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.

Mesial temporal lobe epilepsy treatment

Mesial temporal lobe epilepsy treatment

Stereoelectroencephalography guided radiofrequency thermocoagulation.

see Mesial temporal lobe epilepsy radiosurgery.

see Temporal lobe epilepsy surgery.

Surgical resection is the gold standard treatment for drug-resistant focal epilepsy, including mesial temporal lobe epilepsy (MTLE) and other focal cortical lesions with correlated electrophysiological features.

Surgical approaches for medically refractory mesial temporal lobe epilepsy (MTLE) that previously have been reported include anterior temporal lobectomy (ATL), transcortical selective amygdalohippocampectomy, transsylvian amygdalohippocampectomy, and subtemporal amygdalohippocampectomy.

Each approach has its advantages and potential pitfalls.

see Anterior temporal lobectomy.

Subiculum stimulation

Evidence has been provided that the subiculum may play an important role in the generation of seizures.Electrical stimulation at this target has been reported to have anticonvulsant effects in kindling and pilocarpine rat models, while in a clinical study of hippocampal deep brain stimulation (DBS), contacts closest to the subiculum were associated with a better anticonvulsive effect.

Vázquez-Barrón et al. evaluated the effect of electrical stimulation of the subiculum in patients with refractory mesial temporal lobe epilepsy (MTLE) who have hippocampal sclerosis (HS).

Six patients with refractory MTLE and HS, who had focal impaired-awareness seizures (FIAS) and focal to bilateral tonic-clonic seizures (FBTCS), had DBS electrodes implanted in the subiculum. During the first month after implantation, all patients were OFF stimulation, then they all completed an open-label follow-up of 24 months ON stimulation. DBS parameters were set at 3 V, 450 µs, 130 Hz, cycling stimulation 1 min ON, 4 min OFF.

There was a mean reduction of 49.16% (±SD 41.65) in total seizure number (FIAS + FBTCS) and a mean reduction of 67.93% (±SD 33.33) in FBTCS at 24 months. FBTCS decreased significantly with respect to baseline, starting from month 2 ON stimulation.

Subiculum stimulation is effective for FBTCS reduction in patients with MTLE and HS, suggesting that the subiculum mediates the generalization rather than the genesis of mesial temporal lobe seizures. Better results are observed at longer follow-up times 1).


1)

Vázquez-Barrón D, Cuéllar-Herrera M, Velasco F, Velasco AL. Electrical Stimulation of Subiculum for the Treatment of Refractory Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A 2-Year Follow-Up Study. Stereotact Funct Neurosurg. 2020 Oct 28:1-8. doi: 10.1159/000510295. Epub ahead of print. PMID: 33113540.

Osteoid Osteoma of the Atlas

Osteoid Osteoma of the Atlas

Vertebral osteoid osteoma of the atlas has previously been reported very rarely in the published literature.

Valluzzi et al. reported the first case of osteoid osteoma involving the atlas associated with adverse local tissue reaction 1).

Diagnosis

Among the several etiologies mentioned for neck pain and torticollis, osteoid osteoma of the first 2 cervical vertebrae should be considered as a possible but rare cause 2). In the era before the MRI, if standard cervical spine radiographs are negative, isotope scanning and computed tomography can help to establish the diagnosis. 3).

The traditional standard treatment has been a surgical resection of the nidus.

Even though different kinds of management have been mentioned for osteoid osteoma, resection of the lesion remains the best option for achieving a cure 4).

Computed tomography (CT)-guided radiofrequency ablation (RFA) has gained favor as a more precise alternative treatment. The technique might be contraindicated when the nidus is less than 2 mm away from the neural structures 5).

Valluzzi et al. reported a case of an vertebral osteoid osteoma involving the atlas in a 6-year-old boy, who presented with suboccipital pain and torticollis. Initial radiological findings were ambiguous as magnetic resonance imaging showed mainly edema of upper cervical spine soft tissues. The subsequent computed tomography depicted a lesion of left lamina of C1. As conservative treatment failed, the lesion was surgically resected and the patient became pain free. This is the first case of osteoid osteoma involving the atlas associated with adverse local tissue reaction reported in literature 6).


A case of osteoid osteoma of the C1 lateral mass treated successfully using CT-guided RFA. A 30-year-old woman who presented with a four-month history of occipital and suboccipital pain was treated by CT-guided RFA. The visual analog scale (VAS) assessed the pain before and after RFA. The patient reported significant pain relief and normal activities. The VAS score reduced from 8/7 to 1/0 after the procedure. Therefore CT-guided percutaneous RFA of C1 vertebral osteoid osteoma is a safe and effective method. The technique might be contraindicated when the nidus is less than 2 mm away from the neural structures 7).


Amirjamshidi et al. reported 4 cases of upper cervical osteoid osteoma, 1 involving C-1 and the other 3 C-2, and they discuss different aspects of management in similar cases. The patients were 14, 17, 35, and 46 years old, and all presented with neck pain and various degrees of painful limitation of head rotation not ameliorated by ordinary analgesics. Radionuclide isotope bone scans, CT scanning, and MR imaging were helpful preoperative diagnostic modalities. The first attempt at eradication of the lesions failed in 2 cases and the lesions could be excised totally at a second approach. Postoperatively, the patients all became pain free and gained full range of neck motion. There has been no tumor recurrence and no sign of instability in short- to medium-term follow-up. Among the several etiologies mentioned for neck pain and torticollis, osteoid osteoma of the first 2 cervical vertebrae should be considered as a possible but rare cause. Even though different kinds of management have been mentioned for osteoid osteoma, resection of the lesion remains the best option for achieving a cure 8).


Occipital headache, which was relieved by salicylates, was the major symptom reported by two adolescents. In the first patient, a lesion of C1 was seen on plain radiographs. In the second patient, the diagnosis of osteoid osteoma was suggested by scintigraphic imaging and subsequently by computed tomography.

The pain disappeared in both cases after surgical excision of the lesion. Histologic examination disclosed characteristic features of osteoid osteoma.

Occipital pain in adolescents, which is relieved by aspirin, should raise suspicion about the possibility of an osteoid osteoma of the atlas. If standard cervical spine radiographs are negative, isotope scanning and computed tomography can help to establish the diagnosis. Complete excision eliminates the lesion and produces immediate relief for the patient 9).


Jones DA. Osteoid osteoma of the atlas. J Bone Joint Surg Br. 1987 Jan;69(1):149. doi: 10.1302/0301-620X.69B1.3818723. PMID: 3818723.


1) , 6)

Valluzzi A, Donatiello S, Gallo G, Cellini M, Maiorana A, Spina V, Pavesi G. Osteoid Osteoma of the Atlas in a Boy: Clinical and Imaging Features-A Case Report and Review of the Literature. Neuropediatrics. 2020 Oct 27. doi: 10.1055/s-0040-1715488. Epub ahead of print. PMID: 33111305.
2) , 4) , 8)

Amirjamshidi A, Roozbeh H, Sharifi G, Abdoli A, Abbassioun K. Osteoid osteoma of the first 2 cervical vertebrae. Report of 4 cases. J Neurosurg Spine. 2010 Dec;13(6):707-14. doi: 10.3171/2010.5.SPINE09297. PMID: 21121747.
3) , 9)

De Praeter MP, Dua GF, Seynaeve PC, Vermeersch DG, Klaes RL. Occipital pain in osteoid osteoma of the atlas. A report of two cases. Spine (Phila Pa 1976). 1999 May 1;24(9):912-4. doi: 10.1097/00007632-199905010-00014. PMID: 10327515.
5) , 7)

Yang J, Li W, Yin Y, Li Z, Ni C. Radiofrequency ablation of osteoid osteoma in the atlas: A case report. Interv Neuroradiol. 2018 Feb;24(1):88-92. doi: 10.1177/1591019917742889. Epub 2017 Nov 20. PMID: 29157057; PMCID: PMC5772548.
WhatsApp WhatsApp us
%d bloggers like this: