Vagus Nerve Stimulation Therapy

James W. Wheless

Epilepsy and seizures affect at least 2.3 million individuals in the United States (1). Although antiepileptic drugs (AEDs) are the primary form of treatment, recent outcome surveys reveal only mixed success even with the new AEDs that have become available over the past decade (2,3). Approximately one-third of patients have seizures that are unresponsive to pharmacologic therapy. In addition, safety and tolerability issues associated with both the acute and chronic side effects and toxicity complications further diminish the effectiveness of AEDs (4, 5, 6, 7, 8, 9, 10). Other treatment options are available for select subgroups of patients, including the ketogenic diet, which provides benefit to some children (11,12), and epilepsy surgery, which may manage or lessen poorly controlled seizures in 10% to 25% of patients (1). However, children and adults with uncontrolled seizures continue to carry a sad burden of higher mortality rates, higher rates of accidents and injuries, greater incidence of cognitive and psychiatric impairment, poor self-esteem, higher levels of anxiety and depression, and social stigmatization or isolation compared with the nonepileptic population (13). The shortcomings of AEDs, the ketogenic diet, and epilepsy surgery in improving overall outcome highlight the need for other treatments, one of which is vagus nerve stimulation (VNS) therapy.

HISTORY

The effect of VNS on central nervous system (CNS) activity has been documented, with early attempts in the 1880s linking electrical vagal nerve and cervical sympathetic stimulation and carotid artery compression to the treatment of seizures (14). In the mid-1980s, Jacob Zabara, a biophysicist at Temple University, again suggested that electrical stimulation of the vagus nerve might prevent seizures. VNS therapy resulted from a hypothesis, formulated during his wife’s Lamaze class, that the Lamaze method activated stretch receptors in the lungs, which in turn activated the vagus nerve (15). Vagus stimulation in the neck could quiet the abdominal muscle contractions that produce vomiting; Dr. Zabara likened these contractions to convulsions. Zabara believed that if VNS could alleviate vomiting and affect electroencephalographic (EEG) findings, it might ameliorate epilepsy. This theory was proved in his first canine studies (16), and a company—Cyberonics, Inc. (Houston, Texas)—was founded in 1987 to develop VNS therapy, which would be delivered by a patented method using a generator device modeled after a cardiac pacemaker.

In 1988, the first patient to have a VNS therapy device implanted became seizure free (Table 71.1) (17). Five acute-phase clinical studies analyzing the safety and effectiveness of VNS therapy followed (Table 71.2). The first two single-blind trials showed improved control in adults with intractable partial seizures who were not candidates for epilepsy surgery (17, 18, 19). The subsequent two randomized, blinded, active-control trials (E03, E05) led to approval of VNS therapy by the US Food and Drug Administration (FDA) in July 1997 for the adjunctive treatment of refractory partial-onset seizures among patients 12 years of age or older. VNS therapy is also approved for the treatment of epilepsy and depression independent of age in more than 24 countries around the world, including member nations of the European Union, Canada, and Australia. As of July 2003, more than 22,000 patients have received implants world-wide.

The VNS therapy system is made up of a pulse generator, a bipolar VNS lead, a programming wand with accompanying software for an IBM-compatible laptop or hand-held computer, a tunneling tool, and hand-held magnets (Fig. 71.1) (20,21). The pulse generator transmits electrical signals to the vagus nerve through the bipolar lead. The
software allows placement of the programming wand over the pulse generator for reading and altering stimulation parameters (Fig. 71.2; Table 71.3). Each stimulation is preceded by 2 seconds of ramp-up time and followed by 2 seconds of ramp-down time. Two models of the VNS therapy system are currently in use: the Model 101 and the newer Model 102 (currently available only in the United States). The Model 102 titanium generator is thinner (6.9 mm), lighter (25 g), and has less volume (52.2 mm in diameter) than the previous generator models. (See the Addendum for sources of information on the VNS therapy system.)

TABLE 71.1 HISTORY OF VNS THERAPY

1985	First animal studies
1988	First human implant
1992	First randomized active control study (E03) completed
1994	European community approval
1996	Second randomized active control study (E05) complete
1997	US Food and Drug Administration commercial approval
July 2003	22,000+ implants world-wide

EFFICACY

The two pivotal studies—E03 and E05—were designed to demonstrate that high (therapeutic) and low (nontherapeutic) stimulation of the vagus nerve had different effects on the frequency of partial seizures (22,23). The effects of VNS therapy during the 12-week randomized phases of the studies, which began 2 weeks after implantation, were gauged against 12- to 16-week baseline periods. E03 acute-study patients (N = 114 implanted) had epilepsy for an average of 22 years. Seizure frequency was reduced by at least half in 31% of patients in the high-stimulation group, compared with 14% in the low-stimulation group. No patients became seizure free during the acute phase, but some reported reduced seizure severity and improved postictal recovery periods. Patients in the high-stimulation group either aborted or decreased 59.8% of seizures with the magnet. No factors were identified that predicted response.

TABLE 71.2 EFFICACY OF VNS THERAPY IN CLINICAL STUDIES

Study	Design	Seizure Type	No. of Patients	Age of Patients (y)	First Implant	No. of Patients with >50% Response (%)	Mean Reduction in Seizures/Day (%)
E01	Pilot, longitudinal	Partial	11	20-58	1998	30	24^a
E02	Pilot, longitudinal	Partial	5	18-42	1990	50	40
E04	Open, longitudinal	All types	124	3-63	1990	29	7^a
E03	Randomized, parallel, high/low	Partial	115	13-57	1991	31/14	24^a/6
E05	Randomized, parallel, high/low	Partial	198	13-60	1995	23/16	28^b/15^b
^aP ≤0.05, by student’s t test. ^bP <0.0001, by analysis of variance.

The similarly designed Study E05 was the largest prospective, controlled trial of a device for epilepsy treatment ever conducted (23). Patients (N = 199) had a median of 0.51 to 0.58 seizures per day during baseline. One patient receiving high stimulation became seizure free, and 23.4% of patients had a 50% or more reduction in seizure frequency after 3 months of treatment. The presence or absence of aura did not predict efficacy. Of the implanted patients, 99% completed the study.

Long-Term Studies

All patients exiting Study E03 were offered indefinite open-label treatment at high (effective) stimulation; 100 (88%) of the 114 patients completed an additional 12 months of VNS therapy at therapeutic stimulation levels (14 patients discontinued because of lack of efficacy but were included in the analysis as intent-to-treat). A median 20% reduction in seizure frequency occurred in the first 3 months of the extension study and improved over the ensuing months (24). In two thirds of patients, a minimum 50% reduction during the initial 3 months continued during months 10 through 12. Results among the 195 patients in the continuing long-term E05 study showed a 50% or more reduction in seizure frequency in 35% of patients and a 75% or more reduction in 20% of patients after an additional 12 months of VNS therapy at therapeutic stimulation levels (25). The median reduction in seizure frequency was 45%, with seizure frequency reductions sustained over time and only mild to moderate side effects reported.

One study of 10 adults with intractable partial seizures revealed a 10-fold increase in the mean number of 14-day
seizure-free periods after 50 months of VNS therapy with stable AED dosages (26). Seizure-free periods increased every year; one patient continued to be seizure free after 36.5 months. A prospective, open evaluation of 64 patients reported results for up to 5 years of follow up (27). No change in AED dosages occurred during the first 6 months of VNS therapy, which lasted an average of 20 months. Nineteen of 47 patients with partial seizures, five of nine with idiopathic generalized seizures, and five of eight with Lennox-Gastaut syndrome had a seizure reduction of greater than 50% or more. In this population with refractory seizures, 44% experienced a substantial reduction in severity and frequency over a long period. A recent report on long-term outcomes of 30 patients receiving VNS therapy (28) showed continued improvements over time, with 54% of patients at 1 year and 61% at 2 years exhibiting seizure frequency reductions of 50% or more compared with baseline. The mechanisms underlying the gradual improvements in response to VNS therapy seen over time in these long-term studies, however, have yet to be elucidated.

Figure 71.1 Components of the vagus nerve stimulation therapy system.

Figure 71.2 Therapy stimulation parameters of vagus nerve stimulation.

Pediatric, Elderly, and Special Populations

Studies indicate that response to VNS therapy is independent of age, seizure type, or syndrome. The largest retrospective pediatric study to date showed the same median reduction in seizure frequency of 51% at 6 months among patients aged 12 to 18 years (n = 56) and among those less than 12 years of age (n = 20) (29). Particularly favorable results, including reduced seizure frequency and severity and improved quality of life (QoL), have been reported among patients in open studies of Lennox-Gastaut syndrome and other refractory childhood epilepsies, such as hypothalamic hamartomas, epileptic encephalopathies, and tuberous sclerosis complex (29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41). Verbal performance, alertness, motor and cognitive functions, and general behavior improved, sometimes dramatically (33,36,42,43). A retrospective study (44) showed that improved QoL (particularly in the area of alertness) was associated with VNS therapy in patients with autism (n = 59) or Landau-Kleffner syndrome (LKS; n = 6), with more than half of the patients
in each group also experiencing a 50% or more reduction in seizure frequency at follow-up (12 months of follow up for autism and 6 months for LKS patients). Studies have also shown both seizure frequency reductions and improved QoL among both institutionalized and noninstitutionalized patients with mental retardation/developmental delay (MRDD) (45,46). Small open studies of VNS in patients with symptomatic generalized epilepsy demonstrated reductions in seizure frequency of 41% (median) (47) and 46% (mean) (48). VNS therapy also successfully stopped a case of refractory generalized convulsive status epilepticus in a patient 13 years of age (49).

TABLE 71.3 VNS THERAPY PARAMETERS

	High	Low	Rapid Cycling^a
VNS current (mA)	Up to 3.5	1.2 (0.25-2.75)	Up to 3.5
Frequency (Hz)	30 (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)	1 (to 2)	30
Pulse width (ms)	500	130	500
On time (s)	30 (to 90)	30	7
Off time (min)	5 (to 10)	180 (60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180)	0.2
Magnet current (mA)	Same as VNS	0	Same as VNS
On time (s)	30 (to 90)	30	30
Pulse width (μs)	500	130	500
Values in bold type are the most common settings from the E03 and E05 studies.
^aFrom refs. 27, 33, and 109 with permission.
VNS = vagus nerve stimulation.