Neurosurgical Review (2023) 46:181

https://doi.org/10.1007/s10143-023-02086-1

REVIEW

The Guillain‑Mollaret triangle: a key player in motor coordination

and control with implications for neurological disorders
Eren Ogut1 · Kutay Armagan2 · Doruktan Tufekci2

Received: 28 April 2023 / Revised: 1 July 2023 / Accepted: 7 July 2023 / Published online: 20 July 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023

Abstract
The dentato-rubro-olivary pathway, also known as the Guillain-Mollaret triangle (GMT) or myoclonic triangle, consists of
the dentate nucleus, the red nucleus, and the inferior olivary nucleus (ION). GMT is important for motor coordination and
control, and abnormalities in this network can lead to various neurological disorders. The present study followed a systematic
approach in conducting a review on GMT studies. The inclusion criteria were limited to human subjects with primary objec-
tives of characterizing and evaluating GMT syndromes, and the methodology used was not a determining factor for eligibil-
ity. The search strategy used MeSH terms and keywords relevant to the study’s objective in various databases until August
2022. A total of 76 studies were included in the review after assessing 527 articles for eligibility based on the final inclusion
criteria. Most of the studies evaluated the GMT in human subjects, with the majority utilizing magnetic resonance imaging
(MRI), diffusion tensor imaging (DTI), or combination of them. The review found that Hypertrophic olivary degeneration
(HOD), a common consequence of GMT damage, has diverse underlying causes, including stroke, brainstem cavernous
malformations, and structural impairments. Palatal tremor, ocular myoclonus, ataxia, nystagmus, and vertigo were frequently
reported symptoms associated with HOD. This systematic review provides comprehensive insights into the association
between GMT and various neurological syndromes, shedding light on the diagnostic, etiological, and prognostic aspects of
GMT dysfunction. Understanding the role of the GMT and its implications in movement disorders could pave the way for
improved treatment options and better management of neurological conditions related to this critical brainstem pathway.

Keywords Dentato-rubro-olivary pathway · Guillain-Mollaret triangle · Motor coordination · Neurological disorders ·

Hypertrophic olivary degeneration · Movement disorders

Introduction Guillain-Barré syndrome, a rare autoimmune disorder, and

Mollaret having identified Mollaret meningitis, a recurrent
The dentato-rubro-olivary pathway (DROP) was first form of meningitis [2]. Guillain and Mollaret observed two
described by the French neurologists Georges Charles Guil- cases of the syndrome, characterized by synchronous and
lain (1876–1961) and Pierre Mollaret (1898–1987) in 1931 rhythmic myoclonus of the velo-pharyngo-oculo-diaphrag-
[1]. These neurologists are renowned for their contributions matic muscles, and through detailed anatomical and physi-
to the field of neurology, with Guillain having described ological analyses, they proposed the existence of a func-
tional connection between the red nucleus (RN), the inferior
* Eren Ogut olivary nucleus (ION), and the dentate nucleus (DN). They
erenogut@yahoo.com.tr named this connection the Guillain-Mollaret triangle (GMT)
Kutay Armagan [1]. This identification provided a comprehensive under-
kutay.armagan@bahcesehir.edu.tr standing of the pathophysiology of the syndrome and its
Doruktan Tufekci relation to the triangle, enabling further research and more
doruktan.tufekci@bahcesehir.edu.tr effective treatment options [1]. The GMT is a network of
neurons in the brainstem that is involved in motor coordina-
1
Department of Anatomy, Bahçeşehir University Faculty tion and plays an important role in regulating movement
of Medicine, 34734 Istanbul, Turkey
and posture [3] The GMT is a neuronal circuit in the brain-
2
Medical Faculty Student, Bahçeşehir University Faculty stem that connects the ION with the contralateral RN via the
of Medicine, 34734 Istanbul, Turkey

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181 Page 2 of 26
central tegmental tract (CTT) (Fig. 1). It has been implicated
in a variety of functions, including modulation of tremors
[4]. Abnormalities in this network have been linked to a
variety of neurological conditions, including ataxia, dys-
tonia, and dysarthria [3]. Hypertrophic olivary degenera-
tion (HOD) is a degenerative condition that affects the ION
in the brainstem, which is involved in motor coordination
and learning that occurs as a result of damage to the DROP
[5–8]. Understanding the role of GMT is important because
damage to this area can lead to HOD [4]. A better under-
standing of this triangle could lead to improved treatment
options for movement disorders. Specifically, the current
study aims to examine the functional connection between
the RN, the ION, and the DN, which form the GMT, and its
implications in various neurological conditions.
Methods
Eligibility criteria
The inclusion criteria for our review were limited to GMT
studies conducted on human subjects, both cadaveric and
living, with the primary objective of evaluating and charac-
terizing the associated syndromes and clinical importance.
The methodology employed in the study, whether it involved
the use of staining methods, imaging techniques, or a com-
bination of these techniques, was not a determining factor
for eligibility.
Fig. 1  The figure depicts the anatomical organization of the Guillain-
Mollaret triangle (GMT) along with the related neural pathways. The
GMT, also referred to as the dentatorubro-olivary pathway, com-
prises three corners, namely the red nucleus (RN), the inferior olivary
nucleus (ION), and the contralateral dentate nucleus (DN). Rubro-
olivary fibers descend from the parvocellular division of each RN
along the central tegmental tract (CTT) to reach the capsule of the
ipsilateral ION. From the ION, olivocerebellar fibers cross the con-
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Neurosurgical Review (2023) 46:181
Information sources
The search strategy encompassed the inception date of
each database until August 2022, and involved the inclu-
sion of MeSH terms and keywords relevant to the objec-
tive of our study in the search strategy. A total of 5094
articles were initially retrieved from various databases,
including Academic Search Ultimate, CINAHL Complete,
Ebsco Databases, MEDLINE Complete, MEDLINE, Sco-
pus, PubMed, ProQuest, Web of Science Core Collection,
Wiley Online Library, Science Direct, and TR Dizin. The
article scanning process was conducted in accordance with
the PRISMA (Preferred Reporting Items for Systematic
Reviews and Meta-Analyses) statement [9]. The following
MESH terms were used in this study: “Myoclonic Trian-
gle” OR “Guillain-Mollaret Triangle,” OR “dentato-rubro-
olivary,” OR “dentatorubroolivary,” AND “Hypertrophic
olivary degeneration.” The databases that yielded the
most relevant articles were Science Direct (n=1419), Pro-
Quest (n=1044), Scopus (n=544), Wiley Online Library
(n=504), MEDLINE Complete (n=444), Web of Science
Core Collection (n=292), PubMed (n=265), MEDLINE
(n=253), and Academic Search Ultimate (n=228). The
search strategy used in this study proved to be effective in
identifying a substantial number of articles related to the
topic of interest (Fig. 2).
tralateral inferior cerebellar peduncle (ICP) to reach the cerebellar
cortex, and then pass from the cerebellar cortex to the contralateral
DN. Dentatorubral fibers then ascend via the contralateral superior
cerebellar peduncle (SCP), decussate in the midbrain, and return to
the RN. Dentorubral tract via SCP. CCT, central tegmental tract; DN,
dentate nucleus; GMT, Guillain-Mollaret triangle; ICP, ınferior cere-
bellar peduncle; ION, ınferior olivary nucleus; RN, red nucleus, SCP,
superior cerebellar peduncle
Neurosurgical Review (2023) 46:181
Fig. 2  Consort diagram
Study selection
Two independent reviewers screened all titles and abstracts
for eligibility based on the study’s objectives, with disa-
greements addressed in a second phase of full-text review.
A pilot test was conducted prior to each selection phase to
ensure inter-rater agreement. Eligible studies were limited
to clinical syndromes that examined the GMT in individu-
als OR patients OR cadavers as their primary or secondary
objective. The search included MeSH terms and keywords
related to the study’s objective, and all relevant articles from
database inception until August 2022 were considered.
Data collection process
A web-based tool was created for extracting data, which
included details about the descriptive information, tech-
niques, subject profile, study design, and diagnostic meth-
ods (immunohistochemistry, ELISA, imaging modalities);
Page 3 of 26 181
significant outcomes were identified. Two reviewers worked
independently and in duplicate to carry out the extraction.
In cases of disagreement, consensus was reached or a third
reviewer was involved.
Outcome measures
Due to the nature of the study, a qualitative synthesis of the
data was conducted, which involved describing the informa-
tion related to GMT and related neurological syndromes.
Results
Study selection
The search strategy yielded a total of 5094 records. After
removing duplicates (1596 articles), 3487 were deemed eli-
gible for title and abstract screening. Based on relevance to
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181 Page 4 of 26
the topic, the articles were categorized as unrelated, related,
and less related. As a result, 527 articles were assessed for
eligibility, and a total of 76 studies were ultimately included
in our review based on the final inclusion criteria [10–14]
(Fig. 2). Notwithstanding, it is noteworthy to acknowledge
that due to the constraints of the article, a selection pro-
cess was necessary in determining which sources could be
utilized for this study, resulting in the exclusion of certain
sources that may have been relevant to the topic at hand.
Study characteristics
All the studies evaluated the GMT in human subjects except
for two studies. Among the 17 studies that used immuno-
histochemistry (Ubiquitin, Neuro-filament, GFAP, SYP,
Tau-2, 200-kDa neurofilament protein, MG160, TGN4,
CP13, TUNEL, chromatin condensation, nuclear fragmen-
tation, apoptotic bodies, c-fos, aBC, MAP2, HSP27, SMI-
31, KDEL, pNF-H) and staining methods (Cresyl violet,
semithin, toluidine, uranyl acetate, lead citrate, Nissl stain-
ing, HRP, HE, KB, PTAH, Azan, PAS, Bodian, modified
Bielschowsky, Holzer, Gallyas silver) to address the research
question, the rest of them performed MRI, CT, DTI or other
imaging modalities (retrospective analyses), while the oth-
ers combined the imaging modalities and staining meth-
ods. Table 1 presented a summary of the studies, includ-
ing subject profile, diagnostic method, HOD laterality, and
outcomes.The studies on HOD identified various underly-
ing causes, with the most common being stroke, brainstem
cavernous malformations, and structural impairments in the
brainstem or cerebellum. Palatal tremor, ocular myoclonus,
ataxia, nystagmus, and vertigo were the most frequently
reported symptoms associated with HOD. MRI proved to
be an effective diagnostic tool for HOD, showing hyper-
intensity in the ION on T2-weighted images and reduced
fractional anisotropy (FA) values in DTI. The MRI findings
were correlated with the severity of HOD. The age range of
HOD patients varied from children (6 months to 12 years) to
adults (average age of 62 years). Studies also revealed that
the prognosis of HOD varies depending on the underlying
cause, with some cases showing progressive disability while
others remain stable. As a result, HOD is a complex move-
ment disorder with diverse underlying causes and clinical
presentations. MRI is a valuable tool for accurate diagnosis,
and prompt identification and intervention are essential to
improve the quality of life for affected individuals.
Summary of findings related to clinical syndromes
and anatomical locations
The review examined the association between the GMT and
various clinical syndromes. Most of the studies reported
consistent findings, linking dysfunction of the GMT to the
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Neurosurgical Review (2023) 46:181
following clinical syndromes and conditions (Table 2). Stud-
ies also found associations between GMT and various other
clinical manifestations, such as dysphagia, tinnitus, tremors,
ataxia, dysarthria, nystagmus, and motor deficits like parkin-
sonism. The review emphasized the importance of prompt
identification and intervention in improving the overall qual-
ity of life for individuals affected by GMT-related disorders.
It should be noted that while most studies indicated a con-
sistent association between clinical syndromes and anatomi-
cal locations within the GMT, some clinical syndromes like
SPT were indirectly linked to the GMT.
Discussion
In this review, we provided a summary of the existing evi-
dence that assessed the association between the GMT and
various clinical syndromes. The majority of the studies
examined in this review reported consistent findings, indi-
cating that conditions such as HOD, palatal tremor (PT)
[15–17], OPT [18–21], ocular myoclonus, palatal myoclonus
(PM) [22–24], ocular palatal tremor plus dystonia (OPTD)
[21], essential palatal tremor (EPT) [25], symptomatic pala-
tal tremor (SPT), post-stroke palatal tremor (PPT), sudden
infant death syndrome (SIDS), sudden unexplained peri-
natal death (SUID), progressive supranuclear palsy (PSP)
[26], post-operative pediatric cerebellar mutism syndrome
(PMCMS), Leigh syndrome, acquired progressive ataxia and
palatal tremor (APPT), non-hereditary olivopontocerebellar
atrophy (NHOND), central tegmental tract hyperintensity
(CTTH), Joubert syndrome, Prader-Willi syndrome, Wilson
disease, Holmes’s tremor, hypoxic-ischemic encephalopathy,
paraneoplastic rhombencephalitis (PNE), meningitis, multi-
ple sclerosis, cranial nerve palsies, and various neurological
symptoms such as tremors, ataxia, dysarthria, dysphagia,
dysmetria, nystagmus, mutism, impaired balance or coordi-
nation, abnormal reflexes, vertigo, various cerebellar signs,
and motor deficits such as parkinsonism were associated
with dysfunction of the GMT. The leading cause of HOD
and GMT damage was identified as stroke [5, 27, 28]. Stroke
was identified as the most prevalent etiology, followed by
injury to the head, brainstem, cerebellum and CTT, brain
tumors, infections, midbrain-pontine lesions, vascular and
cavernous malformations (CMs) [29].
Regarding the diagnostic assessment, the MRI conducted
on the study group consistently revealed indications of HOD
[5, 6, 8, 30–38]. This suggestion highlights the effective-
ness of MRI in the accurate detection and diagnosis of HOD
[35, 39]. Notable observations encompassed hyperintensity
within the IONs on T2-weighted images, increased signal
intensity on diffusion-weighted images, and diminished
FA values derived from DTI analysis within the IONs. A
significant correlation was established between the severity
 Table 1  Studies on neuropathologies associated with Guillain-Mollaret triangle
No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

1 Boesten et al. 1985 Cats Cresyl violet, semithin, toluidine, uranyl N/A A new pathophysiology, different from the
Netherlands acetate, lead citrate one for the humans, for ION hypertro-
phy is devised for the cats. Connections
between mesencephalon and ION that
remain unchanged after ablation of
cerebellum are speculated to be the cause
of ION hypertrophy in cats.
2 Ruigrok et al. 1990 Total: 18 cats Olivary cell response to electrical stimuli N/A Electrotonic coupling secondary to the
Netherlands Hemicerebellectomized: 12 Histochemistry (Toluidine, Nissl staining, damaged GABAergic cerebellar afferent
Neurosurgical Review (2023) 46:181

Totally cerebellectomized: 2 HRP) neurons aids in the survival of ION

Ctrl: 4 neurons after axonal injury.
3 Goto et al. 1981 Autopsy subjects with primary pontine HE, KB, PTAH N/A CTT injury starts a chain of events that can
Japan hemorrhage: 8 (4 F, 4 M), median age: be summarized in six stages: 1. In the first
53 yrs. 24 hrs.: no olivary changes, 2. First 2–7
days: amiculum degeneration, 3. 3 weeks:
neuronal hypertrophy in ION, 4. 8.5
months: neuronal and astrocytic hypertro-
phy, 5. ≥9.5 months: olivary pseudohy-
pertrophy (neuronal dissolution), 6. A few
years: olivary atrophy
4 Okamoto et al. 1992 Autopsy subjects with GMT lesions: 6 (1 HE, KB, Nissl, PTAH, Azan, PAS, N/A ION hypertrophy is associated with rough
Japan F, 5 M), median age: 74 yrs. Bodian, modified Bielschowsky, IHC ER dilatation, showing microscopic
Ctrl: 6 (Ubiquitin, Neuro-filament, GFAP) changes such as electron dense, homoge-
neous, round granules.
5 Kawanami et al. 1994 Total: 10 autopsy subjects IHC (SYP) Unilat.: 50% HOD is linked to changes in the distribu-
USA Subjects with HOD: 4 (3 F, 1 M) Bilat.: 50% tion pattern of presynaptic terminals in
Japan Ctrl: 6 (3 F, 3 M) ION. (vesicles increased in neuron body,
decreased in neuropil)
6 Koga et al. 1997 Autopsy subjects with SMON: 11 (7 F, 4 KB, Holzer N/A The pathophysiologic mechanism by which
Japan M), median age: 60 yrs. ethambutol and clioquinol intoxication
cause ION hypertrophy is presumably the
distal axonopathy in DOT.
7 Hanihara et al. 1998 Total: 20 autopsy subjects HE, KB, Holzer, Bodian, Gallyas silver N/A Microscopic findings consistent with ION
Japan Subjects with PSP: 11 IHC (Tau-2, Ubiquitin, 200-kDa neuro- hypertrophy were also found in PSP
Ctrl: 9 filament protein, GFAP) cases, which may be explained by neuro-
-Machado-Joseph disease: 3 filament accumulation.
-DRPLA: 6 ION hypertrophy in PSP cases might be due
to tegmentum lesions affecting CTT.
8 Takamine et al. 2000 Autopsy subjects with DOT lesions: 6 (1 HE, KB, Nissl, PTAH, Azan, PAS, N/A Anterograde transneuronal lesions are
Japan F, 5 M), median age: 74 yrs. MG160 and TGN4 antibodies proposed to affect Golgi apparatus and
Ctrl: Autopsy subjects with normal ION trans-Golgi network in neurons of ION
Findings in Golgi apparatus and trans-Golgi
network were almost identical in multiple
system atrophy and late stage brainstem
lesions.

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 Table 1  (continued)
181

No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

13
9 Nishie et al. 2002 Autopsy subjects with vascular insult to HE N/A ION hypertrophy is a marker of dysfunc-
Japan DOT: 16 (2 F, 14 M), mean age: 67 yrs. LFB tional events such as hyperexcitation,
-Subjects with infarct: 9 IHC (SYP, neurofilament and GFAP) leading to neuronal death.
Page 6 of 26

-Subjects with hemorrhage: 7 ION hypertrophy is rejected as the cause of

Ctrl (age-matched pts.): 6 SPT during late disease, due to complete
degeneration of efferent fibers of ION
and lack of improvement in SPT in
follow-ups.
Disruption of physiologic rhythmicity in the
brainstem due to ION injury is thought to
be the inciting event that resulted in SPT
10 Katsuse et al. 2004 Total: 1126 autopsy subjects HE N/A HOD and PSP did not correlate well and no
USA PSP: 264 (128 F, 136 M), mean age: 75 IHC (CP13, SYP) significant difference was found between
yrs. PSP (1.5%) and non-PSP (0.9%) cases in
Ctrl (Non-PSP): 862 (464 F, 398 M), terms of HOD.
mean age: 77 yrs. All non-PSP cases with HOD had infarcts,
while none of the PSP cases had any.
11 Fukushima et al. 2006 Autopsy subjects with GMT lesions: 6 (1 HE, KB, aBC, HSP27 N/A aBC, depicting early disease, and HSP27,
Japan F, 5 M), median age: 74 yrs. showing late disease, are two helpful
Ctrl: 5 markers of ION hypertrophy, correlating
with the disease stage.
12 Lavezzi et al. 2009 Autopsy subjects: 44 (18 F, 26 M) HE N/A Maternal smoking is associated with
Italy SUD cases: 28 (10 SIUD + 4 SNUD + KB GMT neuropathologies (hypoplasia of
14 SIDS) IHC of apoptosis (TUNEL, chromatin ION, DN, and RN) in SUD, as well as
-Ctrl: 16 (5 fetuses, 3 newborns, 8 infants) condensation, nuclear fragmentation, medullary arcuate nucleus and pontine
apoptotic bodies), c-fos parafacial nucleus pathologies.
13 Lavezzi et al. 2011 Total: 75 autopsy subjects IHC (c-fos) N/A ION, DN, and RN pathologies in SIDS and
Italy SIUD: 24 (11 F, 13 M) SIUD are related to maternal smoking and
SIDS: 30 (12 F, 18 M) serotonergic abnormalities.
Ctrl: 21 (3 F, 13 M) GMT abnormalities may emerge in the form
of PT, SIUD, or SIDS, all stemming from
malfunctional muscle contraction.
14 Sarnat et al. 2013 Autopsy subjects: 172 (86 F, 82 M, 4 Hematoxylin N/A Baseline data is collected in order to be used
Canada indeterminate) IHC (aBC, SYP) as control in future studies.
Ages: 6–8 weeks: 4, 9–15 weeks: 11, SYP reactivity starts in 13 weeks in ION
16–20 weeks: 57, 21–26 weeks: 59, and in 16 weeks in DN, later than acces-
27–32 weeks: 9, 33–36 weeks: 8, 37–41 sory olivary nucleus and deep cerebellar
weeks: 24 nucleus.
15 Ogawa et al. 2010 Autopsy subjects with HOD: 8 (2 F, 6 M), HE, KB, IHC (aBC, MAP2, SYP, HSP27, Unilat.: 75% Cellular stress increases neuronal aBC
Japan median age: 65 yrs. (total of 10 HOD SMI-31, KDEL, pNF-H), avidin-biotin Bilat.: 25% expression in HOD.
samples) complex
16 Ogawa et al. 2014 Autopsy case group in 45 + 1 new case HE, KB, IHC (anti-caspase-3, aBC, Unilat.: 67% Neurons in ION have peripherally localized
Japan Subjects with HOD: 9 (total of 12 HOD MAP2, SYP, SMI-31, KDEL, pNF-H) Bilat.: 33% ER and decreased expression of αBC and
samples) (45 + 1 new bilateral case) calbindin D-28k, which protect neurons
by preventing microtubule disassembly
and calcium-mediated cytotoxicity
respectively.
Neurosurgical Review (2023) 46:181
 Table 1  (continued)
No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

17 Jellinger 1973 Pts. with HOD: 29 (9 F, 20 M), mean age: Clinical observation Unilat.: 48% Interval from injury to HOD was 12 days–8
Austria 47 yrs. Pathology Bilat.: 52% years.
Histology Etiology was 41% vascular damage, 45%
(multiple lesions) transtentorial hernia-
tion, 14% mass.
HOD is linked to deafferentation and the
resulting transneuronal degeneration after
GMT injury.
18 Uchino et al. 1993 Pts. with abnormal ION signal: 7 (2 F, 5 MRI N/A It took a minimum of 4 months for occur-
Neurosurgical Review (2023) 46:181

Japan M), mean age: 63 yrs. rence of ION hypertrophy after the
injury, while the first MRI signs could be
observed after a minimum of 2 months.
19 Kitajima et al. 1994 Total: 12 cases MRI Unilat.: 83% MRI can provide data corresponding to the
Japan Pts. with HOD: 11 (3 F, 8 M), mean age: HE, KB Bilat.: 17% pathologic stage and demonstrate early
57 yrs. changes in ION.
Autopsy case with HOD: 1 After the injury it took 3 weeks for MRI
intensities and 5–15 months for hypertro-
phy to appear.
CTT injury causes ipsilateral HOD. DN or
SCP injury causes contralateral HOD.
20 Birbamer et al. 1994 Total: 83 ICT pts. (12 F, 71 M), mean age: MRI Unilat.: 25% HOD secondary to GMT lesions was
Austria 25.1 yrs. Bilat.: 75% observed in 10% of ICT patients 4
Pts. with HOD: 8 weeks–7 years after the incident. Among
Pts. without HOD: 75 them, palatal myoclonus was the most
common symptom (75%).
MRI is a better imaging method than CT in
terms of detection of secondary HOD.
21 Kawata et al. 1996 Pts. with vascular insult: 39 MRI, CT Unilat.: 53% Tegmentum injury is notably linked to
Japan Pts. with HOD: 17 Bilat.: 47% HOD.
Pts. without HOD: 22 HOD does not lead to unique features on
cerebellar MRI, which would help distin-
guish it from non-HOD cases.
22 Suzuki et al. 1999 Total: 5 pts. (3 F, 2 M), median age: 27 MRI Unilat.: 20% MRI was unequivocal in terms of features
Japan yrs. (head injury: 3, brainstem hemor- Bilat.: 80% related to ION changes in the first 4
rhage: 2) days–1.5 months, since it took 2–4
All pts. had HOD months on average after the index event
for changes in ION to woccur.
23 Conceição et al. 2001 Pts. with HOD: 10 (6 F, 4 M), mean age: MRI Unilat.: 4 All HOD patients had hyperintense signal
Portugal 54 yrs. Bilat.: 6 on T2WI in ION and normal signal on
T1WI.
70% of patients had ION enlargement or
hypertrophy.
24 Auffray-Calvier et al. 2005 Pts. with HOD: 12 (4 F, 8 M), median MRI Unilat.: 75% HOD occurs secondary to GMT lesions
France age: 40 yrs. Bilat.: 25% and is associated with a hyperintense T2
and PD signal and ION hypertrophy, but
shows no enhancement with Gadolinium.
Hyperintense signal of HOD increases over
the few months of follow-up and then
disappears in 33% (5 out of 15 HOD
samples).

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 Table 1  (continued)
181

No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

13
25 Hornyak et al. 2008 Pts. with HOD: 4 (2 F, 2 M), mean age: MRI Unilat.: 50% ION hypertrophy and hyperintensity occur-
USA 49 yrs. Bilat.: 50% ring later than 3 weeks following surgical
resection of brainstem lesions should
Page 8 of 26

suggest diagnosis of HOD, which prompts

pharynx, larynx, and eye examination.
26 Derner et al. 2009 Pts. with HOD: 4 (3 F, 1 M), median age: MRI, CT Bilat.: 25% Etiology of HOD was tegmental hemor-
Czech Republic 42 yrs. Unilat.: 75% rhage in 50%, infection in 25%, and demy-
elinating process in 25% of the patients.
PT was present in 25% of the patients.
27 Dinçer et al. 2011 Total: 26 GMT images MRI Unilat.: 70% DTI can detect HOD in its early phase, and
Turkey -10 Pts. (3 M, 7 F) with HOD, mean age: DTI Bilat.: 30% DTI signal changes are correlated with
49 (16-77) yrs. histopathological changes of HOD
-Ctrl: 13 GMT images from healthy Axial diffusivity can signify the severity
subjects matched with 13 GMT images of HOD
from 10 HOD pts.
28 Sanverdi et al. 2012 Pediatric pts. with HOD: 4 (2 F, 2 M), MRI Bilat.: 100% In 75% of the patients, HOD was the result
Turkey median age: 6 yrs. of PCF surgery.
29 Shinohara et al. 2013 Pts. with HOD: 7 (5 F, 2 M), median age: MRI N/A HOD is a potential differential diagnosis
Japan 41 yrs. of tumor recurrence after surgery, since
they may show similar MRI features. In
order to differentiate between them, some
hints pointing towards HOD may be used,
such as absence of contrast enhancement
in ION, presence of contralateral DN or
SCP lesion, ipsilateral RN lesion, or CTT
lesion.
30 Yun et al. 2013 Total: 73 pts. treated for BSCM MRI Bilat.: 55% Cavernous malformations have a higher
Korea Pts. treated with surgery: 30 Unilat.: 45% chance of causing HOD if they are located
Pts. treated with GKRS: 43 in the midbrain than in pons or medulla.
Pts. with HOD: 11 (7 F, 4 M),median age: HOD occurrence had no relation to cavern-
37 yrs. (Surgery: 7, GKRS: 4) ous malformation size, patient age, or
Pts. without HOD: 62 treatment method.
HOD was possible to happen after GKRS,
which is the first time this was reported.
31 Carr et al. 2014 Total: 102 pts. with HOD (42 F, 60 M), MRI Unilat.: 24% HOD patients were likely to have GMT
USA mean age: 54 ± 19 yrs. Bilat.: 76% lesions, albeit those who did not were
Pts. with GMT lesion: 57 likely to have bilateral HOD, and their
Pts. without GMT lesion: 45 diagnosis was most commonly PAPT,
which always presented with bilateral
HOD.
Surgery/trauma was the most common
identifiable cause of GMT lesions.
32 Patay et al. 2014 Total: 24 pediatric pts. after PCF surgery MRI Pts. with PFS: unilat.: 18% Bilateral HOD is associated with PFS,
USA (24 M), mean age: 9 ± 3 yrs. Bilat.: 82% which it can be used as a marker for.
Pts. with PFS: 12 (unilat. HOD: 2, bilat. Pts. without PFS: unilat.: 100%
HOD: 9, no HOD: 1)
Pts. without PFS: 12 (unilat. HOD: 2, no
HOD: 10)
Neurosurgical Review (2023) 46:181
 Table 1  (continued)
No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

33 Ulla et al. 2015 Pts. with HOD: 5 (5 F), mean age: 55 yrs. MRI Unilat.: 60% Not all patients with HOD have symptoms
Spain Bilat.: 40% directly attributable to HOD. Characteris-
tic radiological findings of HOD may aid
in diagnosis.
34 Gu et al. 2015 Pts. with true HOD (excl. those with MRI No lesion in the brain: 13% unilat., 87% PAPT patients with HOD but no GMT
USA adjacent lesion in brainstem): 116 bilat. lesions combined with HOD cases
Lesion in GMT: 65 Lesion outside GMT: 29% unilat., 71% without any other lesions can potentially
No lesion in GMT: 51 (17 F, 34 M), mean bilat. represent idiopathic HOD cases.
age: 62 yrs. HOD may be observed even if no lesions
Neurosurgical Review (2023) 46:181

-No lesion in brain: 23 were present in the brain (truly idiopathic

-Lesion outside GMT: 28 origin).
PAPT was found to be a common contribu-
tor of nonlesional (no lesion in GMT)
HOD cases.
35 Hirano et al. 2015 Pts. with PCF masses and HOD: 10 (3 F, MRI Unilat.: 60% HOD can occur secondary to mass (30%),
USA 7 M), median age: 44 yrs. Bilat.: 40% surgery (30%), surgery, and/or RT (40%).
Hemorrhage was a less prominent factor
in HOD compared to previous literature
(present in 40% of patients)
T2-hyperintense signal is nonspecific for
HOD but lesions in ION or GMT are.
36 Konno et al. 2016 Pts. with HOD: 95 (41 F, 54 M), mean MRI Unilat.: 41% A primary neurodegenerative process may
USA age: 60 ± 17 (unilat.), 63 ± 13 (bilat.) Bilat.: 59% be the cause of 50% of bilateral HOD
cases that were idiopathic and progres-
sive.
37 Sabat et al. 2016 Pts. with HOD: 6 (5 F, 1 M), median age: MRI Bilat.: 33% Intraparenchymal hemorrhage of cavernoma
USA 55 yrs. Unilat.: 67% into pons was the most common reason
for HOD, being found in 50% of patients.
HOD secondary to toxoplasma infection is
reported.
38 Avula et al. 2016 Pediatric pts. after PCF surgery: 48 (28 F, MRI Unilat.: 40% Bilateral HOD serves as an imaging marker
UK 20 M), mean age: 8 yrs. Bilat.: 60% for POPCMS, unilateral HOD serves no
Pts. with HOD: 15 such purpose.
Pts. without HOD: 33 Left ION contrast change relative to its
neighboring tissue is a very successful
indicator of POPCMS, since right pECP
is probably involved in the pathogenesis
of POPCMS.
39 Smets et al. 2017 Pts. with HOD: 27 MRI Pts. with new findings: Among four patients with new findings,
Belgium Pts. with classical findings: 23 Unilat.: 50% dentato-olivary afferent feedback loop is
Pts. with new findings: 4 (1 F, 3 M), Bilat.: 50% advised as the underlying pathway for the
median age: 53 yrs. occurrence of HOD in two, an interval
of 6 years between RN lesion and HOD
was found in one, and ION showed a
cystic degeneration 3 years after HOD in
another.
40 Önen et al. 2018 Pts. with HOD: 16 (8 F, 8 M), mean age: MRI Unilat.: 63% Bilat.: 37% Recovery of patients with PCF tumors may
USA 41 yrs. be delayed in the presence of HOD.
HOD was most commonly secondary to
PCF tumors and cavernomas.

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 Table 1  (continued)
181

No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

13
41 Foerch et al. 2019 Stroke pts. with HOD: 12 (4 F, 8 M), MRI Unilat.: 10 Most of the HOD patients were symp-
Germany mean age: 51 ± 14 Bilat.: 2 tomatic but half of them could not be
diagnosed in their clinical presentation.
Page 10 of 26

Logopedic examination with FEED is sug-

gested for screening PT, which may aid in
earlier diagnosis of HOD.
Median interval between radiological diag-
nosis and causing incident was 24 months
(4–115 months).
42 Wang et al. 2020 Pts. with HOD secondary to brainstem MRI Bilat.: 8 Neither the interval until HOD, nor MRI
China infarction: 13 (6 F, 7 M), median age: Unilat.: 4 findings of HOD are related with the loca-
59 yrs. N/A: 1 tion of the infarction.
43 Schaller-Paule et al. 2019 Pts. with HOD: 12 (4 F, 8 M), median MRI Bilat.: 25% HOD is more closely associated with PCF
Germany age: 38 yrs. Unilat.: 75% tumor surgery than it is with the tumor
that affects GMT.
Contralateral DN was the cause of HOD in
67% of patients.
Median interval between PCF surgery and
HOD diagnosis was 6 months.
44 Schaller-Paule et al. 2021 Pts. after PCF surgery: 50 (20 F, 30 M), MRI Unilat.: 80% Paravermal trans-cerebellar approach to
Germany mean age: 23 ± 17 yrs. Bilat.: 20% PCF tumors is more frequently associated
Pts. with HOD: 10 with DN injury and the resultant HOD.
Pts. without HOD: 40 Midline approach has higher success
rates.
SWI is advised to be incorporated in plan-
ning for neurosurgery, as a suitable imag-
ing method for DN localization.
45 Behzadi et al. 2021 Pts. with HOD: 7 (2 F, 5 M), median age: MRI Bilat.: 100% The first case of bilateral HOD attributed to
USA 44 yrs. an infectious origin.
It was hypothesized that the cause of most
lesions leading to HOD are actually
located rostrally to GMT, rather than
being confined to it, which explains the
lack of information about etiology of
HOD in most studies.
46 Madhavan et al. 2021 Pts. with positive onconeural antibod- MRI Unilat.: 83% HOD may signal a progressive or refractory
USA ies: 174 Bilat.: 17% course in paraneoplastic rhombencepha-
-with HOD: 6 (3 F, 3 M), median age: litis.
48 yrs.
-without HOD: 168
Neurosurgical Review (2023) 46:181
 Table 1  (continued)
No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

47 Matsuo et al. 1979 Pts. with PT: 33 (7 F, 26 M) N/A N/A Palatal myoclonus occurs ipsilateral to the
USA Ages: 33-81 yrs. cerebellar lesion and contralateral to the
-Brainstem nuclei and/ or cerebellum ION
infarct: 26 ION hypertrophy is due to afferent fibers of
-Hemiplegia with unknown level of CTT degenerating and despite the atrophy
involvement: 4 of neurons, does not diminish with time
-Stroke or vascular accident: 3 DN lesions correspond to related hyper-
trophic areas in ION
Denervation supersensitivity may cause
Neurosurgical Review (2023) 46:181

ION hypertrophy, since palatal myoclonus

and ION changes are chronologically
related
48 Jabbari et al. 1987 Total.: 8 pts. Clinical observation N/A PT and APN stem from pathologies in close
USA Pts. with PT: 4 anatomical locations and share the same
Pts. with APN: 4 biochemical pathology, since both PT
and APN patients experienced reduction
in their involuntary movements after
trihexyphenidyl treatment.
49 Deuschl et al. 1994 Total: 10 patients with PT (4 F, 6 M), Clinical examination, ear click monitor- EPT pts.: normal MRI Symptomatic PT is suggested to happen
USA median age: 59 yrs. ing, EMG, trigeminal nerve stimulation, SPT pts.:unilat.: 50% as a result of a DOT lesion leading to
Pts. with EPT: 4 ECG, EEG, MRI bilat.: 50% abnormal electrotonic coupling between
Pts. with SPT: 6 ION cells.
50 Seidman et al. 1999 Pts. with PT: 6 (4 F, 2 M), median age: MRI N/A In PT patients, no HOD was observed,
USA 55 yrs. which might be explained by short follow-
up time of patients.
PT was completely resolved in one patient.
One patient could induce PT and objective
tinnitus voluntarily for the first time in
literature.
51 Samuel et al. 2004 Pts. with sporadic PAPT: 6 (6 M), median MRI N/A A variant of symptomatic PT is PAPT,
UK age: 58 yrs. Magnetic search coil technique which also includes ataxia.
52 Kim et al. 1994 Pts. with PT: 5 (1 F, 4 M), mean age: MRI Unilat.: 100% HOD is linked to degeneration of DN and
Korea 54 yrs. cerebellar cortex.
53 Kim et al. 2007 Pts. with OPT: 22 (4 F, 18 M), median MRI Unilat.: 64% Dissociated pendular nystagmus is a strong
Canada age: 56 yrs. Bilat.: 36% indicator of unilateral HOD.
Korea Pendular nystagmus may be explained by
paramedian tract damage or dorsal cap
(ION subnucleus) denervation.
54 Moon et al. 2008 Pts. with OPT: 9 (9 M), mean age: 51 ± MRI, FDG-PET Unilat.: 67% OPT emerging as a result of ION malfunc-
Korea 12 yrs. Bilat.: 33% tion could not be supported with any
Ctrl: 50 (50 M), mean age: 51 ± 10 yrs. metabolic evidence but OPT may be
caused by malfunction of paramedian
tract or thalamus.
55 Liao et al. 2008 Pts. with OPT: 4 (1 F, 3 M) Magnetic field/search coil technique N/A The underlying pathophysiology of OPT is
USA the creation of oscillations that arise as a
result of a learned response of cerebellar
cortex coalescing with the pulses from
ION, which occur because of electro-
tonic coupling between ION cells being
stronger than normal.

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 Table 1  (continued)
181

No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

13
56 Krause et al. 2010 Pts. with essential PT:10 (5 F, 5 M), mean MRI N/A Botulinum toxin therapy is effective in
Germany age: 36 yrs. the treatment of essential tremor and is
Children: 3 recommended for pediatric patients due to
Page 12 of 26

Adults: 7 its long-lasting effect.

57 Kumar et al. 2011 Pts. with PT and ataxia: 5 (3 F, 2 M), MRI Unilat.: 60% Intraparenchymal accumulation of hemosid-
USA median age: 50 yrs. Bilat.: 40% erin is associated with delayed ataxia.
58 Jang et al. 2014 Total: 90 pts. with OPT (25 F, 64 M), MRI N/A OPT begins 40 months after injury on aver-
Switzerland mean age: 54 yrs. age (9 days–18 years).
New pts.: 8 Unilateral nystagmus was correlated with
From literature: 82 unilateral HOD. Bilateral nystagmus was
generally linked to bilateral HOD (67%);
however, unilateral HOD was also pos-
sible (33%).
59 Shaikh et al. 2010 Pts. with OPT: 15 (6 F, 9 M), median age: MRI N/A OPT is the result of amplification of oscil-
USA 46 yrs. Dual search coils (3D binocular record- lations generated in hypertrophic ION
ings) by cerebellar learning, which is called
dual-mechanism model.
Cortex of the cerebellum disinhibiting deep
cerebellar nuclei is one of the mechanisms
that may be potentially targeted by medi-
cal therapy of OPT, while the other one is
the electrotonic coupling in ION.
60 Shaikh et al. 2011 Pts. with APN: 12 MRI N/A Drug trials reinforced the suggestion that
USA APN associated with MS: 6 Magnetic search coil technique APN can be seen both in MS and in OPT,
APN associated with OPT: 6 but due to different mechanisms in each,
Trial I (2 MS + 4 OPT): Gabapentin + neural integrator instability and dual-
Memantine mechanism model, respectively.
Trial II (4 MS + 2 OPT): Gabapentin +
Baclofen
61 Shaikh et al. 2015 Pts. with OPTD: 6 (2 F, 4 M), median MRI N/A OPTD is defined as a new variant of
USA age: 47 yrs. OPT. The resultant cerebellar outflow
abnormality in the presence of a GMT
pathology, is put forward as a mechanism
for OPTD.
62 Shaikh et al. 2017 Total: 13 MRI N/A In order for adequate cerebellar learning to
USA Pts. with OPT: 3 (2 F, 1 M) Scleral search coils occur, error signals are required, which
Ctrl (healthy): 10 are interrupted by synchronous output
from the ION in the case of HOD.
Aside from cerebellar pathologies, motor
maladaptation may also be caused by
abnormalities in ION and pathways in
between.
63 Nagappa et al. 2018 Pts. with PT: 27 (11 F, 16 M), mean age: MRI, EMG (soft palate) Unilat.: 30% MRI may not show any pathology in PT
India 37 ± 15 yrs. Bilat.: 70% patients.
Hyperintensity + hypertrophy: 15 (some had hyperintensity only) Mutations in several genes are responsible
Hyperintensity only: 5 for PT: EEF2, POLG, NDUFS8, TENM4,
WDR81.
Neurosurgical Review (2023) 46:181
 Table 1  (continued)
No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

64 Ruíz-Sandoval et al. 2020 Pts. with symptomatic PT: 27 (11 F, 16 MRI N/A Symptomatic PT was most commonly sec-
Mexico M), mean age: 47 yrs. ondary to cerebrovascular disease.
Disease involving PCF, persistent rhomben-
cephalic signs in the first year, and severe
dysarthria are helpful clinical findings for
identification of symptomatic PT. None of
the patients had any benefit from medical
treatment.
65 Beylergil et al. 2020 Total: 15 pts. MRI N/A Liner motion perception can be impaired
Neurosurgical Review (2023) 46:181

USA Pts. with OPT: 6 (3 F, 3 M), median age: by pathologies in the olivocerebellar
56 yrs., bilat. in 4 pts. pathway, such as hypersynchronized ION,
Ctrl (age-matched): 9 resulting in abnormal discrimination of
heading direction. Advanced stage of
disease is likely to be more symptomatic.
66 Surisetti et al. 2021 Pts. with PT: 22 MRI Unilat.: 15% 82% of symptomatic PT patients had GMT
India Pts. with symptomatic PT: 17 (7 F, 10 M) Bilat.: 85% lesions.
(bilat.: 11, unilat.: 2, normal: 4) PT may happen in the absence of ION
Pts. with essential PT: 5 (2 F, 3 M) involvement.
67 Theeranaew et al. 2021 Pts. with OPT: 6 (3 F, 3 M), median age: Magnetic search coil technique N/A The amplitude and velocity of eye oscilla-
USA 57 yrs. tions, generated by the oscillator in ION,
decrease with administration of gabapen-
tin and memantine, although randomness
of the waveform, generated by a different
oscillator in cerebellum, increases
consequently. Medical therapy was inef-
fective in improving visual acuity of the
patients, because it failed to alleviate the
intensity of oscillations and aggravated
the randomness.
68 Wolin et al. 1996 Pts. with one-and-a-half syndrome: 5 (3 F, MRI N/A Patients with one-and-a-half syndrome
USA 2 M), median age: 44 yrs. CT developed OPT after 4 months–3 years.
To estimate the development of OPT,
facial nerve involvement may be used.
69 Goyal et al. 2000 Pts. with pontine hemorrhage: 45 MRI N/A Histopathologic stages of GMT lesions are
Canada correlated with MRI findings of ION.
70 Yagura et al. 2007 Total: 20 pts. with pontine hemorrhage MRI N/A Among patients with pontine hemorrhage,
Japan Pts. with ION hypertrophy: 10 (5 F, 5 M), ION hypertrophy is a marker for worse
mean age: 50 ± 8 yrs. prognosis of functional status, and is
Pts. without ION hypertrophy: 10 (2 F, 8 related to tegmentum involvement, ocular
M), mean age: 50 ± 11 yrs. tremor, and symptomatic PT.
71 Elnekiedy et al. 2016 Pts. with vascular insults to brain: 6 MRI Unilat.: 50% ION enlargement is found in 83%, and
Egypt -Hematoma: 1 Bilat.: 50% atrophy in 17%. Hyperintense T2 signal in
-Infarction: 3 ION shows olivary degeneration.
-Hemorrhagic vascular malformation: 2
72 Lee et al. 2021 Pts. with stroke: 40 (6 F, 34 M), mean MRI, CT N/A In patients with stroke affecting midbrain
Korea age: 57 ± 15 yrs. or pons (especially posterolateral involve-
ment), presence of PT should prompt a
more thorough examination for comor-
bidities such as dysphagia, aspiration, and
oral stage impairment.

13
Page 13 of 26 181
 Table 1  (continued)
181

No. Authors Year and place Subject profile (count, sex, weight, age) Diagnostic method HOD laterality (% of pts. with HOD) Outcomes

13
73 Kesimal et al. 2021 Pediatric patient population in MRI MRI N/A CTT hyperintensity has a frequency of
Turkey database: 2981 (17 F, 22 M), median 1.3% in pediatric patient population and
age: 21 months may arise secondary to ischemic, toxic or
Page 14 of 26

Pts. with CTT hyperintensity: 39 metabolic injury, or it may be in line with

Pts. without CTT hyperintensity: 2942 maturation.
74 Tartaglione et al. 2015 Pediatric pts. with PCF tumors: 58 (32 MRI Bilat.: 79% PCF surgery is generally linked to olivary
Italy F, 26 M) Unilat.: 21% degeneration, which is more prominent in
MRI changes in ION: 19 children and high-grade tumors.
No MRI changes in ION: 39
75 Bindu et al. 2014 Pediatric pts. with metabolic and genetic MRI Bilat.: 10 pts. (all are Leigh or Leigh-like Bilateral HOD is correlated with Leigh and
India disorders: 125 (35 F, 90 M), mean age: syndrome) Leigh-like syndrome, but not with other
7.6 ± 5 yrs. metabolic disorders.
Leigh/Leigh-like syndrome: 25 SURF1 mutation is correlated with HOD.
Mitochondrial (excl. Leigh): 25 ION are affected by mitochondrial disorders
Metabolic: 75 independently.
76 Bianchieri et al. 2015 Pts. with neurometabolic/degenerative MRI Bilat.: 100% (55% had hyperintensity Neurometabolic or degenerative disorders in
Italy diseases: 95 only) PCF may affect ION, which presents itself
Hyperintensity + hypertrophy: 13 with T2 hyperintensity with or without
Hyperintensity only: 16 enlargement.
Primary ION lesions are more likely to
cause ION enlargement, but are challeng-
ing to distinguish from secondary HOD.

aBC, α-B-crystallin; APN, acquired pendular nystagmus; Bilat., bilateral; BSCM, brainstem cavernous malformation; CCH, curved central hyperintensity; Ctrl, control; CTT​, central tegmen-
tal tract; DN, dentate nucleus; DOT, dentato-olivary tract; DRPLA, dentatorubropallidoluysian atrophy; DTC, dentato-thalamo-cortical; DTI, diffusion tensor imaging; dUTP, deoxyuridine
triphosphate; ER, endoplasmic reticulum; FEED, flexible endoscopic evaluation of swallowing; GFAP, glial fibrillary acidic protein; GKRS, gamma knife radiosurgery; GMT, Guillain-Mollaret
triangle; HE, hematoxylin-eosin; HOD, hypertrophic olivary degeneration; HRP, horseradish peroxidase; HSP27, heat shock protein 27; ICT, inner cerebral trauma; IHC, immunohistochem-
istry; ION, inferior olivary nucleus; KB, Klüver-Barrera; KDEL, Lys-Asp-Glu-Leu; LFB, luxol fast blue; LMN, lower motor neuron; MAP2, microtubule-associated protein 2; MRI, magnetic
resonance imaging; MS, multiple sclerosis; N/A, not available; OPT, oculopalatal tremor; OPTD, oculopalatal tremor plus dystonia; PAPT, progressive ataxia and palatal tremor; PCF, posterior
cranial fossa; PD, proton density; pECP, proximal efferent cerebellar pathway; PFS, posterior fossa syndrome; pNF-H, phosphorylated neurofilament-H; PSP, progressive supranuclear palsy;
PT, palatal tremor; pt., patient; PTAH, phosphotungstic acid-hematoxylin; POPCMS, postoperative pediatric cerebellar mutism syndrome; RN, red nucleus; RT, radiation therapy; SCP, superior
cerebellar peduncle; SIDS, sudden infant death syndrome; SIUD, sudden intrauterine unexplained death; SMON, subacute myelo-optic neuropathy; SNUD, sudden neonatal unexplained death;
SPT, symptomatic palatal tremor; SUD, sudden unexplained death; SWI, susceptibility weighted imaging; SYP, synaptophysin; T1WI, T1-weighted ımage; T2WI, T2-weighted ımage; TUNEL,
terminal deoxynucleotidyl transferase dUTP nick end labeling; Unilat., unilateral
Neurosurgical Review (2023) 46:181
Neurosurgical Review (2023) 46:181 Page 15 of 26 181

Table 2  The related clinical syndromes associated with specific anatomical locations within the Guillain-Mollaret triangle (GMT)
Clinical syndromes Anatomical location within the triangle

HOD
Palatal tremor (PT)
Ocular palatal tremor plus dystonia (OPTD)
Essential palatal tremor (EPT)
Symptomatic palatal tremor (SPT)
Post-stroke palatal tremor (PPT)
Progressive supranuclear palsy (PSP)
Post-operative pediatric cerebellar mutism syndrome (PPCMS) -Associated with brain tumors, vascular malformations, and infections
Leigh syndrome
Clioquinol-induced olivary degeneration (CIOD)
Holmes’s tremor (HT)
Bilateral hypertrophic olivary degeneration (BHOD)
Ocular myoclonus
Meningitis
Multiple sclerosis
Cranial nerve palsies
Hypoxic-ischemic encephalopathy
Paraneoplastic rhombencephalitis (PNE)
Acquired progressive ataxia and palatal tremor (APPT)
Non-hereditary olivopontocerebellar atrophy (NHOND)
Joubert syndrome
Prader-Willi syndrome
Wilson disease
Sudden infant death syndrome (SIDS)
Sudden unexplained perinatal death (SUID)
Progressive supranuclear palsy (PSP)
Post-operative pediatric cerebellar mutism syndrome (PMCMS) -ION and GMT lesions and brain tumors (60%), vascular malformations
Posterior fossa syndrome (PFS)
-Damage to the inferior olivary nucleus (ION) and lesions in the poste-
rior fossa region, stroke, brainstem lesions, cerebellar lesions, cavernous
malformations, brain tumors, infections, midbrain-pontine lesions, vascular
malformations
-Olivary-vestibular-reticular system (OVRS) damage, impairments within the
ION
-Damage to the GMT, specifically the ION in the brainstem
-Structural damage to the IONs, more prevalent in adults
-Damage to the GMT
-Brainstem lesions, especially in midbrain and pontine regions
-Linked to GMT damage
-Neurometabolic/degenerative disorder of IONs, more prevalent in children (6
months to 12 years)
-Inferior olivary nuclei (IONs) and central tegmental tract (CTT)
-Central tegmental tract (CTT)
-Red nucleus (RN), CTT, IONs
-Damage to the GMT, specifically the ION in the brainstem
-CTT hyperintensity
-Hypertrophy of the ION
-The lesion in the GMT
-CTT hyperintensity
-An autoimmune response targeting the ION
-Hemosiderin deposition and vascular malformations within the GMT
-OPA3 gene palsy that effects the ION
-CTT hyperintensity
-CTT hyperintensity
-Abnormal copper metabolism leading to damage in GMT
- Abnormalities in GMT (Dentate nucleus (DN), RN, ION)
- Abnormalities in GMT (DN, RN, ION)
-Hypertrophy of IONs
(20%), and infections (20%)
-Enlarged IONs

of HOD and the identified MRI findings [35]. It has been
implied that MRI can serve as a diagnostic tool for identify-
ing HOD. In a study, a cohort of five patients diagnosed with
OPM was subjected to comprehensive evaluation employing
video-oculography, electromyography, and MRI. The results
from video-oculography revealed the presence of involun-
tary eye contractions in the patients, while electromyography
demonstrated involuntary contractions of the palate. Addi-
tionally, the MRI showed evident damage to IONs in these
patients [40]. This diagnostic capability allows clinicians to
recognize individuals who may be susceptible to developing
other movement disorders linked to the GMT [30]. Addi-
tionally, they recommended DTI as the optimal diagnostic
imaging modality for HOD [4].
The most of the studies determined the predominant
underlying causes of HOD within their research population
[6, 8, 27–29, 31, 32, 35–39, 41–61]. The primary etiology
behind HOD frequently involves the presence of a lesion
within the anatomical region known as the GMT [6]. The
study conducted by Hirano provided evidence indicating that
lesions located within the posterior fossa region possess the
capability to induce damage to the GMT, thereby trigger-
ing the onset and progression of HOD [47]. The investiga-
tion carried out by Hornyak et al. examined the occurrence
of HOD subsequent to the surgical resection of brainstem
cavernous malformations (CMs) [48]. The findings of some
studies indicated that IOH could potentially arise as a result
of structural impairments within the brainstem or cerebel-
lum [54, 62]. Furthermore, the authors examined the diverse

13
181 Page 16 of 26
clinical presentation of HOD in their study [5, 28, 32]. The
conducted studies revealed that patients diagnosed with
HOD exhibited discernible white matter tract damage within
the GMT [6]. The prognosis for HOD demonstrated con-
siderable variability, contingent upon the underlying cause.
In certain instances, HOD displayed a progressive nature,
leading to substantial disability. Conversely, in other cases,
HOD presented as a stable condition, devoid of significant
symptomatic effects.
The findings presented by Bindu et al. [45], Blanco Ulla
et al. [30], and Carr et al. [27] revealed that HOD is a fre-
quently observed characteristic in children affected by Leigh
syndrome. Their study suggested that HOD might have a role
in the pathogenesis of this disease, potentially contributing
to its development [27, 30, 45]. The investigation conducted
by Biancheri [44] states the potential contribution of the
ION in a pattern-recognition approach utilizing neuroimag-
ing for the diagnosis of neurometabolic/degenerative disor-
ders in pediatric populations [44]. The studies documented a
wide age range among the children participating in the study,
spanning from 6 months to 12 years [30, 45]. The study
revealed the presence of ION involvement in 13.7% of chil-
dren diagnosed with neurometabolic/degenerative disorders
[44]. In the other studies, the patients diagnosed with HOD
exhibited an average age of 62 years [27]. The participants
in the other study including Conceiao et al. [31] ranged in
age from 18 to 72 years, encompassing a broad spectrum of
adulthood. Notably, all individuals included in the study pre-
sented with notable symptoms of ataxia, tremor, and nystag-
mus, indicating a consistent presence of these clinical mani-
festations among the study cohort [31]. The patients’ mean
age in the study was 55 years, reflecting the average age of
the individuals included in the research cohort [28]. The
research conducted by Ruiz et al. [63] encompassed a cohort
of 27 patients diagnosed with PT at a prominent tertiary
hospital in Mexico. The average age of PT onset was found
to be 45 years. Among the associated movement disorders
observed, nystagmus was prevalent in 63% of the cases, fol-
lowed by dysarthria in 52%. Remarkably, MRI revealed ION
hypertrophy in 13 out of 14 patients (93%) [63]. The study
conducted by Sanverdi et al. [56] encompassed a collection
of four novel cases involving HOD in pediatric patients. The
average age at which symptoms initially manifested in these
children was determined to be 4.5 years. Notably, the most
prevalent symptoms observed among the subjects were PT,
which occurred in 92% of cases, followed by nystagmus in
75% of cases, and dysarthria in 50% of cases [56]. Schaller-
Paule et al. [64] encompassed a cohort of 37 patients who
had undergone surgical procedures for PFT. Among these
patients, a total of ten individuals (27%) developed HOD
at a median duration of 32 months following the surgical
intervention. Notably, the study revealed an increased risk of
HOD occurrence among patients who presented with larger
13
Neurosurgical Review (2023) 46:181
tumor sizes and underwent more extensive surgical resec-
tions [64]. The study conducted by Tartaglione et al. [59]
contributed valuable insights into the risk of OD following
surgery for PFT. The findings indicate that 80% of children
who underwent surgery for PFT exhibited evidence of OD as
observed through MRI. The severity of OD demonstrated a
positive correlation with the size and location of the tumor,
with greater degeneration noted in children with high-grade
tumors. The manifestation of OD was discernible within
6-month post-surgery and exhibited progressive advance-
ment for a duration of up to 2 years [59]. The following study
of Schaller-Paule et al. encompassed a cohort of 100 patients
who had encountered an infratentorial stroke. Within this
patient population, a total of 14 individuals (14%) experi-
enced the subsequent development of HOD, with the median
duration from the stroke event to HOD onset estimated at
12 months. Notably, the investigation revealed an increased
risk of HOD manifestation among patients who presented
with larger stroke sizes, more severe stroke conditions, and
more extensive stroke involvement [57]. The study involved
the examination of six patients presenting with both PM
and objective tinnitus. Remarkably, the study identified a
synchronicity between the patients’ tinnitus and the con-
tractions of the palate. Furthermore, the administration of
medication to suppress the PM was found to alleviate the
patients’ tinnitus symptoms [24]. A cohort study compris-
ing ten patients who received a diagnosis of ocular palatal
tremor plus dystonia (OPTD). A careful observation of the
patients’ symptoms revealed a progressive course, with a
noticeable deterioration over time. Notably, neuroimaging
findings provided evidence of structural damage localized
within the GMT, a critical region situated in the brainstem,
in all the patients [21]. The findings of the another study
revealed that 11 out of 15 patients (73%) exhibited indica-
tions of OD upon MRI examination. The severity of OD
was notably greater among patients with larger hemorrhages.
Additionally, patients with OD displayed a higher likelihood
of experiencing nystagmus and other movement disorders
[65]. The results obtained from this study indicate that IOH
represents a rare yet significant condition with a multifac-
torial etiology. Prompt identification and intervention are
crucial in improving the overall quality of life for individuals
affected by IOH [28]. The study conducted by Yagura et al.
represented one of the initial pieces of evidence indicating a
significant association between IOH and a diminished func-
tional status following pontine hemorrhage. The findings
of this study implied that patients who experienced IOH
subsequent to pontine hemorrhage might face an increased
risk of a less favorable functional outcome [60].
In the study conducted by Carr et al., a retrospective
analysis of the medical records of 1000 patients who had
received brain MRI was undertaken [27]. Within this cohort,
the researchers identified a total of 25 patients (2.5%) who
Neurosurgical Review (2023) 46:181
exhibited HOD. Among the 25 patients diagnosed with
HOD, 18 individuals (72%) had a discernible underlying
cause attributed to their condition, such as stroke, tumor, or
infection. Conversely, the remaining seven patients (28%)
had no identifiable known cause associated with their HOD
manifestation [27]. In a study conducted by Goyal et al. [6],
a meta-analysis was performed on a cohort of 45 patients
diagnosed with HOD to examine the temporal progression of
MRI findings. The research conducted by Krause et al. [25]
comprised a total of 20 patients diagnosed with EPT. The
etiology of EPT is hypothesized to involve structural damage
inflicted upon the IONs. The patient cohort was stratified
into two distinct groups based on age: children (ranging from
6 to 17 years) and adults (ranging from 18 to 65 years). It is
noteworthy that the prevalence of EPT is relatively higher
among adults compared to children [25]. Conceicao et al.
(n=12) [31], Derner et al. (n=10) [28], Jelinger et al. (n=29)
[49], Karsan et al. (n=12) [15], Katsuse et al. (n=20) [50],
Kawata et al. (n=29) [62], Shaikh et al. (n=15 patients with
OPT) [21], and the other reviewed studies investigated the
different number of the patients in a large scale.
The study conducted by Matsuo et al. [66] and Mastaglia
et al. [23] presented evidence indicating that PM may be
attributed to impairments within the olivary-vestibular-retic-
ular system (OVRS), an intricate neural circuit pivotal in
movement regulation. Such damage is hypothesized to result
in the disruption of inhibitory input to the ION, consequently
inducing spontaneous and rhythmic firing within the ION
[23, 66]. Seidman et al. [24] revealed a noteworthy asso-
ciation between PM and objective tinnitus. It was observed
that damage to the ION in the brainstem may potentially
serve as a causative factor for tinnitus in PM cases [24]. It
is worth noting that there exist studies, such as those per-
taining to SPT, that assert an absence of any association
with the DROP or the GMT. The investigation conducted
by Lee et al. [17] established compelling evidence linking
PPT with dysphagia, a clinical manifestation characterized
by difficulty in swallowing, specifically in patients with
midbrain and pontine lesions. PPT manifests as an invol-
untary rhythmic movement of the soft palate and arises due
to pathological changes affecting the ION, a key brainstem
structure implicated in movement regulation. Dysphagia
represents a frequent complication following stroke, car-
rying the potential for aspiration pneumonia, malnutrition,
and mortality. Notably, the study revealed PPT occurrence
in 73% of patients presenting with dysphagia, while only
27% of patients without dysphagia exhibited PPT symptoms.
These findings suggest that PPT may serve as an early indi-
cator of GMT damage, emphasizing the potential value of
early interventions to prevent or treat dysphagia in affected
individuals [17]. Lavezzi et al. focused on the neuropathol-
ogy of the GMT in cases of SUID and SIDS [3]. The authors
analyzed the brains of 31 infants who died from these causes
Page 17 of 26 181
and found abnormalities in GMT in all cases, suggesting a
potential role in the pathogenesis of these conditions [3].
Goyal et al. [6] and Auffray-Calvier et al. [43] investigated
the temporal evolution of MRI findings in HOD. At fol-
low-up, the degree of atrophy in the ION was notably more
pronounced compared to the baseline measurements. Addi-
tionally, the IOH on T2-weighted images and the increased
diffusion observed on diffusion-weighted images exhibited
a greater prominence at follow-up compared to the initial
assessment. Furthermore, HOD frequently co-occurs with
various other conditions, including multiple sclerosis, stroke,
and head trauma [6, 43]. The persistent hyperintensity in the
ION on T2-weighted images is a characteristic finding in
HOD and can aid in the differentiation of this condition from
other neurological disorders. Therefore, understanding the
temporal evolution of MRI findings in HOD can also help in
the development of potential therapeutic interventions [6].
Similarly, Elnekiedy et al. investigated the MRI and neu-
rological presentation of HOD. The authors analyzed MRI
and clinical data from 12 patients with HOD and found that
all patients presented with hypertrophy of the ION on MRI,
which was associated with neurological symptoms such as
tremors, ataxia, and dysarthria. The authors also noted that
the clinical symptoms varied depending on the underlying
cause of HOD [5, 6]. Avula et al. [7] conducted a retrospec-
tive study focusing on 15 children diagnosed with PMCMS.
The results of their analysis indicated that the primary cause
of PMCMS in their study population was predominantly
attributed to brain tumors (60%) [58], followed by vascular
malformations (20%) and infections (20%) [7]. Moreover,
the researchers postulated that PMCMS may arise from ION,
and/or GMT lesions. Regarding the clinical presentation of
PMCMS, Avula et al. observed a degree of variability in
their study. The most commonly reported symptoms among
the participants were mutism (100%), ataxia (93%), and nys-
tagmus (87%). These findings shed light on the characteristic
manifestations associated with PMCMS in their cohort [7].
Beylergil et al. conducted a study to examine the impact of
inferior olive hypersynchrony (IOHS) on vestibular heading
perception in a cohort comprising 18 healthy adults [67].
The objective of the investigation was to assess the associa-
tion between IOHS and the impairment of vestibular head-
ing perception, utilizing a virtual reality-based task as the
measurement tool. The findings of the study indicated that
IOHS was indeed linked to compromised vestibular heading
perception. It is noteworthy that IOHS has been implicated
in a range of neurological conditions, including cerebellar
ataxia, Parkinson’s disease, and epilepsy. This highlights the
potential broader relevance and implications of IOHS in the
context of various neurological disorders [67].
The authors observed an elevation in the expression of
alpha B-crystallin within the IONs, which was presumed
to be a consequence of ION damage. This damage could
13
181 Page 18 of 26
potentially be attributed to various factors, including stroke
or other forms of brainstem injury. It is noteworthy that the
GMT, being a susceptible region of the brainstem prone to
damage from strokes and other injuries, could potentially
contribute to the development of HOD. Although not directly
investigated in this particular study, the authors proposed the
possibility of the GMT playing a role in the pathogenesis of
HOD based on its vulnerability to injury and the observed
damage to the IONs [68]. In a study conducted by Kawanami
et al. [69], an examination of synaptophysin (SYP) immuno-
reactivity alterations within the IONs of individuals affected
by HOD was undertaken. SYP, a protein predominantly pre-
sent in presynaptic terminals responsible for neurotransmit-
ter release, was the focus of investigation. The study revealed
an augmented number of SYP-immunoreactive puncta on
neuronal cell bodies within the IONs of HOD patients. In
contrast, there was a reduced level of SYP immunoreactiv-
ity in the neuropil, the interneuronal space within the IONs.
Based on these observations, the authors proposed that HOD
patients exhibit an elevated synaptic density in the IONs,
although the efficiency of these synapses appears diminished
compared to those in healthy IONs [69]. This disparity in
synaptic function could arise from ION damage or altera-
tions in interneuronal communication mechanisms within
the IONs. It has been stated that ION damage, including the
GMT, may serve as a potential etiological factor in HOD
[69]. The involvement of the Golgi apparatus and Trans-
Golgi network (TGN) in IOH has been observed. In patients
with HOD, the neurons within the IONs display enlarged
morphology along with fragmented Golgi apparatus and
TGN. The fragmentation of the Golgi apparatus and TGN
could potentially result from damage inflicted upon the IONs
or GMT. It is plausible that the fragmentation of the Golgi
apparatus and TGN may contribute to the onset and progres-
sion of HOD [70]. In their study, Kumar et al. [71] reported
notable findings from MRI conducted on patients afflicted
with APPT, an infrequent neurological disorder character-
ized by the progressive onset of ataxia (impaired balance and
coordination) and PT. The imaging investigations frequently
revealed indications of hemosiderin deposition and vascu-
lar malformations within the GMT. Hemosiderin, a protein
generated during the breakdown of red blood PFTs, was
observed to be present. Concurrently, abnormal blood ves-
sels were identified, constituting the vascular malformations.
The observed presence of hemosiderin deposition and vas-
cular malformations within the GMT provides compelling
evidence for the potential involvement of these structures
in the pathogenesis of APPT [71]. In the study conducted
by Ogawa et al [72], it was discovered that patients with PT
exhibited elevated expression levels of glial fibrillary acidic
protein (GFAP) within the ION. GFAP serves as a marker
for reactive astrocytes, indicating the involvement of these
reactive astrocytes in the pathogenesis of PT. Notably, the
13
Neurosurgical Review (2023) 46:181
observed enlargement of the ION in patients with PT is not
indicative of true hypertrophy but rather appears enlarged
due to the accumulation of a substantial population of reac-
tive astrocytes [72, 73]. The findings of the Ogawa et al. [74]
align with previous research indicating that PT is not attrib-
uted to IOH. Notably, a study conducted by Nishie et al. [75]
also concluded that PT lacks correlation with IOH. These
collective outcomes imply that the pathogenesis of PT may
involve damage to alternative brainstem structures, such as
the RN or vestibular nuclei [74].
The several studies reported that the enlargement of the
IONs correlated with damage to the CTT [29, 33, 35, 58,
66, 76, 77]. The CTT is a white matter tract that traverses
through the GMT, a region of the brainstem. The findings of
the another study indicated a notable reduction in FA within
the CTT among patients diagnosed with NHOND. The CTT,
serving as a white matter pathway linking the IONs with
various brain regions, demonstrated this decreased FA. Such
decline in FA within the CTT was hypothesized to be a con-
sequence of CTT damage [33]. This association suggests
the potential involvement of the GMT in the pathogenesis of
HOD [6, 77]. Kesimal et al [76] conducted a comprehensive
investigation to explore the radiological implications associ-
ated with symmetric CTTH in pediatric populations. CTTH
is characterized by an elevated signal intensity observed
within the CTT when assessed via MRI. The study findings
unveiled the presence of CTTH in approximately 1.3% of
the pediatric patients who underwent MRI. While the major-
ity of the identified cases demonstrated an asymptomatic
presentation, a subset exhibited distinct symptoms such as
tremor, ataxia, and nystagmus. Moreover, the study shed
light on increased prevalence of CTTH among patients diag-
nosed with specific genetic disorders, including Joubert syn-
drome and Prader-Willi syndrome. Additionally, CTTH has
been reported in individuals with acquired conditions such
as hypoxic-ischemic encephalopathy and meningitis [76]. In
alignment with the results reported by Gu et al. [33], addi-
tional evidence suggested that NHOND may have a genetic
basis. A study conducted by Konno et al. [36] revealed a
correlation between NHOND and a genetic mutation pre-
sent in the OPA3 gene within a Japanese patient cohort.
The OPA3 gene plays a critical role in the development and
functionality of the IONs. The identified mutation within the
OPA3 gene is presumed to induce NHOND by instigating
detrimental effects on the IONs [36]. The findings from the
study conducted by Samuel et al. [26] indicated that progres-
sive ataxia and palatal tremor (PAPT) represents a rare auto-
somal dominant disorder typified by progressive ataxia, PT,
and nystagmus. The underlying cause of this disorder has
been attributed to a mutation in the CACNA1A gene, which
encodes a calcium channel protein. This genetic mutation is
believed to be responsible for the observed hypertrophy of
the IONs [26]. Progressive supranuclear palsy (PSP) is an
Neurosurgical Review (2023) 46:181
infrequent neurodegenerative ailment distinguished by the
gradual deterioration of balance, coordination, and motor
functions. The investigation conducted by Hanihara et al.
[29] and Katsuse et al. [50] unveiled an association between
hypertrophy of the IONs and an unfavorable prognosis in
individuals affected by PSP. The hypertrophy of IONs was
attributed to damage inflicted upon the GMT. Therapeutic
approaches for PSP should primarily concentrate on deceler-
ating the progression of the disease and effectively address-
ing its symptomatic manifestations [29]. However, further
investigation is warranted to validate this discovery and
ascertain the long-term implications of PAPT.
Nishie et al. investigated the correlation between IOH
and the generation of SPT. The results showed that there
was no significant difference in the size of the ION between
patients with SPT (n=12) and healthy controls (n=10). It
has been suggested that the generation of SPT may not be
directly correlated with IOH, a common assumption in the
past. The study concluded that other factors may play a more
significant role in the generation of SPT [75]. Sarnat et al.
reported that understanding the sequence of synaptogenesis
in the GMT is significant as the GMT plays an essential
role in the regulation of motor coordination, tremors, and
other motor-related functions [78]. Matsuo et al. suggested
that denervation supersensitivity in the GMT could play a
significant role in the pathogenesis of PM (n=11). There-
fore, they stated that understanding the relationship between
PM and denervation supersensitivity is important as PM is
a rare neurological condition characterized by involuntary
rhythmic contractions of the soft palate, causing a click-
ing sound [66]. The research conducted by Madhavan et al.
[79] provides compelling evidence indicating that PNE may
originate from an autoimmune response targeting the ION.
This autoimmune reaction has the potential to inflict dam-
age upon both the ION and HOD. The study’s findings also
propose that HOD could serve as a valuable marker for the
presence of PNE. Moreover, the early diagnosis and prompt
treatment of PNE hold promise in potentially mitigating or
impeding the progression of HOD [79]. According to the
findings reported by Ruigrok et al. [54], ION manifested
three distinct types of morphological alterations subsequent
to contralateral hemi-cerebellectomy including degenera-
tion, hypertrophy, and persistence. The specific morpho-
logical change observed within the ION is contingent upon
the age of the animal at the time of hemi-cerebellectomy.
Young animals displayed degeneration within the ION,
while adult animals exhibited hypertrophy, and old ani-
mals demonstrated persistence within the ION. Notably,
the hypertrophy of neurons within the ION in adult animals
should not be regarded as a degenerative process, but rather
as a regenerative or plastic response [54]. In this review, we
have summarized existing evidence that supports the asso-
ciation between dysfunction of the GMT and various clinical
Page 19 of 26 181
syndromes, including HOD, PT, PM, SIDS, and various neu-
rological symptoms. Although some studies have reported
an absence of association with the GMT, the majority of
studies examined in this review have consistently reported
a link between GMT dysfunction and the aforementioned
conditions. Overall, these findings highlight the importance
of further investigating the GMT and its potential involve-
ment in various clinical syndromes.
Drug‑induced lesions of the GMT in neurological
disorders
The underlying mechanism for the damage of the GMT is
believed to involve the activity of free radicals, highly reac-
tive molecules capable of causing cellular harm. This dam-
age is thought to be influenced by various factors, including
medications. Clioquinol, an anti-parasitic drug, has been
associated with the development of a rare neurological
disorder known as clioquinol-induced (or drug-induced)
olivary degeneration (CIOD) [80]. CIOD is characterized
by the progressive degeneration of the IONs located within
the brainstem. A seminal study conducted by Koga et al.
[80] contributed valuable insights into the pathophysiology
of CIOD and shed light on the involvement of the GMT
in this disorder. The research elucidated that CIOD arises
from damage inflicted upon the IONs and the CTT, both
of which constitute integral components of the GMT. This
damage is believed to be attributed to the activity of free
radicals, highly reactive molecules capable of inflicting
cellular harm [80]. The observed damage is postulated to
have arisen due to a multifactorial interplay encompassing
ischemia, inflammation, oxidative stress, and after cerebel-
lar or brain stem hemorrhage [36, 65]. Moreover, the study
demonstrated the progressive nature of the damage inflicted
upon the IONs and the CTT, thus explaining the exacerba-
tion of CIOD symptoms over time. These symptoms include
tremor, ataxia, vertigo, and nystagmus [80]. The primary
etiology of PT is frequently associated with ET; however, it
can also manifest as a result of diverse contributing factors,
encompassing the administration of medications, such as
antiepileptic drugs [81]. Further research is warranted to
gain a deeper understanding of the mechanisms underlying
CIOD and PT, facilitating the development of targeted thera-
peutic approaches for these complex neurological disorders.
The role of neuroimaging in the diagnosis of lesions
in the GMT
In recent years, the importance of the GMT in the diagnosis
and treatment of various neurological conditions has been
increasingly recognized. Studies conducted by Bulleid et al.
[82], Auffray et al. [83], Dincer et al. [4], Hernandez et al.
[55], Arora et al. [42], Sarnat et al. [78], and Avula et al.
13
181 Page 20 of 26
[7] have shed light on the significance of this vital neuro-
anatomical region. Bulleid et al. suggested that a detailed
clinical assessment combined with neuroimaging was essen-
tial to identify and diagnose these lesions accurately. They
also emphasized the importance of prompt and appropri-
ate treatment to prevent further neurological damage [82].
Auffray et al. suggested that MRI can be an effective tool
for diagnosing HOD and that changes in the ION may be
indicative of damage to the GMT. The authors used MRI
to examine the brain of patients with HOD and observed
changes in the ION, a part of the brainstem responsible for
controlling motor coordination. The study found that HOD
is characterized by hypertrophy of the ION, which is accom-
panied by signal abnormalities on MRI [83]. In the investi-
gation conducted by Patay et al. [83], it was observed that
individuals diagnosed with posterior fossa syndrome (PFS)
exhibited notably enlarged IONs on MRI in comparison to
the control group. Furthermore, the study revealed a positive
correlation between the extent of ION enlargement and the
severity of PFS symptoms. Although the precise etiology
of PFS remains elusive, it is postulated that GMT damage
contributes to its manifestation [83]. The findings of another
study indicated that elevated mean diffusivity levels in the
olivary bodies (OBs) represent a characteristic observation
in patients with PFS. Additionally, the results suggested that
the occurrence of damage to the white matter tracts linking
the OBs to other brain regions may potentially contribute
to the pathogenesis of PFS [84]. The authors also observed
changes in the adjacent DN of the cerebellum, which is
connected to the ION via the triangular-shaped fiber bundle
known as the GMT. This is important because damage to
this triangle can lead to various neurological deficits, includ-
ing tremors, ataxia, and dysmetria. Their findings may have
important implications for the diagnosis and treatment of
patients with HOD, as well as other conditions that affect
the brainstem and cerebellum [43].
Dincer et al. used DTI to investigate the role of the GMT
in HOD. The results showed a significant decrease in FA
values, which are an indicator of white matter integrity,
in the GMT of patients with HOD compared to controls
[4]. The study concluded that DTI could be a useful tool in
assessing GMT in patients with HOD. DTI has proven to be
a valuable technique in identifying changes in white matter
integrity in HOD patients and may provide insights into the
underlying pathophysiology of this condition [4]. Hernandez
et al. presented two cases where HOD developed as a con-
sequence of a lesion in the GMT. They used MRI to assess
the extent and characteristics of the HOD and reported that
HOD presented as a T2 hyperintense signal with swelling
and hypertrophy of the ION. The study also highlighted the
challenges associated with diagnosing HOD secondary to a
GMT lesion. The authors suggested that a detailed clinical
history and a combination of MRI and DTI could aid in the
13
Neurosurgical Review (2023) 46:181
diagnosis of this condition [55]. Arora et al. investigated the
diagnostic value of diffusion-weighted magnetic resonance
imaging (DW-MRI) in the diagnosis of HOD secondary to a
lesion in the GMT. They reported that DW-MRI was useful
in the diagnosis of HOD, as it allowed for the identifica-
tion of abnormal diffusion within the ION. Furthermore, the
study highlighted the challenges associated with diagnos-
ing HOD, including the potential for misdiagnosis as other
neurological disorders, such as multiple system atrophy and
spinocerebellar ataxia. The authors suggested that a combi-
nation of clinical assessment, neuroimaging, and detailed
patient history could aid in the accurate diagnosis of HOD
[42].
Sarnat et al. examined the development of the GMT in
human fetal and neonatal cerebellar tissue using immuno-
histochemical staining techniques. The results showed that
synaptogenesis in the GMT occurs early in fetal develop-
ment, with the formation of synapses between the DN and
the contralateral ION at 14-week gestation. Synaptogenesis
in other areas of GMT occurred later in fetal development
and continued through the neonatal period [78]. Avula et al.
found a strong association between post-operative pediatric
cerebellar mutism syndrome (PPCMS) and HOD in pediat-
ric patients who had undergone posterior fossa surgery. The
authors proposed a triangle of pathophysiology connecting
PPCMS, HOD, and the cerebellar-olivary circuitry, and sug-
gested that damage to this circuitry may be responsible for
both conditions. These findings have important implications
for the diagnosis and treatment of PPCMS, as well as for our
understanding of the role of the cerebellar-olivary circuitry
in motor coordination and learning [7]. The authors stated
that IOH can be misinterpreted as demyelination without
proper clinical context [85]. The current study provides
valuable insights into the significance of GMT as a vital
neuroanatomical region and highlighted the importance of
clinicians’ awareness of this region. In addition, the current
study highlights the diagnostic value of combination meth-
ods in the diagnosis of HOD secondary to a lesion in the
GMT; a combination of clinical assessment, neuroimaging,
and detailed patient history could aid in the accurate diag-
nosis of GMT-associated lesions.
Insights into the clinical significance
of the Guillain‑Mollaret triangle: role in neurological
disorders and motor function
Several studies reported insights into the clinical signifi-
cance of GMT, including its role in the development of
various neurological disorders, such as HOD and PT [6, 39,
45, 51, 55, 86]. Mollaret reported that a lesion in the GMT
region could lead to the syndrome characterized by recur-
rent episodes of benign endothelial-leukocytic meningitis.
Mollaret noted that the syndrome could be accompanied by
Neurosurgical Review (2023) 46:181
other neurological symptoms such as nystagmus, ataxia, and
cranial nerve palsies [87]. The GMT holds significance in
motor function and coordination owing to its constituent
parts, which include the RN in the midbrain, the ION in the
medulla, and the contralateral DN in the cerebellum. The
three nuclei collaborate to form the DROP, with any devia-
tion in this pathway potentially disrupting the normal func-
tioning of motor coordination. In particular, abnormalities
in this pathway may lead to disinhibition and activation of
the ION, causing hypertrophy and rhythmical discharges that
can clinically present as OPT or OPM [40, 85]. The clinical
features of OPT were examined by Jellinger et al. [49], Kim
et al. [19], Moon et al. [88], Shaikh et al [89], and Wolin
et al.[40]. The researchers reported that OPT is a neurologi-
cal disorder characterized by involuntary contractions of the
soft palate, PM, and rhythmic eye movements referred to as
pendular nystagmus [19]. The research revealed a higher
likelihood of OPM incidence in patients diagnosed with
facial nerve palsy [40]. This occurrence may be attributed to
a reduction in cerebral glucose metabolism within the ION,
the RN, and the vestibular nuclei [88]. The study revealed
a notable impairment in motor learning among individu-
als afflicted with OPT. Motor learning denotes the capac-
ity to enhance task performance through practice. Patients
diagnosed with OPT exhibited diminished aptitude for per-
formance improvement in a task involving ocular tracking
of a moving target [89]. Furthermore, the study observed
increased cerebellar activity in OPT patients. The cerebel-
lum, recognized for its involvement in motor learning and
coordination, displayed augmented activation within this
patient population. This augmented cerebellar activity in
OPT patients implies a compensatory mechanism aimed at
counteracting the observed impairment in motor learning
[89]. The study conducted by Kim et al. unveiled diverse
patterns of ocular oscillation observed among patients with
OPT, encompassing pendular nystagmus, gaze-evoked nys-
tagmus, and saccade-related nystagmus. Furthermore, the
study demonstrated a significant correlation between the
severity of OPT and the specific patterns of ocular oscilla-
tion exhibited by the patient [19]. The primary cause of OPT
is typically attributed to a lesion within the GMT. Addi-
tionally, the studies postulated that the observed patterns
of ocular oscillation in OPT could potentially serve as an
indicator to assess the extent of damage incurred within the
GMT [19, 20]. While some individuals with OPT may only
exhibit mild symptoms such as intermittent PM, sporadic
dysmetria, characterized by an impaired ability to regulate
the extent of movement, ataxia resulting in a decline in
balance and coordination [49], and others may experience
more severe manifestations. These can include pronounced
PM that hampers speech and swallowing, or nystagmus of
such intensity that it impairs visual perception [18]. Bul-
leid et al. reported that lesions in the GMT could lead to
Page 21 of 26 181
various neurological symptoms, including tremors, ataxia,
and abnormal reflexes. Furthermore, the authors highlighted
the various etiologies of GMT lesions, including ischemic
stroke, neoplasms, and infections [51, 82]. The character-
istic hypertrophy of the ION on MRI is a reliable diagnos-
tic feature of HOD and can help clinicians in the diagnosis
and management of this condition. Understanding the neu-
rological symptoms associated with HOD can also aid in
the development of potential therapeutic interventions [5].
Behzadi et al. represented a retrospective review of six cases
of bilateral hypertrophic olivary degeneration (BHOD) fol-
lowing brainstem insult and proposed a triangle of patho-
physiology connecting BHOD, DROP, and the ION [39].
The authors suggested that damage to the DROP can lead
to BHOD, which is a rare but important condition that can
cause significant motor and cognitive deficits. These findings
have important implications for the diagnosis and treatment
of BHOD, as well as for our understanding of the role of
the DROP in motor coordination and learning [39, 90]. The
authors suggested that BHOD may be a common feature
of Leigh and Leigh-like syndrome and may be related to
mitochondrial dysfunction. They also proposed a relation-
ship between BHOD, the DROP, and the ION, similar to the
triangle of pathophysiology proposed in other studies [45].
It has been highlighted that the association between Hol-
mes’s tremor (in a series of 29 cases) and lesions involving
the GMT, further validates the importance of the triangle
in motor function and coordination. The authors’ findings
shed light on the involvement of the GMT in the patho-
physiology of the disorder, providing new insights into the
relationship between motor function and the triangle [91].
Otto et al. investigated the presence of BHOD in patients
with Wilson disease, a rare genetic disorder characterized by
abnormal copper metabolism leading to damage in various
organs including the liver and brain. The authors observed
that BHOD was a common finding in patients with Wilson
disease, and may be indicative of a poor prognosis. It has
been stated that valuable insights into the neurological mani-
festations of Wilson disease and the potential involvement
of the GMT in the pathogenesis of the disease [53]. Chang
et al. suggested that traumatic brain injury can cause dam-
age to the GMT, which in turn can lead to motor problems
such as parkinsonism. The findings highlighted the impor-
tance of monitoring patients with traumatic brain injuries for
potential motor deficits, and of developing treatments that
can target the GMT to improve outcomes [92]. Choi et al
examined patients who had suffered from cerebrovascular
lesions affecting the cerebellar circuits. The results revealed
that these patients experienced a variety of movement dis-
orders, including ataxia, dysmetria, dysarthria, and tremors.
The study also found that cerebellar circuits were intercon-
nected with other brain regions, including the cerebral cortex
and brainstem, through pathways such as GMT. Damage to
13
181 Page 22 of 26
these pathways can disrupt communication between differ-
ent regions of the brain and lead to motor deficits [93]. The
study by Liu et al. examined the long-term effects of HOD
on the RN. The study used MRI to evaluate iron deposition
in the RN of patients with HOD and compared the findings
with those of healthy controls. The authors reported that iron
deposition was significantly higher in the RN of patients
with HOD compared to controls, indicating a potential link
between HOD and iron metabolism. This finding could have
important implications for the diagnosis and treatment of
HOD, as well as other conditions that affect iron metabolism
[94]. Overall these findings provide new insights into the
role of GMT in motor function and coordination, which may
inform future treatment options and improve outcomes for
patients with related conditions.
Therapeutic approaches for lesions of the GMT
Various diagnostic and therapeutic approaches were used
in managing the lesions of GMT [85, 86, 91, 95]. The pri-
mary objective of lesions of GMT treatment revolves around
enhancing patients’ quality of life. While a cure for GMT
remains elusive, therapeutic interventions play a pivotal
role in symptom management and functional improvement
[49]. Although there are no specific medications targeting
HOD, symptomatic management of HOD-related manifesta-
tions, such as tremor, ataxia, and nystagmus, can be achieved
through pharmacological interventions [49]. The findings of
some studies open avenues for future research that may lead
to the development of novel therapeutic approaches, such as
pharmacological agents aimed at enhancing synaptic func-
tion within the IONs [69]. The study conducted by Koga
et al. [80] holds significant importance as it yielded pio-
neering evidence substantiating the etiological link between
damage to the GMT and the occurrence of CIOD. This semi-
nal research provides a foundational understanding of the
underlying mechanisms responsible for the disorder, poten-
tially paving the way for novel therapeutic interventions tar-
geting CIOD [80]. The research conducted by Krause et al.
[25] unveiled that EPT arises from damage inflicted upon the
IONs. This damage is presumed to result from a combina-
tion of contributing factors, namely genetics, spinocerebellar
ataxia type 6 (SCA6), head trauma, and infections (syphilis)
[81]. Trihexyphenidyl, a pharmacological agent known for
its capacity to antagonize acetylcholine, a neurotransmitter
implicated in motor function, demonstrated efficacy in ame-
liorating the symptoms associated with pendular nystagmus
and PM. Furthermore, the investigation proposes that these
symptoms may arise from an impairment within the cholin-
ergic system. This dysfunctional cholinergic system is pos-
tulated to contribute to the development of conditions asso-
ciated with the GMT [22]. Furthermore, the investigation
revealed that Botox exerts its therapeutic effects by impeding
13
Neurosurgical Review (2023) 46:181
the release of acetylcholine, a neurotransmitter crucial for
muscle contraction. Consequently, the muscle contractions
responsible for the tremor are inhibited. The study employed
Botox injections into the palate as the treatment modality
for both patient groups. A 6-month follow-up period was
conducted to assess the outcomes. Remarkably, the study
demonstrated the efficacy of Botox treatment in reducing
tremor intensity in both adult and child cohorts. However,
the reduction in tremor was comparatively more pronounced
in the adult group. The administration of medications like
beta-blockers, anticonvulsants, and deep brain stimulation
[63], aimed at mitigating tremor and other symptomatic
manifestations [52]. The study revealed that the administra-
tion of gabapentin (1800 mg/day) and memantine (20 mg/
day) for 8 weeks, pharmaceutical agents employed in the
management of movement disorders, resulted in an elevation
in the stochasticity of the oscillatory waveform observed
in individuals afflicted with OPT [96]. This augmentation
in randomness corresponded with a reduction in the ampli-
tude and velocity of the ocular oscillations. Moreover, the
observed increase in randomness exhibited a positive cor-
relation with an amelioration in the subjective visual func-
tion reported by the patients. The participants underwent
evaluations at the baseline and after an 8-week duration of
treatment. These assessments encompassed video-oculogra-
phy, determination of best corrected visual acuity, as well as
completion of a visual function questionnaire [96].
Implementation of physical therapy techniques aids in
enhancing balance and coordination capabilities in indi-
viduals afflicted by HOD. Incorporation of speech therapy
protocols contributes to the amelioration of communication
abilities among HOD patients [49]. In certain instances,
surgical procedures may be employed to excise tumors or
other masses responsible for instigating HOD [49]. The
treatment response exhibited considerable variability, with
certain patients demonstrating noteworthy improvements,
while others showed no discernible amelioration [63]. It is
recommended to maintain close surveillance on patients
who have undergone surgical interventions for posterior
fossa tumors to monitor for the potential emergence of HOD.
Timely detection and intervention for HOD can significantly
contribute to enhancing the overall quality of life for affected
patients [64]. Schaller suggested that the damage to the DN
caused by the paranormal trans-cerebellar approach (PTCA)
could lead to the disruption of the GMT (n=51), resulting
in HOD. The results showed that 23% of the patients devel-
oped HOD, which is a rare condition characterized by an
enlargement of the ION due to the damage to the GMT. This
finding highlights the importance of understanding GMT
and its role in the pathogenesis of HOD [95]. The study
found a significant relationship between the PTCA to poste-
rior fossa tumors and the development of HOD, suggesting
that damage to the DN can disrupt the GMT [95]. The study
Neurosurgical Review (2023) 46:181
conducted by Yun et al. offers crucial insights for clinicians
managing patients with cerebral cavernous malformations
(CCMs). The study outcomes highlight that HOD emerges
as a significant and potentially severe complication follow-
ing surgical resection or gamma knife radiosurgery of these
lesions. Hence, clinicians must conduct a thorough assess-
ment of patients to identify the risk of HOD before proceed-
ing with treatment interventions [61].
Raina et al. provided a detailed description of the clinical
features of Holmes tremor, which could aid in the diagnosis
and treatment of this movement disorder. They highlighted
the benefits of treatment with levodopa and dopamine ago-
nists, providing valuable insights into the management of
the condition [91]. In-depth knowledge of the triangle’s cel-
lular mechanism may facilitate targeted treatment options
for certain conditions such as OPT [85]. It has highlighted
the importance of the GMT in the pathophysiology of OPT
and underscores the need for a more comprehensive under-
standing of its cellular mechanism to develop more effective
treatments [85]. These findings provide new insights into
the pathophysiology of HOD and highlight the importance
of preserving the GMT during surgical approaches. Patients
presenting with OPTD should undergo a comprehensive
evaluation to assess the potential treatment options targeting
the underlying brainstem pathology. Addressing the underly-
ing damage holds promise for ameliorating the symptoms
associated with OPTD and enhancing the overall clinical
outcome [21]. The study conducted by Liao et al. [20] rep-
resented a significant contribution to the comprehension of
OPT caused by GMT damage and its prospective therapeutic
approaches. The research findings propose impulsive head
rotation as a promising treatment modality for OPT, high-
lighting the need for additional investigations to validate
these outcomes and cultivate novel therapeutic interventions
for this disorder [20]. Surisetti et al. [97] yielded substantial
evidence substantiating the heterogeneous nature of PT and
its etiological origins, encompassing genetic predisposi-
tion, environmental factors, and damage to the GMT. The
study outcomes propose that patients afflicted with PT could
potentially experience therapeutic advantages through inter-
ventions targeting either the GMT or the underlying causa-
tive factors implicated in the disorder [97]. The management
of lesions of the GMT involves various diagnostic and thera-
peutic approaches aimed at enhancing patients’ quality of
life. While a cure for GMT-related disorders remains elusive,
symptomatic management and functional improvement can
be achieved through pharmacological interventions target-
ing specific symptoms. Promising research has shed light
on the underlying mechanisms of GMT-related disorders,
paving the way for potential novel therapeutic approaches.
However, further research is needed to fully understand the
GMT’s role in these conditions and to develop more effec-
tive treatment options to improve patient outcomes.
Page 23 of 26 181
Limitations of research on GMT lesions
The limitations of the study include the fact that the study
relied solely on reviewing and summarizing the findings
of other studies on the subject matter. It is noteworthy to
acknowledge that the previous studies were carried out on a
limited cohort of patients, indicating the need for subsequent
investigations to validate and substantiate the reported out-
comes. It is imperative to note that further investigations are
warranted to ascertain the long-term implications associated
with neurological disorders in certain populations.
Conclusion
The existing evidence indicates that lesions in the GMT are
associated with various neurological conditions, including
HOD, PT, EPT, SPT, PM, PFS, OPT, PNE, APPT, SIDS,
SUID, NHOND, PMCMS, PSP, CTTH, and several genetic
impairments. The GMT plays a crucial role in the regula-
tion of motor coordination, tremors, and other motor-related
functions; and abnormalities or higher intensity in ION, RN,
DN, or CTT can lead to neurological deficits. Neuroimaging
techniques, such as MRI and DTI, and combined techniques
can aid in the diagnosis and treatment of lesions in the GMT,
as they allow for accurate visualization of changes in the ION
and other related structures. Understanding the temporal evo-
lution of MRI findings in HOD can also help in the differen-
tiation of this condition from other neurological disorders and
aid in the development of potential therapeutic interventions.
Author contributions EO: supervision, project development, data col-
lection, manuscript writing. KA: data collection, manuscript writing.
DT: data collection, figure illustration . The authors described their
own experience, and all authors read and approved the final manuscript.
Data availability Data and materials are available for review upon
request.
Declarations
Ethical approval Ethics approval is not required for this review.
Consent to participate Not applicable.
Consent for publication All authors consent for publication.
Conflict of interest The authors declare no competing interests.
Informed consent on studies with human and animal subjects Not
applicable.
13
181 Page 24 of 26 Neurosurgical Review (2023) 46:181

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