Keywords
a tremor effect - deep brain stimulation - Parkinson’s disease - propofol
Introduction
The anesthetic goals for deep brain stimulation (DBS) are to ensure patient comfort
for insertion of electrodes through burr holes while avoiding all drugs that interfere
with microelectrode recordings (MERs) and macrostimulation. There are few studies
which examine the effects of anesthetic drugs on MER during deep brain nucleus (DBN)
localisation. This has led some neurosurgical teams to totally avoid sedation, especially
propofol, during DBS. We would like to report a case, however, where the anti tremor
effect of propofol was used to facilitate MER.
The patient gave written permission for the authors to publish the report.
Case Report
A 51-year-old male with medically refractory Parkinson’s disease (PD) was scheduled
for bilateral DBS under conscious sedation. Despite taking levodopa of 125 mg and
amantadine of 100 mg twice daily, he suffered severe resting tremor in all limbs affecting
his daily activities. The parkinsonian drugs were withheld on the day of surgery.
He had no other significant medical history.
A Leksell stereotactic frame was placed on the patient using a local anesthetic to
pin sites before computed tomography scan of the head and transferred to the operation
room. No premedication was given. The standard monitoring, including electrocardiogram,
pulse oximetry, and non invasive blood pressure monitoring were used. Propofol infusion
(30-50 µg/kg/min) was used for sedation during the creation of first burr hole on
the right side. Twenty minutes before MER, propofol was stopped in accordance with
our institution’s protocol, to avoid possible interference with MER. During MER, the
patient developed severe sustained whole-body tremors leading to violent shaking of
the Leksell head frame and operating table. The tremors caused so many artefacts in
the MER that they prevented identification of the inferior border of the right subthalamic
nucleus (STN) ([
Fig. 1
]). MER was suboptimal despite 45 min of mapping with repeated trajectories. The final
placement of the right DBS electrode was based on the neurological examination with
macrostimulation of the electrode.
Fig. 1 (A) Right hemispheric anterior microelectrode shows excessive tremor artefacts throughout
the entire length of the recording. The superior subthalamic nucleus is detected 1.5
mm above target. Inferior border of subthalamic nucleus is not detected, (B) Right hemispheric center microelectrode shows excessive tremor artefacts throughout
the entire length of the recording. The superior subthalamic nucleus is detected 1
mm above target. Inferior border of subthalamic nucleus is not detected.
Propofol infusion at a rate of 30 to 50 µg/kg/min was recommenced for the creation
of the left burr hole, and soon after, all tremor activity ceased. A decision was
made to continue propofol during MER. With propofol infusion at a rate of 20 µg/kg/min,
there was no recurrence of tremor activity, and the patient obeyed verbal commands
and spoke fluently. With the absence of tremor artefact in MER, left STN spike activity
was better identified ([
Fig. 2
]). Then, propofol was stopped to allow the tremor resurface-which it did within 7
min after cessation of propofol. Macrostimulation and neurological testing took place
for the final placement of the left DBS electrode. Following this, general anesthesia
was instituted for stage 2-tunneling and insertion of the generator.
Fig. 2 (A) Left hemispheric anterior microelectrode shows fewer tremor artefacts throughout
the entire length of the recording. The superior subthalamic nucleus is detected 4
mm above target. Inferior border of subthalamic nucleus is 2 mm above target. (B) Left hemispheric center microelectrode shows very few tremor artefacts throughout
the entire length of the recording. The superior subthalamic nucleus is detected 0.5
mm below target. Inferior border of subthalamic nucleus is 3.5 mm below target.
At 6-months post-DBS, the patient’s symptoms had improved significantly, and he was
weaned off levodopa.
His simplified Movement Disorders Societies-Unified Parkinson’s Disease Rating Scale
III, a rating score used by our neurologists, was markedly reduced from 18.5 to 6.5
(stimulation-on; medication off state), equivalent to 65% reduction in symptoms ([
Table 1
]).
Table 1
Pre- and postoperative simplified Unified Parkinson’s Disease Rating Scale scores
in our patient
|
MDS-UPDRS
|
Preoperative score with medication-on
|
Postoperative score with stimulation-on, medication-off
|
|
Right
|
|
Left
|
Right
|
|
Left
|
|
Abbreviations: MDS, Movement Disorder Society; UPDRS, Unified Parkinson’s Disease
Rating Scale.
|
|
Rigidity
|
1
|
|
4.5
|
1.5
|
|
0
|
|
Finger tapping
|
0
|
|
2
|
0
|
|
1
|
|
Hand movements
|
0
|
|
3
|
1
|
|
0.5
|
|
Heel tapping (toe tapping)
|
0
|
|
2
|
0
|
|
1
|
|
Tremor
|
3
|
|
2
|
0
|
|
0
|
|
Gait
|
|
0
|
|
|
0
|
|
|
Arising from chair
|
|
0
|
|
|
1
|
|
|
Body bradykinesia
|
|
0
|
|
|
0.5
|
|
|
Postural stability
|
|
1
|
|
|
0
|
|
|
Subtotal score
|
4
|
|
13.5
|
2.5
|
|
2.5
|
|
UPDRS III score
|
|
18.5
|
|
|
6.5
|
|
Discussion
In this case, we observed a reversible anti-Parkinsonian tremor effect associated
with the administration of low dose propofol, facilitating MER, which might be helpful
in many other DBS cases with a similar intraoperative problem. Spurious movement or
tremor can interfere with MER during DBS. Tremor is the most common cardinal symptom
in PD, which is found in three-quarter of PD patients.[
1
] As expected, tremor-related artefacts interfering MER are commonly encountered clinically.
In addition, the typical target nucleus (e.g., STN) is only a few millimetres in diameter,
precise placement of DBS electrode, a crucial step to achieve desired therapeutic
effect, is technically challenging, especially in a patient with severe tremor.[
2
] DBS electrode placement is a blind procedure; the risks of intracranial hemorrhage
or injury to vital structures are correlated to the number of microelectrode trajectories.[
3
] We would like to use this case as a discussion point to review the current understandings
on the anti-Parkinsonian effect of propofol, as well as to discuss the concerns about
propofol interferences on MER.
Antitremor Effect of Propofol
Tremor pathophysiology involves complex anatomical pathways between basal ganglia,
cerebellar circuits and motor cortex ([
Fig. 3
]). Tremor is exhibited as there is increased cerebellothalamocortical circuit activity.
For example, dopaminergic depletion of the palladium in PD or gamma-aminobutyric acid (GABA)-ergic
dysfunction of the cerebellar dentate nucleus and brain stem in essential tremor (ET)
cause hyperactivity of cerebellothalamocortical circuit, resulting in clinical tremor
in both diseases.[
4
]
Fig. 3 Pathophysiology of tremor. The basal ganglia and cerebellum have separate pathways
to the thalamus. The globus pallidus internus sends inhibitory gamma-aminobutyric
acid (GABA)-ergic fibres to the ventrolateral thalamus anterior nucleus (restraining
motor cortical activity), whereas the cerebellar nuclei send excitatory glutamatergic
innervation to ventrolateral thalamus posterior nucleus (facilitating motor cortical
activity). Subthalamic nucleus functions as a connection hub to conduct signals to
the motor cortex in tremor pathophysiology. The left side of the diagram illustrates
the links between basal ganglia and motor cortex (blue), which are involved in Parkinson’s
disease. The right side of the diagram demonstrates the links between the cerebellum
and motor cortex (orange) that are responsible for essential tremor. Subthalamic nucleus
anatomically connects the cerebellum to basal ganglia (black arrow) and is thought
to be responsible for the shared tremor mechanisms between Parkinson’s disease and
essential tremor. deep brain stimulation at deep brain nucleus (subthalamic nucleus,
globus pallidus), ketamine, levodopa and propofol reduces the hyperactivity of cerebellothalamocortical
circuit, resulting in an antitremor effect (arrows indicating sites of action). GPi,
internal part of the globus pallidus; GPe, external part of the globus pallidus; ILN,
thalamic intralaminar nucleus; IO, inferior olive; RN, red nucleus; STN, subthalamic
nucleus; VLa, anterior part of the ventrolateral thalamus; VLp, posterior part of
the ventrolateral thalamus; ILN, thalamic intralaminar nuclei; SNc, substantia nigra
pars compacta; DBS, deep brain stimulation; DBN, deep brain nucleus; PD, Parkinson’s
disease.
The role of GABA in the pathophysiology of tremor is well described in neurology literature,
especially in ET. It is interesting to know that GABA agonists, such as primidone,
topiramate, gabapentin, and ethanol, are used to treat ET.[
5
] In contrast to ET, the role of GABA are less well studied in PD and atypical parkinsonian
syndromes.[
6
]
,
[
7
] A previous neuro-radiology study has demonstrated the decrease in [
[11
]C]-flumazenil uptake in striatum on positron emission tomography scan, suggesting
of GABA depletion, was inversely correlated with the motor symptoms in vascular Parkinsonian
patients.[
8
] Hall et al. performed an interesting study in unilaterally symptomatic PD patient using magnetoencephalography (MEG)
to characterise neuronal network activity of the primary motor cortex. Following administration
of benzodiazepine (0.05 mg/kg of Zolpidem), tremor and other parkinsonism symptoms
on the contralateral side were significantly reduced, and less movement-related beta
desynchronisation was demonstrated on the MEG.[
9
] The author concluded that the anti-Parkinsonian tremor effect is acting through
GABA activation. In echoing with our case, a previous report described a similar observation
that propofol abolished tremor for 8 h in two parkinsonian patients after thalamotomy.
In that case, the authors postulated that propofol might act through the GABA receptor
in extra-thalamic tremor pathway.[
10
] With the available evidence, it suggests GABA activation in a certain part of tremor
pathway might play a key role in the anti-Parkinsonian tremor effect on PD patients.
Although the precise underlying mechanism of anti-Parkinsonian tremor effect of propofol
is not well investigated, it is not uncommon to observe loss of resting tremor in
unparalysed PD patients during anesthetic induction in non-DBS procedures, which might
thought to be related to cortical suppression. One of the interesting observation
in our case is the dose of propofol when anti-Parkinsonian tremor effected, is quite
low, which has no interference with DBN activities on MER. It implied the effective
dose for anti-Parkinsonian tremor is much lower than the effective dose for sedation,
indicating the differential sensitivity of DBN (subcortical neurons) and cortical
neurons towards anesthetic agents. It is also reasonable to question whether other
anesthetic agents (GABA agonists) possess the same effect. A previous case report
described ketamine abolished tremor and dyskinesia in a PD patient, which postulated
to be through N-methyl-D-aspartate receptor activation.[
11
] Further study is required to evaluate the underlying mechanism, dose-response relationship
and whether other anesthetics exert similar effects in the tremor pathway. On the
other hand, propofol can also cause myoclonus; however, the dose-response relationship
between myoclonus and the anti-tremor effect is yet to be determined.
Concerns of Propofol during Microelectrode Recording
The common methods of DBN localisation include neuronavigation, MER and macrostimulation
techniques.
High fidelity magnetic resonance imaging enables generation of highly accurate coordinates
to grossly locate the DBN, and placement of DBS electrode is further finely adjusted
according to the MER and microstimulation.
MER is typically started at 10 to 15 mm above the targeted nucleus. The electrode
is advanced by a microdrive and look for occurrence and disappearance of STN-specific
bursting pattern of electrophysiological activity to determine the border of STN.
The length of the STN, the presence of movement-responsive neurons, and distance from
the STN border to adjacent structures are used as MER criteria to determine the best
trajectory for permanent electrode implantation. Since the electrophysiological activities
of DBN are very small (50-200 μV) and sensitive to anesthetic agents, anesthetic suppression
of MER during placement of electrodes becomes one of the major concerns affecting
the accuracy of mapping during DBS.[
2
]
Macrostimulation, referring to an in vivo test stimulation of deep brain electrode, physical examination is used to check for
side effects due to overstimulation of surrounding nucleus and to assess the clinical
effect of DBS. A fully awake patient is required to participate neurological examination
during macrostimulation. A previous study has showed adjustment of electrode placement
after macrostimulation were required in 17%-87% of STN-DBS patients with average target
adjustments of 1 to 4 mm.[
2
] Thus, a highly controlled anesthetics is desirable to achieve the best procedural
benefit.
The anesthetic effects on MER are complex. Several factors can modify the effect of
anesthetics, including the site of target nuclei (STN, globus pallidus internus [GPi],
ventromedial thalamic nucleus), the disease state (PD, ET and dystonia), the severity
of the disease (variable degree of neuronal depletion). Following the report that
propofol infusions at 50 μg/kg/min significantly decreased STN neuronal activity (-23.2%),[
12
] many neurosurgical teams decided to avoid propofol altogether during DBS. There
was also similar report about anesthetic suppression (propofol) on MER during GPi-DBS
in dystonia patients, where the anesthetic suppression was more pronounced in dystonia
patients than PD patients.[
13
]
In contrast to these reports, there are several case series reporting successful MER
and motor outcomes in PD patients undergoing STN-DBS with general anesthesia (propofol
or volatile anesthetics) ([
Table 2
]).[
14
]-[
18
] Interestingly, all these studies found MER were not affected by controlled general
anesthesia and were able to detect bursting STN pattern in all study cases. Although
one of the typical features of STN (widening of background noise baseline) were lost
during general anesthesia, the overall motor outcomes and symptoms improvement were
comparable between general anesthesia and historical controlled data under local anesthesia.[
14
]-[
18
] While anesthetic suppression is a genuine phenomenon; but under controlled general
anesthesia condition, presumably a higher dose of anesthetics were used, MER and patient
outcomes were no clinical differences based on non-randomized data. The avoidance
of propofol or other anesthetic agents on MER in all DBS patients appears to be over-concerned,
especially in some patients who might benefit from adequate sedation during this prolonged
procedure.
Table 2
Review of patient outcomes following deep brain stimulation using microelectrode recording
technique under general anesthesia
|
Study
|
Study design
|
Sample size
|
Anesthetic agents
|
UDPRS-III score reduction
|
LEDD reduction
|
Conclusion
|
|
Abbreviations: CS, case-series; N/A, not available; GA, general anesthesia; LA, local
anesthesia; LEDD, levodopa equivalent dose; UDPRS, Unified Parkinson’s Disease Rating
Scale; TCI, target controlled infusion; MERs, microelectrode recordings; STN, subthalamic
nucleus; MAC, minimum alveolar concentration.
|
|
Kim et al[
19
]
|
Comparison study
|
8
|
Propofol + remifentanil (one side) LA (the contralateral side)
|
67%
|
N/A
|
No significant difference in the mean firing rate between the left and the right side
MERs
|
|
Fluchere et al[
14
]
|
CS
|
213
|
Sevoflurane
|
61% (1 y) 37% (5 y)
|
46% (1 y) 49% (5 years)
|
STN stimulation performed under controlled GA is efficient and has similar short-
and long-term motor effects to local anesthesia
|
|
Harries et al[
15
]
|
CS
|
82
|
Isoflurance + N2O (26 patients) Propofol + remifentanil (56 patients)
|
22.89 (1 y)
|
58.1% (1 y)
|
Satisfactory MER of the STN were able to obtain under GA
|
|
Lin et al[
16
]
|
CS
|
10
|
Desflurance (0.5-1 MAC)
|
5.42% (6 mo)
|
N/A
|
Typical neuronal firing patterns of the STN and substantia pars nigra reticulata were
able to observe in all patients
|
|
Hertel et al[
17
]
|
CS
|
9
|
Propofol (0.1-0.2 mg/kg/min) Remifentanil
|
24%
|
N/A
|
All patients had satisfactory MER and STN
|
|
Maltête et al[
18
]
|
Case-control study
|
30 (15:15)
|
Propofol (TCI: 0.8-2 ng/mL)
|
N/A
|
N/A
|
Both GA and LA group has was markedly improved the parkinsonian motor disability score
The GA group has higher residual parkinsonian motor score than LA group
|
Conclusion
We present an interesting DBS case where low dose propofol infusion suppressed Parkinsonian
tremor, facilitated MER and the successful placement of DBS electrodes. Further studies
are needed to investigate the dose-response relationship of propofol and if other
drugs can facilitate MER during DBS.
