Treatment-Resistant Focal Seizures: Pharmacotherapy or Neuromodulation?
A 61-year-old man with focal-onset seizures that began during childhood presents to the hospital for follow-up. Despite taking lacosamide 100 mg twice daily, he continues to experience as many as 2 seizures a month, accompanied by more than 10 episodes of confusion that is characteristic of focal impaired-awareness seizures. Treatment with 6 antiseizure medications has not been helpful. Along with dysfunctional memory, the patient has sustained several injuries as a result of seizures.
Magnetic resonance imaging (MRI) and computed tomographic (CT) imaging reveal suprasellar calcifications, with partial calcifications extending onto the cerebellum and into areas of the hypothalamus. Electroencephalography (EEG) reveals bilateral temporal spikes; stereoelectroencephalography confirms bilateral temporal seizures with widespread interictal spiking. However, video-EEG monitoring fails to localize the seizures, with activity detected in the temporal lobe and some frontal regions.
Antiseizure drugs (ASDs) are the first-line treatment for seizures. In this patient, however, medications have proven ineffective, indicating that other treatment modalities should be considered. Although resective surgery is typically prescribed as a feasible alternative to pharmacotherapy, the patient’s seizures have proved hard to localize to a single resectable region.
The decision was made to treat the patient with thalamic deep brain stimulation (DBS), which does not require distinct localization of seizure origin. In the first 5 months following implantation of electrodes, seizure frequency declined rapidly — eventually reaching zero.
Mr Smith, 61 years of age, is experiencing sporadic seizures accompanied by episodes of confusion and sensations of imbalance. His seizures are likely to have started in childhood but would have been experienced as episodes of confusion. At the age of 10 years, he was involved in a motor vehicle accident that caused moderate head trauma. Mr Smith reports that his brother was also given a diagnosis of a seizure disorder as a child, but there is no other known family history of epilepsy.
Before his diagnosis of epilepsy at 45 years, Mr Smith reported smelling a “funny” odor, followed by loss of consciousness and an episode of a tonic–clonic seizure. His wife says that, for the past 24 years, he has experienced at least 2 tonic–clonic seizures a year.
Currently, Mr Smith is experiencing sensations of imbalance, to the extent that he must sit down, about twice a month. His wife reports that he experiences as many as 10 episodes of confusion a month, which is typical of focal impaired-awareness seizures (formerly known as complex partial seizures).
In addition to sustaining injuries because of seizures, Mr Smith presents with rapidly dysfunctional memory. Having not benefited from 6 ASDs, he is taking only lacosamide (Vimpat®) 100 mg twice daily.
Testing and Diagnosis
Mr Smith undergoes MRI and CT imaging, which reveal calcifications focused in the suprasellar region of the brain and scattered outward into the cerebellum and hypothalamic areas. These findings are consistent with prior brain infection with the tapeworm parasite Taenia solium (neurocysticercosis) or an inactive tumor.
Mr Smith undergoes EEG, which reveals independent bilateral temporal spikes (Figure 1). Subsequently, video-EEG monitoring identifies origins of seizures in the temporal lobe and some frontal regions, rendering seizure activity difficult to localize.
Stereoelectroencephalography (SEEG) with depth wires reveals bilateral temporal seizures and widespread interictal spiking. Seizures are mostly localized to the temporal lobe, but activity is also detected in the orbitofrontal regions.
Potential Treatment Approaches
The 2017 International Classification of Seizures by the International League Against Epilepsy (ILAE) categorizes seizures as those of focal, generalized, and unknown onset.1 In adults, focal seizures (with or without secondary generalization) are most common, with most originating in the mesial temporal lobe.
Treatment with ASDs is the mainstay of therapy for seizures; 26 are available in the United States and effectively stop seizures in approximately two-thirds of cases.2 Yet, there remain more than 1 million people in the United States whose epilepsy is not effectively controlled. The ILAE defines medication resistance as the failure of at least 2 drugs, given at an appropriate dosage, to control seizures.3 Mr Smith’s seizure disorder meets this definition, having been proven resistant to 7 ASDs.
Were there a localized, unilateral focus to Mr Smith’s seizures, preferred therapy would be surgical resection, either by open craniotomy or with laser ablation under MRI visualization.4 In suitable candidates, temporal lobectomy provides freedom from seizures for more than 50% of patients with medication-resistant seizures.5 In Mr Smith’s case, however, the seizures are poorly localizable. They are also multifocal, being of bitemporal and frontal origin.
Quiz question: What is the best course of treatment for Mr Smith?
A. Deep brain stimulation of the anterior thalamus bilaterally
B. Temporal lobectomy
C. Pharmacotherapy with a novel agent (eg, cenobamate tablets)
D. Vagus nerve stimulation
E. Responsive neurostimulation
Correct answer: A. Deep brain stimulation of the anterior thalamus bilaterally
When seizures cannot be localized, neuromodulation should be considered. Neuromodulation can be administered by DBS of the thalamus, vagus nerve stimulation (VNS), or responsive neurostimulation (RNS) over 1 or 2 seizure foci.
Knowledge of the site of origin of seizures is not required for DBS, but this modality should be used with caution in patients with severe depression because there is an identified bidirectional relationship between DBS and depression. Although this relationship has not been fully elucidated, DBS has been shown to induce — more often, transiently — depressive symptoms in patients with a history of depression.6
Although VNS has the advantage of being less invasive, it was determined to be unlikely to help Mr Smith. The use of RNS allows seizure logging over time. Neuromodulation with VNS, RNS or thalamic DBS offers distinct benefits over pharmacotherapy but is only palliative. For suitable candidates, VNS offers, on average, an approximately 50% reduction in seizure frequency; RNS and DBS offer, on average, a 75% reduction.7
Because RNS is typically applied to only 1 or 2 well-localized seizure foci, only VNS and DBS of the bilateral anterior thalamus remain workable options for Mr Smith. VNS is less invasive and DBS is more likely to produce longer stretches of seizure freedom.
Therefore, DBS is chosen and implanted on September 14, 2019. Over the next 5 months, seizure frequency declines to zero and remains at zero as of the most recent report (January 2021).
This case study highlights several key clinical learnings.
1. Epilepsy often goes undiagnosed for a long time, especially with nonconvulsive seizures.
Nonconvulsive seizures in early childhood are generally dismissed as benign. However, focal impaired-awareness seizures often evolve into focal to bilateral tonic–clonic seizures, with more than 30% resistant to pharmacotherapy.8 Furthermore, 60% of children experience widespread brain dysfunction and neuropsychiatric comorbidities, such as cognitive problems and depression, as a result of untreated seizures.9
Mr Smith also presented with suprasellar calcifications that suggest prior cysticercosis, a parasitic infection by the larval stage of the tapeworm Taenia solium. Cysticercosis of the brain (neurocysticercosis) causes reactive seizures and epilepsy in several populations and is one of the most common causes of acquired epilepsy worldwide.10,11 Although the relationship between the parasite and epilepsy has not been fully elucidated, cysticercosis is thought to act as a precipitating lesion, leading to hippocampal damage.12 Of interest is that drug-resistant temporal lobe seizures, the most common type of seizure associated with cysticercosis , were detected in Mr Smith.12
Mr Smith also reported traumatic brain injury of childhood, which, in 20% of cases, contributes to development of epilepsy.13 It follows that early risk stratification could have prompted early treatment and improved prognosis. Although secondary clinical presentations of focal impaired-awareness seizures, such as automatisms and tonic–clonic components, have proven variable, tools such as MRI, magnetoencephalography, and EEG can be more sensitive for diagnosing and localizing seizures.14
2. As the Early Randomized Surgical Epilepsy Trial demonstrated, antiseizure medications fail in approximately one-third of patients with epilepsy, with failure declaring itself within the first couple of years of treatment. Nevertheless, many clinicians delay consideration of surgery or neuromodulation.
Although several novel ASDs have been developed in the past decade, approximately 60% of patients for whom pharmacotherapy is prescribed are not seizure free.15,16 Patients who do not benefit from 2 or more drugs, alone or in combination, are unlikely to become seizure free with any ASD.17
In Mr Smith’s case, lacosamide was prescribed after several other ASDs failed. Unlike other typical ASDs, such as carbamazepine (Tegretol®), which blocks fast inactivation of sodium channels, lacosamide acts by enhancing inactivation of voltage-gated sodium channels, thus stabilizing hyperexcitable nerve membranes. In clinical trials, lacosamide demonstrated efficacy in reducing the frequency of focal seizures with minimal adverse events.18 Yet, lacosamide does not prove superior in rendering seizure freedom.19
In contrast, cenobamate (Xcopri®), a novel tetrazole alkyl carbamate derivative recently approved by the US Food and Drug Administration (FDA) for the treatment of focal seizures, demonstrates a 55.6% median decrease in focal seizures and a 77.0% median decrease in tonic-clonic seizures. Furthermore, 28.3% of patients treated with cenobamate remained seizure free during the maintenance period.20 Cenobamate acts similarly to other ASDs in inhibiting voltage-gated sodium channels, but the drug also acts as an allosteric modulator of γ-aminobutyric acid receptors. The drug is scheduled for approval in Europe.21
Two important therapeutic adjuncts have emerged for the management of drug-resistant epilepsy:
- Cannabidiol (Epidiolex®), derived from Cannabis sativa, reduces mean monthly seizure frequency by approximately 43%. At least 5% of treated patients becoming seizure free.22
- Fenfluramine (Fintepla®) has demonstrated a 74.9% reduction in median monthly seizure frequency.23
Epidiolex and Fintepla have both been approved by the FDA and the European Medicines Agency as add-on therapies for management of seizures.24,25 However, evidence for these 2 drugs so far has been directed mainly at relatively rare epilepsy syndromes, such as Dravet syndrome and Lennox-Gastaut syndrome. Efficacy in other seizure types and syndromes is under study.
3. Surgery has an approximately 50% chance of eliminating or almost eliminating mesial temporal seizures and providing significant benefit in other types of seizures.
Resective surgical procedures that ablate the seizure focus are an effective treatment option for drug-resistant focal seizures. On average, 2% of patients with focal seizures are treated with surgery, but only 50% of these remain seizure free for as long as 2 years. The impact of resective surgery has remained confounding. Some studies document ongoing debilitating seizures and a heightened risk of neurocognitive dysfunction in approximately 40% of cases; others show that 85% of patients report seizure freedom, along with enhanced socialization and quality of life.26
Eligibility for resective surgery is determined by multimodal evaluation:
- Neurologic history and examination;
- Assessment of the semiology of a seizure;
- Video-EEG monitoring of seizures;
- Interictal EEG activity neuroimaging with MRI and fluorodeoxyglucose-positron emission tomography;
- Neuropsychological and psychiatric evaluations; and
- Occasionally, other specialized studies.
Resection requires a well-localized seizure focus in a region that can be safely removed.27,28 An alternative to open-resective surgery is MRI-guided laser ablation, which has demonstrated efficacy while being less invasive than craniotomy. Although laser surgery usually results in fewer neuropsychiatric comorbidities than ablative surgery, concerns remain regarding memory deficits following laser ablation of the hippocampus, especially on the speech-dominant side. For Mr Smith, ablative surgery could lead to worsening of his already-reported memory dysfunction.29,30
4. The 3 neuromodulation modalities — VNS, RNS, and DBS — often are good options for patients with medication-refractory seizures who are not a candidate for resective surgery. The choice of modality depends on the individual patient’s circumstances.
Neuromodulation is a good option when drug-resistant seizures cannot be treated by resection. VNS has generated the most experience since its approval by the FDA in 1997 for treating focal epilepsy.31
RNS, a device that provides closed-loop neurostimulation in response to an EEG-detected seizure, has shown efficacy in treating multifocal epilepsy. In some patients with temporal lobe seizures, RNS has also been shown to complement neurosurgery. RNS showed a mean reduction in seizures of 41.5% in the first 3 months of a blinded study and as much as a 74% median reduction in seizures by several years.32,33
DBS, using intracranial electrodes, is also utilized in the treatment of epilepsy, with the anterior nucleus of the thalamus being the only approved target. Promising results have been obtained by stimulating the hippocampus, the centromedian nucleus, and a few other sites.34,35 In a long-term follow-up trial, DBS of the anterior nucleus of the thalamus reduced seizures by a median of 40.4% in the 3-month, double-blind phase and by 69% at 5 years.36 DBS does not require that a seizure focus be unitary or well localized. In support of this evidence of efficacy in clinical trials, Mr Smith experienced a sequential decrease in seizure frequency and achieved seizure freedom 5 months after the start of thalamic DBS.
Considering Mr Smith’s history of resistance to ASDs, his physicians accurately predicted that neuromodulation using DBS of the anterior thalamus bilaterally would be effective in reducing seizure frequency. However, given that DBS might exacerbate Mr Smith’s memory dysfunction, it is important that he be consistently monitored for potential adverse events.
1. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522-530. doi:10.1111/epi.13670
2. Brodie MJ. Diagnosing and predicting refractory epilepsy. Acta Neurol Scand Suppl. 2005;181:36-39. doi:10.1111/j.1600-0404.2005.00507.x
3. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-1077. doi:10.1111/j.1528-1167.2009.02397.x
4. Kang JY, Wu C, Tracy J, et al. Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy. Epilepsia. 2016;57(2):325-334. doi:10.1111/epi.13284
5. Wiebe S, Blume WT, Girvin JP, Eliasziw M; Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311-318. doi:10.1056/NEJM200108023450501
6. Järvenpää S, Peltola J, Rainesalo S, Leinonen E, Lehtimäki K, Järventausta K. Reversible psychiatric adverse effects related to deep brain stimulation of the anterior thalamus in patients with refractory epilepsy. Epilepsy Behav. 2018;88:373-379. doi:10.1016/j.yebeh.2018.09.006
7. Markert MS, Fisher RS. Neuromodulation – science and practice in epilepsy: vagus nerve stimulation, thalamic deep brain stimulation, and responsive neurostimulation. Expert Rev Neurother. 2019;19(1):17-29. doi:10.1080/14737175.2019.1554433
8. Beniczky S, Rubboli G, Covanis A, Sperling MR. Absence-to-bilateral-tonic-clonic seizure: a generalized seizure type. Neurology. 2020;95(14):e2009-e2015. doi:10.1212/WNL.0000000000010470
9. Kessler SK, McGinnis E. A practical guide to treatment of childhood absence epilepsy. Paediatr Drugs. 2019;21(1):15-24. doi:10.1007/s40272-019-00325-x
10. Del Brutto OH, Arroyo G, Del Brutto VJ, Zambrano M, García HH. On the relationship between calcified neurocysticercosis and epilepsy in an endemic village. A large scale, CT-based population study in rural Ecuador. Epilepsia. 2017;58(11):1955-1961. doi:10.1111/epi.13892
11. Carpio A, Fleury A, Romo ML, Abraham R. Neurocysticercosis: the good, the bad, and the missing. Expert Rev Neurother. 2018;18(4):289-301. doi:10.1080/14737175.2018.1451328
12. Bianchin MM, Velasco TR, Wichert-Ana L, Dos Santos AC, Sakamoto AC. Understanding the association of neurocysticercosis and mesial temporal lobe epilepsy and its impact on the surgical treatment of patients with drug-resistant epilepsy. Epilepsy Behav. 2017;76:168-177. doi:10.1016/j.yebeh.2017.02.030
13. Fordington S, Manford M. A review of seizures and epilepsy following traumatic brain injury. J Neurol. 2020;267(10):3105-3111. doi:10.1007/s00415-020-09926-w
14. Stefan H, Trinka E. Magnetoencephalography (MEG): past, current and future perspectives for improved differentiation and treatment of epilepsies. Seizure. 2017;44:121-124. doi:10.1016/j.seizure.2016.10.028
15. Hanaya R, Arita K. The new antiepileptic drugs: their neuropharmacology and clinical indications. Neurol Med Chir (Tokyo). 2016;56(5):205-220. doi:10.2176/nmc.ra.2015-0344
16. Conte F, Legros B, Paesschen WV, Avbersek A, Muglia P, Depondt C. Long-term seizure outcomes in patients with drug resistant epilepsy. Seizure – European Journal of Epilepsy. 2018;62:74-78. doi:10.1016/j.seizure.2018.09.020
17. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75(3):279-286. doi:10.1001/jamaneurol.2017.3949
18. Farkas V, Steinborn B, Flamini JR, et al; SP0969 Study Group. Efficacy and tolerability of adjunctive lacosamide in pediatric patients with focal seizures. Neurology. 2019;93(12):e1212-e1226. doi:10.1212/WNL.0000000000008126
19. Hoy SM. Lacosamide: a review in focal-onset seizures in patients with epilepsy. CNS Drugs. 2018;32(5):473-484. doi:10.1007/s40263-018-0523-7
20. Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. 2020;94(22):e2311-e2322. doi:10.1212/WNL.0000000000009530
21. Steinhoff BJ. Cenobamate tablets as a treatment for focal-onset seizures in adults. Expert Rev Clin Pharmacol. 2021;14(2):161-172. doi:10.1080/17512433.2021.1879637
22. Devinsky O, Cross JH, Laux L, et al; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618
23. Lagae L, Sullivan J, Knupp K, et al; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394(10216):2243-2254. doi:10.1016/S0140-6736(19)32500-0
24. The European Commission approves Zogenix’S FINTEPLA® (fenfluramine) oral solution for the treatment of seizures in Dravet syndrome. Press release. Intrado GlobeNewswire. December 21, 2020. Accessed March 19, 2021. http://www.globenewswire.com/news-release/2020/12/21/2148581/0/en/The-European-Commission-Approves-Zogenix-s-FINTEPLA-Fenfluramine-Oral-Solution-for-the-Treatment-of-Seizures-in-Dravet-Syndrome.html
25. GW Pharmaceuticals receives European Commission approval for EPIDYOLEX® (cannabidiol) for the treatment of seizures in patients with two rare, severe forms of childhood-onset epilepsy. Press release. GW Pharmaceuticals. September 23, 2019. Accessed March 19, 2021. https://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-receives-european-commission-approval
26. Jarosiewicz B, Morrell M. The RNS System: brain-responsive neurostimulation for the treatment of epilepsy. Expert Rev Med Devices. 2020 Sep 16;1-10. Online ahead of print. doi:10.1080/17434440.2019.1683445
27. Zamora C, Castillo M. Sellar and parasellar imaging. Neurosurgery. 2017;80(1):17-38. doi:10.1093/neuros/nyw013
28. Vakharia VN, Duncan JS, Witt J-A, Elger CE, Staba R, Engel J Jr. Getting the best outcomes from epilepsy surgery. Ann Neurol. 2018;83(4):676-690. doi:10.1002/ana.25205
29. Xinghua T, Lin L, Qinyi F, Yarong W, Zheng P, Zhenguo L. The clinical value of long-term electroencephalogram (EEG) in seizure-free populations: implications from a cross-sectional study. BMC Neurol. 2020;20(1):88. doi:10.1186/s12883-019-1521-1
30. Duncan J. Vagus nerve stimulation for epilepsy. Pract Neurol. 2020;20(3):186. doi:10.1136/practneurol-2019-002474
31. Tran DK, Tran DC, Mnatsakayan L, Lin J, Hsu F, Vadera S. Treatment of multi-focal epilepsy with resective surgery plus responsive neurostimulation (RNS): one institution’s experience. Front Neurol. 2020;11:545074. doi:10.3389/fneur.2020.545074
32. Middlebrooks EH, Domingo RA, Vivas-Buitrago T, et al. Neuroimaging advances in deep brain stimulation: review of indications, anatomy, and brain connectomics. AJNR Am J Neuroradiol. 2020;41(9):1558-1568. doi:10.3174/ajnr.A6693
33. Razavi B, Rao VR, Lin C, et al. Real-world experience with direct brain-responsive neurostimulation for focal onset seizures. Epilepsia. 2020;61(8):1749-1757. doi:10.1111/epi.16593
34. Cukiert A, Cukiert CM, Burattini JA, Mariani PP, Bezerra DF. Seizure outcome after hippocampal deep brain stimulation in patients with refractory temporal lobe epilepsy: a prospective, controlled, randomized, double-blind study. Epilepsia. 2017;58(10):1728-1733. doi:10.1111/epi.13860.
35. Son B-C, Shon YM, Choi J-G, et al. Clinical outcome of patients with deep brain stimulation of the centromedian thalamic nucleus for refractory epilepsy and location of the active contacts. Stereotact Funct Neurosurg. 2016;94(3):187-197. doi:10.1159/000446611
36. Salanova V, Witt T, Worth R, et al; SANTE Study Group. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015;84(10):1017-1025. doi:10.1212/WNL.0000000000001334
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Clinical Pain Advisor had no role in this content’s preparation.
Reviewed March 2021