Journal of Clinical Neuroscience xxx (2018) xxx–xxx

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Journal of Clinical Neuroscience
journal homepage: www.elsevier.com/locate/jocn

Case report

Deep brain stimulation of the ventralis intermedius nucleus of the
thalamus and posterior subthalamic area for Holmes’ tremor secondary
to brainstem hemorrhage: A case report
Chang Duk Yuk a, Jun Hyong Ahn a,b, Jae Keun Oh a, In Bok Chang a, Joon Ho Song a, Ji Hee Kim a,b,⇑
a
b

Department of Neurosurgery, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea
Kangwon National University College of Medicine, Chuncheon, Republic of Korea

a r t i c l e

i n f o

Article history:
Received 10 August 2018
Accepted 6 October 2018
Available online xxxx
Keywords:
Deep brain stimulation
Holmes’ tremor
Posterior subthalamic area
Rubral tremor
Thalamic stimulation
Ventralis intermedius

a b s t r a c t
Holmes’ tremor is a rare but severely disabling movement disorder characterized by a combination of
resting, action, and intention tremor. Because Holmes’ tremor is usually resistant to pharmacotherapy,
surgical treatment is required for symptom control in most cases. We report the case of a 56-year-old
man who was diagnosed with Holmes’ tremor and treated with stimulation of the ventralis intermedius
nucleus of the thalamus and posterior subthalamic area. Deep brain stimulation alleviated the patient’s
tremor over a 3-year follow-up period.
Ó 2018 Elsevier Ltd. All rights reserved.

1. Introduction
Holmes’ tremor (HT), first described by Gordon Holmes in 1904,
is a rare but severely disabling movement disorder that is characterized by symptomatic low-frequency (<4.5 Hz) resting tremor
that is exacerbated by posture and action [1,2]. Also known as
rubral tremor or midbrain tremor, HT is generally unilateral and
typically involves the proximal limbs [3]. HT arises from
underlying structural lesions of the upper brainstem, cerebellum,
thalamus, areas adjacent to the red nucleus, substantia nigra, and
nigrostriatal tract that are usually caused by cerebral hemorrhage,
ischemia, trauma, infection, metabolic disorders, demyelinating
disease, neoplasms, or radiation [4,5]. Clinically, HT is defined by
the Movement Disorder Society as: (1) the presence of both resting
and intention tremor; (2) tremor frequency below 4.5 Hz; and
onset with variable delay between lesion occurrence and the first
appearance of symptoms [2]). Pharmacological treatments for tremor, including levodopa, have a low success rate in HT [6], thus, in
refractory cases, surgical treatment such as stereotactic
thalamotomy or thalamic stimulation is recommended.

⇑ Corresponding author at: Kangwon National University College of Medicine,
Hallym University Sacred Heart Hospital, 22, Gwanpyeong-ro170 beon-gil, Dongangu, Anynag-si 14068, Republic of Korea.
E-mail address: kimjihee.ns@gmail.com (J.H. Kim).

Here, we describe a rare case of HT secondary to spontaneous
intracerebral hemorrhage located at the left midbrain to pons that
was successfully improved with simultaneous deep brain stimulation (DBS) of the ventralis intermedius nucleus of the thalamus
(VIM) and posterior subthalamic area (PSA).

2. Case report
A 55-year-old man with a 3-month history of resting and action
tremor affecting mostly his right hand and head was referred to
our institution. He had developed right-sided hemiparesis secondary to a hypertensive brainstem hemorrhage 9 months prior.
At that time, brain computed tomography (CT) showed an acute
hemorrhage in the left midbrain to pons (Fig. 1). After conservative
management and physical therapy, the patient showed gradual
improvement but still had significant motor weakness. Nine
months after the brainstem hemorrhage, he exhibited severe resting, postural, and kinetic tremor affecting the right upper limb and
head as well as focal hand dystonia on neurological examination.
At that time, axial T2-weighted magnetic resonance imaging
(MRI) demonstrated encephalomalatic changes, cystic degeneration, and hemosiderin around the lesion (Fig. 2). He was treated
with several medications including propranolol, levodopa/
carbidopa, clonazepam, and baclofen, but his symptoms persisted.
He had no history of using neuroleptics or tremor-inducing drugs

https://doi.org/10.1016/j.jocn.2018.10.041
0967-5868/Ó 2018 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Yuk CD et al. Deep brain stimulation of the ventralis intermedius nucleus of the thalamus and posterior subthalamic area
for Holmes’ tremor secondary to brainstem hemorrhage: A case report. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.041

2

Case report / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

Fig. 1. Preoperative computed tomography imaging showing acute intracerebral hemorrhage in the left midbrain and pontine tegmentum.

Fig. 2. Preoperative T2-weighted axial magnetic resonance imaging revealing the resolution of acute hemorrhage. Encephalomalatic changes, cystic degeneration, and
hemosiderin around the lesion were also observed.

prior to or after the brainstem hemorrhage and no family history of
a movement disorder.
2.1. Surgical procedure
Surgery was performed in accordance with established DBS procedures. Briefly, unilateral DBS electrode implantation was per-

formed under local anesthesia using a Leksell stereotactic frame
and MRI-guided targeting (Philips, Eindhoven, the Netherlands)
with a Stealthstation Framelink system (Medtronic, Inc., Minneapolis, MN, USA). The VIM target was set at 13.5 mm lateral to
the midline and 25% anterior to the posterior commissure in the
intercommissural plane. PSA localization was verified using MRI
and a brain atlas. After localizing the VIM target, the electrode

Please cite this article in press as: Yuk CD et al. Deep brain stimulation of the ventralis intermedius nucleus of the thalamus and posterior subthalamic area
for Holmes’ tremor secondary to brainstem hemorrhage: A case report. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.041

Case report / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

3

Fig. 3. Position of the deep brain stimulation electrode as visualized by postoperative computed tomography.

was advanced to the PSA while maintaining the determined angle
of trajectory using T2-weighted MRI. Single-track microelectrode
recording was performed and cell activity was recorded starting
from 10 mm above the VIM target. We identified the ventral thalamic border and tremor cells inside the VIM. After precise localization of the target point, a quadripolar DBS electrode (model 3387,
Medtronic, Inc.) was placed and intraoperative test stimulation
was performed to verify tremor control in the absence of
stimulation-induced side effects. After electrode implantation,
postoperative CT was performed and merged with preoperative
MRI to verify the location of the electrode (Fig. 3). Furthermore,
in merging with Atlas, we confirmed that the proximal electrodes
(contacts 0 and 1) were positioned at the PSA and the distal
electrodes (contacts 2 and 3) at the VIM. The DBS electrode was
connected subcutaneously to a pulse generator (IPG, Activa SC,
Medtronic, Inc.) that was implanted in the infraclavicular area
under general anesthesia.

2.2. Clinical outcome
The patient experienced a remarkable reduction of tremor from
the microlesion effect. Stimulation was initiated 3 days after surgery. Parameters were titrated to provide optimal tremor control
without side effects. We evaluated the degree of tremor using
quantitative analysis with the 3-part clinical rating scale for tremor
(CRST), which is a widely used assessment tool for tremor [7]. The
CRST was administered before surgery and at 1 month, 3 months,
1 year, 2 years, and 3 years post-surgery (Fig. 4). The initial DBS
setting had an amplitude of 1.5 V, a pulse width of 60 ms, and a
frequency of 180 Hz with monopolar configuration using contact
0-negative. After initial simulation, the tremor severity slightly

Fig. 4. Clinical rating scale for tremor (CRST) scores for tremor location and severity
(part A), specific motor tasks (part B), and functional disabilities (part C) before
surgery and 1 month, 3 months, 1 year, 2 years and 3 years post-surgery.

improved. However, since the tremor was still severe, the
amplitude was increased to 3.0 V and two additional contacts
(1-negative and 2-negative) were selected. The tremor severity
gradually improved whenever we added a contact and raised the
amplitude. However, the IPG exhaustion rate was too fast if all
the contacts were used, so we decided to use only three contacts.
After parameter optimization, the patient experienced a remarkable reduction in tremor; however, focal dystonia affecting the
right hand was unchanged. He was discharged with the following
VIM and PSA stimulator settings: monopolar, contact 0-negative,
1-negative, 2-negative, 3.2 V, 60 ms, 180 Hz. The patient did not
exhibit any stimulation-induced side effects at the time of
discharge.
At 1 month post-surgery, the patient showed improvement in
the CRST part A score (symptom severity) from 16 to 8, CRST part
B score (specific motor task function) from 31 to 25, and CRST part
C score (functional disabilities) from 30 to 21 compared with his
preoperative scores. The alleviation of tremor severity was sustained over the following 3 years as evidenced by decreased CRST
part A scores; however, specific motor task function and functional
disabilities were slightly worse at 1 year and 2 years post-surgery(Fig. 4). No changes in focal dystonia of the right hand were
observed after surgery or during the follow-up period.
3. Discussion
Although simultaneous VIM and PSA stimulation has previously
been described as an effective treatment for essential tremor (ET),
this is the first report to describe its successful use in HT [8]. The
success of thalamotomy and prolonged thalamic stimulation in
ET first led to their applications in HT [9,10], and have driven a
majority of studies regarding DBS for HT to focus on thalamic
areas. Yet, the outcome of VIM DBS alone has been unsatisfactory
in patients with HT. Thus, other targets have been proposed as
alternatives to achieve better outcomes, including stimulation
with multiple leads [11–14]. Although the precise pathophysiology
of HT is still unclear, it is believed that both the dopaminergic
nigrostriatal and cerebellothalamic systems are involved in the
generation of resting and kinetic tremor [15–18]. For this reason,
the stimulation of a larger area or the implantation of multiple
leads may be necessary in patients with HT.
Several previous reports have described the implantation of
dual or multiple leads for the treatment of tremor. Romanelli
et al. noted that stimulation of the VIM or subthalamic nucleus
(STN) alone failed to resolve mixed tremor, whereas combined
VIM-STN stimulation produced relief without side effects [12].
Goto and Yamada reported a patient with pontine hemorrhage in
whom a combination of VIM DBS and pallidotomy abolished HT.
Moreover, Foote et al. described the successful treatment of
patients with tremor rebound after stimulation of the border
between the VIM and the ventralis oralis posterior (VOP) with

Please cite this article in press as: Yuk CD et al. Deep brain stimulation of the ventralis intermedius nucleus of the thalamus and posterior subthalamic area
for Holmes’ tremor secondary to brainstem hemorrhage: A case report. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.041

4

Case report / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

additional stimulation of the border between the ventralis oralis
anterior (VOA) and the VOP [11]. Kobayashi et al. recently showed
that dual DBS with one electrode implanted at the VOA or VIM and
the other in the subthalamic area (SA) was effective in 4 patients
with HT [14],importantly, the authors demonstrated that
stimulation with 2 electrodes exerted a greater therapeutic effect
than did stimulation with 1 electrode. Recently, Toda et al.
reported a patient with HT who showed effective tremor control
for six years through coaxial interleaved stimulation of the VO
and subthalamic region [19]. In our case, stimulation at multiple
contacts, including both the VIM and PSA, similarly produced a
better response than did stimulation at 1 electrode contact alone.
Taken together, it appears that large stimulation areas are required
to achieve sufficient tremor control in patients with HT.
One year after continuous VIM and PSA stimulation, the patient
in our case still showed significant improvements in his head and
arm tremor, but he showed no improvement in hand dystonia.
Accordingly, the patient still experienced significant disability at
1 and 2 years post-surgery. Future studies are necessary to identify
approaches for more comprehensive symptom control; to this end,
it may be useful to more extensively assess quality of life and
activities of daily living in patients with HT in future research.

4. Conclusions
We demonstrated that DBS of the VIM and PSA was safe and
produced sufficient tremor control without stimulation-induced
side effects in a patient with medically intractable HT. Additional
follow-up and case accumulation is needed to elucidate the
pathophysiological mechanisms of HT and to identify optimal
DBS targets in these patients.

Disclosure
No portion of the paper has been presented or published
previously.

Funding
No funding was received for this research.

Conflict of interest
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such
as honoraria; educational grants; participation in speakers’ bureaus;
membership, employment, consultancies, stock ownership, or other
equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional
relationships, affiliations, knowledge or beliefs) in the subject
matter or materials discussed in this manuscript.

Acknowledgements
We would like to thank So Young Park, Byung Min Kim, Jae Min
Lee, and Young Nam Kim for data acquisition and assistance with
writing this manuscript.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jocn.2018.10.041.
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Please cite this article in press as: Yuk CD et al. Deep brain stimulation of the ventralis intermedius nucleus of the thalamus and posterior subthalamic area
for Holmes’ tremor secondary to brainstem hemorrhage: A case report. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.041