Epilepsy & Behavior 2, 563–567 (2001)doi:10.1006/ebeh.2001.0286, available online at http://www.idealibrary.com on

Vagus Nerve Stimulation for Patientsin Residential Treatment Facilities1

John Gates, M.D.,* ,2 Roger Huf, M.D.,† and Michael Frost, M.D.**Minnesota Epilepsy Group, PA, St. Paul, Minnesota 55102; and†Huntington Memorial Hospital, Pasadena, California

Received June 4, 2001; revised September 25, 2001; accepted for publication October 1, 2001

This analysis compared the effectiveness of vagus nerve stimulation (VNS) therapy among patientswith intractable seizures: a group living in residential treatment facilities (RTF) with a group not livingin RTFs (non-RTF). Among a constant cohort of patients with baseline, 3-month, and 12-month data,the RTF group had significantly (P < 0.05) larger numbers of patients with generalized seizures,previous callosotomy, psychiatric disorders, behavioral problems, and Rett’s syndrome. Medianseizure reductions after 3 months were 33% in the RTF group and 49% in the non-RTF group (P <0.001); after 12 months, 50% (RTF) and 56% (non-RTF). After both 3 and 12 months, alertness, mood,postictal recovery, and cluster seizures improved in more than a third of patients in both groups.Because VNS therapy does not interact with medications and is delivered automatically, it should beseriously considered for patients with intractable epilepsy who reside in RTFs. © 2001 Elsevier Science

Key Words: epilepsy; institutionalized; residential treatment facility; database; registry; vagus nervestimulation.

INTRODUCTION

Among the estimated 50 million persons worldwidewith epilepsy, 20 to 30% have seizures that are consid-ered refractory to standard antiepileptic therapies (1, 2).Approximately 10 to 20% of cognitively challenged per-sons have epilepsy (3), and approximately 45% haveintractable seizures (4). Furthermore, among patientswith deficits severe enough to justify placement in resi-dential treatment facilities (RTFs), the prevalence of ep-ilepsy ranges from 40 to 60%.

Patients who have epilepsy and are receiving treat-ment in RTFs often have additional disabilities thatfurther complicate their medical management. Suchdisabilities may include cerebral palsy, attention def-icit disorder, autism, dysphasia, dyslexia, motor skilldisorders, and comorbid psychiatric disorders (3). Inaddition to requiring AEDs for epilepsy, patients mayrequire additional medications to treat their other dis-

1 This work was supported in part by a grant from Cyberonics,Inc, Houston, Texas.

2 To whom correspondence should be addressed at MinnesotaEpilepsy Group, PA, 310 Smith Avenue North, Suite 300, St. Paul,MN 55102. Fax: (651) 220-5248. E-mail: GATERAIR@aol.com.

1525-5050/01 $35.00© 2001 Elsevier ScienceAll rights reserved. 563

orders. Receiving multiple medications renders thisgroup particularly vulnerable to medication side ef-fects, systemic safety effects, and drug interactions.Furthermore, neurotoxic effects may worsen an al-ready poor prognosis.

In July 1997, the U.S. Food and Drug Administration(FDA) approved vagus nerve stimulation (VNS) as anadjunctive therapy for patients aged 12 years and olderwho have refractory partial onset seizures. Because VNSdoes not have pharmacokinetic interactions with AEDtherapies and does not require supervised administra-tion, it is an attractive therapy for patients who haveintractable epilepsy and who are living in RTFs.

Our goal for this study was to compare the effec-tiveness of VNS therapy among patients who haveintractable seizures and are living in RTFs with thatamong similar patients who are not living in RTFs.

METHODS

Objective

This analysis compared changes in seizure fre-quency and quality of life during the first 12 months of

564 Gates, Huf, and Frost

VNS therapy among patients who were in RTFs (RTFgroup) with those among patients who were not inRTFs (non-RTF group). We hypothesized that re-sponses to VNS therapy are similar for both groups.

Patient Outcome Registry Methodology and DataCollection

Data for the analyses were drawn from the VNSPatient Outcome Registry (registry). The registry col-lects information on patient demographics, device set-tings, quality of life, and effectiveness of seizure con-trol among patients receiving VNS therapy. Physi-cians voluntarily submit patient data at the initiationof VNS therapy and at various time points thereafter.Medical history forms are submitted at the initiationof therapy, and follow-up forms are submitted at sub-sequent office or clinic visits. To comply with FDAregulations, information about adverse events is col-lected in a separate database rather than the patientregistry (5).

During January 2001, the registry was queried forpatients who were and patients who were not in RTFswhen VNS therapy was initiated. A constant cohort ofpatients with data at initiation of VNS therapy and at3- and 12-month follow-ups were identified. Patientswho achieved reductions in seizure frequency of 50%or more were classified as responders. The data weresummarized into tables with descriptive statistics,such as means, medians, and percentages. Changesover time and differences between treatments werecompared with nonparametric methods for ordinaldata including the two-sample test and Wilcoxon two-sample test. The signed rank test was used to measurechanges within groups. The repeated-measures anal-ysis of variance for percentage change was used tomeasure time effect and interaction between time andgroup. Statistical significance was assumed when P ,0.05. All analyses were performed with SAS software(SAS Institute Inc; Cary, NC).

During each follow-up visit, physicians subjectivelyassessed changes in patient quality of life in the areasof alertness, verbal communication, memory, achieve-ment at work or school, mood, postictal period, andseizure clustering. To compare the patient’s quality oflife before initiation of VNS therapy with follow-updata, ratings were assigned according to an unvali-dated 5-point scale (much worse, worse, same, better,or much better). Ratings of much worse and worse aswell as better and much better were collapsed to sim-plify analysis and provide three levels of scores:worse, same, and better.

© 2001 Elsevier ScienceAll rights reserved.

Treatment Description

Vagus nerve stimulation is delivered through theNeuroCybernetic Prosthesis (NCP) System (Cyberon-ics, Houston, TX). The pulse generator component ofthe system is implanted subcutaneously just below theclavicle. The bipolar lead component is subcutane-ously tunneled from the stimulation site on the leftvagus nerve just above the clavicle to the pulse gen-erator. Implantation is typically accomplished duringa surgical procedure lasting 1 to 2 hours. Some pa-tients recover sufficiently to be discharged from thehospital on the day of implantation. The physicianuses a laptop or handheld computer to program de-vice settings and provide continual VNS cycles tai-lored for the patient. Patients receive NCP magnets toswipe over the pulse generator and initiate an extraburst of stimulation that might interrupt or reduce theseverity of a seizure. The magnet can also be tapedover the pulse generator to interrupt the VNS cycles(6). With regard to AEDs and other medications, phy-sicians continue, add, discontinue, or adjust dosagesaccording to their medical judgment.

RESULTS

Demographics

Query of the registry yielded a constant cohort of 86patients living in RTFs and 690 patients not living inRTFs and with data available at initiation and afterboth 3 and 12 months of VNS therapy. Table 1 pro-vides demographics for both groups. Because thesevariables were not normally distributed in each pa-tient group, the Wilcoxon two-sample test was used tocompare the medians of each group. Statistically sig-

TABLE 1

Demographics

Variable Group Mean SD Median Range

Age (years)a RTF 31.2 111.9 30 7–59Non-RTF 27.6 114.8 27 2–79

Age at onset (years)a RTF 4.2 14.3 3 0–17Non-RTF 8.1 19.5 5 0–53

Duration of epilepsy(years)a

RTF 26.4 111.8 24.5 3–56Non-RTF 19.4 112.7 16 1–63

Weight (lb) RTF 145.9 150.4 138 34–280Non-RTF 137.4 156.3 140 28–323

Number of AEDsbefore implanta

RTF 2.7 10.9 3 1–5Non-RTF 2.4 10.9 2 0–5

a Statistically significant differences (P , 0.05).

565VNS for Patients in Residential Treatment Facilities

nificant differences between groups were observed forage (P 5 0.0102), age at onset (P 5 0.0046), durationof epilepsy (P , 0.0001), and baseline anticonvulsant(AED) count (P 5 0.0051). The RTF group had 58males and 28 females and the non-RTF group had 345males and 345 females. The greater number of malesin the RTF group was statistically significant (P 50.0023, Wilcoxon).

The medical history of the two groups varied con-siderably. Table 2 provides the percentage of patientsin each group whose medical history forms indicatedthe presence of the particular characteristic. Statisti-cally significant differences were observed in the per-centage of patients with generalized seizures: RTF33.7%, non-RTF 18.8% (P 5 0.0013, Wilcoxon); previ-ous callosotomy: RTF 11.6%, non-RTF 5.5% (P 50.0264); psychiatric disorders: RTF 40.7%, non-RTF22.2% (P 5 0.0002); behavioral problems: RTF 43.0%,non-RTF 20.6% (P , 0.0001); and Rett’s syndrome:RTF 2.3%, non-RTF 0 (P , 0.0001).

In descending order, at baseline the five most fre-quently prescribed AEDs in the RTF group werecarbamazepine, valproate, lamotrigine, topiramate,and phenytoin. In the non-RTF group, the order wascarbamazepine, lamotrigine, topiramate, valproate,and phenytoin.

TABLE 2

Medical History Percentage Reported as “YES”

Variable RTF Non-RTF

Etiology known 39.5 42.8Abnormal MRI 60.8 51.6Localized syndrome 45.3 66.5Generalizeda 33.7 18.8Lennox–Gastaut syndrome 18.6 12.2Juvenile myoclonic epilepsy 0.0 0.0Congenital brain malformation 16.3 11.6Meningitis encephalitis 10.5 10.1Vascular brain malformation 1.2 3.0Evaluated for epilepsy surgery 55.8 65.7Previous callosotomya 11.6 5.5Previous lobectomy 7.0 11.2Previous any other intracranial surgery 5.8 8.4Brain tumor 2.3 5.1Head injury 11.6 15.7Psychiatric disordera 40.7 22.2Depression 4.7 10.9Behavioral problemsa 43.0 20.6Cerebral palsy 8.1 4.8Autism 2.3 2.5Rett’s syndromea 2.3 0.0Tuberous sclerosis 1.2 1.4

a Statistically significant differences (P , 0.05).

Reduction in Seizure Frequency

Mean seizure frequency was reduced after 3 monthsof VNS therapy in the RTF group by 27% (median33%) and in the non-RTF group by 36% (median 49%).Within-group reductions after 3 months of treatmentwere statistically significant (P , 0.001, signed rank).After 12 months of therapy, mean seizure frequencywas reduced in the RTF group by 28% (median 50%)and in the non-RTF group by 39% (median 56%).Within-group changes after 12 months of treatmentwere not statistically significant. The percentage ofchange in seizure frequency from baseline was notnormally distributed in either group. Between-groupcomparisons (two-sample test or Wilcoxon performedfor both time points) do not suggest statistically sig-nificant differences in percentage change betweengroups. The repeated-measures analysis of variancefor percentage change found no evidence of time effectfor either time point or interaction between time andgroup. However, the P value of 0.0735 approachesstatistical significance for the between-group compar-ison.

After 3 months of VNS therapy, 41% of the patientsin the RTF group and 50% of the non-RTF group wereclassified as responders (.50% reduction in seizurefrequency). After 12 months, 55% of the RTF groupand 56% of the non-RTF group were classified asresponders. Table 3 lists the percentages of patientsachieving reductions in seizure frequency of .50%,.75%, .90%, and no seizures reported for bothgroups at both time points. Between-group differenceswere not statistically significant at either time point forseizure reductions .50%, .75%, and .90% and for noseizures reported.

Device Settings

Table 4 shows that median device settings wereidentical for both groups at each time period. Pulsewidth, frequency, and ON time remained unchanged.Output current increased and OFF time decreased.

TABLE 3

Percentage Change in Seizure Frequency

3 Months 12 Months

RTF Non-RTF RTF Non-RTF

.50% reduction 41 50 55 56

.75% reduction 21 28 34 36

.90% reduction 9 13 16 19No seizures reported 1 5 1 6

© 2001 Elsevier ScienceAll rights reserved.

566 Gates, Huf, and Frost

These device settings reflect a trend of patients receiv-ing more stimulation more often. After 12 months,VNS therapy was discontinued in one patient in theRTF group and four patients in the non-RTF group.

Quality of Life

Improvements in alertness, verbal communication,memory, achievement at school or work, mood, post-ictal period, and seizure clustering were noted inpatients in both groups, with improvement in morepatients after 12 months than after 3 months (Table 5).At both 3 and 12 months, more than one-third ofpatients in both groups reported better or much betteralertness, mood, postictal recovery period, and clusterseizures. The improvement in memory among thenon-RTF group was significantly greater than in theRTF group at both 3 months (P 5 0.0236, Wilcoxontwo-sample test) and 12 months (P 5 0.0004).

TABLE 4

Device Settingsa

Setting

Initial visit

RTF Non-RTF

Output current (mA) 0.25 (0.25–1.00) 0.25 (0.25–2.00) 1Pulse width (ms) 500 (250–500) 500 (130–1000)Frequency (Hz) 30 (20–30) 30 (2–30)ON time (s) 30 (30–30) 30 (7–60)OFF time (min) 5.0 (0.5–10) 5.0 (0.2–180)

a Values given as median (range).

TABLE 5

Quality of Life: Percentage of Patients Reportedas “Better” or “Much Better”

3 Months 12 Months

RTFgroup

Non-RTFgroup

RTFgroup

Non-RTFgroup

Alertness 58 52 57 61Verbal communication 26 34 30 36Memorya 16 27 19 35School or professional

achievements 17 26 31 33Mood changes 35 34 47 42Postictal state 57 50 56 57Cluster seizures 38 41 51 46

a Statistically significant improvements after 3 months of VNS(P 5 0.0236, Wilcoxon) and after 12 months of VNS (P 5 0.0017).

© 2001 Elsevier ScienceAll rights reserved.

DISCUSSION

Patients who live in RTFs often have complex be-havioral, emotional, physical, and cognitive chal-lenges that are exacerbated by medically refractoryseizures. This analysis shows that the responses toVNS therapy are similar among patients in RTFs andthe remaining patients in the outcome registry.

In our clinical practice, we have observed that thebehavioral difficulties that can result in placement ofpatients in RTFs are more common among male thanfemale patients. In this constant cohort, more thantwice as many males as females were living in RTFs,whereas males and females were equally distributedin the non-RTF group.

Evaluation of patients in RTFs can be particularlychallenging, especially in light of the multiple disor-ders that characterize this population. In this study,partial seizures were reported for 45% of the RTFgroup. Given the extent of brain damage typicallypresent in patients in RTFs, partial seizures may havebeen underreported.

The unique treatment profile of VNS may presentinherent advantages and disadvantages that should beconsidered for patients in RTFs. Of considerable im-portance among RTF populations is the lack of medi-cation interactions with VNS therapy. Because comor-bid conditions are the rule rather than the exceptionfor patients in RTFs, these patients typically receive agreater number of medications than non-RTF patients.Vagus nerve stimulation can serve as an adjunctivetherapy to an existing drug regimen without concernsfor interactions with other medications that the patientmay receive either concurrently or emergently.

Another consideration is that VNS has no reportedCNS-related side effects such as lethargy, cognitivedullness, and idiosyncratic reactions, e.g., rash, renalimpairment, or bone marrow suppression that accom-

3-Month visit 12-Month visit

F Non-RTF RTF Non-RTF

–3.0) 1.25 (0.25–3.5) 1.75 (0.5–3.5) 1.75 (0.25–3.5)0–750) 500 (130–1000) 500 (130–1000) 500 (130–1000)–30) 30 (10–40) 30 (15–30) 30 (5–40)60) 30 (7–60) 30 (7–60) 30 (7–60)–10) 5.0 (0.2–60) 3.0 (0.2–30) 3.0 (0.2–30)

RT

.25 (0.5500 (2530 (2030 (7–5.0 (0.2

567VNS for Patients in Residential Treatment Facilities

pany many AEDs. Recent information indicates thatgiven careful consideration, some concurrent AEDsmay be reduced during VNS therapy (7).

Quality-of-life benefits such as improved cognition,reduced seizure severity, improved mood, and en-hanced memory have been associated with VNS ther-apy (7). As observed in this study, the quality of life ofboth the RTF and non-RTF groups clearly benefitedfrom VNS.

Compliance with medication regimens is a frequentissue among patients in RTFs. A patient’s refusal totake medications can result in hospitalization for theadministration of intravenous medications. BecauseVNS therapy is delivered automatically, compliance isnot a concern.

Given the complex medical conditions characteristicof many patients in RTFs, patient evaluation for VNStherapy should include several considerations. First,implanting the pulse generator requires a surgical pro-cedure. Relatively straightforward and simple, thesurgery has been associated on rare occasions withinfection and nerve damage (8). Severe vagal damagehas been associated with vocal cord paralysis andswallowing difficulties (9). Additionally, VNS therapydelivered at higher stimulation settings has been as-sociated with increased apneic events in patients withpreexisting apnea. Adjusting stimulation can elimi-nate apneic events, but they should be consideredbefore initiating treatment (10).

Limitations of Study

This study was not an “intent to treat” prospectivestudy; rather, the data were collected retrospectively.The number of patients in the two groups differedgreatly. Because data were submitted voluntarily,some bias could be present. If so, the bias is probablypresent in reports of both groups. Because these datawere collected retrospectively, there were no protocolrequirements requiring standardization of stimulationparameters or maintenance of number and dose ofcomedications. Because physicians were at liberty toadd, discontinue, or change the dosage of AEDs orother medications during the 12-month study,changes in seizure frequency and quality of life couldreflect changes in medications.

CONCLUSIONS

Patients in RTFs who also have intractable seizurespresent unique challenges for medical management.This comparison of outcome data of patients in RTFswith data on other patients in the registry revealedthat both groups responded similarly to VNS therapy.After 12 months of VNS therapy, responder rates of 55and 56% were obtained for the RTF and non-RTFgroups, respectively. Because VNS treatment does notinteract with medications and can be automaticallydelivered to the patient without intervention from thecaregiver, VNS treatment should be seriously consid-ered for patients who are in RTFs and have intractableepilepsy. The decision should be balanced againsteach patient’s estimated tolerance for the implantationprocedure.

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© 2001 Elsevier ScienceAll rights reserved.