Clinical manifestations

Presentation and course

	• The main phases in clinical manifestation of focal to bilateral tonic-clonic seizures are aura, onset of generalization, tonic, clonic, and postictal.
	• Focal-onset seizures can start with auras that are focal-onset aware seizures characterized by perceived symptoms and absence of observable signs.
	• Auras can proceed to focal impaired awareness seizures and eventually propagate bilaterally and lead to tonic and then clonic phases.
	• Certain localizing and lateralizing signs can be seen at the time of bilateral propagation (generalization).

Focal to bilateral tonic-clonic seizures have been typically divided into specific stages. Marked heterogeneity exists between phase durations and clinical expression, suggesting multiple cortical and subcortical routes of spread. The most commonly described stages are as follows (40).

Aura. In focal-onset seizures, about 40% to 70% of patients may experience an antecedent focal aware seizure, characterized by localized or nonlocalized symptoms in the absence of observable signs. When an observable sign is present, the convention is to categorize that phenomenon as a focal-onset seizure rather than aura. The most common classification of auras include abdominal, somatosensory, olfactory, gustatory, auditory, or psychic auras. Focal aware seizures may progress to focal impaired awareness or directly to generalized tonic-clonic seizures. Focal impaired awareness seizures consist of localized signs or symptoms with “alteration of consciousness” and amnesia. Clinically these are often associated with automatisms such as orofacial grimacing, chewing, lip-smacking, fumbling, picking, or repetitive movements of the hands and arms. They may also include unresponsive staring.

Onset of bilateral propagation (generalization). The transition between the aura or antecedent seizure and remaining phases of generalized tonic-clonic seizures can sometimes be identified by presence of localizing or lateralizing signs such as head version; more information is described in details under localization below. Clonic jerks that are usually irregular and asymmetric may precede the tonic phase.

Tonic phase. The tonic phase begins with a rigid muscular contraction that usually consists of a brief phase of flexion followed by a longer phase of extension. The flexion phase usually begins in the head and trunk and then extends to the extremities and is usually symmetric. The extension phase usually begins with axial muscle contractions, along with laryngeal spasm that may produce an ictal cry and apnea. Autonomic signs such as tachycardia, hypertension, and diaphoresis may begin during this phase. The tonic phase usually lasts for 10 to 30 seconds.

Clonic phase. The tonic phase gives way to clonic convulsive movements, in which rhythmic jerking lasts for a variable period of time. During the clonic phase, muscle relaxation interrupts tonic contraction and produces generalized rhythmic jerks, which slow down until the seizure ends. Deep, often stertorous respiration occurs at the end of the clonic phase, as other muscles relax. Urinary incontinence and tongue biting may occur in this phase. The clonic phase usually lasts for 30 to 50 seconds.

Postictal state. The postictal state includes a period during which the patient becomes quiet in deep sleep, begins breathing deeply, and then gradually wakes up, often confused, with some automatic behaviors; the patient may later complain of feeling stiffness, generalized soreness, and headache.

Localization. Generalized seizures have long been thought to involve the entire brain. Research has indicated that idiopathic or focal to bilateral generalized seizures may not result in diffuse cortical activation and may activate only specific circuits. A complex model of epileptogenic circuitry involving cortical and subcortical “nodes” may be instrumental in propagation of seizure activity (26).

Several clinical manifestations have been found to have localizing or lateralizing value for focal-onset seizures, including forced versive head turning, ictal aphasia, dystonic limb posturing, asymmetric tonic limb posturing, unilateral automatisms, ictal spitting, ictal vomiting, unilateral eyelid blinking, peri-ictal water drinking, and postictal nose wiping (25; 09). In some cases, particularly in the frontal and parietal lobes, the spread of the ictal discharge is rapid, and localizing features may not be apparent.

In focal to bilateral tonic-clonic seizures, head (and eye) version has a reliable lateralizing value in frontal and temporal lobe epilepsies, with seizure onset zone being contralateral to the direction of head turning when it is forced and immediately precedes bilateral generalization. It most likely is the result of activation of frontal eye and motor areas anterior to the precentral gyrus.

Ictal aphasia. Ictal aphasia is related to the ictal activity in the language-dominant hemisphere.

Dystonic posturing. Dystonic posturing of the contralateral extremities is a reliable lateralizing sign to the contralateral hemisphere in temporal lobe seizures. The proposed mechanism includes propagation of ictal discharges to involve sensory motor area, anterior cingulate gyrus, and ventral striatum and pallidum.

Asymmetric tonic limb posturing. Asymmetric tonic limb posturing, where one elbow is extended while the other is flexed (figure-of-4 sign), has been described as a lateralizing sign with a positive predictive value of about 90%. The extended elbow is contralateral to the side of ictal onset. Activation of the supplemental motor area (SMA) is believed to be the underlying mechanism.

Unilateral automatism. Unilateral automatism in association with dystonic limb posturing in the opposite limb is predominantly ipsilateral to the seizure onset zone in mesial temporal lobe epilepsy, and contralateral in neocortical temporal lobe epilepsy.

Ictal spitting. Ictal spitting is a rare semiological event in right temporal lobe epilepsy that probably involves the autonomic networks.

Ictal vomiting. Ictal vomiting initially was reported to be associated with a very small percentage of seizures from right temporal lobe; however, studies have casted doubt on the reliability of lateralization value of ictal nausea and vomiting.

Unilateral eye blinking. Unilateral eye blinking has been reported to be associated with ipsilateral ictal discharges and is thought to be the result of involvement of inferior postcentral cortex.

Peri-ictal water drinking. Peri-ictal water drinking might be considered a rare automatism during or within 2 minutes of an electrographical seizure that can be seen in temporal lobe epilepsy, in the nondominant right hemisphere in the majority.

Postictal nose wiping. Postictal nose wiping can be associated with temporal lobe seizures more than frontal lobe seizures on the ipsilateral side of the hand that is used to wipe the nose.

Postictal paresis (Todd paralysis) is another lateralizing feature that is reported in around 3% to 16% of focal to bilateral tonic-clonic seizures, indicating onset in the contralateral hemisphere. Postictal features can be transient and must be assessed shortly after the seizure.

Table 1. Summarizing Clinical Features Suggesting Lateralization in Focal to Bilateral Tonic-Clonic Seizures

Clinical Feature	Localization or Lateralization
Forced head version	Contralateral hemisphere
Ictal aphasia	Language-dominant hemisphere
Dystonic limb posturing	Contralateral hemisphere
Figure-of-4 sign	Contralateral hemisphere to extended elbow
Unilateral motor automatism	Ipsilateral hemisphere
Ictal spitting	Right hemisphere
Ictal vomiting	Possibly right hemisphere
Unilateral eye blinking	Ipsilateral hemisphere
Peri-ictal water drinking	Possibly nondominant right hemisphere
Postictal nose wiping	Ipsilateral temporal lobe (less frequent extratemporal)
Postictal paresis	Contralateral hemisphere

Prognosis and complications

The available prognostic data are conflicting because of differing design, classification, duration of follow up in different studies, and etiology of the seizures. Prognosis for individuals with focal to bilateral tonic-clonic seizures is less favorable than that of patients with most types of idiopathic generalized tonic-clonic seizures.

Many studies have found that two of the strongest predictors of seizure recurrence in focal to bilateral tonic-clonic seizures are focal changes in brain imaging and abnormal interictal discharges in EEG (04; 20). In its evidence-based guideline of management of an unprovoked first seizure in adults, American Academy of Neurology (AAN) lists the following four factors as having the strongest evidence for increased risk of recurrence of seizures: a prior brain insult, epileptiform abnormalities in EEG, abnormal brain imaging, and a nocturnal seizure (21).

In a large cohort for prognostic patterns and predictors in epilepsy, 1006 children and adults were followed for a median of 16 years (05). During follow-up, the 1-year remission was 91.7%, and the 5-year remission was 77.1%. Factors confirmed to be associated with 5-year remission were fewer seizures (one or two seizures) before diagnosis, generalized epilepsy, absence of psychiatry comorbidity, and treatment with one to two antiseizure medications.

Complications that may occur in the ictal or immediate postictal period following a tonic-clonic seizure include:

• Oral trauma • Head trauma • Stress fractures and joint dislocation • Aspiration pneumonia • Pulmonary edema • Abrasions, lacerations, and ecchymoses due to external trauma) • Scleral and petechial hemorrhages occurring from capillary bleeding with internal pressure changes. • Sudden unexpected death in epilepsy (SUDEP)

The most important risk factors for sudden unexpected death in epilepsy include high frequency of generalized tonic-clonic seizures and living alone, especially not sharing bedroom with anyone (38). Other risk factors such as young age at onset, duration of epilepsy, and intellectual disability were reported in individual studies with not as strong evidence.

As the relationship between SUDEP, cardiac arrhythmias, and ictal asystole is further clarified, close attention on video-EEG monitoring to cardiac arrhythmias becomes of prime importance (15). A pacemaker may be indicated in some patients with ictal asystole or bradycardia.

There is growing information about the complex genetic interactions predisposing individuals to SUDEP both in genetic and acquired epilepsies (16). In addition, the possible role of dysfunction of the brainstem leading to dysregulation of autonomic system in SUDEP has been investigated (28).

Biological basis

	• Etiology of focal epilepsies is categorized as “known,” broken down to structural, genetic, infectious, metabolic, and immune etiologies, and “unknown.”
	• Excitatory positive feedback is characteristic of epileptic networks. Neuronal loss or damage and sprouting new connections can be mechanisms leading to excitatory positive feedback.
	• Inflammatory and immunological mechanisms are thought to be involved in pathogenesis of not only autoimmune epilepsies but also epilepsies with other etiologies.
	• Synchronization of inhibitory interneurons by synchronized ictal excitation eventually can lead to inhibitory termination of seizure.

Etiology and pathogenesis

In their 2017 epilepsy classification, the ILAE included etiological classification of epilepsy, and some changes in terminology was proposed (35). In previous ILAE classifications, the term “cryptogenic” referred to unknown or suspected etiology other than possible hereditary predisposition, and idiopathic generalized epilepsies (IGE) encompassed four epilepsy syndromes: childhood absence epilepsy syndromes, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone. The new classification proposes that using genetic generalized epilepsies (GGE), where the clinician is comfortable with invoking a genetic etiology, is more meaningful. In addition, instead of using the terms symptomatic (known structural lesions) and cryptogenic (unknown causes), the etiology is referred to either as “known,” which is broken down into five subgroups, and “unknown.” The five subgroups of known etiologies include structural, genetic, infectious, metabolic, and immune.

Pathophysiology

Pathophysiology can be divided broadly into three main processes: epileptogenesis, mechanisms of spread, and termination of seizures.

Epileptogenesis. Epileptogenesis is referred to as processes that alter the function of a normal brain network in a way that enhances the probability of the brain to generate spontaneous recurrent seizures (SRSs). Several molecular and cellular plasticity mechanisms that are involved in generation of the first unprovoked seizure continue beyond the initial seizure and contribute to progression of the epileptic condition (32). Several broad mechanisms may be involved in epileptogenesis of focal-onset seizures including excitatory positive feedback, which is a characteristic of epileptic networks, enabling them to switch back and forth between normal and epileptic modes of activity. One of the mechanisms that leads to this phenomenon is possibly uncovering preexisting positive feedback because of loss of inhibitory circuits due to neuronal cell loss or damage, for example, in the hippocampus. Another mechanism is development of positive feedback in sprouting new synaptic connections, for example, after brain injury.

Various mechanisms have been proposed for tumor-associated epilepsy, including altered intrinsic properties of the tumor cell membranes and gap junctions, high concentration of glutamate in extracellular space, GABA receptor downregulation, and changes in potassium and chloride receptors and transporters that can lead to compromise of the GABAergic inhibitory circuits (27; 24).

Inflammatory and immunological mechanisms are thought to be involved in pathogenesis of not only autoimmune epilepsies (39) but also epilepsies with other etiologies. In a large cohort study, the plasma level of various cytokines (interleukins and interferons), inflammatory markers and neurotrophic factors were found to be abnormal in 446 patients with epilepsy of various etiologies compared to 166 healthy controls. Among these, soluble tumor necrosis factor receptor 1 (sTNFr1) was found to have a relation with seizure frequency and was proposed as a potential biomarker for epilepsy (02). A meta-analysis of 66 articles about the role of inflammatory neuromodulators in epilepsy found a significant increase in interleukin (IL)-6 and IL-17 in serum and IL-1β and IL-10 in CSF of patients with epilepsy with various etiologies (10).

Mechanisms of spread. Epileptic discharges may remain localized to a small area due in part to “surround inhibition” and other less clear mechanisms. In cases of focal to bilateral seizures, the epileptic focus propagates through fibers of cortico-cortical networks and multiple brain circuits to reach larger cortex areas and subcortical structures. Spread occurs when the focal seizure is adequately intense and when the surrounding activity is less inhibitory. In a study that analyzed 39 seizures in patients with temporal lobe epilepsy, it was found that all the seizures that became bilateral (generalized) involved the posterior lateral temporal region, suggesting that this region may serve as a gateway that is involved in controlling propagation of temporal lobe seizures (46).

Termination of seizures. Potential mechanisms include synchronization of inhibitory interneurons by synchronized ictal excitation, which leads to inhibitory termination (31), upregulation of the inhibitory neurons in the seizure onset zone (45), and endogenous adenosine by attenuating depolarization of GABA-A receptor-mediated signaling (43).

Epidemiology

	• A meta-analysis reports the point prevalence of active epilepsy to be 6.38 per 1000 persons and an incidence rate of epilepsy to be 61.44 per 100,000 persons.
	• There was no clear difference between the point prevalence or cumulative incidence of epilepsy in low-middle income countries (LMIC) vs. high-income countries (HIC); however, the incidence rate was higher in LMIC compared to HIC.

A meta-analysis of incidence and prevalence of epilepsy from reported world-wide data was published in 2017 (12). The pooled point prevalence of active epilepsy was 6.38 per 1000 persons (95% CI, 5.57-7.30), and the pooled lifetime prevalence was 7.60 per 1000 persons (95% CI, 6.17-9.38). The annual cumulative incidence of epilepsy was 67.77 per 100,000 persons (95% CI, 56.69-81.03). The incidence rate was 61.44 per 100,000 persons (95% CI, 50.75-74.38). There was no clear difference between the point prevalence or cumulative incidence of epilepsy in low-middle income countries versus high-income countries. However, the incidence rate was higher in low-middle income countries compared to high-income countries, possibly explained by higher rates of CNS infections, greater exposure to perinatal risks, and higher rates in traumatic brain injuries.

Incidence of epilepsy tends to be higher in males than females and is thought to be at least partially due to higher rate of concealment of epilepsy in females in certain sociocultural environments. Incidence of epilepsy is generally higher in the youngest and oldest age groups.

Distribution of epilepsy syndromes in newly diagnosed patients has been reported in several studies. One of the largest cohort studies in France reported 47.4% of newly diagnosed epilepsy cases with history of more than one seizure to be focal, including focal to bilateral tonic-clonic seizures, comprising of 13.5% with known structural etiology (symptomatic), 29.2% with unknown etiology (cryptogenic), and 4.7% idiopathic with genetic etiology, whereas 33.8% were genetic (primary) generalized (18).

Differential diagnosis

Confusing conditions

The diagnosis of seizures relies critically on history. Usually, it is not difficult to distinguish generalized tonic-clonic seizures from other epileptic disorders. However, it is often difficult to distinguish focal to bilateral tonic-clonic from generalized-onset tonic-clonic seizures. The focal onset is usually recognized when a slow onset with a well-defined focal seizure evolves into generalized tonic-clonic seizure. However, spread of the seizure can be extremely rapid making it difficult to appreciate clinically or even electroencephalographically. A focal-onset seizure can sometimes arise from a focus deeper in the cortex or with a dipole orientation not detectable by recording scalp electrodes. Differentiation is then helped by indirect evidence, such as semiology of seizures, focal brain lesions on imaging, or focal interictal epileptiform activity. If needed, other tests such as long-term video EEG monitoring, intracranial monitoring, ictal SPECT, PET, or MEG can be used for further evaluation and localization.

Functional (psychogenic nonepileptic) seizures are the most common differential diagnosis. Some of the features suggestive of functional seizures include:

• Triggers that are unusual for epileptic seizures (conditions promoting feelings of anxiety or guilt) • Episodes mainly occurring in the presence of an audience • Past medical history of abuse, fibromyalgia, chronic pain, or chronic fatigue syndrome.

Phenomena strongly associated with functional seizures include gradual onset or termination, pseudo sleep, irregular or asynchronous activity, including side-to-side head movements, pelvic thrusting, opisthotonic posturing, stuttering, weeping, preserved awareness with bilateral motor activity, and persistent eye closure.

In contrast, symptoms in favor of epileptic seizures include occurrence out of sleep, incontinence, significant injuries, tongue bites of the lateral part of the tongue, and postictal confusion. The definite diagnosis requires video-EEG monitoring, which is the “gold standard” for diagnosis. Provocative techniques, activation procedures, or induction can be useful for the differential diagnosis of functional seizures, particularly when no spontaneous episodes occur during monitoring, although some controversies in utilization of these techniques exist (08).

Associated and underlying disorders

Focal to bilateral tonic-clonic seizures can occur in focal epilepsies with known structural, genetic, or unknown etiologies. Common pathological conditions that can cause focal epilepsies in adults include:

• Malformations of cortical development • Neoplasms • Head injuries, often producing contusions of the frontal and temporal polar regions • CNS infections • Vascular malformations • Neuronal migration disorders—some with an identified genetic basis

Common focal epilepsies causing focal to bilateral tonic-clonic seizures occur mainly in children and include:

• Benign childhood epilepsy with centrotemporal spikes • Childhood epilepsy with occipital paroxysms.

Diagnostic workup

	• A complete history and physical examination are essential in diagnostic workup of epilepsy.
	• The yield of EEG in finding interictal abnormalities increases with repeated studies.
	• Various imaging modalities such as MRI, fMRI, PET, DTI, and MEG are utilized in workup of focal epilepsies.

Diagnosis of epilepsy starts with a complete history and physical examination of the patient. A detailed history of the semiology of the seizure can help identify signs or symptoms prior to bilateral propagation. Focal neurologic abnormalities are useful, especially if they correlate with the localization of the initial ictal manifestations (see localization under clinical manifestations section). Various diagnostic tools can then be used to confirm location of the epileptic focus or functional deficit, including EEG and imaging studies such as PET, SPECT, MEG, fMRI, and DTI.

Electroencephalogram (EEG). EEG is an important diagnostic tool for diagnosis, localization, and determination of an epilepsy syndrome. The EEG abnormalities that can be observed in focal to bilateral tonic-clonic seizures include interictal, ictal, and postictal patterns.

Interictal pattern. The interictal pattern includes spikes, sharp waves, and, less often, polyspike and spike-and-wave complexes. Up to 40% of patients with epilepsy do not demonstrate any interictal epileptiform EEG findings on initial EEGs; however, with repeated studies, including sleep-deprived EEG and EEG with additional leads (eg, subtemporal), the yield approaches 90%.

Ictal pattern. During the tonic phase of convulsion, a progressively higher amplitude and lower frequency discharge pattern is seen simultaneously in cortical hemispheres. This pattern then becomes slower and intermixed with bilateral high-amplitude spikes and a progressively greater amount of rhythmic delta activity. During the clonic phase, progressive repetitive complexes of high-amplitude spike-and-slow waves are observed.

Postictal pattern. EEG generally shows a period of diffusely slow and low-amplitude activities; focal or lateralized slowing indicates focal onset.

Imaging studies. MRI and CT have been used routinely in diagnosis and management of epilepsy. MRI is recommended for patients with suspicion of focal epilepsy. Coronal FLAIR, T1 and T2 sequences with 1 to 3 mm cuts should be used to detect hippocampal sclerosis, and 3D volumetric studies including SPGR sequences, with multiple planes of reconstruction, are currently best for detecting cortical dysplasias.

Positron emission tomography (PET). PET scans produce metabolic maps of the brain. The most commonly used tracer is 18F-flourodeoxyglucose (FDG), although flumazenil is also useful. Epileptic foci and surrounding areas may have decreased metabolism during the interictal period, with sensitivities ranging from 30% to 90% depending on location.

Single-photon emission computed tomography (SPECT). Stabilized technetium 99m is most commonly used in focal onset seizures. Ictal SPECT requires injection during or shortly after the seizure onset, usually during video-EEG monitoring. The isotope distribution is proportional to blood flow, and regions of maximal seizure activity show hyperperfusion.

Magnetoencephalography (MEG). This technique detects the magnetic fields associated with electrical discharges in the cortex. It is complementary in detecting some dipoles not seen on scalp EEG.

Functional magnetic resonance imaging (fMRI). Rarely, seizures have been captured during scanning and show clear areas of seizure involvement. The fMRI is usually used in conjunction with neuropsychological testing and invasive cortical stimulation to identify eloquent language areas as well as the sensory and motor cortex to guide electrode placement and to delimit surgical resection.

Diffusion tensor imaging (DTI). DTI is an MRI imaging that allows visualization of white matter anatomy of the brain. This modality has been used in guiding the plan for epilepsy surgery, especially in temporal lobe epilepsies (37).

Management

	• Medications, neurostimulation, and surgery are the main therapeutic options.
	• Monotherapy with a single ASM is preferred, although rational polytherapy, combining ASMs with different mechanisms of action for better efficacy, is a common practice in refractory epilepsy.
	• VNS, RNS, and DBS are FDA-approved neurostimulations for adjunct therapy in medically refractory focal epilepsy. VNS is the only neurostimulator that is approved in children above age 4.
	• Epilepsy surgery should always be considered in patients with medically refractory focal epilepsy.
	• Common disorders that can be successfully addressed with surgery include low-grade tumors, vascular lesions, cortical dysplasia, and mesial temporal or hippocampal sclerosis.

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

Medical therapy. Medical therapy with a single antiseizure medication (ASM; also called antiepileptic drugs: AED), is the initial primary approach to management of focal to bilateral tonic-clonic seizures. The use of a single antiseizure medication reduces the risks of idiosyncratic and dose-related toxic reactions, the cost of medications, and chances of drug-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 2004 American Academy of Neurology guidelines of efficacy and tolerability of antiepileptic drugs, use of lamotrigine, gabapentin, topiramate, and oxcarbazepine, in addition to the well-established carbamazepine and phenytoin, are effective in new-onset focal epilepsy (14). Additional recommendations in the 2018 update to the 2004 AAN guidelines include that lamotrigine, levetiracetam, and zonisamide may be considered in decreasing seizure frequency in adults with new-onset focal epilepsy (19). The recommended medication for patients 60 years of age or above is lamotrigine, and gabapentin can also be considered. A few newer generation medications have been approved for monotherapy in focal epilepsies such as lacosamide, eslicarbazepine, perampanel, and cenobamate. Table 2 lists the medication available for monotherapy or adjunct therapy in focal epilepsies along with recommended adult doses and common or important side effects (01).

Rational polytherapy, combining antiseizure medications with different mechanisms of action for better efficacy, is a common practice in refractory epilepsy, although there are no robust guidelines and little evidence-based data for clinicians to follow (44).

Achieving seizure control is inversely correlated with the number of failed drug regimens (07). ILAE proposed a definition for drug resistant epilepsy as failure of adequate trials of two tolerated, appropriately chosen and used AEDs (whether as monotherapies or in combination) to achieve sustained seizure freedom (22). Wrong diagnosis, non-compliance, and inadequate or inappropriate treatment are common reasons for pseudo-resistance that need to be identified in cases of drug resistant epilepsy (23). 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 responsive intracranial stimulation.

Table 2. Medications for Focal Epilepsy

Medication	Monotherapy (M) vs. adjunct (A)	Adult Initial dose	Adult Maintenance dose	Common or serious side effects
Brivaracetam	M	50 mg bid	100 mg bid	Sedation, dizziness, fatigue, mood change
Carbamazepine	M	200 mg bid	400 to 800 mg bid	Sedation, ataxia, dizziness, fatigue, hyponatremia, bone marrow suppression
Cenobamate	M	12.5 mg/day	200 to 400 mg/day	Sedation, dizziness, fatigue, diplopia, shortening of QT interval
Eslicarbazepine	M	400 mg/day	800 to 1200 mg/day	Sedation, ataxia, fatigue
Felbamate	M	600 mg bid	600 to 1200 mg tid	GI irritation, aplastic anemia, fulminant hepatitis
Gabapentin	A	300 to 400 mg/day	600 to 1200 mg tid	Sedation, dizziness, ataxia, fatigue
Lacosamide	M	50 mg bid	100 to 300 mg bid	Sedation, dizziness, headache, ataxia, prolonging PR interval
Lamotrigine	M	25 mg/day	100 to 600 mg/day	Sedation, dizziness, diplopia, tremor, Stevens-Johnson syndrome
Levetiracetam	M	500 mg/day	3000 to 4000 mg/day divided bid	Sedation, dizziness, fatigue, mood change, irritability
Oxcarbazepine	M	150 to 300 mg bid	800 to 1200 mg bid	Sedation, ataxia, fatigue, hyponatremia
Perampanel	M	2 mg/day	8 to 12 mg/day	Sedation, dizziness, ataxia, headache, mood changes
Phenobarbital	M	30 to 60 mg/day	1 to 2.5 mg/kg/day	Sedation, osteoporosis
Phenytoin	M	200 to 400 mg/day	Keep the serum level at 10 to 20 mg/L	Ataxia, nystagmus, osteoporosis
Pregabalin	A	75 mg/day	75 to 300 mg bid	Sedation, dizziness, weight gain, peripheral edema
Rufinamide	A	400 mg/day	800 to 1600 mg bid	Sedation, dizziness, fatigue, shortening of QT interval
Tiagabine	A	4 mg/night	8 to 16 mg tid	Dizziness, mood changes, nonconvulsive status epilepticus, encephalopathy
Topiramate	M	25 mg/day	50 to 200 mg bid	Sedation, dizziness, cognitive slowing, renal stone, weight loss
Valproate	M	500 mg/day	1000 to 2000 mg/day	Sedation, tremor, weight gain, hair loss, pancreatitis
Vigabatrin	A	500 mg bid	1500 mg bid	Sedation, dizziness, ataxia, mood changes, concentric visual field constriction
Zonisamide	M	100 mg/night	300 to 600 mg/night	Sedation, dizziness, ataxia, irritability, weight loss, Stevens-Johnson syndrome

Neurostimulation. Vagus nerve stimulation (VNS), brain-responsive neurostimulation (RNS), and deep brain stimulation (DBS) are the main Food and Drug Administration-approved adjunctive therapies available for patients with medically refractory focal epilepsies.

Vagus nerve stimulation (VNS). Vagus nerve stimulation was the first neurostimulation device approved for treatment of epilepsy. It consists of a pulse generator that is implanted usually below the left clavicle and a lead that is wrapped around the left vagus nerve. In a meta-analysis, the pooled odds ratio from three randomized controlled trials and three comparative observational studies for experiencing a 50% or more reduction in seizure frequency with implantation of vagus nerve stimulation was 2.27 (03). In addition, the pooled adds ratio from two randomized controlled trials and three comparative observation studies for experiencing a 75% or more reduction in seizure frequency was 3.56. There was no difference in odds of seizure freedom. Despite studies in animals and human, which show changes in brain electrophysiology, metabolism, and neurochemistry, the mode of action remains uncertain. The programmable generator allows adjustments 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. The current generation of VNS devices includes the ability to detect ictal tachycardia and deliver enhanced stimuli to try to interrupt the seizures. Although the rate of rise in heart rate is rapid in seizures, adequate reliability of ictal detection and response must be balanced with tolerability of intermittent stimuli from other instances of rapid tachycardia.

Brain-responsive neurostimulation (RNS). The brain-responsive neurostimulation system consists of a programmable neurostimulator that is implanted in the skull and is connected to depth or subdural cortical strip leads. The leads are placed in or close to the identified seizure focus or foci. RNS system provides responsive, closed-loop focal cortical stimulation when abnormal electrocorticographic (ECoG) activity is detected: the neurostimulator continually senses the ECoG activity and can detect specific patterns that have been previously programmed by the physician as ictal patterns. In response to detection of ictal patterns, the RNS system delivers stimulus pulses. The initial 2-year randomized blinded controlled trial showed median 44% reduction in seizures at 1 year and 53% at 2 years (06). Out of the 256 patients treated in the initial trial, 230 participated in the long-term prospective open-label trial, and the data on safety, efficacy, and quality of life (QOL) over the additional 7 years were published in 2020 (29). The results showed 73% of patients responded to the device with a median 75% reduction in seizure frequency. In addition, there was significant improvement in quality of life and some aspects of cognitive function. Suggested mechanisms involved in effectiveness of direct stimulation include changes in cellular inhibition or excitation, changes in synaptic plasticity, neurogenesis, or cortical reorganization. The main adverse events include infection (4.1% risk per procedure), intracranial hemorrhage (2.7%), and status epilepticus (8.2%; more than half were nonconvulsive). One point six percent of patients reported adverse effects related to depression, but the majority of them were not considered to be device related.

Deep brain stimulation (DBS). Bilateral stimulation of anterior nucleus of thalamus, delivered from a pulse generator via implanted electrodes, has been approved as an adjunctive therapy for refractory focal epilepsy in adults. In the initial clinical trial study (SANTE) of 110 patients who underwent bilateral anterior thalamic stimulation, 41% experienced a median reduction of in seizure frequency at 1 year and 69% at 5 years (34). Patients with temporal lobe epilepsy experienced the most benefit from deep brain stimulation. Most complications included hemorrhage (4.9%), infection (1.7%), worsening or new seizures, neurologic symptoms such as paresthesia (22.7%), and memory and cognitive changes (4%).

Surgical therapy. Surgery should be considered as a treatment option in patients with medically refractory 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 modalities, including PET scans, ictal SPECT, magnetic resonance spectroscopy, fMRI, and DTI are being 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 (11).

Less invasive surgical techniques such as stereotactic radiosurgery or laser ablation have been used to target specific epileptogenic foci (30). Laser ablation is undergoing an increasing role in treatment.

Treatments on the horizon. 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 precursor lines can now be synthesized in vitro, and research is ongoing in molding differentiation, survival, and integration of these precursors (33). Grafting primary GABAergic cells in the epileptogenic areas of the brain has shown promising results in animal models (36).

Outcomes

Complete control with ASMs can be achieved in approximately 45% to 55% of patients with focal to bilateral tonic-clonic seizures. The remaining cases have varying response to treatment based on the etiology, location, and modality of treatment.

Special considerations

Pregnancy

There are various challenges in medical care of women of childbearing age with epilepsy. There are over one million patients with epilepsy in the United States who are in the childbearing age. Seizures during pregnancy can have potential harmful effects on fetus. On the other hand, the teratogenic effects of antiseizure medications are always of great concern to the patient and health care providers.

About 84% to 92% of patients who had no seizures at least 9 to 12 months prior to the pregnancy remain seizure free during pregnancy. Pregnancy registries have provided key information that usually guides the counseling and treatment of women with epilepsy in their reproductive years (17).

Major congenital malformation (MCM) rate in the general population is estimated to be around 1.6% to 3.2%. With exposure to antiseizure medications during pregnancy, this rate can increase 2- to 3-fold higher, depending on the specific medication exposure. The available data confirm that the risk of major congenital malformation in antiseizure medication polytherapy is higher compared to monotherapy.

Valproate is well recognized to be associated with higher risk of MCMs and adverse effects on cognitive function in offspring of women with epilepsy. This medication has a higher risk of causing spina bifida and hypospadias than other antiseizure medications. The absolute risk of MCM is about 6% to 9% of exposed pregnancies during first trimester, which appears to be dose related. Therefore, this medication should be avoided in this population of patients as much as possible.

Association of exposure to topiramate in first trimester and risk of facial cleft has been reported from several pregnancy registries and studies. In utero exposure to carbamazepine has been confirmed to be associated with spina bifida with an odds ratio of 2.6% (CI 1.2 to 53). Levetiracetam seems to be associated a low risk of MCMs with rate of about 2.4%.

Data from European and International Registry of Antiepileptic Drug and Pregnancy (EURAP) revealed a close relationship between dose of most antiseizure medications and associated major congenital malformations risk. These data also showed the lowest risk was with lamotrigine at doses less than 325 mg/day. Associated risk with levetiracetam and oxcarbazepine were not dose dependent and were approximately the same as the risk of lower dose lamotrigine, and lower than high dose (greater than 700 mg/day) of carbamazepine (42).

Adverse effect of fetal exposure to some antiseizure medications on the IQ, namely valproate and phenobarbital, has been demonstrated in retrospective and prospective studies. Data about other antiseizure medications are emerging. A review of data about major congenital malformations from the pregnancy registries is provided by Tomson and colleagues (41).

There is some evidence that taking folic acid supplementation during pregnancy reduces the risk of MCMs, especially neural tube defect and cognitive disabilities in offspring of women with epilepsy who are taking antiseizure medications. The recommended dose is 4 mg/day. However, the data from EURAP did not provide confirmatory data about protective effect of folic acid.

The blood level of antiseizure medications may decrease during pregnancy due to multiple factors including induced metabolism of some medications secondary to hormonal changes. Therefore, frequent monitoring and dose adjustment are of importance in these cases.

Anesthesia

Anesthesia-induced seizures are rare. Enflurane, sevoflurane, and etomidate are among anesthetic agents that can induce epileptiform discharges and seizures and, therefore, it is recommended these agents be avoided in patients with epilepsy, if possible.