Clinical Investigative Study

Frequency of Bilateral Hypertrophic Olivary Degeneration

in a Large Retrospective Cohort
Carrie M. Carr, MD, Christopher H. Hunt, MD, Timothy J. Kaufmann, MD, Amy L. Kotsenas, MD, Karl N. Krecke, MD,
Christopher P. Wood, MD
From the Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905

ABSTRACT
BACKGROUND AND PURPOSE Keywords: Hypertrophic olivary degen-
Hypertrophic olivary degeneration (HOD) is an uncommon type of transneuronal degen- eration, bilateral.
eration. Case reports and case series described in the literature provide a foundation of Acceptance: Received October 30,
our current knowledge of HOD. These reports have described HOD most frequently to be 2013, and in revised form January 10,
unilateral and occurring in association with lesions in the dentato-rubro-olivary pathway. 2014. Accepted for publication January
Our purpose was to evaluate the rate of bilateral versus unilateral HOD in a large case 18, 2014.
series. Correspondence: Address correspon-
METHODS dence to Carrie Carr, Department
A retrospective review was performed to identify patients in which the phrase “hyper- of Radiology, Mayo Clinic, 200 First
Street SW, Rochester, Minnesota 55905.
trophic olivary degeneration” occurred in the radiology report. A diagnosis of HOD was
E-mail: carr.carrie@mayo.edu
confirmed on imaging if there was focal hyperintensity on T2-weighted images confined
to either or both inferior olivary nuclei. No funding was received for this study.
Part of this research was presented at
RESULTS
ASNR May 2012.
A total of 102 patients had findings consistent with HOD. Of these, 76% had findings
bilaterally. In 44%, a lesion could not be identified to explain HOD. Bilateral HOD was J Neuroimaging 2014;00:1-7.
common in both lesional and nonlesional group, though more common in the nonlesional DOI: 10.1111/jon.12118
group.
CONCLUSION
This study demonstrates that HOD is frequently bilateral. In slightly over 50% of patients
with HOD, a lesion can be identified. In just under 50% patients with HOD, a lesion could
not be identified and in these cases HOD was present bilaterally in the majority.

Background and Purpose HOD is thought to occur due to transneuronal degenera-

Hypertrophic olivary degeneration (HOD) was first described
in 1887 by Oppenheim who observed pathological enlarge-
ment of the inferior olivary nucleus (ION) at postmortem
examination.1 Subsequently in 1931, Guillain and Mollaret re-
ported an associated pathway composed of the ipsilateral ION,
the dentate nucleus of the contralateral cerebellum, and the
ipsilateral red nucleus (Guillain-Mollaret triangle).2 A lesion
occurring in this dentato-rubro-olivary pathway (DROP) can
result in HOD (Fig 1).2,3 A variety of causative lesions have
been described including infarction, toxic, trauma or surgery,
tumor, vascular malformations or hemorrhage.3–11 Unilateral
cases have been reported to significantly outnumber bilat-
eral cases, perhaps due to the fact that previously reported
cases of HOD in the literature have focused on identifying
HOD secondary to a structural lesion in the DROP.5,12 Idio-
pathic cases of HOD have been infrequently described and
are felt to be rare with only a single case report in the English
literature.9
tion when there is loss of synaptic, afferent input to a cell. This
is a unique type of degeneration which results initially in hy-
pertrophy of affected neurons. However, over time the hyper-
trophy resolves and results in subsequent atrophy12 often with
residual hyperintensity on T2-weighted images. Classically, pa-
tients present with symptomatic palatal tremor (PT), previously
known as palatal myoclonus. This movement disorder can ei-
ther be present in isolation or in association with progressive
ataxia and palatal tremor (PAPT).
Single case reports and smaller case series have been de-
scribed in the literature and is the foundation of our current
knowledge of HOD. As such, the current understanding of
HOD is viewed as usually a unilateral process due to lesional
involvement in the DROP. Anecdotally, we believe that HOD
occurs bilaterally at a higher rate than reflected in the litera-
ture. The intent of this study was to evaluate the rate of bilateral
versus unilateral HOD in a large case series of patients with
HOD.

Copyright ◦ 2014 by the American Society of Neuroimaging

C 1

Fig 1. The dentato-rubro-olivary pathway (Guillain-Mollaret trian-
gle). HOD frequently and classically occurs due to disruption of the
afferent pathways between the ION and dentate nucleus or red nu-
cleus. A lesion in the inferior cerebellar peduncle is considered un-
likely to result in HOD since this affects an efferent pathway between
the ION and dentate nucleus. A lesion in the red nucleus or cen-
tral tegmental tract would cause ipsilateral HOD. Contralateral HOD
occurs when the lesion disrupts the superior cerebellar peduncle or
dentate nucleus. In this lesional scheme, bilateral HOD would occur
when lesions involve both the red nucleus or the central tegmental
tract with involvement of the dentate nucleus or the superior cerebel-
lar peduncle.
Methods
This retrospective study was reviewed and approved by the In-
stitutional Review Board at our institution which is a tertiary
referral center. The departmental radiology report database
for all head MRI reports performed between 7/1/2002 and
7/1/2011 was queried for cases in which either the phrase “hy-
pertrophic olivary degeneration” or “HOD” occurred in both
adult and pediatric patients. Given the size of our referral cen-
ter, the reports of 151,895 patients who underwent clinical head
MRIs from 7/1/2002 to 7/1/2011 were searched. All of these
head MRIs were initially read and dictated by board certified
subspecialty neuroradiologists who practice neuroradiology ex-
clusively. These patients had been scanned on either a 1.5 or
3.0 Tesla closed MRI scanner.
The search of the database returned 123 patients. Fifteen
patients were subsequently excluded when review of the re-
port revealed negative results for HOD, that is, when a phrase
such as “no evidence of HOD” was used. A neuroradiology
fellow and a board certified neuroradiologist reviewed the
MR images of the remaining 108 patients for imaging fea-
tures consistent with HOD as defined below. By consensus
review, HOD was confirmed if there was focal rounded hy-
perintensity on T2-weighted images confined to either or both
inferior olivary nuclei (ION) which is the diagnostic imaging
criteria for HOD that has been reported in the literature.4,5,13
FLAIR images were also reviewed in conjunction with the T2-
2 Journal of Neuroimaging Vol 00 No 0 xxxx 2014
weighted images. The presence of a lesion in the triangle of
Guillain-Mollaret, presence or absence of enhancement and
unilateral versus bilateral involvement were recorded. In addi-
tion, patients were to be excluded if there was lesional exten-
sion into the ION as this would suggest the T2 hyperintensity
could be related to the lesion rather than representing true
HOD.
A total of 6 patients were excluded after the review. One
patient was excluded as a large cavernoma was immediately
adjacent to the ION and there appeared to be T2 hyperinten-
sity directly extending into the ION. Two patients were ex-
cluded due to the T2 hyperintensity being in the medullary
pyramids rather than the ION. Three patients were excluded
on the basis of equivocal findings. In these last 3 patients, the
reports had raised the diagnostic possibility of HOD but there
was subtle if any T2 hyperintensity without any definite en-
largement or any lesion in the DROP. Although these could
potentially represent HOD during the late atrophic phase, these
were excluded since the findings were very subtle and a diag-
nosis could not be confidently made. After these patients were
excluded, there were a total of 166 MRI’s from 102 patients
with a diagnosis of HOD made by the initial neuroradiologist
and subsequently confirmed that were then included in the
study.
Each patient’s electronic medical record was reviewed by
a neuroradiology fellow for any documented history of PT or
PAPT (either at the time of the MRI or subsequently) that was
performed by a neurologist as well as for basic demographic
information.
Results
A total of 102 patients (60 males; age range 11-92 years; mean
54 ± 19.1 years) had head MRI examinations meeting the in-
clusion criteria. A total of 166 MRI’s from these 102 patients
were reviewed. The majority of patient’s (68) had a single MRI
exam available for review.
Seventy-eight patients (76%; mean age 57.7 years [range
11-92]; male = 44 [56.4%]) had findings of HOD bilaterally
presenting both symmetric and asymmetric in size and signal.
Two patients with clearly unilateral HOD on the initial MRI
developed bilateral asymmetric findings on subsequent exams,
8 months and 5 years after initial MRI, respectively (Fig 2).
Neither of these patient’s had an identifiable lesion within the
DROP. The T2 hyperintensity and inferior olive hypertrophy
was greatest on the originally involved side with asymmetric
development of contralateral findings. Of note, in the second
patient, they initially had unilateral PT which subsequently be-
came bilateral when the follow-up MRI demonstrated bilateral
findings of HOD.
Bilateral HOD findings were common in both the group
of patients with a lesion (“lesional”) (n = 39/57, 68%; mean
age 45.1 years [range 11-81]; female = 20 [51.3%]) (Figs 3,
4, and 5) and the nonlesional (n = 39/45, 87%; mean age
61.9 years [range 15-82]; male = 26 [68.4%]) group (Figs 2
and 6), though more commonly seen in the group of pa-
tients without a lesion (“nonlesional”) in the DROP (P < .03)
(Table 1). Overall, HOD was most frequently seen in conjunc-
tion with a discrete lesion within the DROP and a lesion was

Fig 2. MR images of a 44-year-old female without an identifiable
lesion in the DROP. (A) Axial spin echo T2-weighted MR image from
the initial scan demonstrates enlargement and T2 hyperintensity of
the right ION (arrow) and a normal appearance to the left ION. (B)
Eight months later on follow-up imaging, axial spin echo T2-weighted
MR image demonstrates involvement of the left ION (dashed arrow)
but the configuration is asymmetric with the right ION (arrow) larger
and having greater T2 hyperintensity. No lesion was visualized within
the DROP on any of the patient’s MRIs.
Fig 3. Fifty-year-old male with multiple surgeries for recurrent mid-
brain epidermoid cyst. (A) and (B) Axial fast spin echo T2 and FLAIR
MR images obtained 1 year after two partial resections of a recurrent
midbrain epidermoid cyst demonstrate marked abnormal increased
signal and enlargement of the ION bilaterally.
identified in 56% (57/102; mean age 47.7 years [range 11-81];
male = 30 [52.6%]) of patients. Review of these lesions demon-
strated a wide variety of causes for disruption of the DROP
and subsequent HOD. The most common lesions resulting in
HOD include surgery/trauma in 32% (18/57), a vascular mal-
formation in 21% (12/57), and infarction in 16% (9/57) of cases
(Figs 4 and 5 and Table 2). The remaining 31% (18/57) of the
lesional cases had a spectrum of causes including demyelina-
tion, tumor, or hemorrhage without MR imaging evidence for a
vascular lesion. In 44% (45/102) of the patients with MRI find-
ings of HOD, a definite lesion could not be identified within the
DROP to explain the HOD (Figs 2 and 6). None of the cases of
HOD demonstrated enhancement.
Carr et al: Bilateral HOD in a large cohort 3
Fig 4. Forty-two-year-old female presenting with a pontine cavernoma. (A) Axial gradient echo imaging demonstrates marked hypointensity
in the mid-posterior pons consistent with the pathology proven pontine cavernoma (white arrow) which was resected. (B) and (C) Axial fast
spin-echo T2 and T2-weighted FLAIR MR images, respectively, demonstrate increased signal and enlargement of the right ION.

Fig 5. Thirty-one-year-old female who had a remote history of basilar artery occlusion resulting in multiple posterior circulation infarcts. (A)
and (B) Axial fast spin-echo T2 and T2-weighted FLAIR, respectively, demonstrate enlargement and increased T2 signal in the ION bilaterally.
There is also encephalomalacia involving the left side of the cerebellum from chronic infarction. (C) Axial fast spin-echo T2 demonstrates small
chronic infarcts in the red nuclei bilaterally.

The presence of PT was more common in the nonlesional
group occurring in 49% (22/45) compared with 23% (13/57)
of patients with a lesion within the DROP (P < .004). In the
patients without a demonstrable lesion, progressive ataxia and
palatal tremor (PAPT) was the most common clinical diagnosis
in 22% (10/45) of patients (Fig 6). Of note, all of the cases of
PAPT demonstrated bilateral findings of HOD. In addition, of
the bilateral nonlesional cases there was a single diagnosis of
multiple system atrophy and of olivopontocerebellar atrophy.
Discussion
As initially described by Guillain and Mollaret,2 the connec-
tions of the DROP run between the contralateral dentate nu-
cleus of the cerebellum, the ipsilateral red nucleus of the mid-
brain, and the ipsilateral ION of the medulla. The afferent
connection from the dentate nucleus to the contralateral red
nucleus is made via the superior cerebellar peduncle. At this
point these fibers then decussate within the brachium conjunc-
tivum and enter the red nucleus.14 The afferent fibers from the
red nucleus pass through the central tegmental tract and into
the ION. The efferent connection between the ION and the
contralateral dentate nucleus is made via the inferior cerebellar
peduncle. HOD is thought to occur when there is a disruption
of the afferent pathways to the ION (dentate nucleus to red
nucleus and red nucleus to ION) and results in transneuronal
degeneration. A lesion in the efferent pathway between the
ION and dentate nucleus via the inferior cerebellar peduncle

4 Journal of Neuroimaging Vol 00 No 0 xxxx 2014


Fig 6. Seventy-year-old female who presented with progressive
ataxia and palatal myoclonus diagnosed with PAPT syndrome, spo-
radic type. (A) and (B) Axial spin echo T2 and FLAIR MR images,
respectively, demonstrate increased signal and enlargement of both
ION. The conspicuity of the increased T2 signal is better visualized
on spin echo T2 rather than FLAIR. No lesion was identified in the
DROP.
is reported to be unlikely to result in HOD.12,15 When a lesion
occurs in the red nucleus or central tegmental tract, HOD is
thought to occur in an ipsilateral manner. Contralateral HOD
is thought to occur when the lesion disrupts the superior cere-
bellar peduncle or dentate nucleus. Bilateral HOD is thought to
occur when lesions involve both the red nucleus or the central
tegmental tract (CTT) and the dentate nucleus or the superior
cerebellar peduncle.2–4,6,10,13
Our cohort of patients demonstrates that HOD is com-
monly bilateral and occurs in patients with an evident lesion
in the DROP as well as those without a specific DROP lesion.
HOD has previously been described as primarily a unilateral
process.5,12,16–18 Increased prevalence of bilateral HOD in this
series may be due to a referral bias at a tertiary referral center
or a population otherwise skewed toward patients with PAPT
which is typically a bilateral process.19 Included in referral bias
is passage of additional time for signs, symptoms, and imag-
ing findings to progress into a more coherent picture. Small
symmetric lesions may escape detection due to technical and
human factors issues including posterior fossa MRI artifacts of
CSF flow pulsation and field inhomogeneity shading, location
of the abnormality on the first or last images in a series, and
the reliance on asymmetry to prompt recognition of a potential
abnormality.
The cases of lesional HOD did lend support to the presence
of the DROP. For example, in Figure 5, the patient had infarcts
of both red nuclei. In this case, HOD is seen bilaterally, as
would be inferred. Likewise, in Figure 4, the pontine cavernoma
is to the right of midline which would affect the traversing
CTT resulting in ipsilateral HOD of the right ION, as would
be expected. In the case of the multiply recurrent midbrain
epidermoid cyst (Fig 3), this was a midline lesion. HOD was
seen bilaterally, as would be predicted.
In the cases of bilateral HOD, the findings in the ION were,
on occasion, found to be asymmetric in size and shape. In-
cluded in this cohort were two patients whose MRI exams
demonstrated hypertrophy of the ION initially unilaterally and
subsequently became bilateral (Figs 4 and 5) with an asymmet-
ric appearance. Asynchronous timing may account for other
cases with an asymmetric appearance.12
As this study demonstrates, imaging findings of HOD can
be present without a clearly defined lesion in the above de-
scribed pathway. There is only one report of idiopathic HOD9
within the English-language literature to our knowledge. In our
series, we identified 45 patients without a visualized lesion in
the DROP. Within the group of patients without a lesion in
the DROP, the largest single clinical diagnosis was PAPT. The
patients with the clinical diagnosis of PAPT were all found
to having findings of HOD bilaterally. PAPT is a condition
in which there is progressive ataxia, both sporadic and famil-
ial forms, with additional cerebellar features. These patients
often develop visual disturbance, dysarthria, dysphagia, arm
ataxia, and difficulty walking and standing. This syndrome is
typically idiopathic. Structurally there may be brainstem and
cerebellar atrophy as well as hypertrophy of the ION. Familial
forms of PAPT usually have normal ION and this is thought
to be a functional, rather than structural, abnormality resulting
in PT.19,20
PT is divided into two categories: essential and symptomatic
PT. Essential PT is defined as occurring in the setting of a struc-
turally normal MRI. Symptomatic PT is defined as occurring
when there is a definable lesion in the brainstem or cerebellum.
In patients with symptomatic PT, HOD is typically present.20
Carr et al: Bilateral HOD in a large cohort 5
Table 1. Summary of Imaging and Clinical Findings
Lesional
Unilateral
No. of patients 18
Age in years (mean, range) 53.5 (11-81)
Gender M = 11 (64.7%)
Clinical findings
Palatal tremor
Progressive ataxia with PT
Asymptomatic
Total
*
The nonlesional PAPT patients are a subset of the 22 patients with clinically documented palatal tremor.
Table 2. Breakdown of Types of Lesions within the DROP Found in
Patients with HOD
Surgery Vascular
or Trauma Malformation Infarct Other Total
Number of patient’s 18 12 9 18
with a lesion in
the DROP
However, the lack of PT does not exclude the diagnosis of
HOD. In our series, only 33% of all patients with findings of
HOD had PT. Of those who had a definable lesion in the
DROP, only 22% had PT. Since many of these patients had
other clinical issues (eg, trauma, recent neurosurgery for poste-
rior fossa tumors, etc) it is possible that PT was not aggressively
sought on physical exam and could have been overlooked since
it can be a subtle physical exam finding. In our series, PT pre-
sented more commonly in patients with HOD in which there is
no demonstrable lesion in the DROP. Of the 45 patients with-
out a lesion in the DROP, 10 of these patients had the clinical
diagnosis of PAPT.
Further study is warranted for the nonlesional cases, espe-
cially those without PAPT. In these cases it would be useful to
determine if there are lesions outside of the triangle of Guillain-
Mollaret, that could produce HOD, potentially via pathways
which are either separate from or secondarily affect this tri-
angle. Additional investigation of cases of bilateral HOD may
help clarify the degree to which these occur in an asynchronous
fashion and/or asymmetric pattern.
This study has several limitations. This is a retrospective re-
view and is limited as such. Cases were identified from a cohort
of patients in whom HOD had been reported as a diagnos-
tic possibility by a neuroradiologist. Therefore, there exists the
potential for having missed cases not appreciated by the ini-
tial neuroradiologist, which could include subtle cases or those
without a classic history of PT. The study is also limited in that
the reference standard for the diagnosis of HOD was the opin-
ion of the neuroradiologists, based upon the MRI appearance
of the ION. Although this is an imperfect method of diagnosis,
a pathologic diagnosis is typically not feasible in this disorder.
There may also be a referral bias since we are a tertiary care
center.
6 Journal of Neuroimaging Vol 00 No 0 xxxx 2014
Nonlesional
Bilateral Unilateral Bilateral
39 6 39
45.1 (17-78) 69.5 (53-92) 61.9 (15-82)
F = 20 (53.5%) M = 4 (66.7%) M = 26 (68.4%)
13 22
0 10*
44 22
57 45
Conclusion
This study demonstrates that HOD is frequently bilateral. HOD
may present as a unilateral process or, more commonly, a bilat-
eral process which can be asymmetric in signal and shape and
may be asynchronous. In slightly over 50% of our patients with
57
HOD a lesion was identified in the DROP. Surgery or trauma,
infarction, and vascular lesions were the most common in our
cohort. In just under 50% patients with HOD, no lesion was
identified in the DROP; HOD was present bilaterally in the
majority of these cases.
Authors thank Angela Majerus for her contributions in editorial assis-
tance and manuscript submission.
References
1. Oppenheim H. Uber. Olivendegeneration bei Atheromatese der
basalen Himarterien. Berl Klin Wschr 1887;34:638-639.
2. Guillain GMP. Deux cas de myoclonies synchrones et
rhythmes velo-pharyngo-layrngo-oculo-diaphragmatiques. Rev
Neurol 1931;2:545-566.
3. Shah R, Markert J, Bag AK, et al. Diffusion tensor imaging in
hypertrophic olivary degeneration. Am J Neuroradiol 2010;31:1729-
1731.
4. Asal N, Yilmaz O, Turan A, et al. Hypertrophic olivary degenera-
tion after pontine hemorrhage. Neuroradiology 2012;54:413-415.
5. Gatlin JL, Wineman R, Schlakman B, et al. Hypertrophic olivary
degeneration after resection of a pontine cavernous malformation:
a case report. J Radiol Case Rep 2011;5:24-29.
6. 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) 2008;150:149-156; discussion 156.
7. Kitajima M, Korogi Y, Shimomura O, et al. Hypertrophic oli-
vary degeneration: MR imaging and pathologic findings. Radiology
1994;192:539-543.
8. Sanchez Hernandez J, Paniagua Escudero JC, Carreno Moran
P. Hypertrophic olivary degeneration secondary to a Guillain-
Mollaret triangle lesion. Neurologia 2013 Jan-Feb; 28(1):59-61.
9. Sanverdi SE, Oguz KK, Haliloglu G. Hypertrophic olivary degen-
eration in children: four new cases and a review of the literature
with an emphasis on the MRI findings. Br J Radiol 2012;85:511-516.
10. Vaidhyanath R, Thomas A, Messios N. Bilateral hypertrophic oli-
vary degeneration following surgical resection of a posterior fossa
epidermoid cyst. Br J Radiol 2010;83:e211-e215.
11. 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). Pe-
diatr Radiol 2012;42:481-485.
12. Goyal M, Versnick E, Tuite P, et al. Hypertrophic olivary degener-
ation: metaanalysis of the temporal evolution of MR findings. Am
J Neuroradiol 2000;21:1073-1077.
13. Gerace C, Fele MR, Luna R, et al. Neurological picture. Bilat-
eral hypertrophic olivary degeneration. J Neurol Neurosurg Psychiatry
2006;77:73.
14. Dincer A, Ozyurt O, Kaya D, et al. Diffusion tensor imaging of
Guillain-Mollaret triangle in patients with hypertrophic olivary de-
generation. J Neuroimaging. 2011;21:145-151.
15. Trelles JO. La oliva bulvar: su estructura function y patologia. Rev
Neuro-Pisquat 1943;6:433-521.
16. Birbamer G, Buchberger W, Felber S, et al. MR appearance of
hypertrophic olivary degeneration: temporal relationships. Am J
Neuroradiol 1992;13:1501-1503.
17. Birbamer G, Buchberger W, Kampfl A, et al. Early detection of
post-traumatic olivary hypertrophy by MRI. J Neurol 1993;240:407-
409.
18. Hirono N, Kameyama M, Kobayashi Y, et al. MR
demonstration of a unilateral olivary hypertrophy caused
by pontine tegmental hematoma. Neuroradiology 1990;32:340-
342.
19. Brinar VV, Barun B, Zadro I, et al. Progressive ataxia and palatal
tremor. Arch Neurol 2008;65:1248-1249.
20. Samuel M, Torun N, Tuite PJ, et al. Progressive ataxia and palatal
tremor (PAPT): clinical and MRI assessment with review of palatal
tremors. Brain 2004;127:1252-1268.
Carr et al: Bilateral HOD in a large cohort 7