Seizure: European Journal of Epilepsy 88 (2021) 95–101

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Seizure: European Journal of Epilepsy

journal homepage: www.elsevier.com/locate/seizure

Closed-loop vagal nerve stimulation for intractable epilepsy: A

single-center experience
Graham M. Winston a, *, Sergio Guadix a, Miguel Tusa Lavieri a, Rafael Uribe-Cardenas a,
Gary Kocharian a, Nicholas Williams b, Evan Sholle c, Zachary Grinspan d, Caitlin E. Hoffman a
a
Department of Neurological Surgery, Weill-Cornell Medicine/NewYork-Presbyterian Hospital, 525 East 68th Street, Box 99, New York, NY, USA
b
Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, USA
c
Information Technologies & Services Department, Weill Cornell Medicine, New York, USA
d
Department of Population Health Sciences and Pediatrics, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Purpose: A new class of heart-rate sensing, closed-loop vagal nerve stimulator (VNS) devices for refractory ep­
Epilepsy ilepsy may improve seizure control by using pre-ictal autonomic changes as an indicator for stimulation. We
Refractory epilepsy compared our experience with closed- versus open-loop stimulator implantation at a single institution.
Vagal nerve stimulator
Methods: We conducted a retrospective chart review of consecutive VNS implantations performed from 2004 to
Closed-loop vagal nerve stimulator
2018. Bivariate and multivariable analyses were performed to compare changes in seizure frequency and clinical
outcomes (Engel score) with closed- versus open-loop devices. Covariates included age, duration of seizure
history, prior epilepsy surgery, depression, Lennox Gastaut Syndrome (LGS), tonic seizures, multiple seizure
types, genetic etiology, and VNS settings. We examined early (9-month) and late (24-month) outcomes.
Results: Seventy subjects received open-loop devices, and thirty-one received closed-loop devices. At a median of
8.5 months, there was a greater reduction of seizure frequency after use of closed-loop devices (median 75% [IQR
10–89%]) versus open-loop (50% [0–78%], p < 0.05), confirmed in multivariable analysis (odds ratio 2.72 [95%
CI 1.02 – 7.4]). Similarly, Engel outcomes were better after closed-loop compared to open-loop confirmed in the
multivariable analysis at the early timepoint (OR 0.26 [95% CI 0.09 – 0.69]). These differences did not persist at
a median of 24.5 months.
Conclusions: This retrospective single-center study suggests the use of closed-loop VNS devices is associated with
greater seizure reduction and more favorable clinical outcomes than open-loop devices at 9-months though not at
24-months. Expansion of this study to other centers is warranted to increase the generalizability of our study.

1. Introduction
Vagus nerve stimulation (VNS) has been used to treat refractory
epilepsy since the late 1990s. The vagus nerve is stimulated by an
implanted lead connected to a subcutaneous pulse generator that sits
just below the clavicle. In clinical practice, VNS is well established as a
therapeutic option that reduces both seizure frequency and severity.
Early studies of efficacy in adults with partial-onset seizures compared
groups receiving high- and low-frequency stimulation, and found
seizure response rates of approximately 30% in the high-frequency
stimulation group [1,2]. More recent studies and meta-analyses have
found VNS implant predicts a greater than 50% reduction in seizure
frequency, with an average seizure reduction of 45% [3]. Response rates
for the pediatric population (55% decrease), patients with generalized
epilepsy (58% decrease), and Lennox-Gastaut Syndrome (LGS, 48%
decrease) were similar or higher than the response rates of the overall
cohort [3]. Additionally, large, pooled studies have demonstrated that
VNS therapy leads to reduction of severity of the post-ictal state,
decrease in seizure clustering, and increase in quality-of-life measures
such as alertness, vocational improvements, and memory [4,5].
Standard VNS devices use open-loop technology, delivering stimu­
lation to the vagus nerve at specified, pre-programmed intervals. The
stimulus interval and intensity are only modified at clinical visits, based
on side effects and clinical response. Developments in VNS technology
over the past two decades have resulted in decreased generator size and
the ability to pre-program multiple ramp-up protocols. Recent

* Corresponding author.
E-mail address: gmw2002@nyp.org (G.M. Winston).

https://doi.org/10.1016/j.seizure.2021.03.030
Received 31 January 2021; Received in revised form 26 March 2021; Accepted 29 March 2021
Available online 1 April 2021
1059-1311/© 2021 British Epilepsy Association. Published by Elsevier Ltd. This article is made available under the Elsevier license (http://www.elsevier.com/open-
access/userlicense/1.0/).
G.M. Winston et al.
advancements include “closed-loop” systems that respond to pre-ictal
changes in heart rate [6]. These devices deliver an increased stimulus
in response to rapid changes in heart rate, and can be programmed to
deliver different stimulation programs at different times based on a
patient’s specific seizure history. Closed-loop devices can successfully
discharge within 2-minutes of seizure onset, which may improve the
chance of seizure arrest [7].
Single center studies have demonstrated that closed-loop devices
have response rates (greater than 50% reduction in seizure frequency) of
30–62% [7–10]. While prior studies have indirectly compared models
by evaluating patient response before and after exchange of an
open-loop device for a closed-loop device [9,10], it is less clear how
closed-loop devices compare directly to open-loop devices at time of
initial implant. Our center adopted closed-loop VNS devices after many
years of using open-loop devices, allowing us to provide a single-center
comparison.
2. Methods
2.1. Study design
Retrospective chart review was performed for consecutive VNS im­
plantations at our institution from 2004 to 2018 with approval from the
Weill Cornell Medicine Institutional Review Board under protocol
number 1708018443.
2.2. Population
All patients with first-time VNS implantation for epilepsy at our
institution were included. Those who had a VNS generator change, lead
change, or revision of any kind as their first surgery at our institution
were excluded. Cases were identified using existing institutional infra­
structure for secondary use of patient electronic health record (EHR)
data [11]. We first identified patients who had an instance of Current
Procedural Terminology (CPT-4) codes 64568, 64569, 64570, and
64573 (codes specific to the insertion, revision, or removal of VNS de­
vices), as well as a more non-specific code, 61885 (“Insertion or
replacement of cranial neurostimulator pulse generator or receiver,
direct or inductive coupling”), ordered or billed in the EHR. This cohort
was then screened to remove patients receiving neurostimulator im­
plants to treat Parkinson’s Disease (PD), essential tremor, sleep apnea, or
other disorders by stipulating that patients must also have received a
structured diagnosis of epilepsy, as defined by a problem list entry or
encounter diagnosis corresponding to ICD-9 345* or ICD-10 code G40*
(“Epilepsy and recurrent seizures”) (Supplemental Figure 1).
2.3. Patient characteristics
Demographics including age, gender, race, and ethnicity were
collected. We also abstracted medical and psychiatric comorbidities.
Clinical characteristics including age of onset, seizure etiology, history
of febrile seizures, history of infantile spasms, history of traumatic brain
injury, history of status epilepticus, prior epilepsy surgery, seizure types,
seizure frequency, and number of antiseizure medications (ASMs) were
collected.
2.4. Open loop vs. closed loop
The VNS model implanted was recorded for all patients. AspireSR
106 and Sentiva 1000 models were considered closed-loop due to their
ability to discharge in response to heart rate changes. All other VNS
models, including Aspire models 102, 102R, 103, 104, and 105, were
considered open-loop devices (LivaNova, London, UK).
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Seizure: European Journal of Epilepsy 88 (2021) 95–101
2.5. Outcomes assessment
The primary outcome was decrease in seizure frequency. We assessed
seizure frequency before and after VNS insertion. Seizure frequency was
abstracted by provider history in all cases, with 33 providers responsible
for quantification of frequency at 293 clinic visits. The top four providers
were responsible for the majority (157/293, 53.6%) of visits, and the
majority of patients (58/101, 57.4%) had the same provider quantify
frequency at all three visits. We also abstracted the change in number of
antiseizure medications, change in seizure type, VNS settings (including
output current and duty cycle), Engel classification, surgical morbidity,
and subsequent surgical procedures within the follow-up period. Per­
centage change in seizure frequency was calculated. Changes in seizure
frequency were also quantified by the proportion of patients reaching
specified threshold changes in seizure frequency. Seizure decrease was
described as no reduction (including seizure frequency increase), >
0 and ≤ 25% reduction, > 25 and ≤ 50% reduction, > 50 and ≤ 75%
reduction, > 75 and ≤ 90% reduction, and greater than 90% reduction
(Table 1A). Clinical outcome was assessed using the Engel Epilepsy
Surgery Outcome Scale [12], a clinically verified and widely used clas­
sification system to determine outcomes after epilepsy surgery
(Table 1B). Outcomes were assessed at 9-months and 24-months. There
were 10 patients for whom the 9-month and 24-month were calculated
from the same visit, these patients were not excluded from the analysis.
2.6. Statistical analysis
Data for each patient were collected via REDCap [13] and Microsoft
Excel (Microsoft Corp; Redmond, WA) databases for subsequent anal­
ysis. We examined the bivariate relationship between outcomes and VNS
device group (open vs. closed loop), as well as the following covariates:
history of prior epilepsy surgery, LGS diagnosis, seizure type (focal vs.
general, single vs. multiple), diagnosis of depression, diagnosis of anx­
iety, diagnosis of cerebral palsy, developmental delay, history of trau­
matic brain injury (TBI), history of status epilepticus, age, duration of
seizure history, VNS output current (mA), and VNS duty-cycle (%). We
used the chi-square test and Fisher’s exact test to compare categorical
variables between groups, the Wilcoxon rank sum test to compare
continuous and ordinal variables between groups, and Pearson corre­
lation to compare continuous variables.
A multivariable analysis was performed using an ordinal logistic
regression model, using ordinal outcomes of percentage decrease in
seizure frequency and Engel classification. Selection of variables was
guided by the bivariate analysis, preoperative and postoperative dif­
ferences between the two cohorts, and current areas of investigation
regarding VNS therapy. These investigation-based variables included
age [14,15], duration of seizure history [16,17], diagnosis of depression
[18–20], LGS diagnosis [4,21,22], history of prior epilepsy surgery
[22–24], and the VNS device settings of output current [1,2,25] and
Table 1
Outcome definitions. 1A. Outcome assessment table of change in seizure fre­
quency. 1B Definitions of Engel classification.
Table 1A. Categorization of Change in Seizure Frequency
Category Change in Seizure Frequency
0 < 0% Reduction
1 0–25% Reduction
2 25–50% Reduction
3 50–75% Reduction
4 75–90% Reduction
5 > 90% Reduction
Table 1B. Engel Classification
Engel Class Definition
I Free of Disabling Seizures
II Rare Disabling Seizures
III Worthwhile Improvement
IV No Worthwhile Improvement
G.M. Winston et al. Seizure: European Journal of Epilepsy 88 (2021) 95–101

duty cycle [26–28]. VNS device group was the primary predictor, with Table 2
the following covariates: patient age (continuous), history of prior epi­ Preoperative Characteristics.
lepsy surgery (binary), diagnosis of depression (binary), LGS diagnosis Open-Loop (n Closed-Loop (n P-
(binary), diagnosis of developmental delay (binary), duration of seizure = 70) = 31) value
history (continuous), tonic seizure type (binary), multiple seizure types Age (Years, IQR) 34 (19-45) 20 (12-42) 0.14
(binary), genetic seizure etiology (binary), output current (continuous), Percentage (Number) Female 44% (31) 41% (13) 0.27
duty cycle (%, continuous). Statistical analyses were performed using R Race - – 0.34
[29]. White 44% 39%
Black 7.1% 9.7%
Asian 4.3% 3.2%
3. Results Middle Eastern 1.4% 6.5%
Other 5.7% 16%
3.1. Preoperative characteristics Unknown 37% 26%
Ethnicity - – 0.61
Non-Hispanic 54% 65%
101 people (44% female) met inclusion criteria (Supplemental Hispanic 19% 16%
Figure 1) with a median age of 32 years [IQR 15 – 46]. Closed-loop Unknown 27% 19%
devices were implanted in 31 patients and open-loop in 70 patients. Follow-up (Months, IQR) 8.6 (7.5 – 9.4) 8.3 (6.7 – 10.1) 0.44
Median follow-up was 23.5 months (IQR 12.8–31.0) for closed-loop Age of Seizure Onset (Years, IQR) 16 (4.5–22) 8.0 (1.0–13) 0.02
Seizure History (Years, IQR) 13 (7.0–28) 10 (7.4–29) 0.87
cohort and 24.1 months (IQR 21.1–26.3) for open-loop patients (p = Seizure Type – – –
0.86). Demographic data, pre-operative seizure characteristics, comor­ Focal Motor 11% 6.5% 0.51
bidities, and prior treatment history appear in Table 2. The mean age of Absence 14% 13% 1.0
epilepsy onset was earlier in the closed-loop group (8.0 ± 12.1 vs. 16.0 Drop Attacks 7.1% 13% 0.45
Tonic Clonic 33% 48% 0.18
± 13.3 years, p = 0.02). A higher percentage of patients in the closed-
Complex Partial 44% 42% 1.0
loop group had tonic seizures (29% vs. 11%; p = 0.04), multiple Infantile Spasms 4.3% 3.2% 1.0
seizure types (71% vs. 43%; p = 0.04), and genetic seizure etiology (23% Tonic 11% 29% 0.04
vs. 7.1%; p = 0.04) preoperatively. There were no other statistically Myoclonic 7.1% 19% 0.09
significant differences between groups. Other Focal 20% 13% 0.39
Other Generalized 7.1% 19% 0.09
Unknown 1.4% 3.2% 0.52
3.2. Outcome: change in seizure frequency Multiple 43% 71% 0.01
Etiology – – –
At 24-month follow-up, there was no significant difference in seizure Genetic 7.1% 23% 0.04
Genetic Structural 0% 0% N/A
frequency reduction between recipients of closed-loop devices (50%;
Structural Congenital 30% 26% 0.81
IQR 12–85% decrease) and open-loop devices (50%; IQR 0–78% Structural Acquired 33% 29% 0.82
decrease; p = 0.48) (Fig. 1). At 9-month follow-up, recipients of closed- Metabolic 1.4% 0.0% 1.0
loop devices had a larger median decrease in seizure frequency, 75% Immune 1.4% 3.2% 0.52
(IQR 10–89% decrease), compared with a median decrease of 50% (IQR Infectious 0% 0% N/A
Multiple 0% 0% N/A
0–78% decrease) for recipients implanted with open-loop devices (p = Unknown 27% 19% 0.46
0.04). At 24-months, 58% of closed-loop VNS recipients achieved a post- Medical Comorbidities – – –
operative seizure frequency reduction greater than 50%, while 56% of Cerebral Palsy 8.6% 9.7% 1.0
open-loop recipients met the same threshold. A bivariate analysis Developmental Delay 26% 32% 0.63
Technical Dependencies 13% 13% 1.0
including the variables described above was conducted, with post-
Genetic Syndrome 7.1% 16% 0.28
operative seizure frequency reduction as the primary outcome mea­ Arrhythmia 0% 0% N/A
sure (Supplemental Table 1). Traumatic Brain Injury 19% 6.5% 0.14
After controlling for covariates, closed-loop VNS devices were asso­ Hypoxic Ischemic Encephalopathy 4.3% 13% 0.20
ciated with a greater odds of seizure frequency reduction (OR = 2.72; Pseudo-Seizures 0% 0% N/A
Unknown 1.4% 3.2% 0.52
95% CI 1.02–7.4; p = 0.047) at the 9-month timepoint. At 24-months, None 54% 48% 0.67
the direction of effect continued to favor closed-loop devices, but the Psychiatric Comorbidities – – –
difference was not statistically significant (OR = 1.85; 95% CI 0.72–4.9; Anxiety 7.1% 13% 0.45
p = 0.2) (Fig. 2, Table 3). At 24-months, multiple seizure types were Depression 10% 25% 0.07
Other Mood Disorder 0.0% 3.2% 0.31
associated with smaller reductions in seizure frequency (OR = 0.31; 95%
Other 5.7% 16% 0.13
confidence interval 0.13–0.70; p = 0.005). No other covariates in the Unknown/None 80% 61% 0.08
model were associated with seizure frequency reduction, including age, Number of ASMs Preoperatively 3 (2-4) 3 (2-4) 0.31
duration seizure history, etiology, or diagnosis of LGS. (IQR)
Percentage (Number) with Prior 26% (18) 26% (8) 0.32
Epilepsy Surgery
3.3. Outcome: engel classification
Table 2. Preoperative characteristics of the closed-loop and open-loop cohorts.
Patients with closed-loop VNS devices had better clinical outcomes Including demographic information, associated clinical variables, and prior
(i.e., a lower score in the Engel classification) after 9-months (OR = treatment history. IQR = Interquartile range.
0.26; 95% CI 0.09–0.69; p < 0.01). At 24-months, the direction of effect
continued to favor closed-loop VNS devices, but the differences were no +/- 0.53 mA vs. 1.03 +/- 0.59 mA; p = <0.001). By contrast, duty cycle
longer statistically significant (OR = 0.51; 95% CI 0.18–1.5; p = 0.22; at last follow-up was lower in the closed-loop VNS group (20% +/-
Fig. 3, Table 4). Having prior epilepsy surgery (OR = 3.55; 95% CI 11.0% vs. 34% +/- 17.7%; p = <0.001). The average change in post-
1.4–9.6; p = 0.01) and having multiple seizure types (OR = 3.15; 95% CI operative ASMs was higher in the open-loop group than the closed-
1.3–7.8; p = 0.01) were both associated with worse clinical outcomes (i. loop group (0.19 decrease +/- 1.4 open-loop vs. 0.35 increase +/-
e., higher score in the Engel classification) at 24-months. No other co- 0.95 closed-loop, p = 0.05), though there was no detectable difference in
variates contributed to the difference in clinical outcomes at 24-months. percentage of patients with a decrease in ASMs (open-loop 34% vs.
Average VNS current was higher in the closed-loop VNS group (1.48 closed-loop 16%, p = 0.09). Complication rates were similar between

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G.M. Winston et al.
Fig. 1. Box plot depicting post-operative seizure frequency change for closed-loop and open-loop VNS device recipients at 9-months (left) and 24-months (right).
Fig. 2. Ordinal logistical regression. Stacked bar chart depicting seizure reduction in each VNS device group at each time point.
device types, with the most common complications being infection (0%
closed-loop vs. 2.9% open-loop, p > 0.99) and hardware removal (0%
closed-loop vs. 1.4% open-loop, p > 0.99). Postoperative change in voice
was more common in the closed-loop group (42% closed-loop vs. 20%
open-loop; p = 0.03).
4. Discussion
4.1. Summary
In this single center retrospective study, closed-loop VNS devices
were associated with greater reduction in seizure frequency and better
Engel scores at nine months compared to older, open-loop devices,
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Seizure: European Journal of Epilepsy 88 (2021) 95–101
though these differences did not persist at two-year follow-up. Having
multiple seizure types and history of prior epilepsy surgery were asso­
ciated with worse outcomes. No other covariates, including age, dura­
tion of seizure history, seizure etiology, or seizure type were associated
with outcome at two-year follow-up.
4.2. Additional findings
Our findings confirm prior literature indicating multiple seizure
types are associated with less favorable clinical outcome [30,31]. Utility
of VNS in patients with prior open-surgical disconnections or resections,
such as corpus callosotomy, remains an active area of clinical investi­
gation [22–24], and the true consequence of our association remains to
G.M. Winston et al. Seizure: European Journal of Epilepsy 88 (2021) 95–101

Table 3 4.3. Clinical significance

Odds ratios of reaching a higher seizure frequency reduction category for the
seizure frequency change multivariable analysis at both 9-months (3A) and at The improved short-term outcomes with closed-loop VNS indicate
24-months (3B). that seizure reduction and clinical improvement occur faster for closed-
Table 3A. 9-Month Seizure Frequency Reduction loop patients, which would help reduce the time lag between time of
Variable Odds-Ratio 95% Confidence Interval P-value implantation and response currently observed for open-loop patients.
Closed-Loop VNS 2.72 1.02–7.40 0.047 While there was no significant difference in seizure frequency reduction
Age 0.99 0.95–1.03 0.78 or clinical outcome measured by Engel score at 24-months, both of these
Prior Surgery 0.46 0.19–1.08 0.08 measures still seemed to favor the closed-loop group. The reasons for the
Depression 0.56 0.17–1.80 0.33
LGS Diagnosis 1.43 0.29–6.91 0.66
Duration of Seizure History 0.99 0.95–1.02 0.43
Table 4
Tonic Seizures 0.78 0.23–2.53 0.68
Odds ratios of achieving a better outcome (lower Engel classification score) for
Multiple Seizure Types 0.45 0.18–1.08 0.08
Genetic Etiology 0.81 0.23–2.92 0.74
the clinical outcome multivariable analysis at both 9-months (4A) and at 24-
Output Current (mA) 3.00 1.33–7.14 0.01 months (4B).
Duty Cycle (%) 1.02 0.99–1.05 0.07 Table 4A. 9-Month Engel Classification
Table 3B. 24-Month Seizure Frequency Reduction Variable Odds-Ratio 95% Confidence Interval P-value
Variable Odds- 95% Confidence P-
Ratio Interval value Closed-Loop VNS 0.26 0.09–0.69 < 0.01
Closed-Loop VNS 1.85 0.72–4.85 0.20 Age 1.01 0.97–1.06 0.52
Age 1.01 0.97–1.06 0.58 Prior Surgery 0.94 0.38–2.30 0.89
Prior Surgery 0.47 0.20–1.10 0.08 Depression 0.24 0.06–0.89 0.03
Depression 1.73 0.59–5.95 0.39 LGS Diagnosis 1.14 0.23–5.95 0.88
LGS Diagnosis 0.49 0.11–2.12 0.34 Duration of Seizure History 0.96 0.93–0.99 0.03
Duration of Seizure History 0.98 0.95–1.02 0.40 Tonic Seizures 0.89 0.27–2.99 0.85
Tonic Seizures 2.44 0.79–7.68 0.12 Multiple Seizure Types 3.03 1.20–7.89 0.02
Multiple Seizure Types 0.31 0.13–0.70 < 0.01 Genetic Etiology 0.88 0.23–3.39 0.86
Genetic Etiology 0.54 0.13–2.18 0.39 Output Current (mA) 0.99 0.97–1.01 0.20
Output Current (mA) 0.72 0.34–1.52 0.39 Duty Cycle (%) 0.96 0.93–0.98 < 0.01
Duty Cycle (%) 1.01 0.98–1.03 0.58 Table 4B. 24-Month Engel Classification
Variable Odds- 95% Confidence P-
Ratio Interval value
be determined. We did not find an effect of several commonly cited Closed-Loop VNS 0.51 0.18–1.47 0.22
Age 0.99 0.94–1.04 0.59
predictors of favorable outcome—shorter duration of seizure history Prior Surgery 3.55 1.38–9.62 0.01
[16,17], genetic etiology [30], and output current [1,2,25] or of worse Depression 0.29 0.08–1.07 0.06
outcomes—younger age [14,15], diagnosis of LGS [21,22], and tonic LGS Diagnosis 1.44 0.27–7.88 0.67
seizures [32]. However, our study was not designed to thoroughly Duration of Seizure History 0.99 0.95–1.03 0.53
Tonic Seizures 0.73 0.22–2.50 0.62
evaluate predictors of outcomes, and so the absence of these effects
Multiple Seizure Types 3.15 1.31–7.82 0.01
should be interpreted with caution. Genetic Etiology 2.36 0.55–10.6 0.25
Output Current (mA) 1.13 0.51–2.54 0.76
Duty Cycle (%) 0.99 0.96–1.02 0.54

Fig. 3. Engel classification outcomes for both closed- and open-loop VNS recipients. Stacked bar chart depicting Engel outcomes in each VNS device group at each
time point.

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G.M. Winston et al.
differences seen at each time point remains unclear and requires further
investigation with expanded cohorts. One plausible cause may be that
the more immediate and targeted anti-seizure effect of closed-loop VNS
is able to help patients faster, though both closed-loop and open-loop
devices ultimately rely on long-term, non-targeted stimulation to
induce neuroplasticity changes. This type of mechanistic study is beyond
the scope of our current study, but will remain an important area of
investigation as the mechanisms behind VNS continue to be elucidated.
Due to the limited number of patients in our study, true subpopu­
lation analysis was not possible. Expansion of our cohort to a size in
which subpopulation analysis would be possible will allow for mean­
ingful predictions about best responders based on variables of interest
including etiology, seizure type, duration of seizure history, and more.
The difference in cost between the two devices should be incorporated
into future analyses, as closed-loop devices cost between $2496-$6498
(8.4–22.0%) more than open-loop devices [33]. Additionally, open-loop
devices may have improved battery life, though this is highly dependent
on individual device settings and utilization. A cost-effectiveness anal­
ysis with inclusion of battery life data is indicated to understand if the
relative benefits of the closed-loop devices merit the added cost. Finally,
the difference in safety profiles of the two VNS classes requires further
investigation. The difference in number of patients in the closed-loop
group with post-operative voice change may be clinically meaningful.
This outcome, as well as other surgical safety outcomes, require further
study.
4.4. Context in literature
Our study adds to a small body of literature investigating the efficacy
of closed-loop devices. In isolation, studies have shown seizure
responder rates (as defined by percentage of patients achieving greater
than 50% reduction in seizure frequency) for de novo implants between
30 and 62% [7–10]. These studies included between 14 and 51 patients
with de novo implanted closed-loop VNS devices at single-centers.
Additional studies investigating individuals who had their device
upgraded from open to closed-loop reported additional benefit between
59 and 71% [9,10].
Our study, of 31 de novo patients, finds similar responder rates when
using this same definition, at 58%. Our study is the first of these to
stratify these patients over multiple timepoints, and to include an
ordinal logistic regression utilizing multiple seizure frequency reduction
thresholds.
4.5. Study limitations
Several limitations merit discussion. First, we report outcomes only
through two years, whereas VNS may provide ongoing benefit up to ten
years following implantation [34]. Second, single-center data limits the
generalizability of our findings. Third, there was no standardized tem­
plate used to quantify seizure frequency during the study period, and
seizure frequency was instead based on interpretation of notes by chart
abstractors. Fourth, the small sample size limits statistical power. This is
particularly relevant as the effect sizes at 24-months were large and
potentially clinically important, in favor of the closed-loop devices.
Fifth, the closed and open loop cohorts were not contemporaneous –
thus there may be additional confounders due to secular trends in
seizure management. Furthermore, due to the novelty of the closed-loop
devices, there were fewer patients in the closed-loop group than the
open-loop group and therefore the groups were not evenly matched.
Sixth, the samples had potentially important baseline differences, such
as age and incidence of tonic seizures. Though we controlled for these
factors in the multivariable analyses, there may have been other un­
measured confounders between the groups.
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Seizure: European Journal of Epilepsy 88 (2021) 95–101
5. Conclusion
Closed-loop devices are associated with greater seizure reduction
and more favorable Engel class outcomes at 9-months, compared to
open-loop devices. Our study did not find that these improvements
persisted at 24-months, though the sample was underpowered to detect
clinically important effects. Additional studies across multiple centers
with larger sample sizes are indicated.
Previous publications
No portion of this work, in part or whole, has been previously pub­
lished. Portions of this work has been presented in abstract form at the
2019 American Epilepsy Society (AES) Annual Meeting.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
Dr. Grinspan receives research funding from the Pediatric Epilepsy
Research Foundation, the Orphan Disease Center, Clara Inspired, and
Weill Cornell Medicine. He has performed paid consultation work for
Alpha Insights, Epilog.care, and Bio-Pharm Solutions (South Korea).
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