Treatment-Resistant Focal Seizures: Pharmacotherapy or Neuromodulation?

Case Scenario

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.

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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.

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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. 

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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).

Clinical Learning

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.

Conclusion

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.

References

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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

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Reviewed March 2021