Neurology
Thirty Years Later: What the Latest Real-World Data Tells Us About VNS in the Modern DRE Treatment Landscape
The publication of this article was funded by LivaNova PLC.
Interview Summary
INTRODUCTION
Epilepsy is a neurological condition characterised by recurrent, unprovoked seizures.1
Individuals with CRSwNP typically have no sense of smell at all, and symptoms such as blocked nose, watery secretions, postnasal drips, as well as cough, facial pain or pressure, can become a constant struggle.1-4
COULD YOU DESCRIBE THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS WITH NASAL POLYPS?
“I believe nasal polyps are a backup defence mechanism, growing in the most vulnerable places in the nose and initially serving a protective function.
"For example, when the body encounters a microorganism it can’t immediately eradicate, it has three options:
"There are three main ways our body defends itself, through different types of inflammation:
eradicate it (you win);
succumb to it (the microorganism wins), causing sepsis or even death; or
build a physical wall, like nasal polyps, where the microorganism stays there (no one wins).
Type 1
(viral infections)
Type 2
(parasitic infections),
and Type 3 (fungal infections).”
CRSwNP is caused by a dysregulated immune response to foreign agents, triggering mucosal inflammation frequently characterised by a Type 2 inflammatory signature.1,3,6 It’s a complex interplay of genetic and environmental factors that triggers the growth of nasal polyps.
In Europe, around 80–85% of patients with CRSwNP exhibit a Type 2 inflammatory endotype, associated with increased IgE production, elevated local IL-5 levels, and prominent eosinophilic infiltration of tissues.9,10
HOW CAN EAR, NOSE, AND THROAT SPECIALISTS ASSESS (TYPE 2) INFLAMMATION IN THEIR CLINICAL PRACTICE?
Today, we understand that IL-5 is not only crucial for eosinophils but also contributes to local IgE production and other pathological processes.11 The Type 2 cytokines (IL-4, IL-5, IL-13) are linked, either directly or indirectly, to IgE production, epithelial barrier dysfunction, tissue damage and remodelling, and nasal polyp formation. (Figure 1)11,12
“When I suspect a patient has CRSwNP, my first step is to perform an endoscopic evaluation to identify key signs of inflammation, such as swelling, secretions, crusting, and the presence of nasal polyps."13
"To confirm the presence of Type 2 inflammation, we can obtain a nasal tissue biopsy for histopathological analysis (e.g. tissue eosinophils), which can determine whether inflammation is Type 2 or a mix of endotypes."
"Additionally, nasal secretions can reveal the presence of small dots called Charcot-Leyden crystals, indicative of Type 2 inflammation and contributing to the thickness of mucosal secretions.”14
Blood tests for eosinophils and IgE are also informative to identify Type 2 inflammation, although blood tests are more meaningful when larger organs like the lungs are involved (i.e., a more systemic disease), and may not always be reflective of what is occurring in a smaller organ like the nose.
The inflammation in the nose and lungs is similar, and I believe that our body likely does not differentiate between the upper and lower airways, and that the two act together as ‘unified airways’, sharing an interconnected inflammatory pattern.
Currently, biopsy or nasal secretion analysis are the best ways of assessing the type of nasal inflammation. Other key indicators that indicate likely Type 2 inflammation in patients with CRSwNP are the comorbidities of asthma, allergic rhinitis, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease.3,10,15,16
WHAT EXCITES YOU ABOUT THE EVOLVING TREATMENT LANDSCAPE IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS?
Therefore, we now perform surgery to remove nasal polyps and the diseased mucosa, opening up the sinuses for better local medication access.4,17,18 Nevertheless, many patients experience recurrence after surgery and may require one or more revision surgeries.3
The recurrence rate of CRSwNP after surgery ranges from 20% to 60% within 18 months to 4 years follow-up, to 79% over a 12-year period (N=38).20 We are able to predict the patients at risk of recurrence and/or revision surgery, such as those with:
Allergies18,20
After surgery or if a patient is unsuitable for surgery, we consider biologics, which have revolutionised patient care. Three biologic therapies are currently approved in the EU for CRSwNP treatment, including anti-IgE, anti-IL5, and anti-IL-4Rα monoclonal antibodies targeting pathways in Type 2 inflammation.2,21-24
I have also observed an unmet need in GP awareness around CRSwNP diagnosis and management, resulting in delays in ENT specialist referral and bottlenecks in the patient pathway.
Poor adherence may lead to a recurrence of symptoms and inflammation
In addition to the limited awareness amongst diagnosing physicians, there is a lack of patient education regarding CRSwNP. There is a significant need for resources to support patients throughout their treatment journey, to streamline management and alleviate the burden on time-poor healthcare professionals.
Fortunately, efforts to create patient resources are already in motion, with the development of the European Forum for Education and Research in Allergy and Airway Diseases (EUFOREA) CRSwNP patient portal, a resource for patients which explores disease information, preparing for consultations, support with diagnosis and treatment, as well as some patient outreach initiatives.26
It’s also important to inform patients that they need life-long treatments, even though that’s not what they want to hear; they would rather be cured. Furthermore, when the responsibility of regular dosing is placed on the patient, they may become less diligent or compliant over time.
In 20 years, I hope we no longer see patients with end-stage disease or with countless revision surgeries due to earlier intervention.
“With the continually advancing growth of biologic therapies and increased possibility of long-term biologic treatment, I believe the future lies in a combined, patient-specific approach of prompt surgery and personalised clinical management. Integrating biologics with surgery could potentially improve surgical and patient outcomes, boost cure rates, and possibly eliminate the need for revision surgeries.”
WHAT ARE THE TREATMENT OPTIONS AVAILABLE, AND WHAT CHALLENGES DO PATIENTS FACE IN RECEIVING EFFECTIVE TREATMENT FOR CHRONIC RHINOSINUSITIS WITH NASAL POLYPS?
The future looks bright. We now understand the disease better, and there are new developments, guidelines, and data in the field almost every week.
"With growing momentum and awareness in the field, although some unknowns and areas for exploration remain, I encourage clinicians to continue documenting their practices and outcomes, and communicate and collaborate effectively to establish and refine optimal treatment strategies for CRSwNP.
"We need to share strategies, our experience, and expertise. CRSwNP is now a moving target, and I hope that in future it will no longer be a challenging disease to manage.
Click here to discover the original article
NX-GBL-EOS-WCNT-250002 | October 2025
References
Support statement: The publication of this article was funded by LivaNova PLC.
Interviewees: Ana Suller-Marti,1 James Wheless,2 Steven Wolf3
1. Western University, London, Ontario, Canada
2. University of Tennessee Health Science Center, Memphis, USA
3. Boston Children’s Health Physicians, New York City, New York, USA
Disclosures: Wheless has received grants from the Shainberg Foundation, Jazz, UCB, Neurelis, Marinus, Stoke, SKLSI, TSC Alliance, NeuroEvent Labs, Praxis, Azurity, Lundbeck, Biocodex, and LivaNova PLC; has acted as a consultant for Jazz, Neurelis, Takeda, Praxis, SJCRH-PTNI, and Azurity; and has taken part in speakers’ bureaus for Jazz, UCB, Neurelis, Marinus, SKLSI, Biocodex, and LivaNova PLC. Wolf has served on a scientific advisory or data safety monitoring board for Assertio; has taken part in speakers’ bureaus for LivaNova PLC, Neurilis, UCB, Monteris, and Marinus; and has received research support from NeuroPace, Eisai, Neurelis, Aguestive, UCB, SK Life Science, Longboard, Takeda, Biohaven, and Assertio, with payment to the institution. Suller-Marti has declared no conflicts of interest.
Disclaimer: The views and opinions expressed in this article are those of the individual speakers and do not necessarily reflect those of LivaNova PLC or EMJ. The speakers have not received honoraria for their participation.
Acknowledgements: Medical writing assistance was provided by Amanda Barrell, freelance medical writer, Brighton, UK. Original
Citation: EMJ Neurol. 2025;13[Suppl 8]:2-10. https://doi.org/10.33590/emjneurol/CFUF8633
Keywords: Drug-resistant epilepsy (DRE), epilepsy, focal onset seizures (FOS), generalised tonic-clonic (GTC) seizures, neuromodulation, quality of life (QoL), vagus nerve stimulation (VNS).
Interview Summary
Epilepsy affects around 50 million people worldwide. Approximately 30% of them experience drug-resistant epilepsy (DRE), which is defined as the failure to achieve freedom from seizures following two or more standard antiseizure medications (ASM). DRE significantly impacts quality of life (QoL), and increases the risk of complications, including cognitive decline, mental health issues, and sudden unexpected death in epilepsy (SUDEP). The neuromodulation therapy vagus nerve stimulation (VNS) was first approved as a DRE treatment in the 1990s. With the advent of newer ASMs in the intervening years, however, its use has become underutilised in some epilepsy and seizure types, and it is often considered only after multiple ASMs have failed.
In this article, Ana Suller-Marti, Associate Professor of Neurology, Western University, London, Ontario, Canada; James Wheless, Professor and Chief of Paediatric Neurology, University of Tennessee Health Science Center, Memphis, USA; and Steven Wolf, Chief of Paediatric Neurology, Boston Children’s Health Physicians, New York City, New York, USA, discuss the role of VNS in the modern DRE treatment pathway. They outline real-world evidence, presented at the American Epilepsy Society (AES)’s 2024 Annual Meeting, that reaffirms the efficacy of the neuromodulatory therapy, and talk about overcoming barriers to effective management. Earlier intervention with VNS, they argue, could enhance seizure control, decreasing the risk of complications while enhancing QoL.
It feels like you are on the third or fourth day of a severe cold, and imagine feeling that way for years. It’s incredibly debilitating, and symptoms negatively impact patients’ lives both emotionally and physically, significantly affecting their quality of life.1,3,5
Sleep is disrupted due to constant nasal blockage, making it hard to breathe.3,4
Your partner might be annoyed because of your constant nasal issues, and at work, it’s hard to concentrate, and due to similarities with the common cold or COVID-19, colleagues may look upon the condition unsympathetically or assume you are contagious.
Patients often feel misunderstood because when they tell someone, ‘I have nasal polyps’, the typical response is, ‘Is it bad? Will you die from it?’ The answer is no, you won’t die from it, but you feel horrible and have to live with it, and that is very challenging
Individuals with CRSwNP frequently have other conditions or comorbidities, and therefore, it is crucial to screen for CRSwNP in patients with asthma, due to the close connection between the two (up to 67% of patients with CRSwNP have asthma).6
Philippe Gevaert
Department of Otorhinolaryngology, Ghent University, Belgium
In my experience, pulmonologists are adept at identifying patients with CRSwNP by asking patients with asthma about their sense of smell. This is crucial for all physicians to note, including general practitioners (GP), to ensure prompt diagnosis and comprehensive care for these patients.
I recommend that specialists, GPs, and other doctors who experience a patient presenting with asthma and/or long-term symptoms similar to the common cold, ask if the patient can smell. If they can’t, then CRSwNP should be considered.
Certain individuals are more vulnerable to developing nasal polyps, such as those with immune deficiencies, or inborn or acquired barrier dysfunction.6
Vulnerability may also be acquired after viral infection or due to a range of environmental factors, such as exposure to Staphylococcus aureus, which is present almost everywhere on everything we touch, and may take advantage of an impaired barrier to persist and drive Type 2 inflammation.4,7,8
WHAT ROLE DO TYPE 2 INFLAMMATION AND TYPE 2 CYTOKINES PLAY IN THE DISEASE?
A heightened Type 2 immune signature is linked with greater disease severity, comorbidities, and disease recurrence after surgical intervention.3,9,10
Type 2 cytokines, such as IL-4, IL-5, and IL-13, play a significant role in driving Type 2 inflammation. Historically, IL-5 was primarily considered the main trigger for eosinophilic inflammation. IL-5 is produced in the tissue and sends a signal through the blood to the bone marrow, where stem cells transform into eosinophils. These eosinophils then travel back through the blood to the tissue where the signal originated.11
To treat CRSwNP, nasal saline irrigation and intranasal corticosteroids are recommended, and in more severe cases, short-course oral corticosteroids (OCS) are prescribed.4 However, intranasal sprays are often insufficient for large nasal polyps, as they only reach the tip of the polyps and not the sinuses.
Whilst OCS can suppress inflammation and reduce symptoms, their benefits wane shortly after discontinuation, and they come with significant and cumulative side effects, making the cost of treating a patient long-term with OCS very high for society.4,17,18
Long-term or cumulative use of OCS is discouraged due to side effects, including diabetes, hypertension, stroke, anxiety, and cardiovascular disease.4,17,18
In patients with severe CRSwNP who are refractory to first-line treatment, surgical intervention should be considered.4,18
Ancient Egyptians and other cultures used snares (looped wires) to remove nasal polyps and rinsed the nose with saline over 4,000 years ago.19 However, simply removing the nasal polyps is like mowing the grass; they tend to come back quickly because CRSwNP is a chronic inflammatory disease of the mucosa.
Asthma18,20
Aspirin or NSAID hypersensitivity18,20
Elevated tissue eosinophils/IL-5/IgE18,20
And those with strong Type 2 Inflammation predominance18,20
Biologics can decrease symptom severity, nasal polyp size, and the need for OCS and surgery.2,19-25 Moreover, it is vital to initiate biologic treatment in a timely manner in order to prevent severe disease progression, which may involve osteitis or thick bone neoformation. “However, only a minority of our patients receive biologics, and there may also be issues around patient self-administration and adherence, as well as a risk of recurrence if the patient discontinues their biologic.”
Currently approved biologics can be self-administered subcutaneously and are given every 2–4 weeks.2,22-24 In my clinical experience, a common obstacle to biologic therapies is the fear of self-administered treatment. Patients are afraid of self-injection. They tell me that it hurts, that they are afraid of blood and needles. In my practice, to educate patients and encourage compliance, the first three injections are administered by the nurse within the hospital setting, though this consumes considerable time from the clinicians and nurses.
Moreover, ENT specialists themselves may be hesitant to prescribe biologics, meaning only a minority of patients will actually receive treatment with biologics. Therefore, early intervention for patients isn’t just about treatment access; it’s about facilitating early referrals to ENT specialists who can perform surgery and/or prescribe biologics.
This dual approach will help us to intervene earlier and manage CRSwNP more effectively, and by raising awareness and educating clinicians, we can diagnose and treat patients earlier.
Prolonged inflammation can increase the risk of complications, like osteitis and disease recurrence
Consistent treatment is essential for long-term management, and treatments that require less frequent dosing could make a difference for patients and for us as physicians.
Early surgical intervention has shown to reduce the need for further surgeries and lower the risk of developing severe asthma in patients with CRSwNP. When signs of recurrence appear post-surgery, we need to act quickly.
Although data on earlier intervention with biologics for CRSwNP are still emerging, the analogy with asthma treatment suggests that timely biologic therapy may modify the course of the disease and improve patient outcomes in the long run, potentially achieving remission.4
Beghi E et al. Global, regional, and national burden of epilepsy, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(4):357-75.
Strzelczyk A et al. The impact of epilepsy on quality of life: findings from a European survey. Epilepsy Behav. 2023;142:109179.
Anwar H et al. Epileptic seizures. Discov. 2020;8(2):e110.
Guery D, Rheims S. Clinical management of drug resistant epilepsy: a review on current strategies. Neuropsychiat Dis Treat. 2021;17:2229-42.
Löscher W et al. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72(3):606-38.
Sen A et al. Vagus nerve stimulation therapy in people with drug-resistant epilepsy (CORE-VNS): rationale and design of a real-world post-market comprehensive outcomes registry. BMJ Neurol Open. 2021;3(2):e000218.
Devinsky O et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016;15(10):1075-88.
Miller JW, Hakimian S. Surgical treatment of epilepsy. Continuum (Minneap Minn). 2013;19(3 Epilepsy):730-42.
Wheless JW et al. Vagus nerve stimulation (VNS) therapy update. Epilepsy Behav. 2018;88:2-10.
Talevi A. Antiseizure medication discovery: recent and future paradigm shifts. Epilepsia Open. 2022;7(Suppl 1):S133-41.
Nascimento FA et al. Focal epilepsies: update on diagnosis and classification. Epileptic Disord. 2023;25(1):1-7.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
References
Wheless J et al. Focal onset seizure response in children 4-18 years at 24 months - outcomes from the CORE-VNS Study. Poster 1.514. AES Annual Meeting, 6-10 December, 2024.
Kodankandath TV et al. Generalized tonic-clonic seizure [Internet] (2020) Treasure Island: StatPearls Publishing. Available at: https://www.ncbi.nlm.nih.gov/books/NBK441957/. Last accessed: 29 July 2025.
Allen LA et al. Peri‐ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic‐clonic seizures. Epilepsia. 2020;61(8):1570-80.
Kunić S et al. Memory efficiency in patients with drug-resistant epilepsy. Acta Clin Bel. 2022;77(1):25-9.
Suller-Marti et al. Long-term outcomes in patients with generalized tonic-clonic seizures following VNS therapy: interim CORE-VNS 36 months. Poster 2.250. AES Annual Meeting, 6-10 December, 2024.
Samanta D. Rescue therapies for seizure emergencies: current and future landscape. Neurol Sci. 2021;42:4017-27.
Becker DA et al. Treatment of seizure clusters in epilepsy: a narrative review on rescue therapies. Neurol and Ther. 2023;12(5):1439-55.
Beaudreault CP et al. Association of reductions in rescue medication requirements with vagus nerve stimulation: results of long-term community collected data from a seizure diary app. Epilepsy Behav. 2024;159:110008.
12.
13.
14.
15.
16.
17.
18.
19.
Xu X et al. Updates in biologic therapy for chronic rhinosinusitis with nasal polyps and NSAID-exacerbated respiratory disease. 2022;77(12):3593-605.
EUFOREA. Chronic Rhinosinusitis. 2025. Available at: https://www.euforea.eu/patient-portal/crs-welcome/. Last accessed: 23 June 2025.
25.
26.
85
85
20
20
Suller-Marti explained that there are more than 30 different subtypes of seizures, falling into the three groups of:
The ideal goal of treatment, explained Wolf, is freedom from seizures.
The first step is clarifying the seizure type or epilepsy syndrome through:
This will inform the choice of ASM, whether that be a sodium channel blocker or a γ-aminobutyric acid agent, for example, he added.3
focal onset
generalised onset
unknown onset
Wolf
Drug-Resistant Epilepsy
Meeting the goal of seizure freedom, however, is not always possible.
“While ASMs aim to control seizures, they do not cure epilepsy,” said Suller-Marti. “Unfortunately, around 30% of individuals with epilepsy do not achieve seizure freedom, even after trying multiple ASMs or combinations of ASMs.”4,5
Wolf said: “We know that there’s a significant drop-off in seizure control after drug number two. So, if drug number two fails, the likelihood of a third drug working becomes…
30
%
DRE is defined as:
the failure of at least two ASMs
used at an efficacious daily dose.4
significantly, exponentially smaller.”4
The impact of DRE can be profound.4-7
“Having repetitive, frequent seizures may affect:
VAGUS NERVE STIMULATION
VNS is an adjunctive neuromodulatory therapy that can be efficacious in reducing the frequency and severity of seizures in people with DRE.6
The long-established non-pharmacological intervention involves a small pulse generator being surgically implanted under the skin of the chest and connected to the left vagus nerve via a lead wire. The generator transmits electrical signals to the vagus nerve.
DRUG-RESISTANT EPILEPSY AND FOCAL ONSET SEIZURES
FOS are the most common seizure type in both children and adults.11
They are important not just because of the numbers, but because we do not have one single treatment that will control all FOS in every patient,” said Wheless.
FOS are not what people typically picture when they think of an epileptic seizure, he went on. “If I had focal seizures, for example, I may:
I may follow you with my eyes if you were to walk in front of me,
but I can’t talk to you; I can’t respond.
That lasts a minute or so, and I will be tired or really groggy for 5 or 10 minutes afterwards, and still not 100% myself for hours.”
just stare off,
maybe have some lip smacking;
I’m not fully aware.
FOS are not what people typically picture when they think of an epileptic seizure, he went on. “If I had focal seizures, for example, I may:
This will stop people from taking part in daily activities, whether that is going to work, going to school, or socialising, he said.
While the ideal is to achieve seizure-free status, Wheless said that there are many people who, “even with all of our best therapies,” do not reach this treatment goal.
He highlighted that DRE does not necessarily mean that ASMs do not work at all. “Instead of having maybe seven seizures a month, they maybe have two. That is still not seizure freedom, which is where we would like them to be,” he said.
In these patients, it is important to minimise seizures and improve QoL, he said.
VAGUS NERVE STIMULATION IN CHILDREN WITH FOCAL ONSET SEIZURES: REAL-WORLD EVIDENCE
Wheless was part of a group that evaluated VNS therapy after 24 months of use in children aged 4–12 years with DRE and FOS. Presented at AES 2024, the subgroup analysis of the prospective, multicentre, multinational observational CORE-VNS study included 150 children with DRE and FOS who were VNS naïve at baseline.12
Figure 1: Seizure frequency reduction (implant naïve to 24 months) percent of subjects reporting.12 M: months
The other key point, he went on, was the side effect profile, which he described as “mild.” Around a quarter (24.7%) of children reported at least one treatment-emergent adverse event. The most common were:
cough (5.3%),
dysphonia (7.3%),
and other respiratory, thoracic, and mediastinal events (10.7%).12
Over the last 30 years, he added, clinicians have learned how best to use the device in a way that minimises both side effects and seizures. “It is unique to have that longevity of data… and it tells us that, if our patient responds to this treatment, […] they are likely to continue to respond over time.”
The CORE-VNS sub-analysis data “reaffirm the efficacy of VNS,” said Wheless. “I think it will make clinicians rethink where they place it in the treatment list. We shouldn’t be waiting until after the sixth or seventh medicine. We should be thinking about this early on because the data supports it.”
DRUG-RESISTANT EPILEPSY AND GENERALISED TONIC-CLONIC SEIZURES
Generalised tonic-clonic (GTC) seizures are one the most common types of generalised seizure, and are associated with loss of consciousness.13
They begin with a tonic phase, where the body becomes very stiff, followed by a clonic phase, which is characterised by rhythmic jerking movements.13
VAGUS NERVE STIMULATION IN GENERALISED TONIC-CLONIC SEIZURES: REAL-WORLD EVIDENCE
In the USA, VNS is approved for use in focal seizures. However, it is licenced for GTC in Europe.6 Suller-Marti’s team’s sub-analysis of CORE-VNS data, also presented at AES 2024, sought to add to the evidence base for the device’s use in this indication, she explained.
A total of 59 participants met the criteria of a diagnosis of primary GTC and receiving VNS for the first time.16
Twelve were implanted within 5 years of diagnosis, while 47 started VNS therapy ≥5 years after.16
Those who were implanted earlier tended to be younger (9.7 versus 25.9 years), and participants had tried a median of six (range: 2–20) ASMs before starting VNS therapy.16
Thirty-six-month follow-up data was available on 40 of these patients. It showed (Figure 2):
This was regardless of the time between diagnosis and implantation.16
70
%
–83.2
%
responder rate
median seizure frequency change
Healthcare Utilisation
There was also, Suller-Marti went on, a “notable reduction” in healthcare utilisation. At baseline, there were a total of 24 emergency department visits and 19 hospitalisations in the previous 12 months.
At 36 months, each of these metrics had dropped to four.16
The results show that “there are treatment options beyond medications for these often-overlooked populations,” Suller-Marti explained, calling VNS “an excellent option.” “While we may not achieve complete seizure freedom, the level of seizure reduction observed is so significant that it dramatically improves patients’ lives and lowers their risk of SUDEP.”
EPILEPSY RESCUE MEDICATIONS: AN IMPORTANT TOOL IN EPILEPSY MANAGEMENT
In recent years, Wolf said he had seen an increase in the number of ASMs people living with epilepsy have tried before VNS implantation.
To validate this, they analysed data from the Seizure Tracker® app (Seizure Tracker LLC, Springfield, Virginia, USA), which enables patients and their families to record seizures and rescue medication use in a diary.
VAGUS NERVE STIMULATION AND RESCUE MEDICATIONS: REAL-WORLD EVIDENCE
The study, presented at AES 2024, included 95 patients. It evaluated trends in rescue administration frequency before and after the first recorded VNS magnet swipe in patients with DRE who had recorded at least one VNS magnet swipe or benzodiazepine rescue medication usage within the 90 days prior to the first swipe. At baseline, the mean seizure frequency reduction rate was 8.3 per month, with a median rescue medication use frequency of 2.1 administrations per month SD: 3.3).19
VAGUS NERVE STIMULATION IN TODAY’S DRUG-RESISTANT EPILEPSY LANDSCAPE
The results of these three studies demonstrate the role of VNS in today’s rapidly expanding treatment landscape, said the clinicians.
I think our paper helps to bring back the conversation of VNS,” said Wolf. “When a treatment is more than 30 years old, people can forget about it. When the new drug with a fancy MOA comes along, they can forget about the true, tried, and tested approaches.” Clinicians may well remember those people who did not respond to VNS, but not those who “still have it in, and are doing really well,” because “they are barely in your office,” he added.
Wolf
CONCLUSION
Real-world evidence presented at AES 2024 complements the decades of existing data that demonstrate VNS’s efficacy in reducing seizure frequency and improving patient outcomes.
It also shows that VNS is often underutilised, with many patients being subjected to prolonged trials of multiple ASMs before neuromodulation is considered. This delay may limit the potential benefits of VNS, particularly for paediatric patients in whom earlier seizure control could mitigate developmental delays and cognitive impairments.
It affects around 50 million people worldwide and can have a significant impact on morbidity, mortality, and QoL.1,2
Focal seizures occur in a localised region of the cerebral cortex, whereas generalised seizures affect both brain hemispheres.3
Generalised seizure
Focal seizure
You want to match the mechanism of action (MOA) to the seizure type, and then keep adding different or complementary MOAs to achieve maximum seizure control.
your ability to focus,
your learning,
your memory,
and your QoL; it stops you from just being able to go out and do things,” Wolf explained.
VNS has the potential to reduce seizure frequency and severity, prolong seizure-free intervals, and reduce the risk of SUDEP, thereby addressing critical unmet needs in this high-risk population.
Suller-Marti
It is still interfering with their QoL and keeping them from doing things they want to do.
Wheless
Highlighting these figures, Wheless said that early intervention was crucial, particularly in children. There should, he said, be a “sense of urgency” around controlling seizures, minimising medication side effects, and enhancing QoL.
“Often, seizures are allowed because they are not convulsive. People think, ‘the child stares off, they recover, and they do fine afterwards’. Yet we know if that goes on for long periods, abnormal connections are set up in the brain. Then when we try to pursue other therapies down the road, they are not as effective as they would have been if we had used them earlier.”
The potential impact on development must also be considered, he went on. “We know there are critical developmental time windows,” he said. “Children are supposed to do things a certain time, and if their seizures (or treatment side effects) interfere with that progress, we can’t just go back when they’re older and fix it.”
Wheless
At 24 months, the responder rate, defined as a ≥50% reduction in FOS frequency over the previous 3 months compared to baseline, was 59.2%. Approximately 40% had a >80% seizure response, and 22% were seizure-free, over the previous 3 months (Figure 1).
The median seizure frequency reduction at 24 months was 64% for focal seizures. The analysis also found QoL improvements in more than half of participants, with only 31.4% reporting no change, and that responsiveness to VNS continued to increase over time.12
Despite VNS being indicated after the failure of at least two ASMs, a median of six (range: 2–17) had been tried in this group. The median age at first implant was 10.4 years (range: 4.05–17.99), with a median duration between diagnosis and informed consent of 6.5 years.12
“I think we sometimes forget that, compared to a lot of other treatments, VNS is very well tolerated.”
Wheless
Reflecting on his own practice, he added that there were various other benefits to VNS in this group. It is not a medicine, meaning that drug–drug interactions are less of a concern, and it is an “automatic treatment” that “works in the background.” “It is one less thing the families and the children have to think about every day. It is like having the thermostat set on your heating at home; it’s just working away.”
VNS can contribute to the lowering of ASMs, thereby reducing side effects, and also have a positive impact on mood, he said. This is important as children grow into adolescence and adulthood, when FOS become closely associated with mental health issues.
GTC seizures may involve hypoxia,14 and “immediate assistance is usually needed,” said Suller-Marti.
Those with earlier implantation were more likely to be responders at 36 months (83.3% versus 67.7%) and have a higher median seizure frequency change (–94.3% versus –76.4%).16
Even though this is not seizure freedom, it is a big change in their lives.
Suller-Marti
The patients included in this study suffered from highly refractory epilepsy and uncontrolled seizures,” she highlighted. “This reduction indicates an improvement in their QoL, as each visit adds stress, which negatively impacts their and their family’s mental health.” It also reduces societal healthcare costs overall, she added. In addition, patients reported a decrease in their perceived severity of epilepsy,16 Suller-Marti went on. “It is all pointing in the same direction: that everything is better overall.
Suller-Marti Summary
Wolf explained: “Over the years, as more and more new ASMs have come on the market, people keep going after medication number two or three,” he said. “By the time they came to our specialist epilepsy practice, they had been on seven or eight medications.” In the clinic, though, his team was noticing a reduction in rescue medication and, in some cases, ASM use, following VNS implantation.
Wolf
Wolf explained: “We wanted to try to make the point of ‘why are you waiting so long to introduce neurostimulation?’” Wolf’s team has been encouraging families to use the app for some time, and it has become a “trove of information,” he added.
Wolf
Moving forward, greater awareness and proactive consideration of VNS earlier on in the treatment pathway could improve outcomes for many people living with DRE.
Clinical history
and a detailed semiological description of the seizures,
as well as brain MRI, EEG, and genetic testing.3
Suller-Marti explained that DRE was associated with higher rates of depression, social isolation, and suicidality.6,7
Epilepsy is associated with two-to-three-fold more mental health comorbidities (including anxiety and depression) than the general population, and suicide risk is three times higher than in the general population.4
Those figures are higher still among those with DRE.4 “The relationship is bidirectional: the seizures negatively impact QoL and contribute to social isolation, which in turn exacerbates the mental health challenge. In addition, some ASMs may also adversely affect mood and emotional wellbeing,” explained Suller-Marti.
One of the most severe potential outcomes of uncontrolled seizures is death.
The incidence of SUDEP increases in line with disease severity. One study showed it to be 1.2 per 1,000 person years in the general epilepsy population, compared to 4.2 in those with DRE. In individuals evaluated for epilepsy surgery, the incidence was 6.2 per 1,000 person years.7
“This may occur through various mechanisms, including drowning accidents, bleeding, or falls. Another major entity is SUDEP, a phenomenon where an individual dies after a seizure, suddenly and unexpectedly,” Suller-Marti added.
Resective epilepsy surgery, which removes the area of the brain from which the seizures originate, remains the most successful strategy for achieving seizure freedom, and can be successful in up to 80% of cases in selected patients.4
However, only a subset of patients, i.e., those with focal onset epilepsy in whom the epileptogenic zone can be clearly identified and does not overlap the eloquent cortex, “are lucky enough to be eligible for epilepsy surgery,” explained Suller-Marti.4,8 “Those with generalised epilepsy, where the seizure involves both hemispheres simultaneously, are not candidates for resective surgery.”
“This may occur through various mechanisms, including drowning accidents, bleeding, or falls. Another major entity is SUDEP, a phenomenon where an individual dies after a seizure, suddenly and unexpectedly,” Suller-Marti added.
Patients with DRE require close follow-up. Neurologists and epileptologists must act proactively, including referring patients to specialised epilepsy centres and arranging for surgical evaluation and epilepsy monitoring,” said Suller-Marti. “You need to explore further treatment options without unnecessary delays.
Suller-Marti
80
%
VNS was approved in people with focal and generalised onset seizures of all ages in Europe in 1994.
In 1997, the USA approved it for use in focal onset seizures (FOS) in people over the age of 12 years, though the label has since been updated to include those with FOS aged 4 years and above.6
However, many new epilepsy drugs have become available over the last 30 years, and as of 2022, more than 40 ASMs were available.9,10 This raises the question, said Wheless, of the intervention’s place in today’s DRE treatment pathway.
During the AES 2024 Annual Meeting, held in Los Angeles, California, USA, in December, researchers presented a number of studies that provide a picture of the current use of responsive VNS in the real world.
Ongoing seizures can have a wide range of consequences,4-7 she went on.
Memory complaints are common and can be associated with the administration of multiple ASMs.15
While seizure control is currently the most effective strategy to improve memory, this remains particularly difficult in cases of DRE,
said Suller-Marti.
“Seizures can be frequent and unpredictable, significantly limiting daily activities, independence, employment, and overall QoL.
Unfortunately, many patients are unable to maintain employment due to the frequency and severity of the seizures, and are not permitted to hold a driving license. In many countries, this severely limits their ability to participate in society, including working, attending school, or even living independently.”
For all these reasons, individuals with epilepsy, especially those with DRE, require comprehensive and multidisciplinary care.
“This will include psychological support and neuropsychological evaluation to assess cognitive function and develop tailored strategies to enhance memory and cognitive performance,” Suller-Marti explained.
“Social support is also essential to ensure access to appropriate treatment and medication. Education plays a critical role in empowering patients, helping individuals better understand their condition and navigate the diagnosis and treatment.”
Treatment Toleration
The most frequent treatment-emergent adverse events were dysphonia (11.9%; n=7), dyspnoea (6.8%; n=4), and implant site pain (5.1%; n=3).16
It was, overall, well tolerated, and there were no major or severe side effects that we did not expect.” It is important to remember, she went on, that many of the side effects can be easily managed with “proper parameter adjustments."
Suller-Marti Summary
Proportion of Patients Reaching Target Dose Range
The sub-analysis also looked at the proportion of patients reaching the target dose range. Suller-Marti explained that, while the device’s manufacturer recommends an output current of 1.625 mA as the therapeutic dose, this can vary in clinical practice according to the patient’s tolerability and even physician preference.
“It is possible that this was associated with some of the positive results,” she said. It is important to remember, however, that some patients respond at a lower dose. “It must be adjusted based on the patient’s tolerability,” she added.
Suller-Marti Summary
At 12 months, 60% of patients were in the therapeutic range, and this rose to 70% at Month 24.16
60
%
Rescue medications are an important tool in epilepsy management. They can:
Abort prolonged seizures with the potential to evolve into status epilepticus.
Prevent subsequent repeat, or cluster seizures, explained Wolf.17
We know that there is a subset of patients who, if they have one seizure, are going to have another one in the next 24 hours. If you can interrupt that with a rescue medication, that will drop the likelihood of a subsequent seizure and allow them to get on with their day.17,18
Wolf
VNS as a rescue treatment:
VNS has become something of a rescue treatment in recent years, Wolf said, explaining that a magnet stimulus can be passed over the device to temporarily increase the dose.19 “Some people can feel an aura coming on. They want to be proactive, but they know a pill will take half an hour; swiping the magnet allows for rapid treatment,” Wolf explained. “Then you have the patient who is having 30 seizures a day. There’s no way you can give that many benzodiazepine-type medications; they become too sleepy. The family finds it really beneficial to have the VNS magnet as a rescue treatment.
Wolf
What does Wolf think of VNS as a rescue medication? He also explained that clinicians often use the frequency of rescue medication use as a marker of disease activity and control.19 “If someone is using a lot of rescue medications, whatever I am doing as the baseline, daily preventative treatment is not enough. If they needed no rescue medications, and only had one small seizure, then maybe their treatment just needs a small tweak.”
No seizures and no rescue medications are an indication that the current treatment plan is working, he said.
Significant reductions in rescue medication usage were observed at 91–180 days post first VNS magnet swipe (median: 0.33 [quartile 1 (Q1)–quartile 3 (Q3): 0.00–2.30]; p=0.046), 181–360 days (median: 0.33 [Q1–Q3: 0.00–1.83]; p=0.009), 361–540 days (median: 0.17 [Q1–Q3: 0.00–0.83]; p<0.001), and at 541–720 days (median: 0.00 [Q1–Q3: 0.00–0.42]; p<0.001). Wolf highlighted that the magnitude of reduction increased over time (Figure 3).19
The decreased use of rescue medications tells you a lot about how the patient is doing,” he said. “If you are not using the rescue medications as often, your brain is less exposed to benzodiazepines, which can slow you down and make you sleepy. That is a real plus.”
It is a fair assumption, he added, that fewer seizures translate to “patients feeling better and having a lower risk of SUDEP.”
“If the risk of your day being interrupted, your memory being wiped out, or missing a birthday party or going out for dinner is lower, then your QoL has got to be better,” he added.
Wolf
What is important about these data, Wolf went on, is that they are “real numbers” from a “real, honest collective group” over 20 years.
“It is a regimented group who are making sure they, their children, or their loved ones are taking their medication,” he said. “Patient perspectives are extremely valuable and we have to listen to them. I do not think this is the singular, perfect study; I think it is complementary to and validates the other studies that have shown the benefits… You need multiple sources of information to decide whether something is reliable.”
We know that if a patient responds to VNS, they are going to continue to respond over time. It can be part of their foundation therapy, he said.
Wolf
Unfortunately, said Wheless “we are still trying too many medicines before we get to the other options.”
“We have a lot of faith in our modern medicines, and I think we delay because we think ‘we have all these good medicines, surely one of them will work’.”
Wheless also noted that, as a non-pharmacological therapy, VNS can be used in combination with any ASM, without concerns around drug–drug interactions. That means new drugs can be added as and when they become available and/or indicated, or reduced or withdrawn if they are poorly tolerated.
Both Wolf and Wheless acknowledged that it is often easier to write a prescription than to refer a patient for neuromodulation. That does not, however, make it the right approach, they added.
One challenge when talking to patients and their families is the pure number of options available, Wheless added. “I think it helps to tell families that VNS is a reasonable option, and that we should not wait 2 or 5 years or until they have had multiple medications before we do it. If we are going to do it, it will be better to do it at the front end, when you will get the most benefit,” he said.
At his centre, they start this process of outlining the pros and cons of VNS at the failure of two ASMs. “We tell them that there are three groups of patients,” he went on.
“In one group, it does not do anything…
We have a group that has a huge seizure reduction, and when they use the magnet, it stops the seizures…
Then we have the group [which] has maybe a 50% to 60% reduction in seizures, but when they use the magnet, it aborts the seizure or prevents seizures going forwards.”
It “might not be perfect” in that middle bracket, but it is “certainly better” than what they are used to, and may allow for the reduction of ASMs and their associated side effects, he added.
Wolf said: You need to think about at which number of medications you should start the conversation. That does not necessarily mean you pull the trigger, but you talk about neuromodulation as a possible option.
Wolf
Explaining how the device works and the process of implantation should form part of those initial conversations. Wheless said: “We tell families that even though it’s ‘surgery’, it is not what they are typically thinking of. It is not permanently removing anything… and it is totally reversible. Worse case scenario, it does not work and we take it out.”
One potential barrier is patient or family reluctance, though this is often based on the misconception that VNS involves brain surgery. Open and honest conversations are vital, they agreed.
