Focal (Partial) Epilepsy 

Updated: Mar 14, 2022
Author: Muhammad H Jaffer, MD; Chief Editor: Helmi L Lutsep, MD 

Overview

Background

Epilepsy is a disease associated with a pathologic and enduring tendency to have recurrent seizures. Focal epilepsies, also termed partial or localization-related epilepsies, are seizure disorders that originate within a neuronal network limited to one hemisphere, whether unifocal or multifocal. This is in contrast to generalized epilesies, where seizures rapidly engage bilateral distributed networks.

Focal epilepsies represent the most common type of adult-onset epilepsy. By definition, there is focal abnormality that underlies focal epilepsies; while these structural abnormalities can sometimes be identified with imaging, they often remain of unknown etiology (eg, negative MRI). When a cause is found, it can include various structural lesions (eg, mesiotemporal sclerosis, traumatic scars, neoplasms, vascular malformations, strokes, neuronal heterotopias, etc.). In children, cortical dysplasias and low-grade neoplasms are the most commonly identified causes (see Etiology).

Obtaining a description of the seizures from the patient and any witnesses is critical. The description needs to include a description of the patient’s level of awareness during the seizure, the most prominent early motor and non-motor semiological features, and whether the seizure subsequently evolved into a bilateral tonic-clonic seizure (see Clinical Presentation). “Focal aware seizure” replaces the previous term “simple partial seizure” and a “focal impaired awareness seizure” replaces the term “complex partial seizure.”

Further evaluation, which may include neuroimaging, laboratory studies, and electroencephalography, is important for determining the specific disorder to determine prognosis and guide therapy (see Workup).

Focal epilepsies are generally treated with antiseizure medications (ASMs). Nonpharmacologic treatments in refractory cases include surgery, neurostimulation, and dietary modification (see Treatment and Management).

Go to Epilepsy and Seizures for a general overview of this topic.

Pathophysiology

Seizures may be understood as paroxysmal cerebral dysrhythmias, whereby there is a “transient occurrence of signs and symptoms due to abnormal excessive or synchronous activity in the brain.”[1]

In focal seizures, this pattern of transient electrical hypersynchrony begins in a circumscribed hyperexcitable neuronal population, termed the epileptic focus. An alteration in voltage-gated ion channels caused by decreased inhibitory and increased excitatory neurotransmission mediates this hyperexcitability. The pathological correlate on a neurophysiologic level for this aberrant electrical activity is embodied in the paroxysmal depolarization shift, whereby a cortical neuron undergoes a calcium-dependent depolarization followed by a prolonged hyperpolarization phase. If several million neurons discharge at once, the summated electrical potential may be seen on scalp EEG as a focal interictal epileptiform spike. This local aberrant activity may cause a cascade of hypersynchronous discharges throughout larger brain networks, culminating in the clinical and electrophysiological manifestation of a seizure. Therefore, while the epileptic focus may be restricted to a small focus, it is possible for it to secondarily involve generalized cerebral networks.

In turn, focal epilepsy represents a permanent alteration in the epileptic focus, a process termed epileptogenesis, such that the individual develops a propensity for repeated seizures. Epileptogenesis may be mediated by congenital (genetic conditions or migrational defects) or acquired processes (cerebral infarctions, neoplasms, or infections), although the underlying etiology is sometimes unknown.

Although the traditional understanding of focal epilepsy has focused on hypersynchrony precipitated by the epileptic focus alone, there is increasing recognition that patients with focal epilepsy suffer from widespread brain dysfunction. Over time, aberrant coupling between different neuronal populations that synchronously fire may potentiate the development of epileptic networks and new epileptogenic foci distant to the original focus.[2, 3, 4]

Etiology

In the 2017 International League of Epilepsy (ILAE) classification syndrome, epileptic etiologies are divided into six non-mutually exclusive categories: structural, genetic, infectious, metabolic, immune, and unknown.[5] It should be noted that the terms “symptomatic” and “cryptogenic” were confusing and are no longer used in the current classification scheme.

Most focal epilepsies do not have a clear cause visible on imaging. A structural etiology may be related to genetic causes, such as cortical malformations, or acquired, such as stroke, trauma, or infection. One of the most common structural correlates in surgically amenable temporal lobe epilepsy is hippocampal sclerosis, characterized by CA1 and CA4-predominant neuronal loss and associated epileptogenesis.[6] In children, cortical dysplasias are the most implicated structural lesions, while lesions related to cerebral infarction are the most common cause of focal epilepsy in the elderly. When a structural lesion has a well-defined etiology, one may use both etiological terms concomitantly. As an example, tuberous sclerosis, which may present with focal epilepsy secondary to cortical tubers, is caused by mutations in genes encoding hamartin and tuberin; in this case, it is acceptable to reference both structural and genetic etiologies.

A genetic etiology may be invoked if there is a known or inferred mutation that is thought to account for the focal epilepsy syndrome. Supporting evidence for a genetic etiology may be garnered based on familial inheritance patterns or molecular/twin research studies in patients with the same syndrome. It should be noted that a genetic etiology does not always imply an inherited condition, as de novo mutations are also possible. Owing to phenotypic and genetic heterogeneity, genetic focal epilepsies remain under heavy investigation. Autosomal dominant forms of frontal and temporal lobe epilepsies as well as familial focal epilepsy syndromes have well-described genetic associations (CHRNA2, CHRNA4, LGI1, DEPDC5, etc.) and are often related to dysregulation in the mechanistic target of rapamycin complex 1 (mTORC1) pathway.[7] Next-generation sequencing has also recently uncovered a possible genetic basis for the epilepsy–aphasia spectrum epilepsies, with up to 20% of patients with mutations on the NMDA glutamate receptor subunit gene GRIN2A.[8]

Infectious etiologies represent the most common worldwide etiology for focal epilepsies. This designation is only used to describe enduring epilepsies resulting from infectious causes and not acute seizures in the setting of infection. Infectious focal epilepsies may not always have a structural correlate on diagnostic workup.

Metabolic etiologies may overlap with genetic etiologies and often result in generalized epilepsy syndromes. However, there are some well-characterized focal epilepsy syndromes purported to result from structural defects induced by metabolic syndromes. As an example, the rare hepatocerebral disorder Alpers’ syndrome caused by POLG1 mutations is strongly correlated with intractable focal epilepsy secondary to its cortical involvement.[9]

Immune etiologies of focal epilepsy should be considered when there is evidence of autoimmune-mediated central nervous system inflammation with recurrent seizures; in most cases, limbic and/or cortical involvement is seen in cases of focal immune-related epilepsy. While some antibodies have been implicated (see Table below), many remain undiscovered. Interestingly, some antibodies have been associated with particular semiologies; for instance, LGI-1 antibody encephalitis has been associated with faciobrachial dystonic seizures. An increasing recognition of the heterogeneity in autoimmune encephalitides has resulted in the proposal of various anatomical, serological, and etiological classification schemes.[10] As our knowledge of immunology expands, it is expected that further immune causes for focal epilepsy will be appreciated.

Up to one-third of focal epilepsies have no clearly defined etiology and are therefore categorized as “unknown” in the 2017 ILAE etiological classification. This may be either due to inadequate patient access to diagnostic resources or to microscopic lesions that elude contemporary diagnostic modalities. In many patients with normal MRIs who undergo epilepsy surgery, focal pathologies such as microgyria and gliosis are identified later histopathologically.[11]

Table. (Open Table in a new window)

Etiology Associated Conditions*
Structural

Malformations of cortical development (focal cortical dysplasias, lissencephaly, polymicrogyria, schizencephaly, hemimegalencephaly, hypothalamic hamartoma)

 

Vascular lesions (arteriovenous malformations, cerebral angiomas)

 

Hippocampal sclerosis

 

Hypoxic-ischemic lesions (ischemic and hemorrhagic strokes, cerebral venous sinus thrombosis, hypoxic-ischemic brain injury, porencephalic cysts)

 

Neoplasms (dysembryoplastic neuroepithelial tumors, gangliogliomas, metastatic tumors, etc.)

 

Traumatic brain injury

 

Syndromic conditions (Sturge Weber syndrome, Tuberous Sclerosis, Rasmussen syndrome
Genetic

Tuberous sclerosis, Sturge Weber Syndrome, Autosomal-dominant nocturnal frontal lobe epilepsy, Autosomal-dominant lateral temporal lobe epilepsy, familial mesial temporal lobe epilepsy, familial focal epilepsy with variable foci

 

Presumed genetic cause: benign focal epilepsies of childhood, epilepsy-aphasia spectrum
Infectious Bacterial meningoencephalitis, viral encephalitis, neurocysticercosis, HIV, cytomegalovirus, toxoplasmosis, Lyme disease
Metabolic Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, Alpers’ syndrome, peroxisomal disorders, pyridoxine-dependent epilepsy
Immune Rasmussen syndrome, antineuronal nuclear antibody type 1 (anti-Hu) encephalitis, anti-N methyl-D-aspartate (anti-NMDA) receptor encephalitis, anti-leucine-rich glioma inactivated 1 (anti-LG1) encephalitis, dipeptidyl-peptidase-like protein 6 (DPPX-6) encephalitis, Contactin-associated protein-like 2 (CASPR2) encephalitis, Glutamic acid decarboxylase 65-antibody (GAD65) encephalitis
Unknown This represents up to one-third of focal epilepsies

*The example conditions provided are not exhaustive but represent some of the most common conditions associated with focal epilepsy. This list has been compiled based on the ILAE diagnostic manual available at www.epilepsydiagnosis.org.

Epidemiology

In a large 2017 meta-analysis, Fiest et al. reported that the lifetime prevalence of epilepsy was approximately 7.6 per 1000 (95% CI 6.17–9.38) in the United States and internationally. Low/middle-income countries have a statistically significant increased prevalence of epilepsy (8.75 per 1000, 95% CI 7.23–10.59) vs high-income countries (5.18 per 1000, 95% CI 3.75–7.15); this discrepancy is likely related to greater environmental risk factors and poorer access to healthcare in lower income countries.[12]

Approximately 60% of adult-onset epilepsies are focal epilepsies. Males are slightly more affected; however, this is thought to be related to females being more likely to conceal their epilepsy diagnosis. There is an age-related incidence pattern that follows a U-shaped curve, with a peak in the first year of life and an increase during the sixth and seventh decades. (See the image below.)

Over the last decade, the incidence of epilepsy in younger age groups has declined, perhaps due to improvements in perinatal care. Meanwhile, the incidence has increased in the elderly, perhaps owing to an improved life expectancy.[13]

This graph illustrates the 2 peaks of incidence of This graph illustrates the 2 peaks of incidence of epilepsy: early and late in life.

Prognosis

Although originally proposed in 1993, Sander’s prognostic classification for epilepsy patients continues to hold relevance today.[14] He divided patients into four categories as below:

  1. Those with an excellent prognosis (about 20%–30% of total) and high probability of spontaneous remission (eg, benign focal epilepsies of childhood)

  2. Those with a good prognosis (30%–40%) with easy pharmacological control and remission (some focal epilepsies)

  3. Those with an uncertain prognosis (10%–20%) who may respond to drugs but tend to relapse upon withdrawal of treatment (most focal epilepsies)

  4. Those with a poor prognosis (~20%) who tend to have intractable seizures despite intensive treatment (eg, progressive focal epilepsy syndromes)

Specific data are not available for focal epilepsies, however, epilepsy in general carries an increased risk of mortality; this may be secondary to sudden unexplained death in epilepsy (SUDEP), status epilepticus, accidental injuries, or suicide. The 2017 ILAE Mortality Task Force reported that epilepsy carried a standardized mortality ratio (observed deaths/expected deaths) of 2.3 in high-income countries and 2.6 in low-income countries.[15, 16]

In terms of quality of life, in 2016 epilepsy accounted for more than 13 million disability-adjusted life years (DALYs), a 20% decrease in comparison to 1990.[17] This likely represents advances in epilepsy diagnosis and treatment.

Patient Education

For patient education information, see the Brain and Nervous System Center, as well as Epilepsy.

 

Presentation

History

Obtaining a description of the seizures from the patient and any witnesses is critical. The description needs to include a description of the patient’s state of awareness during the seizure. Awareness is a surrogate measure for consciousness and should be assessed by whether the person knows who they are and what is going on around them during their seizure; it is distinct from responsiveness.

A focal aware seizure replaces the previous term “simple partial seizure.” A focal seizure with impaired awareness replaces “complex partial seizure.” If a patient’s awareness is impaired for any portion of the seizure, the seizure should be classified as a focal seizure with impaired awareness. If the integrity of the patient’s awareness is unknown, this descriptor does not need to be included.

Next, an elucidation of the early prominent features of the seizure is important to aid in localizing the epileptic focus. These are generally divided into motor and non-motor manifestations. The term “aura” is used to describe a subjective ictal phenomenon for a patient that may precede an observable seizure; an aura is non-motor focal seizure as described below.

Motor manifestations may include the following:

  1. Automatisms: involuntary but coordinated motor activity, which tends to be purposeless and repetitive (eg, lip smacking, patting)

  2. Atonic: focal loss of tone

  3. Clonic: focal repeated, regularly spaced jerking movements

  4. Epileptic spasms: rapid paroxysms of flexion at the waist and flexion or extension of the arms

  5. Hyperkinetic: excessive and highly variable muscular movement (eg, thrashing, pedaling)

  6. Myoclonic: irregular, brief, unsustained focal jerking

  7. Tonic: focal sustained increased tone or stiffening

Non-motor manifestations may include the following:

  1. Autonomic: changes in heart rate, blood pressure, a sensation of heat or cold, sexual arousal, sweating, flushing, piloerection, or gastrointestinal sensations

  2. Behavior arrest: a cessation of movement. To qualify, this should be the predominant feature of the entire seizure (eg, staring)

  3. Cognitive: changes in language function, thinking, or higher cortical functions (eg, déjà vu, jamais vu, hallucinations)

  4. Emotional: clear emotive changes, whether affective or subjective (eg, fear, anxiety, laughing, crying)

  5. Sensory: a change in sensation, which can be somatosensory, olfactory, visual, auditory, gustatory, or vestibular

It is also important to assess whether a focal seizure evolves to tonic-clonic activity bilaterally. This is classified in the new terminology as a “focal to bilateral tonic-clonic” seizure. This is meant to replace the old designation of “secondary generalized tonic-clonic,” to avoid engendering confusion between focal and generalized seizures.[18]

Finally, during the history-taking one should elicit the duration and evolution of the seizure semiology, the frequency of seizures, whether there is any post-ictal state (fatigue, headache, confusion, or psychosis), if any tongue biting or incontinence occurs, and a detailed anti-seizure medication history.

Clinicians should also ascertain any risk factors for epilepsy (perinatal history, family history of epilepsy, head trauma, febrile seizures, dementia, or childhood seizures). It is also crucial to note any temporal patterns to seizures (diurnal, nocturnal, upon awakening, or none). Careful attention should also be paid to whether there are any known triggers (drug use, stress, sleep deprivation, fasting, illness, menstruation, lights).

Smartphone (cellphone) video recordings have emerged as a potentially reliable and useful way to clarify a seizure diagnosis.[19, 20] This is particularly useful in situations where extended EEG monitoring has not availed in capturing the episode in question. Given the ubiquity of smartphones today, caregivers or family of the patient should always be encouraged to take a clear video recording of the episode to be reviewed by their neurologist.

Physical Examination

A detailed neurological examination should be performed to determine whether a focal brain lesion is present, as this may well be the epileptic focus. Physical examination should also focus on examination of the skin, nails, eyes, and other organ systems to ascertain whether any comorbid conditions that confer an increased risk for epilepsy are present.

Neurocutaneous syndromes such as tuberous sclerosis and Sturge Weber syndrome may often present with dermatologic findings. Special attention should also be paid to any dysmorphic features or intellectual disability, as these may disclose clues regarding the presence of brain malformations.

Finally, one should also pay attention to whether there are any signs of potential injuries from convulsive seizures such as tongue bites, lacerations, compression fractures, or shoulder subluxations.

In most focal epilepsies, physical examination is unrevealing.

 

DDx

Diagnostic Considerations

Understanding the conceptual difference between seizure and epilepsy is important, as the latter carries important prognostic and management considerations. A seizure is defined as a transient neurologic dysfunction resulting from an excessive abnormal electrical discharge of cerebral neurons. In contrast, epilepsy is a disorder characterized by chronic, recurrent seizures caused by abnormalities in electrical activity of the brain. As defined in the 2017 International League of Epilepsy consensus guidelines, epilepsy is diagnosed when either: a) an individual has had at least two unprovoked seizures more than 24 hours apart; b) when an individual has had one seizure with a 60% probability of having another seizure within the next 10 years; or c) diagnosis of an epilepsy syndrome. Unprovoked implies a clearly identifiable acute and transient factor that lowers the seizure threshold. Factors that increase the risk of seizure recurrence include abnormal brain imaging, nocturnal seizures, an EEG with epileptiform abnormalities, or seizures related to a prior brain injury.[21]

Epileptic syndromes

In addition to the above differentiation, there is a recognition of “epilepsy syndromes,” or epileptic conditions in which there are shared common characteristics. Although a full characterization of epileptic syndromes is beyond the scope of this article, we will summarize a number of common epileptic syndromes as below:[22, 23]

Focal epilepsies are the most common type of epilepsy of adult onset, and and again most are of unknown cause (ie, normal MRI). For practical reasons, they can be divided into two categories: mesial temporal epilepsies and neocortical epilepsies.

Mesial temporal epilepsies

Mesial temporal epilepsies are seen in cases where the epileptic focus is located in the hippocampus, amygdala, or parahippocampal gyrus. The most common cause in adults is hippocampal sclerosis. Mesial temporal lobe epilepsies are characterized by focal seizures with impaired awareness, often preceded by an autonomic (commonly epigastric sensation and/or tachycardia), cognitive (déjà-vu or jamais-vu), or sensory (olfactory or gustatory) aura that is recalled by the patient. Hand and mouth automatisms as well as emotional manifestations, specifically fear or laughter, can also be seen. Lateralizing features include the following:

  1. Unilateral automatisms are often ipsilateral to the seizure focus.
  2. Dystonic posturing usually occurs on the contralateral side.
  3. Head deviation at seizure onset is usually ipsilateral to the seizure, while late “versive” head turning is contralateral.
  4. Nose-wiping may be performed by the hand ipsilateral to the seizure focus.
  5. Post-ictal hemiparesis can occur contralateral to the seizure focus.

Mesial temporal epilepsy often manifests by adolescence and there is a statistically significant association with febrile seizures in childhood. A younger age at onset and a history of febrile seizures are associated with an increased risk of drug resistance, and therefore timely surgical management is essential.[24, 25] Diagnosis of mesial temporal lobe epilepsy is supported by temporal sharp waves at the anterior or middle temporal electrodes (F7/F8, T1/T2, T3/T4) as well as temporal intermittent rhythmic theta activity (TIRDA). Bitemporal independent discharges can be observed in up to 40% of patients. Hippocampal atrophy confirmed on high-resolution MRI is usually a highly sensitive localizing feature.[26]

Neocortical focal epilepsies

This term is used to refer to seizures arising from the temporal neocortex as well as extratemporal epilepsies. Seizures may be focal with preserved or impaired awareness, usually with other aspects of semiology governed by the area of affected cortex. In general, neocortical extratemporal epilepsies may be difficult to localize precisely as surface EEG is usually less reliable, especially when the focus is in the deep cortex.

Neocortical temporal lobe epilepsy often overlaps in many clinical characteristics with mesial temporal lobe epilepsy. Auras of auditory hallucinations or complex visual hallucinations without an epigastric aura often suggest a temporal neocortical origin. Congenital malformations and early clonic activity after automatisms are also associated features. On EEG, predominant discharges are seen in the lateral temporal electrodes and MRI usually demonstrates neocortical temporal lesions with a lack of associated mesial temporal pathology.[27]

Frontal lobe epilepsies are usually characterized by short duration (< 30 seconds), nocturnal predilection, a non-specific aura, and complex motor behaviors that may be mistaken for psychogenic non-epileptic events (bicycling, pelvic thrusting, gestural automatisms, asymmetric tonic extension of proximal extremities, and complex vocalizations). Awareness may be spared, even for bilateral motor seizures. Focal motor seizures involving the primary motor cortex will produce contralateral hemiclonic activity that usually spreads across the motor homunculus in a “Jacksonian march.” Supplementary motor area seizures may manifest in the “fencing posture,” whereby the head and eye deviate to the contralateral side with extension of the contralateral arm and flexion of the ipsilateral arm. Medial frontal seizures can manifest in behavioral arrest states lasting for several minutes to hours. Up to one-third of patients do not have a diagnostic ictal EEG during a frontal lobe seizure and an MRI may also fail to disclose the lesion.[28]

Occipital lobe epilepsies may be the product of the benign focal epilepsies of childhood or an underlying structural etiology. Visual auras are well characterized and may include elementary (flashing lights) or complex visual hallucinations, visual distortions (macropsia, micropsia, metamorphosia, dyschromatopsia), or ictal blindness. The visual aura usually manifests in the contralateral visual field. Awareness may be spared. Usually, interictal EEG reveals localized occipital spikes.[29]

Parietal lobe epilepsies are poorly characterized and do not have any specific or sensitive features; contralateral somatosensory and emotional auras have been reported. Asymmetrical tonic-clonic activity and automatisms may also be seen with a post-ictal “Todd paralysis.” EEG is often not reliable in localization and MRI usually discloses structural pathologies in the parietal region.[30]

Less common focal epilepsies

Panayiotopoulos syndrome

This syndrome presents around 3 to 6 years of age and is characterized by prominent autonomic seizures (nausea/vomiting, salivation, tachypnea) that may evolve into focal clonic activity. Awareness is usually preserved during the seizure; two-thirds of the seizures tend to occur out of sleep. There is a presumed genetic basis although it is yet to be elucidated. On EEG, multifocal occipital spikes are seen in approximately 75% of cases, usually elicited by closing the eyes. Most patients suffer from less than five total seizures and the condition usually remits on its own 1 to 2 years after onset without treatment.

Late-onset childhood occipital epilepsy (Gastaut-type)

This syndrome presents between 8 and 11 years of age. It is characterized by focal non-motor sensory visual seizures (hallucinations, hemianopia, visual illusions) with preserved awareness, lasting 3–20 minutes in duration often with post-ictal headaches. Some patients will have ictal blindness lasting up to 3–5 minutes afterwards. Seizure frequency is about 1 to 2 per month and responds dramatically to carbamazepine. A genetic etiology is presumed but has not yet been discovered. Findings on EEG are nearly identical to Panayiotopoulos syndrome. In the majority of cases, seizures remit within 2 to 7 years after onset.

Childhood epilepsy with centrotemporal spikes

This syndrome was formerly known as benign childhood epilepsy with centrotemporal spikes (BCECTS) or Rolandic epilepsy. It accounts for up to 25% of childhood epilepsy and many children with Panayiotopoulos syndrome will evolve into this epilepsy syndrome. The onset peaks around 7 to 10 years of age. It is often nocturnal out of non-REM sleep and is characterized by brief hemifacial clonic focal seizures with preserved awareness. Semiological features may also include oropharyngeal paresthesias, drooling, guttural vocalizations, dysarthria, and/or aphasia. Seizure frequency is approximately 10 lifetime seizures and it does not require treatment. Findings on EEG consist of high-amplitude centrotemporal sharp waves. It is considered to be on the spectrum of epilepsy-aphasia syndromes and has been linked to heterozygous mutations on the GRIN2A gene. In the majority of cases seizures remit 2 to 4 years after onset, although extremely rarely cases may progress to the more severe epilepsy-aphasia diseases such as Landau-Kleffner syndrome.

Autosomal-dominant lateral temporal epilepsy

This syndrome is also referred to as “autosomal dominant epilepsy with auditory features” and presents in the second or third decade of life. Patients present with focal seizures with preserved awareness and distinct auditory hallucinations or receptive aphasia; this may evolve into bilateral tonic-clonic seizures. Interictal EEG may disclose temporo-occipital sharp waves. It is associated with LGI11 and RELN gene mutations. It responds well to anti-seizure medications and the prognosis is good.

Autosomal-dominant nocturnal frontal lobe epilepsy

This genetic epilepsy syndrome usually presents between early childhood and adulthood. Patients present with clusters of focal nocturnal tonic or hypermotor seizures, often preceded by a non-specific aura. Interictal EEG may show rare frontal sharps but is often normal. Several mutations have been implicated, but neuronal nicotinic acetylcholine receptor mutations (CHRNA2, CHRNA4) are particularly common. While most patients will respond well with anti-seizure medications, up to 30% are drug resistant.

Familial mesial temporal lobe epilepsy

These are generally autosomal-dominantly inherited conditions that may be associated with hippocampal sclerosis. Onset is usually in early adulthood with focal cognitive seizures that can evolve to automatisms, focal tonic, and/or bilateral tonic-clonic seizures. Interictal EEG will often show temporal sharp waves. The underlying genetic causes are yet to be discovered. Most cases are well controlled with medications with intractable cases responding to surgical management.

Familial focal epilepsy with variable foci

This entity is highly heterogeneous with an onset at any point from infancy to late adulthood, often with long periods of remission. Although the epileptic focus varies between family members, every individual usually has a single focus. It is characterized by focal motor seizures with preserved awareness, although evolution to bilateral tonic-clonic seizures is sometimes seen. Interictal EEG may reveal focal epileptiform abnormalities in the epileptic focus. Mutations in GATOR complex genes have been implicated.

Special diagnostic considerations in neonates and children

Given their limited language development, neonates and children often cannot properly verbalize their level of awareness and may have difficulties describing their semiology. When possible, caregivers are encouraged to obtain a video recording of the semiology, which is rendered highly possible with current smartphone technology. It has been noted that owing to immaturity of the early brain, children less than 6 years of age will often exhibit very limited ictal behaviors. Clinical seizures often consist of behavioral arrest, atonic or tonic posturing with head or eye version, and myoclonic seizures; the localization value is often highly questionable.[31]

Additionally, there are important differential diagnoses for epileptic seizures in these populations.

In the neonatal population, the differential should include:

  1. Jitteriness
  2. Sleep-related rhythmic movement disorders (body rocking, head banging, etc.)
  3. Self-gratification behaviors
  4. Benign neonatal sleep myoclonus ad benign myoclonus of infancy
  5. Benign paroxysmal torticollis
  6. Spasmus nutans
  7. Opsoclonus-myoclonus syndrome
  8. Hyperekplexia
  9. Alternating hemiplegia
  10. Breath-holding attacks
  11. Pallid syncope
  12. Non-epileptic head drops

In children, the differential should include:

  1. Stereotypies
  2. Tic disorders
  3. Paroxysmal dyskinesias
  4. Episodic ataxias
  5. Benign paroxysmal vertigo
  6. Sandifer syndrome
  7. Narcolepsy or cataplexy
  8. Tantrums or rage reactions
  9. Factitious illness
  10. Daydreaming/eidetic imagery
  11. Cyclical vomiting/abdominal migraine
  12. Panic attacks
  13. Dissociative states

Differential diagnosis

The misdiagnosis of seizures is common, with up to one-third of patients referred for “difficult seizures” having been misdiagnosed. Among the common differential diagnoses one should consider are the following:[32]

Psychogenic non-epileptic events are by far the most common condition misdiagnosed as epilepsy, at least in patients seen at referral centers. These are events that have no electrophysiological correlate or clinical evidence for epilepsy and are psychological in origin. Motor features that distinguish these attacks from seizures include truncal movements, back-arching, asynchronous movements, variable rate and direction of movements, stuttering, eye closure with resistance to passive eye opening, and horizontal movements of the head. Preserved awareness during bilateral motor activity is also characteristic, although rarely supplementary sensorimotor area seizures can also result in bilateral limb involvement with preserved consciousness. The etiology is heterogeneous although psychiatric factors may play a prominent role. Video EEG monitoring and detailed psychological evaluation is recommended to render the diagnosis. 

Syncope refers to a transient loss of consciousness secondary to an abrupt reduction of blood flow to the brain; sometimes there may be associated convulsive movements due to cortical disinhibition of the brainstem. An evidence-based criteria has been developed to differentiate syncope from seizures with very high specificity and sensitivity.[33]

Parasomnias are unusual behaviors that occur while asleep (REM or NREM) or during arousal and are an important differential to consider in patients who present with purported nocturnal seizures. They may easily be confused for frontal lobe seizures. Parasomnias are distinguished by the fact that events are non-stereotyped, clustering is rare, and events are usually long in duration (> 10 min).

Transient ischemic attacks are due to temporary interruption of the blood supply to a cerebral vessel. They may have a stuttering course and typically always present with rapid onset of negative symptoms (numbness, weakness, aphasia) without stiffness or jerking. This should be on the differential of a focal seizure, especially when a patient has several cardiovascular risk factors.

Migraine headaches may present with a visual aura, unilateral headache, nausea, and vomiting. They are characteristically slowly progressive over several hours; in some cases, an aura may be present without any headache, termed an acephalgic migraine. Confusion/inattention in the setting of severe pain can sometimes be seen, however awareness is nearly always preserved. A personal and family history of migraines should always be elicited. Familial hemiplegic migraine is a subtype that can present with focal weakness, dysphasia, and paresthesias prior to the headache.

Differential Diagnoses

 

Workup

Approach Considerations

Laboratory studies, neuroimaging studies, and electroencephalography (EEG) are used in the assessment of focal epilepsies. The following recommendations are derived from the referenced paper.[32]

Laboratory Studies

Because the type of seizure (focal vs generalized) and whether it was provoked or unprovoked may not necessarily be clear only from the history, investigate various possible causes for the seizures including structural abnormalities and toxic and metabolic disturbances. One may consider performing the following tests:

  • Complete blood count and complete metabolic panel
  • A fingerstick glucose
  • Urinary drug screen
  • Blood alcohol levels
  • Urinalysis
  • Chest X-ray
  • ASM levels (if the patient reports use of these medications)
  • Baseline serum prolactin levels and prolactin level 10–20 minutes after a reported event (this has been identified as a possible adjunct in differentiating GTCs from clinical seizures)
  • EKG and/or ECHO (especially if syncope is considered in the differential)
  • Lumbar puncture (specifically in immunocompromised patients or if there are signs/symptoms of central nervous system infection/encephalitis). One should perform at least basic fluid studies (protein, WBC, glucose) and may consider specific serological testing as guided by the clinical suspicion
  • Genetic testing such as genomic hybridization assay, gene panels, and whole exome sequencing (this should be considered in patients with concomitant developmental delay, intellectual impairment, or dysmorphic features)
  • ANA, TPO, and CSF/serum neuronal autoantibody panels (this may be considered if an autoimmune encephalitis is suspected as the etiology)

Computed Tomography

A CT scan of brain without contrast is readily and rapidly available and appropriate in an emergency setting. This is specifically useful to rule out large structural abnormalities, but it may easily miss more subtle findings such as low-grade gliomas, hippocampal sclerosis, and malformations of cortical development.

Magnetic Resonance Imaging

MRI of the brain, with and without contrast, delineates structural detail and pathology. An epilepsy protocol-specific MRI of the brain should include thin, one to three millimeter slices and coronal fluid-attenuated inversion recovery (FLAIR) sequences to assess for focal cortical dysplasias and hippocampal sclerosis. It is also important for the imaging to be reviewed by an expert neuroradiologist to increase the detection of subtle structural abnormalities.

Electroencephalography

Electroencephalographic signals provide a real-time assessment of neurophysiologic function; they measure the summation of post-synaptic electrical potentials generated by pyramidal cells in the cerebral cortex. Pyramidal cells are perpendicularly aligned to the cortical surface, producing a vertical dipole detectable by scalp electrodes. However, given the volume conduction effects, at least 6 cm^2 of synchronously firing cortex is needed to generate a signal that is detectable on scalp EEG. It is extremely important that EEG be read by an experienced electroencephalographer, as physiological and extraphysiological artifacts are commonly seen and can render interpretation challenging.

Given that EEG is a real-time assessment of neurologic function, its diagnostic yield is directly related to the amount of time it records. In patients with epilepsy, a standard 30-minute routine EEG detects epileptiform discharges in only 50% of patients; provocation techniques such as sleep deprivation, hyperventilation, and photic stimulation may be used to increase the sensitivity of detecting epileptiform discharges. In contrast, a 24-to-36-hour recording has a greater than 90% likelihood of detecting epileptiform abnormalities.[34]

Another factor to consider is how emergently to obtain an EEG recording; generally, if a patient does not return to baseline neurological function within 60 minutes of seizure termination, has waxing-waning level of awareness, or displays acute focal neurologic dysfunction without a structural correlate, emergent inpatient EEG may be justified. In other cases, nonemergent EEG may be pursued, either on an inpatient or outpatient basis.

In inpatient EEG monitoring, patients are admitted to the hospital with slow titration of anti-seizure medications and use of provocation techniques to capture the events in question. This type of admission is usually variously referred to as “long-term monitoring” and requires a designated “epilepsy monitoring unit” with well-trained personnel.

Ambulatory outpatient long-term EEG recordings up to 72 hours in duration are increasingly being utilized in clinical practice to avoid necessitation of inpatient admissions; an important caveat in such a setting is the inability to perform provocation techniques. It should be noted that EEG highly favors detection of temporal lobe involvement in epilepsy and may be less sensitive for detection of focal epilepsies in other lobes.[34]

Abnormalities seen in focal epilepsy can be broadly divided into interictal abnormalities and ictal abnormalities Below is a broad summary discussion of these terms, however the updated 2021 ACNS Standardized Critical Care EEG Terminology reference manual should be referenced by electroencephalographers for further specific details.[35]

Interictal abnormalities are defined as sporadic epileptiform discharges or rhythmic/periodic patterns that occur “between seizures,” are distinct from background activity, and resemble electrographic patterns recorded in human subjects with epilepsy. As described in the Pathophysiology section, the physiologic basis for interictal abnormalities is the paroxysmal depolarizing shift. It should be noted that approximately 2% of health adults may have interictal discharges; furthermore, the absence of interictal abnormalities does not necessarily exclude the possibility of epilepsy. Specific interictal abnormalities may be divided into the following:

  1. Sporadic interictal epileptiform discharges: these are defined as apiculate, diphasic or triphasic waves that are slightly asymmetric with a steeper ascending slope than a descending one. They can be of variable duration, with a “spike” defined as lasting from 20 to 70 milliseconds and a “sharp wave” lasting from 70 to 200 milliseconds. “Polyspikes” is a term that refers to 2 or more spikes in succession lasting less than 0.5 seconds. Immediately afterwards, a slow wave can sometimes be seen and the term “spike-and-wave” and “sharp-and-wave” are then used to describe these morphologies.

  2. Rhythmic/periodic patterns: a rhythmic pattern refers to waves that repeat without an interval between consecutive waveforms while a periodic pattern refers to discharges that repeat with clearly regular inter-discharge intervals between them. These patterns should be less than 2.5 Hz in frequency. An added modifier that confers a higher ictal-appearance are whether there are any “plus” features: superimposed fast activity, rhythmic activity, and/or sharp waves.

In describing focal interictal abnormalities on EEG, one should consider whether the pattern in question is lateralized, unilateral independent, bilateral independent, or multifocal. Special attention should also be paid to whether specific lobes are involved; when this is not possible, one can use the term “hemispheric.” There should also be a specification of the prevalence of these interictal abnormalities on the recording.

In contrast, ictal EEG abnormalities refer to electrographic patterns seen during a seizure; an important feature of ictal patterns is evolution in frequency, morphology, or distribution over time. As per consensus 2021 ACNS criteria, electrographic seizures must be either a) epileptiform discharges averaging > 2.5 Hz for 10 seconds; or b) any pattern with definite evolution lasting for > 10 seconds. For focal seizures, status epilepticus is rare but is used to describe seizure that persist for at least 10 minutes.

There is an increasing recognition of “potentially ictal” patterns on EEG with the latest 2021 American Clinical Neurophysiology Society (ACNS) clearly defining two specific terms:

  1. Brief potentially ictal rhythmic discharges (BIRDs): these represent electrographic patterns that resemble ictal abnormalities but are less than ten seconds in duration

  2. Ictal-interictal continuum (IIC): this term is used to refer to electrographic patterns that do not meet the frequency criteria for ictal abnormalities (< 2.5 Hz) and do not evolve but demonstrate a frequency of > 1Hz and are thought to be potentially ictal in at least some sense.

Imaging Studies

As part of a pre-surgical workup, further diagnostic imaging modalities may be pursued. Extremely subtle forms of cortical dysplasia may still be undetectable on high-resolution MRI studies and in such cases, further testing with positron emission tomography (PET) or ictal single-photon emission computed tomography (SPECT) is performed.

Functional MRI and diffusion tensor imaging are also used to map eloquent cortex (parts of the brain that are responsible for key language and memory functions) and visualize white matter bundles that should be avoided during surgery.

Procedures

As part of a pre-surgical workup, there are several further diagnostic tests that may be pursued. For further details regarding pre-surgical work-up, one may refer to the excellent textbook by Stephan Schuele.[36]

Magnetoencephalography (MEG)

This is the only noninvasive technology that directly measures neuronal activation while providing high spatial and temporal resolution. Magnetometers measure the magnetic fields generated by cortical electrical activity to localize epileptiform activity at a sublobar level. It is particularly useful to guide surgical EEG lead implantation in MRI-negative cases.

Wada test

This test involves the intracarotid injection of amobarbital, an anesthetic agent, to selectively anesthetize the ipsilateral cerebral hemisphere. This allows for detailed memory and language testing of the remaining “awake” hemisphere.

Neuropsychiatric testing

This should be performed by a qualified neuropsychologist and allows for functional assessment of the brain, confirmatory evidence for seizure laterality, and provides important information regarding potential post-operative neuropsychological deficits.

Surgical EEG monitoring

Invasive intracranial EEG monitoring is particularly needed when noninvasive data are insufficient to delineate the epileptic focus. This may be pursued via either subdural grids, stereotactic guidance (stereo-EEG), or a combination of both depending on the specific case. Grids are more invasive regarding a craniotomy, but they offer spatial contiguity and are particularly useful when the epileptic focus is in proximity to eloquent cortex. Stereo-EEG is less invasive, however is particularly useful when dep structures are implicated as part of the epileptic network such as the insula or mesial temporal lobe.

Electrocorticography and cortical stimulation

This involves applying electrical stimulation to the cortex either intraoperatively or via intracranial electrodes to map eloquent cortex in real time while also allowing for more precise localization of the epileptic focus.

 

Treatment

Approach Considerations

Focal epilepsies are generally treated with antiseizure medications (ASMs). Nonpharmacologic treatments in certain refractory cases include surgery and dietary modification.

Antiseizure Medication Therapy

Approximately two-thirds of epilepsy patients will respond to either anti-seizure medication (ASM) monotherapy or combination therapy. There are approximately 30 ASMs available and, in general, drugs have similar rates of efficacy with limited comparative data. Important factors in choosing among various drugs include potential adverse effects, dosing schedules, drug interactions, available formulations, and cost.

In patients taking their first ASM, adverse effects are seen in up to 30% of patients, while polytherapy can lead to adverse effects in up to 90% of cases. Most common side effects include dizziness, drowsiness, and slowed cognition; these may be dose-dependent. Some ASMs (phenytoin, carbamazepine, lamotrigine) also can predispose to a rash and severe reactions such as Stevens-Johnson syndrome. Others may lead to weight gain (gabapentin, valproate) or weight loss (topiramate, zonisamide). In pregnant patients or women of childbearing age, it is important to consider teratogenic effects of ASMs and lamotrigine and levetiracetam have the lowest risk profile for congenital malformations.[32]

A “start low, go slow” titration approach over weeks to months is recommended when starting a new ASM and has been shown to reduce the risk of adverse effects. Patients may require ASM changes due to a lack of efficacy or intolerability. If the first ASM fails because of lack of tolerability, it should be replaced with an alternative monotherapy. If the first ASM fails because of a lack of efficacy, one can opt for either replacement of monotherapy or adjunctive therapy. Monotherapy conversion is favored when the first ASM was not well-tolerated or was totally ineffective; this is also preferred in elderly patients who are taking several medications, women of childbearing age contemplating pregnancy, patients with compliance issues, and financial issues. Adjunctive therapy would be preferred if the first ASM was well-tolerated and partially effective. There is a benefit to combining different mechanisms of action and use of redundant mechanisms may predispose to tolerability issues. Tapering or discontinuation of the baseline ASM should only be done once an efficacious dose of the replacement therapy is reached, and this may be facilitated through laboratory drug level monitoring. One should also pay attention to the patient’s schedule and in those with a busy lifestyle, a medication with an extended half-life and one-time daily dosing is recommended.[37] In all cases, a shared decision-making process between the patient and the provider is highly encouraged to improve compliance.[38]

For focal epilepsies, narrow-spectrum agents are typically effective, although broad-spectrum agents can improve seizure frequency in focal epilepsies as well with variable efficacy. Several ASMs, especially those that are inducers or inhibitors of the cytochrome P450 system, may lead to undesirable drug interactions. In childbearing age women, enzyme inducers such as carbamazepine and phenytoin can increase the clearance of oral contraceptives and precipitate unwanted pregnancy; oral contraceptives have been shown to also decrease plasma concentrations of lamotrigine. In patients who are on warfarin, enzyme inhibitors such as valproate can impair clearance of anticoagulation. In patients with multiple comorbidities, use of levetiracetam, lamotrigine, lacosamide, and gabapentin is favored due to limited drug interactions. Finally, use of lamotrigine and valproate in combination may have synergistic effects but a sensitive dosing approach is necessary.

Cost is a sensitive consideration for some patients, especially those without insurance; in such cases it is feasible to switch generic formulations that have Food and Drug Administration (FDA)-validated bioequivalence to their brand-name alternatives.[39]

Of note, new FDA guidelines allow for the extrapolation of ASM efficacy data in adults with focal epilepsy to pediatric populations over the age of four, although safety studies are still required. The FDA has also allowed for adjunctive ASM approval to be extrapolated for monotherapy.[40]

Go to Antiepileptic Drugs for complete information on this topic.

Surgical Care

Approximately 30%–40% of patients with focal epilepsy become intractable despite the use of anti-seizure medications (ASMs). Drug-resistant epilepsy is defined as the failure of adequate trial of two tolerated, appropriate chosen and used ASM schedules to achieve sustained seizure freedom. Several clinical trials have shown the efficacy of surgical over medical treatment for drug-resistant epilepsy, therefore referral of such patients to a qualified epilepsy center is paramount. Unfortunately, only one percent of patients with drug-resistant epilepsy are appropriately referred, and the reasons for this delay may be patient fear, lack of healthcare provider knowledge, lack of adequate healthcare access, or social and cultural issues. Fortunately, epilepsy surgery is highly safe, effective, and can be tailored to the patient’s needs; another highly attractive consideration is that epilepsy surgery is the only therapeutic option that provides a chance for complete remission of epilepsy. The referenced article provides a useful overview of the safety, efficacy, and mortality/outcome data regarding epilepsy surgery.[41]

Resective surgery remains the gold standard and may include variations such as callosotomy, hemispherectomy, and functional disconnection surgeries. If the epileptic focus is difficult to approach via open surgery or a less invasive option is specifically preferred, a thermal laser ablation may be performed and achieves comparable results to open-resection in well-selected patients. An ultrasound-induced thermal ablation may also be considered.

Although surgical resection is the standard of care in such cases, when eloquent cortex is implicated in the epileptic focus there is a risk for significant post-operative neurologic impairment. Neuromodulation devices can serve as a reasonable adjunctive therapy for intractable focal epilepsy in such cases where resection is too high-risk for neurologic injury. These devices utilize an internal pulse generator (IPG) to deliver electrical impulses that may disrupt hypersynchrony at the site of seizure initiation, produce a conduction block in seizure propagation, and attenuate cortical hyperexcitability and gating networks.  We will review here the three FDA-approved neuromodulation devices with attention to their mechanisms, their advantages/disadvantages, and the clinical evidence to support their use. Further details may be found in the reference article attached.[42]

Vagal nerve stimulation (VNS) is one of the earliest devices to have received FDA approval: a coiled lead is threaded around the vagus nerve and connected to an IPG implanted superficially to the pectoral muscle. VNS is an open-loop system, meaning that it delivers continuous electrical stimulation in a pre-defined pattern. However, several models now include a tachycardia detection algorithm that can deliver extra stimulation under the presumption of ictal tachycardia. VNS is theorized to increase activity in the nucleus tractus solitarius, activating the locus coeruleus and raphe nuclei which release norepinephrine and serotonin respectively; both neurotransmitters have been found to have anti-epileptic effects in the brain. Advantages of VNS include its safer extracranial implantation, its conditional compatibility with MRI, and its easy programmability; disadvantages/risks include vocal cord paralysis, bradycardia, cough, and neck pain. In prospective multicenter studies, the median percentage seizure reduction with VNS was 40%  after three years with nearly 22.5% achieving greater than 90% reduction in seizures.

Responsive neurostimulation (RNS) is a closed-loop device (ie, delivers targeted stimulation only when ictal activity is detected) which delivers electrical impulses to the putative seizure-onset zone. The electrodes rest on the neocortex and serve the dual purposes of recording brain activity (electrocorticography) and delivering abortive stimulation; meanwhile, the battery and circuit board are recessed in a ferrule under the scalp. Functioning analogously to a cardiac pacemaker, RNS detects and disrupts synchronized epileptiform activity in the focus of interest through direct electrical stimulation while also altering the long-term plasticity of epileptogenic networks. Advantages include targeted/intermittent stimulation, the potential for long-term electrocorticography (can track seizure patterns longitudinally), and high efficacy; disadvantages include lack of MRI compatibility, necessity to specifically localize the seizure-onset zone, and approximately 2% risk of infection/intracranial hemorrhage. A multicenter clinical trial with 191 patients enrolled demonstrated median percent seizure reduction of 60%–70% by 6 years post-implantation.

Deep brain stimulation (DBS) is an open-loop device in which 2 depth electrodes with 4 contact points are placed within the brain parenchyma and connected via a wire to an IPG that resides in the subclavicular region. Although many targets are still under active investigation (centromedian nucleus of thalamus, hippocampus, nucleus accumbens), the implantation site most supported by the current data is the anterior nucleus of the thalamus: a pivotal study in 2010 known as SANTE (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) demonstrated 69% seizure reduction at 5 years post-implantation. Although the mechanism remains theoretical, the anterior thalamic nucleus plays a role in the Papez circuit that involves several of the limbic structures involved in epilepsy. It is thought that stimulation at the anterior nucleus of the thalamus may desensitize the neural network and thus increases the precipitation threshold for seizures. Advantages to DBS include its relatively high efficacy and its plausibility to also improve outcomes in multifocal epilepsy; however, disadvantages include implant site infections, lead misplacement, and neurobehavioral impairment.

Go Vagus Nerve Stimulation and Epilepsy Surgery for complete information on these topics.

Dietary Modification

Consider the ketogenic diet or a modified Atkins diet as an alternative therapy for epileptic seizures. It is effective, even in highly refractory cases, but very strict; compliance may be extremely cumbersome.[43]

Activity Restriction

In the United States, each state has its own laws and regulations about driving with epilepsy. Strict enforcement is nonexistent and depends on reporting by patients. In a few states, reporting the condition is mandatory for physicians. A loophole exists for interstate drivers, in that state governments have no regulations and regulations are poorly enforced federally. Required seizure-free periods for US drivers range from 3 months (many states) to 2 years.[44]

Consultations

As previously discussed, if seizures are refractory to the first 2–3 trials of medication, refer patients to a comprehensive epilepsy center to evaluate other treatment options. This is important not only for surgical considerations in drug-resistant epilepsy but also to identify “pseudoresistance,” which may be secondary to medication non-compliance, misdiagnosed non-epileptic events, or failure to identify a treatable cause.

 

Medication

Medication Summary

Anti-seizure medications (ASMs) are the first-line treatment for partial epilepsy. All ASMs are effective, but all have potential adverse effects.

Classic (old) agents include phenobarbital, primidone, phenytoin, carbamazepine, and valproate. After a 15-year hiatus in drug approvals, many new AEDs became available, starting in the early 1990s. Newer drugs approved in the United States include felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), topiramate (Topamax), tiagabine (Gabitril), levetiracetam (Keppra), brivaracetam (Briviact), zonisamide (Zonegran), oxcarbazepine (Trileptal), pregabalin (Lyrica), lacosamide (Vimpat), vigabatrin (Sabril), eslicarbazepine (Aptiom), and cenobamate (Xcopri).  Specific details regarding each of these agents may be found in their respective drug profiles below.

Antiepileptic agents

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Phenytoin (Dilantin, Phenytek)

Phenytoin may act in the motor cortex, where it may inhibit spread of seizure activity. Dose should be individualized. Administer larger dose before retiring if dose cannot be divided equally.

Carbamazepine (Tegretol, Carbatrol, Equetro, Epitol)

Carbamazepine may block posttetanic potentiation by reducing summation of temporal stimulation.

Valproic acid (Depakote, Depakene, Depacon)

Valproic acid is chemically unrelated to other drugs that treat seizure disorders. Although its mechanism of action not established, its activity may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. It also may potentiate postsynaptic GABA responses, affect potassium channels, or have a direct membrane-stabilizing effect.

For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% every 2 weeks. This reduction may start at initiation of therapy or be delayed by 1-2 weeks if concern that seizures may occur with reduction. Monitor patients closely during this period for increased seizure frequency.

As adjunctive therapy, divalproex sodium may be added to patient's regimen at 10-15 mg/kg/d. The dose may be increased by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses of less than 60 mg/kg/d.

Gabapentin (Neurontin, Horizant, Gralise)

Gabapentin is structurally related to GABA, but does not interact with GABA receptors; it is not converted metabolically into GABA or a GABA agonist, and is not an inhibitor of GABA uptake or degradation. Nor does it exhibit affinity for other common receptor sites.

Titration to effect can take place over several days (300 mg on day 1, 300 mg bid on day 2, 300 mg tid on day 3).

Topiramate (Topamax, Qudexy XR, Trokendi XR)

Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic activity that may have a state-dependent sodium channel-blocking action. This agent potentiates the inhibitory activity of GABA and may block glutamate activity. Monitoring of plasma concentrations is not necessary to optimize therapy. On occasions, the addition of topiramate to phenytoin may require adjustment of the dose of phenytoin to achieve optimal clinical outcome.

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

A triazine derivative used in neuralgia, lamotrigine inhibits release of glutamate and inhibits voltage-sensitive sodium channels, leading to stabilization of neuronal membrane.

Felbamate (Felbatol)

An oral AED with weak inhibitory effects on GABA-receptor binding and benzodiazepine-receptor binding, felbamate has little activity at the MK-801 receptor-binding site of the N-Methyl-D-aspartate (NMDA) receptor-ionophore complex. However, felbamate is an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. Felbamate is not indicated as first-line antiepileptic treatment.

Oxcarbazepine (Trileptal, Oxtellar XR)

Oxcarbazepine has pharmacologic activity primarily through its 10-monohydroxy metabolite (MHD). This agent may block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. Its anticonvulsant effect may also occur by affecting potassium conductance and high-voltage activated calcium channels. Drug pharmacokinetics are similar in older children (>8 y) and adults. Young children (< 8 y) have 30-40% greater clearance than older children and adults. Children younger than 2 years have not been studied in controlled clinical trials.

Eslicarbazepine (Aptiom)

Eslicarbazepine acetate is a prodrug that is activated to eslicarbazepine (S-licarbazepine), the major active metabolite of oxcarbazepine. It stabilizes neuronal membranes by blocking sodium channels. This action may inhibit repetitive firing and may decrease the propagation of synaptic impulses. It may also increase potassium conductance and modulate the activity of high-voltage activated calcium channels. It is indicated as adjunctive treatment or monotherapy for partial-onset seizures in adults.

Primidone (Mysoline)

This agent decreases neuron excitability and increases seizure threshold.

Tiagabine (Gabitril)

Tiagabine's mechanism of action against seizures is unknown, but is believed to be related to the ability to enhance activity of GABA, which is a major inhibitory neurotransmitter in the CNS.

Tiagabine may block GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on surfaces of postsynaptic cells; it also may prevent propagation of neural impulses that contribute to seizures by GABAergic action.

When adding tiagabine to the antiepileptic regimen, modification of concomitant AEDs is not necessary unless clinically indicated.

Zonisamide (Zonegran)

Zonisamide is indicated for adjunct treatment of partial seizures with or without secondary generalization. Evidence suggests that it is also effective in myoclonic and other generalized seizure types.

Levetiracetam (Keppra, Roweepra, Spritam)

Levetiracetam is used as add-on therapy for partial seizures. Its mechanism of action is unknown. It has a favorable adverse effect profile, with no life-threatening toxicity reported.

Brivaracetam (Briviact)

Precise mechanism of action is unknown. Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect. It is indicated as adjunctive therapy for partial-onset seizures in adults and children aged 16 y or older.

Pregabalin (Lyrica)

Pregabalin is a structural derivative of GABA. Its mechanism of action is unknown. It binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, it reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. Pregabalin is FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.

Lacosamide (Vimpat)

Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. It is indicated as monotheray or adjunctive therapy for partial-onset seizures in children and adults ≥4 years.

Vigabatrin (Sabril)

The precise mechanism of action of vigabatrin is unknown. It is an irreversible inhibitor of GABA transaminase (GABA-T). GABA-T metabolizes GABA, an inhibitory neurotransmitter, thereby increasing CNS GABA levels. The use of vigabatrin must be weighed against the risk of permanent vision loss with this agent, which is available only from restricted access program.

Vigabatrin is indicated for adjunctive treatment for complex partial seizures in adults who have had inadequate response to first-line therapy.

Ethotoin (Peganone)

Ethotoin may act in the motor cortex, where it may inhibit the spread of seizure activity. The activity of brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited.

Cenobamate (Xcopri)

The precise mechanism is unknown, but it has shown to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of GABA-A ion channel. It is indicated for adults with partial-onset seizures as either monotherapy or adjunctive therapy.