Vagus nerve stimulation for drug-resistant epilepsy

Vagus nerve stimulation for drug-resistant epilepsy

see also Responsive neurostimulation.


Vagus nerve stimulation for drug-resistant epilepsy was first approved in Europe in 1994 and in the United States (US) in 1997. Subsequent modifications improved the safety and the efficacy of the system. The most recent application of vagal neurostimulation is represented by transcutaneous devices that are claimed to have strong therapeutic potential. In a review, Toffa et al. sought to analyze the most meaningful available data describing the indications, safety and efficacy of the different approaches of VNS in clinical practice. Therefore, they identified studies reporting VNS efficacy and/or safety in epilepsy and its comorbidities from January 1990 to February 2020 from various databases including PubMed, Scopus, Cochrane, US government databases and VNS manufacturer published resources. In general, VNS efficacy becomes optimal around the sixth month of treatment and a 50-100 % seizure frequency reduction is achieved in approximately 45-65 % of the patients. However, some clinically relevant differences have been reported with specific factors such as epilepsy etiology or epilepsy classification, patient age as well as the delay of VNS therapy onset. VNS efficacy on seizure frequency has been demonstrated in both children and adults, in lesional and non-lesional cases, in focal and generalized epilepsies, on both seizures and epilepsy comorbidities. Regarding the latter, VNS can lead to an improvement of about 25-35 % in depression scores, 35 % in anxiety scores and 25 % in mood assessment scores. If non-invasive devices are undeniably safer, their efficacy is limited due to the scarcity of large cohort studies and the disparity of methodological approaches (study design and stimulation parameters). Overall, they believe that there is a progress margin for improving the safety of implantable devices and, above all, the effectiveness of the various VNS approaches 1).

see also Vagus nerve stimulation for drug-resistant epilepsy in children

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 2).


Vagus nerve stimulation (VNS) is becoming an increasingly popular therapy for patients with drug resistant epilepsy 3) 4) 5) 6) 7) 8) 9) 10).

The use of functional neuroimaging such as SPECT, PET and fMRI in patients undergoing peripheral nerve stimulation can help us to understand these mechanisms.

Bari et al., reviewed the literature for functional neuroimaging performed in patients implanted with peripheral nerve stimulators. These studies suggest that brain activity in response to peripheral nerve stimulation is a complex interaction between the stimulation parameters, disease type and severity, chronicity of stimulation, as well as nonspecific effects. From this information we may be able to understand which brain structures are involved in the mechanism of peripheral nerve stimulation as well as define the neural substrates underlying these disorders 11).

Connor et al., performed a review of available literature published between 1980 and 2010. Inclusion criteria for articles included more than 10 patients evaluated, average follow-up of 1 or more years, inclusion of medically refractory epilepsy, and consistent preoperative surgical evaluation. Articles were divided into 4 classes of evidence according to criteria established by the American Academy of Neurology.

A total of 70 publications were reviewed, of which 20 were selected for review based on inclusion and exclusion criteria. There were 2 articles that provided Class I evidence, 7 that met criteria for Class II evidence, and 11 that provided Class III evidence. The majority of evidence supports VNS usage in partial epilepsy with a seizure reduction of 50% or more in the majority of cases and freedom from seizure in 6%-27% of patients who responded to stimulation. High stimulation with a gradual increase in VNS stimulation over the first 6 weeks to 3 months postoperatively is well supported by Class I and II data. Predictors of positive response included absence of bilateral interictal epileptiform activity and cortical malformations.

Vagal nerve stimulation is a safe and effective alternative for adult and pediatric populations with epilepsy refractory to medical and other surgical management 12).


A study looked at the research available on the effectiveness, safety, and cost of two types of electrical stimulation devices currently licensed for treatment of epilepsy for adults and children in Canada: vagus nerve stimulation (VNS) and deep brain stimulation (DBS). Both approaches appear to be effective at reducing the frequency of seizures in adults. However, the evidence on DBS is limited to a single study with adults; Chambers and Bowen found no studies of DBS with children. Studies on VNS showed that both adults and children had fewer hospitalizations and emergency department visits after the procedure. Both procedures carry serious risks, but several longer-term studies have found that adverse events appear to be limited. The cost of VNS, including the process of assessing whether or not patients are good candidates for the procedure, is estimated to be about $40,000 per person (and higher for DBS because the device is more expensive and the operating time is longer). Of the 70,000 people in Ontario with epilepsy, about 1,400 (300 children and 1,110 adults) may be candidates for VNS to reduce their seizures 13).

Complications and failure of the device can result from lead fracture, device malfunction, disconnection, or battery displacement and can result in a variety of symptoms.

D’Agostino et al., present an interesting case of stimulator malfunction with increased impedance change seen only with a change in head position.

The patient is a 25-year-old male with a vagal nerve stimulator (VNs) placed for medically refractory epilepsy who presented with neck pain and an electrical pulling sensation in his neck whenever he turned his head to the right. Initial interrogation of the VNs showed normal impedance. Subsequent interrogation with the patient’s head turned found increased impedance only when the head was turned to the right. The patient had successful removal and replacement of the device with resolution of his preoperative complaints. Partial lead fracture was seen at explant.

Vagus nerve stimulator malfunction can present in atypical ways. Positional maneuvers may help with its timely diagnosis 14).

It is still difficult to predict which patients will respond to VNS treatment and to what extent.

Liu et al., aimed to explore the relationship between preoperative heart rate variability (HRV) and VNS outcome. 50 healthy control subjects and 63 DRE patients who had received VNS implants and had at least one year of follow up were included. The preoperative HRV were analyzed by traditional linear methods and heart rhythm complexity analyses with multiscale entropy (MSE). DRE patients had significantly lower complexity indices (CI) as well as traditional linear HRV measurements than healthy controls. We also found that non-responders0 had significantly lower preoperative CI including Area 1-5, Area 6-15 and Area 6-20 than those in the responders0 while those of the non-responders50 had significantly lower RMSSD, pNN50, VLF, LF, HF, TP and LF/HF than the responders50. In receiver operating characteristic (ROC) curve analysis, Area 6-20 and RMSSD had the greatest discriminatory power for the responders0 and non-responders0, responders50 and non-responders50, respectively. Our results suggest that preoperative assessment of HRV by linear and MSE analysis can help in predicting VNS outcomes in patients with DRE 15).


Data suggest that sudden unexpected death in epilepsy patients (SUDEP) risk significantly decreases during long-term follow-up of patients with refractory epilepsy receiving VNS Therapy. This finding might reflect several factors, including the natural long-term dynamic of SUDEP rate, attrition, and the impact of VNS Therapy. The role of each of these factors cannot be confirmed due to the limitations of the study 16).

Boon et al., conducted a systematic review on the currently available neurostimulation modalities primarily with regard to effectiveness and safety.

For vagus nerve stimulation (VNS), there is moderate-quality evidence for its effectiveness in adults with drug-resistant partial epilepsies. Moderate-to-low-quality evidence supports the efficacy and safety of deep brain stimulation (DBS) and responsive neurostimulation (RNS) in patients with DRE. There is moderate-to-very low-quality evidence that transcranial direct current stimulation (tDCS) is effective or well tolerated. For transcutaneous vagus nerve stimulation (tVNS), transcranial magnetic stimulation (TMS) and trigeminal nerve stimulation (TNS), there are insufficient data to support the efficacy of any of these modalities for DRE. These treatment modalities, nevertheless, appear well tolerated, with no severe adverse events reported.

Head-to-head comparison of treatment modalities such as VNS, DBS and RNS across different epileptic syndromes are required to decide which treatment modality is the most effective for a given patient scenario. Such studies are challenging and it is unlikely that data will be available in the near future. Additional data collection on potentially promising noninvasive neurostimulation modalities like tVNS, TMS, TNS and tDCS is warranted to get a more precise estimate of their therapeutic benefit and long-term safety 17).

see Vagus nerve stimulation for drug resistant epilepsy case series.

Arhan et al., describe the first child with drug-resistant epilepsy in whom vagus nerve stimulation aggravated seizures and emerged status epilepticus after the increase in vagal nerve stimulation current output.

A 13-year-old girl presented with refractory secondary generalized focal epilepsy. Vagal nerve stimulator was implanted because of drug-resistant epilepsy. After the increase of vagal nerve stimulator current output to a relatively high level, the patient experienced seizure aggravation and status epilepticus.

They conclude that vagus nerve stimulation may induce paradoxical seizures and may lead to status epilepticus, similarly to some antiepileptic drugs 18).


1)

Toffa DH, Touma L, El Meskine T, Bouthillier A, Nguyen DK. Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: A critical review. Seizure. 2020 Oct 10;83:104-123. doi: 10.1016/j.seizure.2020.09.027. Epub ahead of print. PMID: 33120323.
2)

Yamamoto T. Vagus nerve stimulation therapy: indications, programing, and outcomes. Neurol Med Chir (Tokyo). 2015;55(5):407-15. doi: 10.2176/nmc.ra.2014-0405. Epub 2015 Apr 28. Review. PubMed PMID: 25925759; PubMed Central PMCID: PMC4628168.
3)

Alexopoulos AV, Kotagal P, Loddenkemper T, Hammel J, Bingaman WE (2006) Long-term results with vagus nerve stimulation in children with pharmacoresistant epilepsy. Seizure 15: 491–503. pmid:16859931 doi: 10.1016/j.seizure.2006.06.002
4)

Chambers A, Bowen JM (2013) Electrical stimulation for drug-resistant epilepsy: an evidence-based analysis. Ont Health Technol Assess Ser 13: 1–37. pmid:24379898
5)

Coady MA, Adler F, Davila JJ, Gahtan V (2000) Nonrecurrent laryngeal nerve during carotid artery surgery: case report and literature review. J Vasc Surg 32: 192–196. pmid:10876223 doi: 10.1067/mva.2000.105680
6)

Elliott RE, Rodgers SD, Bassani L, Morsi A, Geller EB, et al. (2011) Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases. J Neurosurg Pediatr 7: 491–500. doi: 10.3171/2011.2.PEDS10505. pmid:21529189
7)

Englot DJ, Chang EF, Auguste KI (2011) Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. Journal of neurosurgery 115: 1248–1255. doi: 10.3171/2011.7.JNS11977. pmid:21838505
8)

Milby AH, Halpern CH, Baltuch GH (2009) Vagus nerve stimulation in the treatment of refractory epilepsy. Neurotherapeutics 6: 228–237. doi: 10.1016/j.nurt.2009.01.010. pmid:19332314
9)

Rutecki P (1990) Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation. Epilepsia 31 Suppl 2: S1–6. pmid:2226361 doi: 10.1111/j.1528-1157.1990.tb05843.x
10)

Tanganelli P, Ferrero S, Colotto P, Regesta G (2002) Vagus nerve stimulation for treatment of medically intractable seizures. Evaluation of long-term outcome. Clin Neurol Neurosurg 105: 9–13. pmid:12445916 doi: 10.1016/s0303-8467(02)00018-5
11)

Bari AA, Pouratian N. Brain imaging correlates of peripheral nerve stimulation. Surg Neurol Int. 2012;3(Suppl 4):S260-8. doi: 10.4103/2152-7806.103016. Epub 2012 Oct 31. PubMed PMID: 23230531; PubMed Central PMCID: PMC3514912.
12)

Connor DE Jr, Nixon M, Nanda A, Guthikonda B. Vagal nerve stimulation for the treatment of medically refractory epilepsy: a review of the current literature. Neurosurg Focus. 2012 Mar;32(3):E12. doi: 10.3171/2011.12.FOCUS11328. Review. PubMed PMID: 22380853.
13)

Chambers A, Bowen JM. Electrical stimulation for drug-resistant epilepsy: an evidence-based analysis. Ont Health Technol Assess Ser. 2013 Oct 1;13(18):1-37. eCollection 2013. Review. PubMed PMID: 24228081; PubMed Central PMCID: PMC3817921.
14)

D’Agostino E, Makler V, Bauer DF. Vagal Nerve Stimulator Malfunction with Change in Neck Position: Case Report and Literature Review. World Neurosurg. 2018 Mar 16. pii: S1878-8750(18)30551-5. doi: 10.1016/j.wneu.2018.03.073. [Epub ahead of print] PubMed PMID: 29555606.
15)

Liu HY, Yang Z, Meng FG, Guan YG, Ma YS, Liang SL, Lin JL, Pan LS, Zhao MM, Qu W, Hao HW, Luan GM, Zhang JG, Li LM. Preoperative Heart Rate Variability as Predictors of Vagus Nerve Stimulation Outcome in Patients with Drug-resistant Epilepsy. Sci Rep. 2018 Mar 1;8(1):3856. doi: 10.1038/s41598-018-21669-3. PubMed PMID: 29497072; PubMed Central PMCID: PMC5832772.
16)

Ryvlin P, So EL, Gordon CM, Hesdorffer DC, Sperling MR, Devinsky O, Bunker MT, Olin B, Friedman D. Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy. Epilepsia. 2018 Mar;59(3):562-572. doi: 10.1111/epi.14002. Epub 2018 Jan 16. PubMed PMID: 29336017.
17)

Boon P, De Cock E, Mertens A, Trinka E. Neurostimulation for drug-resistant epilepsy: a systematic review of clinical evidence for efficacy, safety, contraindications and predictors for response. Curr Opin Neurol. 2018 Apr;31(2):198-210. doi: 10.1097/WCO.0000000000000534. PubMed PMID: 29493559.
18)

Arhan E, Serdaroğlu A, Hirfanoğlu T, Kurt G. Aggravation of seizures and status epilepticus after vagal nerve stimulation therapy: the first pediatric case and review of the literature. Childs Nerv Syst. 2018 Apr 22. doi: 10.1007/s00381-018-3806-x. [Epub ahead of print] PubMed PMID: 29680919.

Dopamine agonist resistant lactotroph adenoma

Dopamine agonist resistant lactotroph adenoma

While dopamine agonists are a primary method of therapeutic treatment for Lactotroph adenoma, the rate of resistance to these drugs continues to increase each year.

Surgery is typically indicated for patients who are resistant to medical therapy or intolerant of its adverse side effects, or are experiencing progressive tumor growth. Surgical resection can also be considered as a primary treatment for those with smaller focal tumors where a biochemical cure can be expected as an alternative to lifelong dopamine agonist treatment. Stereotactic radiosurgery also serves as an option for those refractory to medical and surgical therapy 1).


Coopmans et al., reported a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy , a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis, or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin receptor 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis, or both in prolactinomas 2).


During previous long-term clinical investigations, Hu et al., from Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, GuangzhouChina, found that partial resistant prolactinomas exhibited significantly more fibrosis than did sensitive adenomas, suggesting a role of fibrosis in their drug resistance. Furthermore, resistant adenomas with extensive fibrosis mainly express type I and type III collagens. Since TGF-β1 is the key factor in the initiation and development of tissue fibrosis, including in the pituitary, in this study, they aimed to determine whether TGF-β1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using immunochemistry and western blotting, they found that the TGF-β1/Smad3 signaling pathway-related proteins were elevated in resistant prolactinoma specimens with high degrees of fibrosis compared to levels in sensitive samples, suggesting that this pathway may play a role in prolactinoma fibrosis. In vitro, TGF-β1 stimulation promoted collagen expression in normal HS27 fibroblasts. Furthermore, the sensitivity of rat prolactinoma MMQ cells to bromocriptine decreased when they were co-cultured with HS27 cells treated with TGF-β1. The TGF-β1/Smad3 signaling-specific inhibitor SB431542 counteracted these effects, indicating that TGF-β1/Smad3-mediated fibrosis was involved in the drug-resistant mechanisms of prolactinomas. These results indicate that SB431542 may serve as a promising novel treatment for preventing fibrosis and further improving the drug resistance of prolactinoma3).

References

1)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.
2)

Coopmans EC, van Meyel SWF, Pieterman KJ, van Ipenburg JA, Hofland L, Donga E, Daly AF, Beckers A, Van der Lely AJ, Neggers SJCMM. Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma. Eur J Endocrinol. 2019 Jun 1. pii: EJE-19-0279.R1. doi: 10.1530/EJE-19-0279. [Epub ahead of print] PubMed PMID: 31167168.
3)

Hu B, Mao Z, Jiang X, He D, Wang Z, Wang X, Zhu Y, Wang H. Role of TGF-β1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma. Brain Res. 2018 Jul 26. pii: S0006-8993(18)30408-6. doi: 10.1016/j.brainres.2018.07.024. [Epub ahead of print] PubMed PMID: 30055965.

Book: Controversial Pain Syndromes of the Arm: Pathogenesis and Surgical Treatment of Resistant Cases

Controversial Pain Syndromes of the Arm: Pathogenesis and Surgical Treatment of Resistant Cases
By Albrecht Wilhelm

Controversial Pain Syndromes of the Arm: Pathogenesis and Surgical Treatment of Resistant Cases

List Price: $59.99
This concise, well-illustrated monograph explains the true pathogenesis, hitherto unsolved, of five key pain syndromes of the arm and describes diagnosis, indications for surgery, surgical techniques, and results. The syndromes in question are tennis elbow, golf elbow, proximal radial nerve compression syndrome, so-called coracoiditis, and Sudeck’s dystrophy. In each case, the neurogenic pathogenesis is identified and deficiencies of other interpretations, for example that these conditions are the result of degenerative processes, are discussed. Appropriate surgical techniques in resistant cases are described in the context of pathogenesis, and treatment outcomes are documented. The fact that these outcomes are excellent in the large majority of cases may be taken as support for the author’s interpretation of pathogenesis. This book will be informative and instructive for all hand, orthopedic, trauma, plastic, general, and neurosurgeons as well as neurologists and hand therapists.
About the Author
Albrecht Wilhelm was born in 1929 in Braunau, Bohemia (now in the Czech Republic). He studied at Würzburg and Munich Universities and in 1955 was awarded his PhD (magna cum laude). In spring 1954 he embarked on an internship in the surgical department of Würzburg University and the results obtained with surgical methods that he subsequently developed in Würzburg formed the basis for his Habilitationsschrift, “Joint Denervation and its Anatomical Basis – A New Principle in Hand Surgery” (1966). In 1970 Dr. Wilhelm was appointed Professor of Surgery and also assumed responsibility for the Surgical Department at Aschaffenburg Hospital. Throughout his career, Dr. Wilhelm has had a keen interest in hand surgery and surgery of peripheral nerves. He has authored 139 scientific publications, 32 of which have been book contributions. He has developed 20 new surgical techniques, including 18 relating to the upper extremity and has provided solutions to the disputed pathogenesis of various conditions. Since his retirement in 1994 he has continued to conduct scientific research and voluntary surgical activities. Dr. Wilhelm has been the recipient of various honors: He received the Federal Medal in 1989. He served as President of the German Society of Hand Surgery (DGH) in 1992 and was made a member of honor of the society in 1994. He was named as an IFSSH “Pioneer of Hand Surgery” in 2004 and became a member of honor of the DAH (“German-Speaking Hand Surgery Association”) in 2013.

Product Details

  • Published on: 2015-10-12
  • Original language: English
  • Number of items: 1
  • Dimensions: 6.46″ h x .59″ w x 9.61″ l, .0 pounds
  • Binding: Hardcover
  • 154 pages
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