Outcome of long-term vagus nerve stimulation for intractable epilepsy

The outcome of long-term vagus nerve stimulation (VNS) was evaluated in 13 Japanese patients with intractable epilepsy, all followed up for more than 4 years (48-91 months, median 56 months). VNS achieved a long-lasting and cumulative seizure-control effect in nine of 13 patients. The mean reduction of seizure frequency in the 1st to 4th year was 28%, 47%, 54%, and 63%, respectively. The percentage of patients with >60% seizure reduction in the 1st to 4th year was 15%, 46%, 54%, and 69%, respectively. One patient did not respond to the treatment at all. No patient became completely free from seizure or free from medication, but the number and/or dosage of antiepileptic drugs was reduced in five patients. Ten patients underwent exchange of the generator and continued treatment, and two patients underwent removal of the generator because of the unsatisfactory result. VNS controlled more disabling seizures earlier and more efficiently than less disabling seizures in seven patients. The cumulative reduction of seizures was partly associated with changes in the device setting toward increased stimulation. These effects were similar in patients with or without previous resective surgery. Long-term VNS therapy achieved a favorable outcome in a significant proportion of patients with intractable epilepsy.     

Experience with vagus nerve stimulation for intractable epilepsy: some questions and answers.

Vagus nerve stimulation (VNS) is gaining increasing popularity and credibility as a treatment option for patients with intractable epilepsy. VNS is a relatively recent innovation, however, and like many other incipient developments, it has engendered a number of unresolved controversies and perplexities. Limitations in our current understanding of how VNS works lie at the crux of these uncertainties. In this article, we present our clinical experience with VNS and review the fundamental issue which remain unsettled, such as the mechanism of VNS action, the factors underlying variability in patient outcome, and the selection of ideal candidates for VNS therapy. Although many enigmas persist, VNS has proven to be a safe, feasible, and potentially effective method of reducing seizures in select patient populations. It offers several advantages over extant treatments and, as a result, holds much promise for future therapy of medically refractory epilepsy.     

Long-term multicenter experience with vagus nerve stimulation for intractable partial seizures: results of the XE5 trial

OBJECTIVE: Intermittent stimulation of the left cervical vagus nerve trunk (VNS) with the NeuroCybernetic Prosthesis (NCP) is emerging as a novel adjunct in the management of medically refractory epilepsy. We review the safety and efficacy of VNS 1 year after completion of the E05 study, the largest controlled clinical trial of VNS to date. METHODS: One hundred and ninety-nine patients with intractable epilepsy and at least 6 complex partial or secondarily generalized seizures per month enrolled in a randomized, double-blinded, partial crossover trial of high versus low parameters of stimulation (E05). After 3 months, all patients received high stimulation during an open-label, nonblinded extension trial (XE5). Seizure frequency, adverse events and multiple physiologic variables were monitored at regular intervals. RESULTS: At 3 months, the mean reduction in seizure frequency among patients receiving high stimulation during E05 was 28%. Of the 199 subjects participating in this acute-phase trial, 195 continued in the long-term protocol. Among the latter patients, 21 subsequently exited the study due to lack of efficacy, and 2 others died from causes unrelated to VNS. Complete data were obtained for 164 of the remaining subjects. Using a declining N analysis, the mean and median reduction in seizure frequency at 15 months was 37 and 45%, respectively. A last visit carried forward analysis, which controls for dropouts and incomplete follow-up, yielded comparable results (34 and 45%, respectively), indicating little potential for selection bias. At 15 months, 39% of the subjects had a greater than 50% reduction in seizures, including 21% who had a greater than 75% reduction, and 2% have remained seizure free. Few serious adverse events, physiological perturbation or device failures were reported. CONCLUSIONS: The long-term multicenter safety, efficacy, feasibility and tolerability of VNS, as well as the durability of the NCP device have been confirmed. Unlike chronic therapy with antiepileptic medication, the efficacy of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time.     

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response

Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80-1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.     

Vagal nerve stimulation: overview and implications for anesthesiologists

Vagal nerve stimulation is an important adjunctive therapy for medically refractory epilepsy and major depression. Additionally, it may prove effective in treating obesity, Alzheimer's disease, and some neuropsychiatic disorders. As the number of approved indications increases, more patients are becoming eligible for surgical placement of a commercial vagal nerve stimulator (VNS). Initial VNS placement typically requires general anesthesia, and patients with previously implanted devices may present for other surgical procedures requiring anesthetic management. In this review, we will focus on the indications for vagal nerve stimulation (both approved and experimental), proposed therapeutic mechanisms for vagal nerve stimulation, and potential perioperative complications during initial VNS placement. Anesthetic considerations during initial device placement, as well as anesthetic management issues for patients with a preexisting VNS, are reviewed.     

Vagus nerve stimulation therapy for seizures

Of the 3 million patients with seizures in North America approximately 70% have effective seizure control with medications. In the group refractory to medical treatment only a minority fit the criteria for surgical therapy. Vagus nerve stimulation therapy seems to be a suitable nonpharmacologic therapy for reducing seizure frequency in these cases. It is a simple device with 2 electrodes and an anchor loop implanted on the midcervical portion of left vagus nerve and the impulse generator is implanted subcutaneously in the left infraclavicular region. The left vagus is the preferred site as the right vagus innervates the sinoatrial node and influences the heart rate. Data from laboratory studies suggest that it most probably works by increasing the release of norepinephrine in the locus ceruleus, which in turn increases the seizure threshold. More than 32,000 devices have been implanted since it was approved in 1997. There is class I evidence that vagus nerve stimulator reduces the frequency of seizures. In addition it also elevates the patients' mood-independent of seizure control. In one of the studies 50% reduction in seizure frequency was 37% in the first year and 44% in the second and third year. The side effects commonly reported are constriction in the throat, change in voice, and throat pain which most patients are able to tolerate and continue the use of the device. In conclusion VNS seems to be an effective nonpharmacologic therapy for medically refractory partial onset seizures.     

Vagus Nerve Stimulation Therapy: Indications,Programing, and Outcomes

Vagus nerve stimulation (VNS) provides palliation of seizure reduction for patients with medically refractory epilepsy. VNS is indicated for symptomatic localization-related epilepsy with multiple and bilateral independent foci, symptomatic generalized epilepsy with diffuse epileptogenic abnormalities, refractory idiopathic generalized epilepsy, failed intracranial epilepsy surgery, and other several reasons of contraindications to epilepsy surgery. Programing of the parameters is a principal part in VNS. Output current and duty cycle should be adjusted to higher settings particularly when a patient does not respond to the initial setting, since the pivotal randomized trials performed in the United States demonstrated high stimulation made better responses in seizure frequency. These trials revealed that a ≥ 50% seizure reduction occurred in 36.8% of patients at 1 year, in 43.2% at 2 years, and in 42.7% at 3 years in 440 patients. Safety of VNS was also confirmed because side effects including hoarseness, throat discomfort, cough, paresthesia, and headache improved progressively during the period of 3 years. The largest retrospective study with 436 patients demonstrated the mean seizure reduction of 55.8% in nearly 5 years, and also found 75.5% at 10 years in 65 consecutive patients. The intermediate analysis report of the Japan VNS Registry showed that 60% of 164 cases got a ≥ 50% seizure reduction in 12 months. In addition to seizure reduction, VNS has positive effects in mood and improves energy level, memory difficulties, social aspects, and fear of seizures. VNS is an effective and safe option for patients who are not suitable candidates for intracranial epilepsy surgery.     

Efficacy of vagal nerve stimulation in children with medically refractory epilepsy

OBJECTIVE: The effects of vagal nerve stimulation (VNS) on seizure frequency and quality of life were analyzed retrospectively in children with medically refractory epilepsy. METHODS: Thirty-eight children aged 11 months to 16 years underwent implantation of vagal nerve stimulators. Age of seizure onset, duration of epilepsy, and seizure type and frequency were recorded preoperatively. Age at implantation, length of follow-up, seizure type and frequency, and change in quality of life (QOL) were recorded postoperatively. Changes in QOL were assigned a QOL score by the caretakers on a visual analog scale of -1 (much worse) to +1 (much improved). RESULTS: The median follow-up period was 12 months (range, 10-18 mo). Eleven (29%), 15 (39%), 5 (13%), and 7 (18%) children had greater than 90% reduction, 50 to 90% reduction, less than 50% reduction, and no reduction in seizure frequency, respectively. For all children, seizure reduction by seizure type was as follows: atonic (80%), absence (65%), complex partial (48%), and generalized tonicoclonic (45%). The mean change in QOL score was 0.61. Eighty-six percent of the children had QOL scores of 0.5 (improved) or higher. Follow-up of at least 6 months was associated with greater seizure reduction (P = 0.05) and higher QOL score (P < 0.01). Seizure reduction was greater in children with onset of epilepsy after 1 year of age (P < 0.05). The age of the child and duration of epilepsy were not associated with greater or lesser degrees of seizure reduction. CONCLUSION: VNS provided improvements in seizure control for the majority of children regardless of age. QOL was improved in the majority of children with VNS. VNS should be considered for children with medically refractory epilepsy who have no surgically resectable focus.     

Convulsive and nonconvulsive status epilepticus in children

Opinion statement  Status epilepticus (SE) is a common pediatric neurologic emergency that requires rapid assessment and management. Treatment of pediatric SE involves two equally important factors. First, rapid identification of the underlying etiology is essential, as decisions on how to treat and prognosticate depend on the cause of SE. Second, the timing of treatment initiation with adequate doses is crucial, as early action is most effective in terminating SE and decreasing morbidity and mortality. Currently, early treatment with adequate doses of a benzodiazepine is appropriate, followed by treatment with phenytoin, phenobarbital, or valproic acid. If the seizure does not stop or repetitive seizures continue, the addition of other medications (eg, levetiracetam) or pharmacologic coma induction may be indicated. This review evaluates treatment protocols for acute SE, prolonged SE, and nonconvulsive SE, including some management strategies that use newer anticonvulsants.     

Vagal nerve stimulator implantation: an otolaryngologist's perspective.

OBJECTIVE: This study was conducted to compare an otolaryngologist's experience with a cohort of epilepsy patients implanted with a vagal nerve stimulator (VNS) to previously published data. METHODS: Demographics, preoperative seizure frequency, medications, and complications were retrospectively collected from patients implanted by the senior author. Postoperative medications and seizure frequency were obtained from referring neurologists. RESULTS: Seventeen patients were implanted over a 24-month period. Average age was 28.3 years. Patients presented with petit mal (n = 3), tonic-clonic (n = 6), complex partial (n = 5), and grand mal (n = 8) seizures. Mean follow-up postimplantation was 13.5 months. Most patients had at least a 50% reduction of seizure frequency, with 3 patients being seizure free. There were no postoperative infections. One patient had left vocal cord immobility. The most common side effect was voice disturbance during device activation. CONCLUSION: Otolaryngologists are well equipped to perform VNS implantation and to diagnose and treat possible laryngeal side effects. EBM rating: C-4.     

Efficacy of vagus nerve stimulation for epilepsy by patient age, epilepsy duration, and seizure type

Medically refractory epilepsy is a morbid condition, and many patients are poor candidates for surgical resection because of multifocal seizure origin or eloquence near epileptic foci. Vagus nerve stimulation (VNS) was approved in 1997 by the US Food and Drug Administration as an adjunctive treatment of intractable epilepsy for individuals aged 12 years and more with partial epilepsy. Controversy persists regarding the efficacy of VNS for epilepsy and about which patient populations respond best to therapy. In this article, the authors retrospectively studied a patient outcome registry and report the largest, to their knowledge, analysis of VNS outcomes in epilepsy.     

Syncope after administration of epidural analgesia in an obstetric patient with a vagus nerve stimulator

Vagus nerve stimulation (VNS) is an adjunctive therapy for medically refractory epilepsy and depression. Vagus nerve stimulation is generally well-tolerated, but cardiac arrhythmias or asystole are rare complications that have been reported. This case report describes an obstetric patient who received epidural analgesia and subsequently experienced two episodes of syncope synchronous with stimulation from her VNS device. These resolved after deactivating the device. This is the first report of a suspected arrhythmia during VNS in the setting of epidural analgesia.     

Electrical Stimulation in Epilepsy: Vagus Nerve and Brain Stimulation

Vagus nerve stimulation (VNS) for epilepsy is a well established and effective treatment for medically intractable epilepsy. VNS is indicated if resective epilepsy surgery is unsuccessful or is not an option. About 50% of patients with VNS have a seizure reduction greater than 50%, but less than 10% become seizure-free. VNS also has an alerting effect on patients and may allow a reduction in sedating medications. The major adverse event is hoarseness, but treatment is generally well tolerated. The therapeutic effect can be delayed: patients may improve several months after VNS implantation. Direct brain stimulation (DBS) is an emerging treatment for epilepsy. Scheduled stimulation is similar to brain stimulation in Parkinson’s disease. Only the anterior thalamic nucleus has been studied in a larger randomized, controlled trial, in which patients with the stimulator turned on had a significantly reduced seizure frequency. Responsive stimulation applies an electrical stimulus at the site of seizure onset to terminate the seizure if one occurs. The seizure-onset zone must be well defined before implantation. Responsive stimulation requires seizure detection and application of a stimulus online. A large pivotal trial showed a significant reduction in seizure frequency. Both DBS and responsive neurostimulation are well tolerated, but there has been some concern about depression with DBS. Infection, hemorrhage, and lead breakage are adverse events possible with any type of stimulator. None of the brain stimulation devices have been approved by the US Food and Drug Administration, but final approval is expected soon. These devices are indicated for patients with bilateral seizure onset or seizure onset in eloquent areas. Although the initial trials of brain stimulation do not show overwhelming improvement in seizure frequency, the technology will improve with time as we continue to learn about the use of brain stimulation for epilepsy. Optimization of VNS has been going on for 10 years, and we need to ensure that brain stimulation is similarly developed further. In addition, sophisticated devices such as responsive neurostimulators can greatly enhance our understanding of the pathophysiology of epilepsy.     

A case report of Vagus nerve stimulation for intractable hiccups

IntroductionIntractable hiccups frequently result from an underlying pathology and can cause considerable illness in the patients. Initial remedies such as drinking cold water, induction of emesis, carotid sinus massage or Valsalva manoeuvre all seem to work by over stimulating the Vagus nerve. Pharmacotherapy with baclofen, gabapentin and other centrally and peripherally acting agents such as chlorpromazine and metoclopramide are reserved as second line treatment. Medical refractory cases even indulge in unconventional therapies such as hypnosis, massages and acupuncture. Surgical intervention, although undertaken very rarely, predominantly revolves around phrenic nerve crushing, blockade or pacing. A novel surgical strategy is emerging in the form of Vagus nerve stimulator (VNS) placement with three cases cited in literature to date with varying degrees of success. Here the authors report a case of VNS placement for intractable hiccups with partial success, in accordance with SCARE-2018 guidelines.Presentation of the caseAn 85-year-old gentleman with a 9-year history of intractable hiccups secondary to pneumonia came to our hospital. The hiccups were symptomatic causing anorexia, insomnia, irritability, depression, exhaustion, muscle wasting and weight loss. The patient underwent countless medical evaluations. All examinations and investigations yielded normal results. The patient underwent aggressive pharmacotherapy, home remedies and unconventional therapies for intractable hiccups but to no avail. He also underwent left phrenic nerve blocking and resection without therapeutic success. The patient presented to our hospital and decision for VNS insertion was taken for compassionate reasons considering patient morbidity. The patient demonstrated significant improvement in his symptoms following VNS insertion.DiscussionA temporary hiccup is an occasional happening experienced by everyone. However, intractable hiccups are associated with significant morbidity and often mortality. Several medical, pharmacological, surgical and novel treatment options are available for intractable hiccups.ConclusionVNS insertion is a novel surgical option for the treatment of intractable hiccups.     

Optimal Vagus Nerve Stimulation Frequency for Suppression of Spike‐and‐Wave Seizures in Rats

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for drug‐resistant epilepsy and results in a 50% seizure reduction in up to 50% of treated patients. The VNS frequency used in the clinic today is in the range of 10–30 Hz. The evidence for choosing the stimulation frequency is limited, and little knowledge is available on the effect of other VNS frequencies. Deep brain, trigeminal nerve, or spinal cord stimulation studies have suggested the use of stimulation frequencies above 80 Hz for seizure control. Therefore, our objective for the present study was to investigate if VNS using frequencies higher than those currently used in the clinic could be more effective in attenuating seizures. Spike‐and‐wave (SW) discharges were induced in 11 rats, which then were subjected to VNS sessions applied at the frequencies of 10, 30, 80, 130, and 180 Hz combined with control intervals without stimulation. The anticonvulsive effect of VNS was evaluated by comparing the normalized mean power (nMP) and frequency (nMSF) of the SW discharges derived from intracortical recordings collected during the stimulation and control intervals. Compared with the control intervals, all the tested VNS frequencies significantly reduced the nMP (in the range of 9–21%). However, we found that 130 and 180 Hz VNS induced a 50% larger attenuation of seizures than that achieved by 30 Hz VNS. In addition, we found that 80, 130, and 180 Hz VNS induced a significant reduction of the nMSF, that is by 5, 7, and 8%, respectively. These results suggest that a VNS stimulation frequency in the range of 130–180 Hz may be more effective in inhibiting seizures than the 30 Hz VNS applied in the clinic today.     

Insertion of vagal nerve stimulator using local and regional anesthesia

BACKGROUND: Vagal nerve stimulation (VNS) is a valuable therapy for patients with intractable epilepsy. Placement of a vagal nerve stimulator typically requires general anesthesia, which frequently interrupts anticonvulsant therapy. Insertion of the stimulator using regional/local anesthesia may offer the advantages of continuity of anticonvulsant therapy and implantation in the outpatient setting. METHODS: We retrospectively compared the first 10 consecutive patients undergoing VNS implantation under general anesthesia with the first 12 consecutive patients undergoing VNS implantation under regional/local anesthesia. Patients for the regional/local anesthesia were selected on the basis of their ability to cooperate and follow commands. Regional anesthesia for implantation of the VNS leads was achieved by performing superficial and deep cervical plexus blocks. A local anesthetic field block of a small area of the posterior chest provided anesthesia for insertion of the generator. RESULTS: All of the patients undergoing regional/local anesthesia completed the procedure without difficulty and on an outpatient basis. None complained of discomfort, sedation, nausea, or vomiting and none had seizures in the perioperative period. These results contrasted with the group that underwent general anesthesia (n = 10), who had an 80% incidence of nausea and vomiting and a 30% incidence of postoperative seizures. CONCLUSION: VNS implantation under regional/local anesthesia is proficiently performed as an outpatient procedure with minimal postoperative side effects.     

Thalamic stimulation for epilepsy

With the growing applications for deep brain stimulators (DBS) in recent years, interest in using DBS as an option for patients with epilepsy has increased. Thalamic DBS appears to be a viable minimally invasive treatment for patients experiencing medically intractable seizures. Thalamic DBS has been associated with significant reduction in seizure frequency and an improvement in overall quality of life, especially in patients who have failed maximal antiepileptic drugs or other surgical alternatives. However, further work is necessary to identify the subgroups of patients experiencing medically intractable seizures who may benefit from DBS, and also to indentify optimal stimulation parameters and mode of stimulation.     

Intraoperative and perioperative complications with a vagus nerve stimulation device

Vagus nerve stimulation (VNS) for medically refractory seizures has been an approved therapy by the Food and Drug Administration since 1997, with additional approval as an adjunct therapy for major depression granted in 2005. Potential applications for VNS therapy in obesity, neuropsychiatric disorders, and chronic pain syndromes are under investigation. Bradyarrhythmias, including asystole, may occur during VNS device placement or as a delayed complication. A peritracheal hematoma may develop following VNS device placement, necessitating emergent management. Other respiratory complications may include vocal cord movement abnormalities with potential for aspiration. Vagus nerve stimulation results in sleep-related breathing pattern changes, with an associated increase in the number of obstructive apneas and hypopneas in both children and adults, which may impact perioperative care.     

Avoiding the pocket: A case report of coiling of distal shunt catheter into subcutaneous pocket

IntroductionHydrocephalus is one of the most common disorders of neurosurgery and ventricular shunting, the primary surgical intervention, malfunctions in 85% of patients by 10 years.Presentation of caseHere we present a case of a 12-year-old girl with history of a vagal nerve stimulator (VNS) and ventricular shunt, most recently revised from ventriculoatrial (VA) to ventriculoperitoneal (VP) shunt at an outside hospital. The patient presented with a new left chest bulge, nausea, emesis, and seizures. Imaging revealed the patient’s distal shunt catheter to have completely migrated and coiled into the VNS subcutaneous pocket. Subsequently, the patient’s distal shunt catheter was externalized, and later internalized back to a VA shunt.DiscussionPotential spaces from previous surgeries such as VNS can lead to coiling of distal shunt catheters. In this case, the coiled distal shunt catheter led to hydrocephalus and the patient’s presenting symptoms.ConclusionIt is imperative to recognize patients with previous surgeries, especially those involving subcutaneous implants and to avoid passing of distal shunt catheters through these potential spaces.     

Levetiracetam monotherapy for liver transplant patients with seizures

Selecting an appropriate anticonvulsant for treatment of recipients of orthostatic liver transplants who have new-onset epileptic seizures can be challenging because first-line agents may contribute to worsening encephalopathy, alter the plasma concentration of immunosuppressive agents, and result in hepatotoxicity. We describe the case of a 55-year-old man who underwent orthotopic liver transplantation because of end-stage liver disease due to alcoholic cirrhosis and hepatitis C. He required two repeat transplantation procedures. After the last procedure, epileptic seizures developed, which were initially managed with phenytoin. However, the patient remained stuporous and mental status fluctuated. Breakthrough seizures later developed in the setting of rejection. Levetiracetam (500 mg orally, twice a day) was chosen for its favorable pharmacokinetic properties as an alternative to phenytoin. By the third day of levetiracetam therapy, the patient became more responsive. At most recent follow-up, 3 months after the start of levetiracetam therapy, the patient was still treated with levetiracetam monotherapy, and seizure control was judged to be excellent.