Secondarily generalized tonic-clonic seizures

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By Robert L Beach MD PhD and Rajdeep Singh MD

Therapeutic options of secondarily generalized tonic-clonic seizures include medical therapy and surgery. Along with therapy, management should include counseling of the patient regarding the condition and providing knowledge of standard seizure precautions.

Medical therapy.Medical therapy with a single AED is the initial primary approach to management of secondarily generalized tonic-clonic seizures. The use of a single AED reduces the risks of idiosyncratic and dose-related toxic reactions, the cost of medications, and chances of drug interactions, and it increases the compliance of therapy. The initial drug selection is based on consideration of syndrome and seizure type, potential side effects, cost, comorbidities, and drug interactions. According to the American Academy of Neurology guidelines, gabapentin, lamotrigine, oxcarbazepine, and topiramate are among the newer agents that can be used in initial monotherapy (French et al 2004). The guidelines published by ILAE in 2006 provide evidence for long-term efficacy or effectiveness of initial monotherapy for patients with newly diagnosed or untreated epilepsy (Glauser 2006). Carbamazepine has generally been considered a first drug of choice in the treatment of SGTCS (Ramsay and DeToledo 1997). A large, unblinded, randomized control trial (SANAD) compared carbamazepine with newer AEDs, including gabapentin, lamotrigine, oxcarbazepine, and topiramate (Marson et al 2007). The trial found lamotrigine to be significantly better for time-to-treatment failure for any reason (inadequate seizure control or unacceptable side effects). Further analysis showed lamotrigine to be better mainly because of its better tolerability than carbamazepine. Carbamazepine was still slightly better than lamotrigine for the secondary efficacy outcome of time to first seizure. Rational polytherapy, combining AEDs for better efficacy, is a common practice in refractory epilepsy; however, there is a lack of robust guideline and evidence of clinicians to follow (Brodie and Sills 2011).

Achieving seizure control is inversely correlated with the number of failed drug regimens (Brodie et al 2012). ILAE proposed a definition for drug resistant epilepsy as failure of adequate trials of 2 tolerated, appropriately chosen and used AEDs (whether as monotherapies or in combination) to achieve sustained seizure freedom (Kwan et al 2010). Wrong diagnosis, non-compliance, and inadequate or inappropriate treatment are common reasons for pseudoresistance that need attention in cases of drug resistant epilepsy (Kwan et al 2011). Early identification of patients with drug resistant epilepsy is important in order to consider other modalities to achieve seizure control including vagal nerve stimulation, surgical intervention, and deep-brain stimulation.

Vagus nerve stimulation (VNS).Vagus nerve stimulation is used as an adjunctive therapy to intractable seizures. A meta-analysis demonstrated up to 50% reduction in seizure frequency; however, seizure freedom is rarely achieved (Englot et al 2011). Vagus nerve stimulation involves repeated stimulation of the left vagus nerve through implanted electrodes. Despite studies in animals and human, which show changes in brain electrophysiology, metabolism, and neurochemistry, the mode of action remains uncertain. Stimulation is delivered via a programmable generator, allowing variation in current, pulse, frequency, and duty-cycle. Adverse surgical outcomes are acceptably low in experienced hands. Stimulation-induced effects, such as hoarseness, cough, and dysphagia, are intensity dependent, diminish over time, and are usually not treatment-limiting.

Intracranial stimulation.Direct brain stimulation has received renewed attention in the treatment of epilepsy. A randomized blinded controlled trial with a device that provides responsive, closed-loop focal cortical stimulation has been shown effective as adjunctive therapy in adults with refractory epilepsy with no more than 2 epileptogenic foci, with median 44% reduction in seizures at 1 year and 53% at 2 years (Bergey et al 2015). Suggested mechanisms involved in effectiveness of direct stimulation include changes in cellular inhibition or excitation, changes in synaptic plasticity, neurogenesis or cortical reorganization.

A study of 110 patients who underwent bilateral anterior thalamic stimulation experienced a median reduction of 41% at 1 year and 69% reduction at 5 years in seizure frequency (Salanova et al 2015).

Surgical therapy.Surgery should be considered as a treatment option in patients with drug resistant epilepsy. Common disorders that can be successfully addressed with surgery include low-grade tumors, vascular lesions, cortical dysplasia, and mesial temporal or hippocampal sclerosis. The key to successful epilepsy surgery is multimodal localization of the seizure focus. Video-EEG recording with scalp, and if needed, intracranial recording, plays a vital role in localization. Several imaging technologies, including PET scans, ictal SPECT, magnetic resonance spectroscopy, fMRI, and DTI are being increasingly used to help in localization and placement of intracranial electrodes. Seizures related to benign tumors and mesial temporal sclerosis respond best to surgery. Surgery is less effective if there is no lesion in the MRI, or if the lesion is in extratemporal location. A randomized trial of early surgical therapy for drug-resistant mesial temporal lobe epilepsy showed 2-year seizure freedom in 11 of 15 surgically-treated patients when compared to 0 of 23 in the medical arm (Engel et al 2012).

Other surgical techniques such as stereotactic radiosurgery or laser ablation have been used to target specific epileptogenic foci (Nowell et al 2014).

Other therapies. Stem cell and gene therapies are making progress and may play a role in treatment of intractable epilepsy in the future. Several neuronal and glial precursors can now be synthesized in vitro, and research is ongoing in molding differentiation, survival, and integration of these precursors (Naegele et al 2010).

In This Article

Historical note and nomenclature
Clinical manifestations
Differential diagnosis
Diagnostic workup
Syndromes and diseases in which the seizure type occurs
Prognosis and complications
Special considerations
References cited