in 2006

31. Case 1
Axial contrast enhanced T1 weighted image and axial T2 FLAIR images demonstrate a peripherally enhancing lesion with surrounding T2FLAIR signal hyperintensity predominantly located in the left superior cerebellar peduncle, the lower midbrain predominantly on the left, and the left superior cerebellar vermis.

32. 2006
Axial T2 FLAIR images demonstrates T2FLAIR hyperintensity in the right inferior olivary nucleus.

33. 2006
-- If A, then B --
If the lesion is in the dentate nucleus or the superior cerebellar peduncle, then there is contralateral HOD
Axial T2 FLAIR images demonstrates T2FLAIR hyperintensity in the right inferior olivary nucleus, on the contralateral side of the initial insult.

34. 2011
Axial T2 FLAIR images now demonstrates T2FLAIR hyperintensity in the bilateral inferior olivary nucleus.

35. 2011
-- If A, then B --
If the lesion is in the lower midbrain (which contains bilateral SCP fibers), this will cause bilateral HOD.
Axial T2 FLAIR images now demonstrates T2 FLAIR hyperintensity in the bilateral inferior olivary nucleus. Although the initial insult was in the region of the left superior cerebellar peduncle, there was also involvement of the lower midbrain. Since the bilateral superior cerebellar fibers cross through the lower midbrain, an eventual progression to bilateral hypertrophic olivary degeneration is not unexpected.

36. 2011
2013
Bilateral hypertrophic olivary degeneration, atrophic phase. On these axial T2 FLAIR images, there is interval decrease in the caliber of the inferior olivary nuclei, which is compatible with the expected evolutionary atrophic stage of HOD.

37. Case 2 52 year old with midbrain cavernoma in lower midbrain
Axial GRE image demonstrates a susceptibility focus in the left lower midbrain subjacent to the superior cerebellar peduncle

38. Case 2
Axial T2 FLAIR images demonstrate bilateral hypertrophic olivary degeneration

39. Case 3 45 year old female with an anaplastic ependymoma
Initial pre-operative images obtained on 7/2011; note close proximity and involvement of bilateral dentate nuclei

40. Case 3
2011
2013
Axial T2FLAIR images demonstrate the atrophic phase of bilateral HOD after 2 years
Axial T2FLAIR images demonstrate bilateral HOD

41. Case 4
69 year old male with history of dizziness

42. Case 4 Axial T2 images demonstrate bilateral HOD
Axial T2FLAIR images demonstrate bilateral HOD

43. Case 4 Nonlesional Hypertrophic Olivary Degeneration
Axial T2 image demonstrates no evidence of lesion at the level of the pons and the superior cerebellar peduncles. No other lesion was found in the brain

44. Conclusion
HOD is a rare transsynaptic degeneration that usually appears on the order of weeks to months following insult to the GM triangle.
An idiopathic non-lesional form has also recently been characterized
T2 prolongation and hypertrophy are the distinguishing imaging characteristics of this entity.
It is important to be cognizant of this entity to avoid the pitfall of misdiagnosis as a mass.
The inferior olivary nucleus may remain atrophic or hypertrophic with signal abnormalities that remain in perpetuity.

45. Bibliography
Oppenheim H. Uber Olivendegeneration bei Atheromatese der basalen Hirnarterien. Berl Klin Wschr 1887;34:638–9
S. Vattoth, F.Y. Ahmed, R.C. Telford, and G.H. Roberson. Hypertrophic Olivary Degeneration: Review of Anatomy, Pathology, and Imaging. Neurographics 4:114–122 September 2014
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 JNeuroradiol 21:1073–1077, 2000
Kurachi M, Nakamura I, Katsukawa K, Kobayashi K, Sano Y, Isaki K, Yamaguchi N Folia. Olivary hypertrophy in a case with palatal myoclonus: light- and electron-microscopic study. Psychiatr Neurol Jpn. 1985; 39(4):
Dubinsky RM, Hallett M, Di Chiro G, Fulham M, Schwankhaus J. Increased glucose metabolism in the medulla of patients with palatal myoclonus. Neurology 1991;41:557–62
Kim SJ, Lee WY, Kim BJ, Kim JY, Hong SB, Tae WS, et al. Isolated tongue tremor after removal of cerebellar pilocytic astrocytoma: functional analysis with SPECT study. Mov Disord2007;22:1825–8
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. The British Journal of Radiology. 2012;85(1013):
Kim SJ, Lee JH, Suh DC. Cerebellar MR changes in patients with olivary hypertrophic degeneration. AJNR Am J Neuroradiol 1994;15:1715–19
Goto N, Kaneko M. Olivary enlargement: chronological and morphometric analyses. Acta Neuropathol54:275–282, 1981
Choh NA, Choh SA, Jehangir M. Hypertrophic olivary degeneration: the forgotten triangle of Guillain and Mollaret. Neurol India. 2009;57:507–509.
Franco-Macías E, Roldán-Lora F, Martínez-Agregado P, Cerdá-Fuertes N, Moniche F. Neuro-Behçet: Pons Involvement with Longitudinal Extension to Midbrain and Hypertrophic Olivary Degeneration. Case Reports in Neurology. 2015;7(2):
Z. Patay, J. Enterkin, J.H Harreld et al. MR imaging evaluation of inferior olivary nuclei: comparison of postoperative subjects with and without posterior fossa syndrome. AJNR Am J Neuroradiol 2014 Apr;35(4):
Gunes Orman, Thangamadhan Bosemani, et al. Hypertrophic olivary degeneration in a child following midbrain tumor resection: longitudinal diffusion tensor imaging studies. J Neurosurg Pediatrics 13:408–413, 2014
R Shah, J markert, AK Bag, JK Cure. Diffusion Tensor Imaging in Hypertrophic Olivary Degeneration. AJNR Am J Neuroradiol 2010; 31:
Dinçer A, Özyurt O, Kaya D, Koşak E, Öztürk C, Erzen C, Pamir MJ. Diffusion tensor imaging of Guillain-Mollaret triangle in patients with hypertrophic olivary degeneration. J Neuroimaging Apr; 21(2):
Litkowski P, Young RJ, Wolden SL, Souweidane MM, Haque S, Gilheeney SW. Collision in the inferior olive: hypertrophic olivary degeneration complicated by radiation necrosis in brainstem primitive neuroendocrine tumor. Clinical imaging. 2012;36(4):
Araujo NA, Raeder MT, da Silva Junior NA, et al. Hypertrophic olivary degeneration secondary to central tegmental tract injury. Radiol Bras. 2015; 48(3):
Gu CN, Carr C, Ktsenas AL, Hunt CH, Wood CP. MRI findings in Nonlesional Hypertrophic Olivary Degeneration. J Neuroimaging Sep-Oct; 25(5): 813-7