Comparison of utilization and cost of healthcare services and pharmacotherapy following implantation of vagus nerve stimulation vs. responsive neurostimulation or deep brain stimulation for the treatment of drug-resistant epilepsy: analyses of a large United States healthcare claims database

Figures & data

Figure 1. Sample attrition for VNS and RNS/DBS cohorts. All percentages above are calculated using the population from the prior category. As neurostimulation may be used for several indications (e.g., epilepsy, Parkinson's disease, essential tremor), we required the presence of a diagnosis of epilepsy on the date of procedure to maximize the likelihood that the patient received implantation for treatment of epilepsy; to provide further confirmation of chronic epilepsy (a prerequisite for consideration of neurostimulation), the longer 1-year period was applied to assess ASM use. The cohorts therefore represented patients with evidence of: (1) chronic epilepsy; (2) ASM use; and (3) use of neurostimulation for epilepsy.

Table 1. Demographic and clinical characteristics on index date, by match status and cohort.

Characteristic	Before matching			After matching
	VNS (N = 640)	RNS/DBS (N = 152)	Standardized difference	VNS (N = 148)	RNS/DBS (N = 148)	Standardized difference
Age (in years)			0.50			0.06
Mean (SD)	25.2 (16.1)	32.1 (16.8)		32.8 (17.2)	31.7 (16.7)
Median (range)	21 (2–72)	27.5 (2–76)		30 (3–72)	26.5 (2–76)
IQR (Q1–Q3)	23 (13–36)	27 (19–46)		27.5 (19–46.5)	25 (19–44)
Male	286 (44.7%)	74 (48.7%)	0.13	68 (45.9%)	71 (48%)	0.09
Region
North East	80 (12.5%)	40 (26.3%)	0.33	33 (22.3%)	38 (25.7%)	0.03
North Central	143 (22.3%)	33 (21.7%)	0.05	28 (18.9%)	33 (22.3%)	0.13
South	276 (43.1%)	54 (35.5%)	−0.18	54 (36.5%)	53 (35.8%)	−0.01
West	137 (21.4%)	25 (16.4%)	−0.14	33 (22.3%)	24 (16.2%)	−0.16
Unknown	4 (0.6%)	–		–	–
Duration of follow-up (month)			−0.07			−0.01
Mean (SD)	16.3 (8.1)	15.7 (8.1)		15.6 (8)	15.4 (8.1)
Median (range)	19 (0.1–24)	16.9 (0.2–24)		17.6 (0.2–24)	16.7 (0.2–24)
IQR (Q1–Q3)	14.9 (9.1–24)	15.8 (8.2–24)		14.8 (9.2–24)	16.1 (7.9–24)
CCI			0.66			−0.14
Mean (SD)	1 (1.5)	1 (1.5)		1.2 (1.8)	1 (1.5)
Median (range)	0 (0–11)	0 (0–9)		0.5 (0–11)	0 (0–9)
IQR (Q1–Q3)	2 (0–2)	1.5 (0–1.5)		2 (0–2)	1.5 (0–1.5)
Selected comorbidities
Depression	162 (25.3%)	52 (34.2%)	0.21	49 (33.1%)	50 (33.8%)	0.03
Anxiety	168 (26.3%)	63 (41.4%)	0.31	51 (34.5%)	60 (40.5%)	0.11
Cognitive impairment	69 (10.8%)	23 (15.1%)	0.18	25 (16.9%)	22 (14.9%)	0
Vitamin deficiencies	97 (15.2%)	32 (21.1%)	0.17	31 (20.9%)	30 (20.3%)	0
Headache	207 (32.3%)	74 (48.7%)	0.30	66 (44.6%)	73 (49.3%)	0.04
Number of unique ASM received			−0.18			0
Mean (SD)	4.4 (1.7)	4.3 (1.9)		4 (1.5)	4.3 (1.9)
Median (range)	4 (1–12)	4 (1–11)		4 (1–9)	4 (1–11)
IQR (Q1–Q3)	2 (3–5)	2 (3–5)		2 (3–5)	2 (3–5)
Any use of head CT/MRI	398 (62.2%)	137 (90.1%)	0.53	134 (90.5%)	143 (96.6%)	−0.04
Any epilepsy-related inpatient admission	328 (51.3%)	122 (80.3%)	0.51	105 (70.9%)	118 (79.7%)	0.04
Number of epilepsy-related ED visits			−0.28			−0.35
Mean (SD)	1.8 (2.7)	1.3 (2)		2 (3.5)	1.3 (2)
Median (range)	1 (0–21)	0 (0–9)		1 (0–21)	0 (0–9)
IQR (Q1–Q3)	3 (0–3)	2 (0–2)		2 (0–2)	2 (0–2)
Number of epilepsy-related physician visits			−0.20			−0.05
Mean (SD)	8.9 (8.8)	7.9 (5.4)		7.8 (5.9)	8.1 (5.4)
Median (range)	8 (0–175)	7 (0–27)		7 (0–31)	7 (0–27)
IQR (Q1–Q3)	6 (5–11)	7 (4–11)		6 (4–10)	7.5 (4–11.5)
Any epilepsy-related physician visits	611 (95.5%)	142 (93.4%)	−0.28	131 (88.5%)	139 (93.9%)	−0.02
Cost ratio
≤1	473 (73.9%)	83 (54.6%)	−0.34	89 (60.1%)	82 (55.4%)	0.03
1<–≤2	105 (16.4%)	45 (29.6%)	0.27	43 (29.1%)	42 (28.4%)	−0.09
2<–≤3	24 (3.8%)	12 (7.9%)	0.16	7 (4.7%)	12 (8.1%)	0.08
>3	38 (5.9%)	12 (7.9%)	0.06	9 (6.1%)	12 (8.1%)	0.03
Epilepsy-related total costs (matched on cost ratio)			0.15			−0.01
Mean (SD)	$88,392 (151,133)	$115,465 (114,799)		$99,726 (122,717)	$115,782 (116,216)
Median (range)	$47,481 (18.9–1,516,001)	$81,580 (97–733,489)		$67,995 (19–922,455)	$80,831 (97–733,489)
IQR (Q1–Q3)	$73,889 (20,650–94,538)	$96,603 (45,440–142,043)		$102,637 (28,631–131,268)	$100,059 (44,160–144,219)

Abbreviations. ASM, anti-seizure medications; CCI, Charlson Comorbidty Index; CT, computed tomography; DBS, deep brain stimulation; ED, emergency department; MRI, magnetic resonance imaging; RNS, responsive neural stimulation; VNS, vagus neural stimulation.

Note. Unless otherwise noted, values are number of patients (%).

Table 2. Healthcare resource following neurostimulation.

Utilization measure	Including index date						Excluding index date
	12-month follow-up		p-Value	24-month follow-up		p-Value	12-month follow-up		p-Value	24-month follow-up		p-Value
	VNS (N = 148)	RNS/DBS (N = 148)		VNS (N = 148)	RNS/DBS (N = 148)		VNS (N = 148)	RNS/DBS (N = 148)		VNS (N = 148)	RNS/DBS (N = 148)
All-cause
Hospitalizations
≥1 admissions	31 (20.9%)	148 (100%)	<.001	43 (29.1%)	148 (100%)	<.001	30 (20.3%)	59 (39.9%)	<.001	42 (28.4%)	66 (44.6%)	.004
Median (range)	0 (0–7)	1 (1–9)		0 (0–11)	1 (1–10)		0 (0–7)	0 (0–8)	.01	0 (0–11)	0 (0–9)	.09
IQR (Q1–Q3)	0 (0–0)	1 (1–2)		1 (0–1)	1 (1–2)		0 (0–0)	1 (0–1)		1 (0–1)	1 (0–1)
Mean (SD) LOS	2.0 (6.6)	11.5 (10.8)	<.001	3.4 (11.2)	12.1 (11.6)	<.001	1.6 (5.8)	2.7 (6.1)	.01	3.0 (10.4)	3.3 (6.8)	.07
ED visits
≥1 visits	56 (37.8%)	58 (39.2%)	.80	61 (41.2%)	75 (50.7%)	.08	56 (37.8%)	58 (39.2%)	.80	61 (41.2%)	75 (50.7%)	.08
Mean (SD) visits	1 (2)	0.8 (1.5)	.54	1.5 (2.7)	1.2 (2)	.47	1.0 (2)	0.8 (1.5)	.60	1.5 (2.7)	1.2 (2)	.47
Median (range)	0 (0–14)	0 (0–9)		0 (0–14)	1 (0–17)		0 (0–14)	0 (0–9)		0 (0–14)	1 (0–17)
IQR (Q1–Q3)	1 (0–1)	1 (0–1)		2 (0–2)	2 (0–2)		1 (0–1)	1 (0–1)		2 (0–2)	2 (0–2)
Physicians’ visits
≥1 visits	136 (91.9%)	137 (92.6%)	.82	139 (93.9%)	137 (92.6%)	.6374	136 (91.9%)	137 (92.6%)	.82	139 (93.9%)	137 (92.6%)	.64
Mean (SD) visits	10.7 (12)	7.4 (7.2)	.002	15.1 (21.5)	11.3 (11.5)	.04	10.6 (12)	7.4 (7.2)	.002	15.1 (21.5)	11.2 (11.5)	.04
Median (range)	8 (0–114)	6 (0–56)		11 (0–228)	8 (0–84)		8 (0–114)	6 (0–56)		11 (0–228)	8 (0–84)
IQR (Q1–Q3)	10.5 (3.5–14)	7 (2.5–9.5)		16 (4–20)	12 (3–15)		10.5 (3.5–14)	6.5 (2.5–9)		16 (4–20)	12 (3–15)
Neurologist visits
≥1 visits	93 (62.8%)	100 (67.6%)	.41	98 (66.2%)	100 (67.6%)	.81	93 (62.8%)	100 (67.6%)	.41	98 (66.2%)	100 (67.6%)	.81
Mean (SD) visits	4.8 (9.9)	2.4 (2.6)	<.001	6.5 (18.7)	3.3 (3.7)	.01	4.8 (9.9)	2.4 (2.6)	<.001	6.4 (18.7)	3.3 (3.7)	.01
Median (range)	3 (0–112)	2 (0–11)		4 (0–223)	2 (0–17)		3 (0–112)	2 (0–11)		4 (0–223)	2 (0–17)
IQR (Q1–Q3)	7 (0–7)	4 (0–4)		9 (0–9)	5.5 (0–5.5)		7 (0–7)	4 (0–4)		9 (0–9)	5.5 (0–5.5)
Epilepsy-related
Hospitalizations
≥1 admissions	30 (20.3%)	147 (99.3%)	<.001	42 (28.4%)	147 (99.3%)	<.001	29 (19.6%)	57 (38.5%)	<.001	41 (27.7%)	64 (43.2%)	.01
Median (range)	0 (0–7)	1 (0–9)		0 (0–10)	1 (0–10)		0 (0–7)	0 (0–8)	.01	0 (0–10)	0 (0–9)	.09
IQR (Q1–Q3)	0 (0–0)	1 (1–2)		1 (0–1)	1 (1–2)		0 (0–0)	1 (0–1)		1 (0–1)	1 (0–1)
Mean (SD) LOS	1.9 (6.6)	11.4 (10.7)	<.001	3.2 (10.1)	12.0 (11.5)	<.001	1.6 (5.8)	2.5 (5.6)	.01	2.8 (9.3)	3.2 (6.5)	.08
ED visits
≥1 visits	38 (25.7%)	36 (24.3%)	.78	44 (29.7%)	48 (32.4%)	.61	38 (25.7%)	36 (24.3%)	.78	44 (29.7%)	48 (32.4%)	.61
Mean (SD) visits	0.6 (1.3)	0.5 (1.1)	.73	0.9 (1.9)	0.7 (1.6)	.39	0.6 (1.3)	0.5 (1.1)	.80	0.9 (1.9)	0.7 (1.6)	.39
Median (range)	0 (0–9)	0 (0–7)		0 (0–11)	0 (0–13)		0 (0–9)	0 (0–7)		0 (0–11)	0 (0–13)
IQR (Q1–Q3)	1 (0–1)	0 (0–0)		1 (0–1)	1 (0–1)		1 (0–1)	0 (0–0)		1 (0–1)	1 (0–1)
Physicians’ visits
≥1 visits	123 (83.1%)	121 (81.8%)	.76	128 (86.5%)	123 (83.1%)	.41	123 (83.1%)	121 (81.8%)	.76	128 (86.5%)	123 (83.1%)	.41
Mean (SD) visits	5.7 (5.2)	3.6 (3.6)	<.001	7.2 (6.4)	5 (5)	.001	5.7 (5.2)	3.6 (3.6)	<.001	7.2 (6.4)	5 (5)	.002
Median (range)	5 (0–27)	3 (0–23)		6 (0–32)	4 (0–26)		5 (0–27)	3 (0–23)		6 (0–32)	4 (0–26)
IQR (Q1–Q3)	7 (1–8)	4 (1–5)		9 (2–11)	6 (1–7)		7 (1–8)	4 (1–5)		9 (2–11)	6 (1–7)
Neurologist visits
≥1 visits	92 (62.2%)	95 (64.2%)	.73	97 (65.5%)	95 (64.2%)	.82	92 (62.2%)	95 (64.2%)	.73	97 (65.5%)	95 (64.2%)	.82
Mean (SD) visits	4.0 (4.3)	2.2 (2.5)	<.001	4.9 (5.2)	3.1 (3.7)	.004	3.9 (4.3)	2.2 (2.5)	<.001	4.9 (5.2)	3.1 (3.7)	.004
Median (range)	3 (0–18)	2 (0–11)		4 (0–18)	2 (0–17)		3 (0–18)	2 (0–11)		4 (0–18)	2 (0–17)
IQR (Q1–Q3)	7 (0–7)	4 (0–4)		8 (0–8)	5 (0–5)		7 (0–7)	4 (0–4)		8 (0–8)	5 (0–5)
ASM use
Number unique ASMs prescribed
1	20 (13.5%)	16 (10.8%)	.51	18 (12.2%)	16 (10.8%)	.72	21 (14.2%)	17 (11.5%)	.51	19 (12.8%)	17 (11.5%)	.72
2	34 (23.0%)	34 (23.0%)	1	33 (22.3%)	29 (19.6%)	.57	33 (22.3%)	33 (22.3%)	1	32 (21.6%)	28 (18.9%)	.56
3	44 (29.7%)	44 (29.7%)	1	38 (25.7%)	44 (29.7%)	.45	44 (29.7%)	44 (29.7%)	1	38 (25.7%)	44 (29.7%)	.45
≥4	45 (30.4%)	47 (31.8%)	.81	54 (36.5%)	54 (36.5%)	1	45 (30.4%)	47 (31.8%)	.81	54 (36.5%)	54 (36.5%)	1
Mean (SD)	2.8 (1.4)	2.9 (1.5)	.42	3.1 (1.6)	3.1 (1.6)	.52	2.8 (1.4)	2.9 (1.5)	.44	3.1 (1.6)	3.1 (1.6)	.54
Median (range)	3 (0–7)	3 (0–10)		3 (0–8)	3 (0–10)		3 (0–7)	3 (0–10)		3 (0–8)	3 (0–10)

Abbreviations. ASM, anti-seizure medications; DBS, deep brain stimulation; ED, emergency department; LOS, length of stay; RNS, responsive neural stimulation; SD, standard deviation; VNS, vagus neural stimulation.

Note. Follow-up period includes the day of the neurostimulation procedure.

Tests for statistical significance including: Standardized difference before matching: Chi-squared/fisher test for binary/categorical variables; Student’s t-test for normal continuous variables; Wilcoxon rank sum for non-normal continuous variables.

Standardized difference after matching: McNemar test for binary/categorical variables; Paired Student’s t-test for normal continuous variables; Wilcoxon signed rank sum for non-normal continuous variables.

Table 3. Healthcare costs following neurostimulation, by time period of interest.

	Including index date						Excluding index date
Healthcare costs	12 Months following neurostimulation			24 Months following neurostimulation			12 Months following neurostimulation			24 Months following neurostimulation
	VNS (N = 148)	RNS/DBS (N = 148)	p-Value	VNS (N = 148)	RNS/DBS (N = 148)	p-Value	VNS (N = 148)	RNS/DBS (N = 148)	p-Value	VNS (N = 148)	RNS/DBS (N = 148)	p-Value
Epilepsy-related	$96,155 (88,083)	$213,896 (150,259)	<.001	$121,961 (136,861)	$234,293 (164,075)	<.001	$34,385 (59,712)	$60,781 (84,711)	.001	$60,191 (111,615)	$81,178 (106,366)	.003
All-cause	$114,120 (95,701)	$227,733 (153,768)	<.001	$150,242 (156,733)	$254,731 (170,277)	<.001	$52,060 (69,292)	$74,520 (89,009)	.01	$88,181 (134,060)	$101,519 (115,278)	.03

Abbreviations. DBS, deep brain stimulation; RNS, responsive neural stimulation; SD, standard deviation; VNS, vagus neural stimulation.

Unless otherwise indicated, all values are mean (SD).

Costs incurred on the index date were allocated to the follow-up period.

Figure 2. Kaplan–Meier time to event analyses. (a) Composite of epilepsy-related admissions and epilepsy-related ED visits, (b) epilepsy-related admissions, and (c) epilepsy-related ED visits. Abbreviations. CI, confidence interval; DBS, deep brain stimulation; ED, emergency department; NE, not estimable; RNS, responsive neural stimulation; VNS, vagus neural stimulation.

Appendix 1. Patient identification using procedure and diagnostic codes.

Procedure codes for VNS
Code	Description
64568	CPT; Incision for implantation of cranial nerve (e.g. vagus nerve) neurostimulator electrode array and pulse generator
L8680	HCPCS; Implantable neurostimulator electrode, each
Procedure codes for RNS/DBS
61850	CPT; Twist drill or burr hole(s) for implantation of neurostimulator electrodes, cortical
61860	CPT; Craniectomy or craniotomy for implantation of neurostimulator electrodes, cerebral, cortical
61863	CPT; Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g. thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array
61864	CPT; Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g. thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; each additional array (List separately in addition to primary procedure)
61867	CPT; Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g. thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array
61868	CPT; Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g. thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; each additional array (List separately in addition to primary procedure)
61885^a	CPT; Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g. thalamus, globus pallidus, subthalamic nucleus, periventricular, peria\ueductal gray), with use of intraoperative microelectrode recording; each additional array (List separately in addition to primary procedure)
61886^a	CPT; Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g. thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; each additional array (List separately in addition to primary procedure)
00H00MZ	ICD-10; Insertion of Neurostimulator Lead into Brain, Open Approach
00H03MZ	ICD-10; Insertion of Neurostimulator Lead into Brain, Percutaneous Approach
00H04MZ	ICD-10; Insertion of Neurostimulator Lead into Brain, Percutaneous Endoscopic Approach
0JH60BZ	ICD-10; Insertion of single array stimulator generator into chest subcutaneous tissue and fascia, open approach
0JH60DZ	ICD-10; Insertion of multiple array stimulator generator into chest subcutaneous tissue and fascia, open approach
0JH60EZ	ICD-10; Insertion of multiple array rechargeable stimulator generator into chest subcutaneous tissue and fascia, open approach
0NH00NZ	ICD-10; Insertion of Neurostimulator Generator into Skull, Open Approach
Diagnostic codes of epilepsy
345.**	ICD-9; Epilepsy and recurrent seizures
780.3*	ICD-9; Convulsions
G40.**	ICD-10; Epilepsy and recurrent seizures
G41.**	ICD-10; Status epilepticus
R56.**	ICD-10; Convulsions, not elsewhere classified
Procedure codes for cranial epilepsy surgery
61534	CPT; Craniotomy with elevation of bone flap; for excision of epileptogenic focus without ECoG during surgery
61536	CPT; Craniotomy with elevation of bone flap; for excision of epileptic focus, with ECoG during surgery
61537	CPT; Craniotomy with elevation of bone flap; for lobectomy, temporal lobe, without ECoG during surgery
61538	CPT; Craniotomy with elevation of bone flap; for lobectomy with ECoG during surgery, temporal lobe
61539	CPT; Craniotomy with elevation of bone flap; for lobectomy other than temporal lobe, with ECoG during surgery
61540	Craniotomy with elevation of bone flap; for lobectomy other than temporal lobe, without ECoG during surgery
61541	CPT; Craniotomy with elevation of bone flap; for transection of corpus callosum
61543	CPT; Craniotomy with elevation of bone flap; for partial or subtotal hemispherectomy
61566	CPT; Craniotomy with elevation of bone flap; for selective amygdalohippocampectomy
61567	CPT; Craniotomy with elevation of bone flap; for multiple subpial transections, with electrocorticography during surgery

ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification; ICD-10-CM: International Classification of Diseases, Tenth Revision, Clinical Modification; CPT-4: Current Procedural Terminology, 4th Edition; HCPCS: Healthcare Common Procedure Coding System procedure codes.

^aTo be included in the RNS/DBS cohort, patients with CPT 61885 or 61886 (insertion or replacement of neurostimulator) were also required to have procedure codes for twist drill, burr hole, craniotomy, or craniectomy (CPT 61863, 61864, 61850, 61860, 61867, 61868) or procedure codes for insertion of the neurostimulator into the brain or skull (ICD-10 00H00MZ, 00H03MZ, 00H04MZ, 0NH00NZ) on the index date or within 41 days after to identify newly implanted patients.

Appendix 2. ASM medications.

Generic drug name
Adrenocorticotropic hormone
Brivaracetam
CANNABIDIOL
Carbamazepine
Cenobamate
Clobazam
Clonazepam
Diazepam
Divalproex sodium
Eslicarbazepine
Ethosuximide
Everolimus
Felbamate
Fosphenytoin
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Methsuximide
Oxcarbazepine
Perampanel
Phenobarbital
Phenytoin
Pregabalin
Primidone
Rufinamide
Tiagabine
Topiramate
Valproic acid
Valproate sodium
Vigabatrin
Zonisamide