Epilepsy: A Clinical Overview
The diagnosis and treatment of seizures and epilepsy are common tasks of the physician. Approximately 1 in 10 people will have a seizure during their lifetime. Epilepsy, which is the tendency to have unprovoked seizures, is the fourth most common neurologic disorder, affecting 1 in 26 people in the United States and 65 million people worldwide. Evaluation of a patient presenting with a seizure involves excluding an underlying neurologic or medical condition, classifying the seizure type, and determining whether the patient has epilepsy. Proper treatment requires accurate diagnosis of the epilepsy type and syndrome and use of a medication that is effective and does not have adverse effects. Most patients can achieve complete seizure control with medication, but if medication is unsuccessful, surgical treatment with resection or neuromodulation devices can be an option. Special situations in the care of people with epilepsy include status epilepticus, women with epilepsy (WWE), the older adult, and safety issues. The rapid expansion of epilepsy treatment in the last 20 years presents a number of options with increased tolerability, improved efficacy, and decreased invasiveness compared to the past.
Introduction
The word “epilepsy” is derived from the Greek word epilepsia , meaning “to seize or attack.” Seizures and epilepsy are common disorders and have been documented since the earliest recordings of humans. Initially, epilepsy was believed to be a spiritual disease, and the oldest detailed account of epilepsy was in 2000 bcE . It was not until the fifth century bce that epilepsy was described as a brain disease (as Hippocrates identified it in “On the Sacred Disease”). In most cultures, epilepsy has continued to be stigmatized. It is only in the past few decades that there have been more organized efforts to counter the stigma, secrecy, and discrimination that are often associated with epilepsy.
Epilepsy is the tendency to have recurrent nonprovoked seizures. A seizure is a brief, excessive discharge of electrical activity in the brain that transiently alters behavior. Neurons communicate through chemical and electrical signals and form networks with other neurons. In most seizures, a relatively small number of abnormal neurons cause changes in other neighboring or networked neurons. During a seizure there is a progressive recruitment of other neurons in the network, resulting in a pattern of hypersynchrony. This abnormal propagation occurs due to insufficient inhibition and/or excessive excitation within the neuronal network. This abnormal neuronal hypersynchrony can be congenital or may develop at any time during life.
Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. This definition emphasizes that epilepsy consists not only of the neurobiology of seizures but also of the associated neuropsychosocial comorbidities. The most recent definition of epilepsy requires the occurrence of at least one epileptic seizure. After a single seizure, epilepsy can be diagnosed if the seizure was unprovoked (e.g., unrelated to drugs, alcohol, hyponatremia, or glucose abnormality) and the patient has a greater than 60% chance of having another unprovoked seizure. Epilepsy is fully defined as follows:
Epilepsy is a disease of the brain characterized by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 hours apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome.
Epilepsy affects more than 3.4 million people in the United States (1.2% of the US population). The lifetime prevalence rate is 3%. Epilepsy affects people of every age and background but most commonly starts before the age of 1 year and increases again after the age of 50, with the highest incidence after the age of 75. The annual cost of epilepsy in the US is over 12.5 billion dollars. Only 44% of American adults with epilepsy reported having their seizures controlled. However, approximately 70% of patients might become seizure free with appropriate treatment. The remaining 30% of patients have drug-resistant epilepsy (DRE), which is the failure of adequate trials of two tolerated, appropriately chosen and used antiseizure medication (ASM) schedules to achieve sustained seizure freedom.
Classification of Seizures and Epilepsy
There are distinct types of epileptic seizures. The classification of seizure type has important consequences for determining the etiology, best treatment and overall prognosis. Seizures are classified based on the appearance of the seizure and parts of the cerebral cortex involved in the seizure. The 2017 classification system for seizures and epilepsy builds on the original classification system but emphasizes updated terms with the goal of being more understandable ( Fig. 24.1 ).
The first step in classification of seizures is to identify whether the seizures are focal in onset (involving a localized network of neurons) or generalized in onset (rapidly engaging a bilaterally distributed neuronal network). Focal seizures are due to a small group of neurons that have enhanced excitability and the ability to occasionally spread that activity to neighboring regions, thereby causing a seizure. A seizure can begin in any lobe of the brain, but the most common lobe is the temporal lobe, particularly the mesial temporal lobe containing the amygdala and hippocampus. The clinical manifestations of focal seizures will depend on the normal function of the region of cortex that is involved in the seizure ( Table 24.1 ).
| Localization | Signs and Symptoms |
| Mesial temporal (amygdala, hippocampus) | Déjà vu, jamais vu, depersonalization, derealization, olfactory hallucinations, oral and manual automatisms, behavioral arrest, sweating, pallor, piloerection, epigastric sensations, anxiety, fear |
| Temporal lobe | Auditory hallucinations, aphasia (left) |
| Frontal lobe | Contralateral tonic and/or clonic movements, contralateral gaze deviation, contralateral versive head movement, bizarre appearing hypermotor movements |
| Parietal lobe | Contralateral tingling and other somatosensory phenomena |
| Occipital | Visual hallucinations (simple—colors, shapes), more complex visual hallucinations (temporo-occipital), vision loss |
During a focal seizure, there may be preservation of consciousness and full awareness throughout the seizure. In the older nomenclature this type of seizure was referred to as a simple partial seizure or aura. In the 2017 classification system, this type of seizure is more precisely termed a focal aware seizure. During a focal aware seizure, the patient is alert and able to respond and remembers the seizure. This type of seizure is synonymous with an aura. Focal seizures can either progress to altered awareness or begin with altered awareness, during which time the patient has altered responsiveness and memory. This type of seizure is called a focal seizure with impaired awareness and in the older classification system was called a complex partial seizure. Automatisms are common during focal seizures with impaired awareness and can include the eyes (blinking), mouth (lip smacking, chewing), hands (fumbling, picking), vocalizations (grunts, repetition of words or phrases), or more complex acts (walking, attempting to use a cellphone). This type of seizure generally lasts from 30 seconds to 2 minutes and is followed by a brief period of confusion and fatigue. A focal seizure can spread to involve networks in both cerebral hemispheres, leading to tonic-clonic movements. This process is called focal to bilateral tonic-clonic. This term distinguishes convulsions that begin focally and spread, focal to bilateral tonic-clonic, from primary generalized tonic-clonic seizures, which have a different mechanism and etiology.
Primary generalized seizures involve bilaterally distributed networks at onset. The different seizure types include myoclonic, absence, atonic, tonic, clonic, and tonic-clonic seizures. Myoclonic seizures are very quick shock-like jerks of a muscle or group of muscles and typically involve the upper extremities without altered level of awareness. In contrast, the other forms of generalized seizures involve loss or alteration in consciousness. Absence seizures consist of brief episodes (2–15 seconds) of sudden onset and offset staring, impaired responsiveness, and eye fluttering and do not have a postictal confusion (in contrast to focal seizures with impaired awareness). Tonic and atonic seizures consist of sudden changes in muscle tone lasting seconds and often leading to falls. Tonic-clonic seizures are commonly referred to as convulsions or grand mal seizures. They begin with loss of consciousness. The tonic phase can lead to falls and an epileptic cry caused by air forced through contracted vocal folds. The clonic phase consists of jerking of the upper and lower extremities with cyanosis, tongue biting, foaming at the mouth, and incontinence. Following the tonic-clonic seizure, the patient is lethargic and confused and may become agitated as consciousness is regained.
Some forms of epilepsy can be classified as an epilepsy syndrome. Epilepsy syndromes are types of epilepsy in which a clear demographic, seizure type(s), electroencephalography (EEG) pattern, and prognosis are known. Increasingly, the etiology is also known, and it is often genetic. Examples of epilepsy syndromes include infantile spasms (West syndrome), Lennox-Gastaut syndrome, childhood absence epilepsy, and juvenile myoclonic epilepsy.
Etiology
Seizures have different causes, of which epilepsy is one. A diagnosis of epilepsy requires that the seizures are not provoked. Epilepsy also has a wide variety of etiologies. The most likely cause depends on the age of onset ( Table 24.2 ). Often, despite extensive diagnostic testing, the etiology cannot be determined.
| Age Group | Common Causes |
|---|---|
| Infants | Perinatal hypoxia, metabolic disorders, intracranial hemorrhage, genetic disorders, developmental and congenital maldevelopment |
| Children | Perinatal anoxia, injury at birth or later, infections, vascular, metabolic, cortical malformations, genetic disorders |
| Teens and young adults | Trauma, infection, genetic disorders, brain tumors, congenital |
| Adults | Stroke, trauma, brain tumor, infection |
| Older adults (over 60 years) | Stroke, dementia, brain tumor, infection, trauma |
Diagnosis
The diagnosis of epilepsy requires the occurrence of at least one unprovoked seizure and the likelihood of >60% that the patient will have another unprovoked seizure. The likelihood of having a subsequent seizure can be determined by etiology and EEG. However, the initial step in diagnosis is to determine whether the event was in fact a seizure and to explore the possibility that the seizure was provoked. Convulsive syncope and psychogenic nonepileptic seizures (PNES) can appear like epileptic seizures and are often mistaken for epileptic seizures. Syncope, PNES, and epileptic seizures account for 90% of transient loss-of-consciousness episodes and have features that can help to differentiate between them. Syncope often has prodromal symptoms of tunnel vision, dizziness, and palpitations and can have triggers such as fear, micturition, or Valsalva. Episodes are usually brief and do not have disorientation following. PNES can involve crying, hip thrusting, side-to-side head movements, bilateral shaking with preserved awareness. In general, these events are less stereotyped, more prolonged (lasting 5–30 minutes), and often associated with feelings of panic. It is important to note some patients may have both epileptic and nonepileptic seizures. Other seizure mimickers are listed in Table 24.3 . Once a seizure has been determined to be an epileptic seizure, consider whether it was provoked. Illicit and prescription drugs, alcohol withdrawal, and glucose and electrolyte abnormalities are common reasons for provoked seizures ( Box 24.1 ). The International League Against Epilepsy offers an educational website for the diagnosis of epilepsy, which illustrates seizure types and provides video and EEG examples ( https://www.epilepsydiagnosis.org ).
|
Metabolic (hyponatremia, hypoglycemia, hyperthyroidism, nonketotic hyperglycemia, hypocalcemia, hypomagnesemia, renal failure, porphyria)
Medications (benzodiazepine withdrawal, barbiturate withdrawal, phenothiazines, bupropion, tramadol)
Substance abuse (alcohol withdrawal, cocaine, amphetamine, phencyclidine, methylenedioxymethamphetatime [“ecstasy”])
Acute neurologic insults (within 1 week of injury)
Eclampsia
The diagnosis of epilepsy is made by history, examination, neuroimaging, and EEG. Risk factors for the development of epilepsy include complications of pregnancy and childbirth; history of febrile seizures; family history of epilepsy; developmental delay or autism; history of traumatic brain injury, brain infection, or other structural lesion of the cerebral cortex; and dementia. Physical examination for causes of provoked seizures and epilepsy includes blood pressure and other vital signs; skin exam for stigmata of systemic or neurologic disease (café au lait spots seen with neurofibromatosis or adenoma sebaceum seen with tuberous sclerosis); extremity examination for smaller limbs or a smaller thumbnail, which can indicate early life injury to the contralateral cerebral cortex; physical examination for signs of cancer or infection; and a full neurologic examination assessing for cognitive dysfunction and focal abnormalities.
EEG is a necessary component in the evaluation of epilepsy. EEG can help in determining whether the seizure was focal or generalized in onset, which can assist in choosing the appropriate ASM for treatment. If the seizure was focal, EEG can also help to determine the location of the seizure onset. Ambulatory EEG monitoring has increased sensitivity and can be performed at home for several days at a time. In general, interictal EEG sensitivity is only 20%–55%, with only about one-third of initial routine EEGs being abnormal in a patient who is later diagnosed with epilepsy. Sensitivity improves to 80%–90% if EEGs are repeated over time. EEGs with sleep deprivation can reveal epileptiform discharges in 13% of patients who had no epileptiform activity on standard EEG. Thus it is imperative to remember that a normal EEG does not negate a diagnosis of epilepsy. If an EEG does show epileptiform activity, assuming a pretest probability of 50%, patients with epileptiform discharges on routine EEG after a first unprovoked seizure have a 66%–77% probability of having a second seizure and should be started on an ASM to prevent further seizures.
Video EEG is helpful when it remains unclear whether the event in question is an epileptic seizure, especially when events continue despite treatment. Video EEG allows correlation of the event to electrical changes consistent with a seizure on EEG. This is often done in an epilepsy monitoring unit (EMU), where seizures can be provoked by weaning medication in a safe, closely monitored setting. While electroclinical correlation is the gold standard for diagnosis, many patients do not have access to a hospital with an EMU; even if they do, up to one-third of patients may not have an event captured in the time during which they are in the unit. These days, an easier and often more practical option is the use of smartphone video to assist in diagnosis. Studies have shown that videos of events can be taken safely and review of the semiology by a neurologist specializing in seizures can lead to accurate diagnosis even when EEG is not available. Neuroimaging is important in the evaluation of seizures and epilepsy. In nonacute settings, magnetic resonance imaging (MRI) is the preferred imaging modality. MRI can assess for the etiology of the seizure and help to determine the risk of recurrence after a first-time seizure. Typically, MRI brain protocol for epilepsy involves thin cuts through the temporal lobes and can be done with contrast when there is a high suspicion of a mass or infections process as the etiology. Neuroimaging reveals the cause of a first-time seizure approximately 28% of the time and is most sensitive in patients with focal seizures. Neuroimaging can reveal mesial temporal sclerosis, neurocystercercosis, brain tumors, and some neurodevelopmental abnormalities, such as cortical dysplasia, as well as other structural abnormalities. Detection of potentially epileptogenic MRI lesions is generally considered to be associated with a high seizure recurrence risk (>60%). Concordant localizing data, in which seizure semiology, EEG findings, and/or MRI lesions localize to the same region have the most value in establishing a diagnosis of epilepsy after a single seizure.
Treatment of Epilepsy
Antiseizure Medication
Once a diagnosis of epilepsy has been made, an ASM should be initiated. The goal of selecting an ASM is to find a medication that is fully efficacious and to which the patient has no side effects, ideally with monotherapy, though polytherapy is often required. About 70% of patients will have seizures controlled with one of the first two medications that are trialed. The best chance of choosing an ASM that controls seizures with no side effects is to choose one that fits the patient’s epilepsy type and seizure frequency and is likely to be best tolerated, considering the patient’s age, gender, comorbidities, drug interactions, compliance, and ability to obtain the medication. Medications vary in cost, time necessary to achieve therapeutic doses, drug-drug interactions, and teratogenicity.
ASMs are divided into narrow-spectrum and broad-spectrum agents. This is the initial deciding point in choosing an ASM. If the epilepsy type is unknown, a broad-spectrum agent is necessary. Narrow-spectrum ASMs work only for specific types of seizures and may be ineffective with other types of seizures or even worsen them. Narrow-spectrum focal ASMs include carbamazepine, oxcarbazepine, gabapentin, pregabalin, tiagabine, and eslicarbazepine. These ASMs can exacerbate myoclonic and absence seizures. Broad-spectrum ASMs have some efficacy for a wide range of seizures (focal, absence, generalized tonic-clonic, and myoclonic) and include ASMs such as levetiracetam, valproic acid, lacosamide, and clobazam.
Currently, no ASM has been proven to be more effective than another, which makes safety and tolerability of high consideration in choosing and ASM. Adverse reactions can include those that are idiosyncratic, dose related, teratogenic, and worsening of comorbidities. The newer ASMs generally have fewer side effects than the older agents. Potential side effects that common to all ASMs include fatigue, gastrointestinal side effects, mood changes, and cognitive side effects. The older-generation ASMs have more side effects and tend to be strong hepatic inducers which result in increased drug-drug interactions and can affect hormone and vitamin D levels. These include phenytoin, carbamazepine, and phenobarbital. They are associated with an increased rate of fractures due to osteopenia. Bone density screening is recommended for anyone who has taken one of these agents for 5 years or longer: phenytoin, phenobarbital, primidone, valproate, or carbamazepine. The ASMs with the least drug–drug interactions include levetiracetam and lacosamide. Some side effects, especially those that are dose related and reflect the peak effect of drug concentration, may have improved tolerability from extended-release formulations.
Some ASMs can be loaded or at least initiated at immediate therapeutic doses; others require a gradual titration over weeks. Depending on the patient’s seizure frequency, an ASM with a faster ability to reach therapeutic doses may be necessary and part of the consideration in choosing an ASM. Often, when an ASM has been initiated, many clinicians choose to check serum concentrations to determine whether the dose is adequate. However, it is important to remember that reference levels are not representative of efficacy, and doses should be adjusted according to patient response. After initial titration to the lowest therapeutic dose, doses are increased until seizure control is achieved, side effects are present, or further escalation in dose is unlikely to produce increased efficacy. With polytherapy, it is important to consider drug interactions between ASMs.
Ease of availability can affect adherence, which will affect efficacy. Considerations include cost, prior authorizations for insurance coverage, and release of controlled substances. Fig. 24.2 depicts a flowchart for choosing an ASM.
