Vagus nerve stimulation use and effect in epilepsy: what have we learned?

Vagus nerve stimulation (VNS) for epilepsy has been available in the United States for 8 years. Pivotal randomized, blinded clinical trials leading to FDA approval in patients age 12 and older with refractory partial seizures have not been performed for other age groups or epilepsy syndromes. This practical review takes stock of the current information about VNS use and efficacy in various types of epilepsy. We review the evidence for commonly used stimulation parameters, end of battery life, predictors of response including duration of epilepsy, seizure type/epilepsy syndrome, bihemispheric seizures, age at implant, and prior cranial surgery. We review adverse events and VNS effects on respiratory patterns, cardiac function, and mood and behavior. With the recent U.S. approval of VNS for treatment-resistant depression, we anticipate that lessons learned from treating patients with epilepsy will be useful to physicians using VNS to treat patients with depression and possibly other conditions.     

Vagus nerve stimulation for epilepsy: is output current correlated with acute response?

OBJECTIVES: Vagus nerve stimulation (VNS) is an effective treatment for intractable epilepsy. It is unknown whether acute response is correlated with the amplitude of output current. The purpose of this study was to determine if the output current of VNS is correlated with percent reductions in seizure frequency and response. MATERIALS AND METHODS: Retrospective analysis of a multicenter randomized trial of three unique paradigms of VNS was carried out in patients with intractable partial onset epilepsy. Output current at 1 and 3 months was correlated with percent reduction in seizure frequency and response rates. RESULTS: Sixty-one subjects were enrolled and completed the study. Output current, ranging from 0.25 to 1.5 mA, was not correlated with reductions in seizure frequency, or with > or = 50% reduction in seizures. Six of seven initial non-responders did experience > or = 50% reductions in seizures after current was increased. CONCLUSIONS: The output current is not a major determinant of acute response to VNS for epilepsy. Many patients respond to low current (<1 mA). Some (20%) initial non-responders may respond to an increase in output current.     

Vagus nerve stimulation in children with drug‐resistant epilepsy: age at implantation and shorter duration of epilepsy as predictors of better efficacy?

Aim. To study the efficacy of vagus nerve stimulation (VNS) therapy in a highly drug‐resistant childhood epilepsy patient group and to investigate the effect of age at implantation on efficacy. Methods. The efficacy of VNS treatment was analysed in a cohort of 70 patients with drug‐resistant epilepsy. Both children with focal (n=16) and generalized epilepsies (n=54) were included. Age at implantation varied between 19 months and 25 years. Results. Overall, responder rate was 54% with 5.7% children becoming seizure‐free. The only factor in our analysis that could predict good outcome was age at implantation. In the youngest group (<5 years), the responder rate was 77% and this group also included three of the four seizure‐free children. These three seizure‐free children were known to have tuberous sclerosis. There were no outcome differences between generalized and focal epilepsies. Conclusions. Our single centre study confirms previous studies on the efficacy of VNS in children. A larger study using multivariate analysis to disentangle the contribution of different factors (such as age at implantation, aetiology, and epilepsy duration) is necessary to confirm our preliminary finding that younger age at VNS implantation might result in a better outcome.     

Epilepsy surgery in people with intellectual disability – English Version

In patients with refractory epilepsy, evaluation of epilepsy surgery should be part of the diagnostic work-up. Epilepsy and refractory epilepsy are common in people with intellectual disability. Therefore, epilepsy surgery with its chances of success and its risks has to be discussed. The presurgical diagnostic procedures may have to be adapted to the patientʼs cognitive and emotional abilities. Whether people with intellectual disabilities experience postoperative seizure freedom less frequently, has yet to be determined. Patients with genetic epileptic encephalopathies (particularly channelopathies) as well as non-lesional patients usually are not good surgical candidates. Neurocognitive functions usually do not suffer after epilepsy surgery in patients with intellectual disability. Even nonresective epilepsy surgery may be carried out with good outcome both in children and adult patients. Therefore, epilepsy surgery is an important tool in epilepsy care for people with intellectual disability.

     

Auricular transcutaneous vagus nerve stimulation improves memory persistence in naïve mice and in an intellectual disability mouse model

BackgroundVagus nerve stimulation (VNS) using non-invasive approaches have attracted great attention due to their anti-epileptic, anti-depressive and pro-cognitive effects. It has been proposed that auricular transcutaneous VNS (atVNS) could benefit intellectual disability disorders, but preclinical data supporting this idea is limited.ObjectiveTo develop an atVNS device for mice and to test its efficacy on memory performance in naïve mice and in a mouse model for intellectual disability.MethodsNaïve outbreed CD-1 mice and a model for fragile X syndrome, the Fmr1 knockout (Fmr1KO), were used to assess the effect of atVNS in the novel object-recognition memory performance.ResultsWe found that atVNS significantly improves memory persistence in naïve mice. Notably, atVNS was efficacious in normalizing the object-recognition memory deficit in the Fmr1KO model.ConclusionOur data show that atVNS improves memory persistence in naïve mice and in a model of intellectual disability and support further studies taking advantage of preclinical mouse models of cognitive disorders.     

Vagus nerve stimulation in refractory and super-refractory status epilepticus – A systematic review

RationaleRefractory status epilepticus (RSE) is the persistence of status epilepticus despite second-line treatment. Super-refractory SE (SRSE) is characterized by ongoing status despite 48 h of anaesthetic treatment. Due to the high case fatality in RSE of 16–39%, off label treatments without strong evidence of efficacy in RSE are often administered. In single case-reports and small case series totalling 28 patients, acute implantation of VNS in RSE was associated with 76% and 26% success rate in generalized and focal RSE respectively. We performed an updated systematic review of the literature on efficacy of VNS in RSE/SRSE by including all reported patients.MethodsWe systematically searched EMBASE, CENTRAL, Opengre.eu, and ClinicalTrials.gov, and PubMed databases to identify studies reporting the use of VNS for RSE and/or SRSE. We also searched conference abstracts from AES and ILAE meetings.Results45 patients were identified in total of which 38 were acute implantations of VNS in RSE/SRSE. Five cases had VNS implantation for epilepsia partialis continua, one for refractory electrical status epilepticus in sleep and one for acute encephalitis with refractory repetitive focal seizures. Acute VNS implantation was associated with cessation of RSE/SRSE in 74% (28/38) of acute cases. Cessation did not occur in 18% (7/38) of cases and four deaths were reported (11%); all of them due to the underlying disease and unlikely related to VNS implantation. Median duration of the RSE/SRSE episode pre and post VNS implantation was 18 days (range: 3–1680 days) and 8 days (range: 3–84 days) respectively. Positive outcomes occurred in 82% (31/38) of cases.ConclusionVNS can interrupt RSE and SRSE in 74% of patients; data originate from reported studies classified as level IV and the risk for reporting bias is high. Further prospective studies are warranted to investigate acute VNS in RSE and SRSE.     

Is thalamic deep brain stimulation synergistic with vagus nerve stimulation in drug-resistant genetic generalized epilepsy?

Neuromodulation in epilepsy is a proven treatment for people with drug-resistant focal epilepsy. Dual device therapies are increasingly utilized in people with drug-resistant epilepsy. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) target the thalamus involving the primary neurobiological network in patients with genetic generalized epilepsy (GGE). We report a novel case of combined neuromodulation in a patient with drug-resistant GGE who achieved a partial response with seizure reduction after VNS implantation yet following VNS-DBS polyneurostimulation gradually achieved prolonged seizure freedom. We speculate that by combining the indirect activating effects of VNS with the direct inhibitory effects of DBS, this may provide synergy to thalamic modulated networks. We hypothesize a “rational polytherapy” may exist in some patients with GGE undergoing dual neuromodulation.     

Vagus nerve stimulation: where are we?

Now nearly 5 years post-approval, vagus nerve stimulation has emerged as a major non-pharmacological treatment for epilepsy. The place of vagus nerve stimulation among antiepileptic drugs and other surgical therapies is still evolving. This review evaluates the role of vagus nerve stimulation in light of recently published research of its mechanism(s) of action, long-term efficacy, safety and tolerability, and application to other disorders besides epilepsy.     

Why do seizures occur when they do? Situations perceived to be associated with increased or decreased seizure likelihood in people with epilepsy and intellectual disability

Seizure precipitants are commonly reported in the general population of people with epilepsy. However, there has been little research in this area in people with epilepsy and intellectual disability (ID). We conducted a survey of the situations associated with increased or decreased seizure likelihood in this population. The aim of the research was to identify situations of increased seizure likelihood (SISLs) and situations of decreased seizure likelihood (SDSLs) reported by carers of people with an ID and epilepsy. Three study groups were investigated: two groups comprising individuals with ID associated with a specific genetic diagnosis – Rett syndrome or fragile X syndrome – and one group consisting of individuals with a range of other etiologies. Responses relating to 100 people were received: 44 relating to people with Rett syndrome, 25 to people with fragile X syndrome, and 31 to people whose ID had some other etiologies. Ninety-eight percent of the respondents reported at least one SISL, and 60% reported at least one SDSL. Having more seizure types and greater seizure frequency were associated with a higher number of SISLs reported. The most commonly reported SISLs and SDSLs for each of the three groups are presented. The most common SISL overall was illness, which was reported as an SISL by 71% of the respondents. There was less consensus with regard to SDSLs. These findings provide a greater understanding of when seizures occur in those with ID and epilepsy, with possible implications for adjunctive behavioral management of seizures in those with treatment-refractory epilepsy.     

Vagal nerve stimulation in children under 12 years old with medically intractable epilepsy

Objective

This study aims to assess the efficacy and safety of vagal nerve stimulation (VNS) in children less than 12 years old operated on at the University Hospital Wales.

Method

Retrospective review of patients undergoing VNS insertion, over a 3-year period, was undertaken. All children had a minimum follow-up period of 2 years. Sixteen patients were identified via the paediatric epilepsy surgery database. A case note review and telephone evaluation was conducted. Seizure frequency using the McHugh classification was the primary outcome measure, with anti-epileptic drug (AED) use as a secondary outcome measure.

Results

There were 10 males and 6 females. The mean time with epilepsy prior to surgery was 5.7 years and the mean age at the time of surgery was 7.6 years. Overall, nine (56 %) children experienced a reduction in their seizure frequency of 50 % or more. Of these, four (25 %) had a reduction of more than 80 %. Seven children (44 %) had no reduction in their seizure frequency, although two of these patients reported benefit regarding seizure control and post-ictal recovery. The VNS system was removed in two patients due to infection and no benefit, respectively. Half of the cohort (50 %) reduced the number of anti-epileptic drugs post-surgery, and there was an overall mean reduction of AED of 0.5.

Conclusion

This study suggests that VNS is a safe and effective adjuvant therapy in children under 12 years old, with over half reporting significant benefit. Further studies are needed to enable preoperative selection of patients in order to maximise the potential benefit.     

Vagus nerve stimulation: Can it be used in adolescents or children with treatment-resistant depression?

Vagus nerve stimulation (VNS) therapy has been approved by the US Food and Drug Administration for treatment-resistant depression in patients 18 years of age and older and for intractable epilepsy. Long-term studies suggest VNS has an antidepressant effect in adults. This paper reviews the available clinical data for VNS therapy. Its potential application for treatment-resistant depression in adolescents and children is also discussed.     

Vagus nerve stimulation in pediatric patients: Is it really worthwhile?

Vagus nerve stimulation (VNS) seems to be effective in the management of selected cases of pharmacoresistant epilepsy in children. This was a case–control prospective study of children with refractory epilepsy submitted to vagal nerve stimulator implantation and a control group with epilepsy treated with antiepileptic drugs. Patients under 18 years of age who underwent clinical or surgical treatment because of pharmacoresistant epilepsy from January 2009 to January 2012 were followed and compared with an age-matched control group at final evaluation. Statistically significant differences were observed considering age at epilepsy onset (VNS group — 1.33 ± 1.45 years; controls — 3.23 ± 3.11; p = 0.0001), abnormal findings in neurological examination (p = 0.01), history of previous ineffective epilepsy surgery (p = 0.03), and baseline seizure frequency (p = 0.0001). At long-term follow-up, 55.4% of the patients in the VNS group had at least 50% reduction of seizure frequency, with 11.1% of the patients presenting 95% reduction on seizure frequency. Also, a decrease in traumas and hospitalization due to seizures and a subjective improvement in mood and alertness were observed. The control group did not show a significant modification in seizure frequency during the study. In this series, VNS patients evolved with a statistically significant reduction of the number of seizures, a decreased morbidity of the seizures, and the number of days in inpatient care. In accordance with the current literature, VNS has been proven to be an effective alternative in the treatment of pediatric patients with drug-resistant epilepsy.     

MUSAD-Short – A music-based screening tool to assess autism spectrum disorder in people with intellectual disability

BackgroundThe Music-based Scale for Autism Diagnostics (MUSAD) is an observational instrument for assessing ASD in adults with intellectual disability (ID) and limited verbal abilities. The MUSAD prompts diagnostically relevant behaviors in twelve musical interactional situations. This study explores the psychometric properties of a short version (MUSAD-Short) for ASD screening.MethodExcerpts from 60 videotaped assessments conducted with the original MUSAD were re-coded with a reduced item set. Based on these ratings, items were selected for the MUSAD-Short. Criterion validity of the MUSAD-Short was tested by comparing the MUSAD-Short assignment with the clinical ASD diagnosis. Inter-rater reliability was tested on a subsample of 22 individuals. A dichotomous response format was also examined to investigate whether further simplification is possible.ResultsFour situations (congas; ocean drum; symbolic instruments; movement to music) and fourteen items were selected for the MUSAD-Short. The diagnostic accuracy was appropriate, as indicated by sensitivity/specificity values of 73/75% (AUC =0.78). The inter-rater reliability was excellent, measured by the intra-class correlation (ICC) of.77. After item-dichotomization, sensitivity/specificity values were 73/70% (AUC =0.79).ConclusionsThe results indicate that the MUSAD-Short provides adequate diagnostic accuracy and sufficient inter-rater reliability. Shortening the original MUSAD is a promising approach to improving the scale’s applicability. However, future studies are needed that assess the MUSAD-Short's clinical and psychometric utility in an independent sample. Also, testing its practicability in children and adolescents with ID is indicated.     

Participation and service access rights for people with intellectual disability: A role for law?

Abstract

Background Supported decision-making and personal budgets for services are the new paradigms.

Method Supported decision-making proposals from the Australian State of Victoria are analysed against international trends to determine the viability of laws reflecting new international norms of the United Nations Convention on the Rights of Persons with Disabilities 2006 (CRPD).

Results/Conclusions The article concludes that it is desirable to pursue supported decision-making and allied legal reforms, but the contribution of the law is small and the new supported decision-making paradigms have similarities to old paternalist guardianship, as well as possible unintended consequences. It is suggested that realising the equality, support, protection, and socioeconomic service aspirations of the CRPD raise important practical challenges for governments, for service providers, for families, and—centrally—for people with intellectual disability (ID).This article examines the limited contribution law can make to this enterprise.     

Clinicians’ use of sexual knowledge assessment tools for people with intellectual disability

Background Many people with intellectual disability have limited sexual knowledge. Several assessment tools have been developed to assess the sexual knowledge of people with intellectual disability. This paper examines how clinicians’ are using these tools.

Method This research uses a constructivist grounded theory approach. Semistructured qualitative interviews were conducted with clinicians who use sexual knowledge assessment tools.

Findings and Discussion Assessment of sexual knowledge is not routine in disability service provision. Sexual knowledge is typically only assessed when there has been an incident of problematic sexualised behaviour. This reactive approach perpetuates a pathological sexual health discourse.

Conclusions Clinicians using assessment tools said that they need the tools to support work they do in relation to sexual health of people with intellectual disability. However, they also reported that the tools have gaps and are not fully meeting their needs or the needs of people with intellectual disability.     

Are psychotic symptoms related to vagus nerve stimulation in epilepsy patients?

Four patients with refractory epilepsy presented with psychotic symptoms following treatment with vagus nerve stimulation (VNS) to control seizures. Besides its anti-epileptic effect VNS has been shown to have an effect on various cognitive and behavioural functions. VNS is known to increase alertness and reduce sedation, which is independent from seizure control. VNS has also been shown to positively affect cognition and to exert strong antidepressant effects. Co-morbidity in epilepsy often comprises psychiatric illnesses. Increased psychiatric symptoms have mainly been described in association with successful outcome following epilepsy surgery as a result of 'forced normalisation'. Different hypotheses on the underlying aetiology of VNS-induced psychotic symptoms other than the previously described 'forced normalisation' are discussed.