Epilepsy

Laura C. Miller

▪ INTRODUCTION

An epileptic seizure is defined as a transient disturbance of cerebral function caused by paroxysmal abnormal and excessive neuronal discharges. The clinical manifestations are varied, depending on the areas of cerebral cortex involved, but can consist of sudden and transitory abnormal phenomena that may include alterations of consciousness, or motor, sensory, autonomic, or psychic events. Clinical manifestations may be perceived by the patient or witnessed by an observer. Seizures are usually self-limited but are often followed by a postictal period of cortical depression that can manifest itself clinically as localized or diffuse neurological deficits. Epilepsy is defined as recurrent (two or more) epileptic seizures, unprovoked by any immediate cause.

▪ SEIZURE TYPES

Seizures are divided based on clinical manifestations into partial seizures, which originate in a part of one cerebral hemisphere, and generalized seizures, wherein seizure activity begins in both cerebral hemispheres simultaneously (Table 14.1).

Partial Seizures

Partial seizures that do not alter or impair consciousness are called simple partial seizures. When consciousness is altered or impaired, the seizure is complex partial. The clinical manifestations of partial-onset seizures are often determined by the area of cerebral cortex involved and are further subdivided into motor, somatosensory or special sensory, autonomic, or psychic subtypes (Table 14.2). Motor manifestations in simple partial seizures include versive movements, posturing, or clonic movements of a muscle group. In complex partial seizures, motor signs are usually typified by purposeless and repetitive involuntary muscle movements called automatisms. Examples include lip smacking or chewing, upper extremity gesturing or fidgeting, and lower extremity ambulatory movements. Approximately 70% of complex partial seizures arise from the temporal lobe.

The abnormal cortical discharges in a partial-onset seizure can spread to adjacent cortical areas over time. Consequently, the clinical manifestations of a seizure can evolve. For example, the clonic movements of a partial-onset motor seizure may spread to other body parts as discharges involve adjacent areas of the motor cortex (i.e., Jacksonian march). The discharges can also propagate so that a simple partial seizure evolves into a complex partial seizure. Often, patients will refer to the simple partial portion of the seizure as an aura, which is the portion of the seizure that occurs before consciousness is altered or lost. Either a simple partial seizure or a complex partial seizure can evolve, or secondarily generalize, into a generalized convulsive seizure.

TABLE 14.1 CLASSIFICATION OF EPILEPTIC SEIZURES

SEIZURE TYPE	KEY FEATURES
*Partial Seizures*
Simple partial	May have motor, somatosensory, special sensory, autonomic, or psychic manifestations Consciousness is preserved
Complex partial	May have motor, somatosensory, special sensory, autonomic, or psychic manifestations Consciousness is altered or impaired
*Generalized Seizures*
Tonic-clonic	Tonic rigidity followed by synchronous jerking movements of the extremities May be accompanied by incontinence, tongue biting Followed by period of postictal confusion
Absence	Brief (usually <10 seconds) lapse in consciousness with arrest of ongoing activity Rapid onset and offset May be accompanied by automatisms like blinking, orobuccal movements Characteristic 3-Hz spike-and-wave electroencephalogram pattern
Myoclonic	Characterized by single or multiple muscle jerks Consciousness is preserved Usually bilateral and symmetrical but can be regional
Atonic	Brief synchronous loss of muscle tone
Tonic	Prolonged muscle contraction
Clonic	Repetitive alternating jerking and relaxation of an extremity

TABLE 14.2 CLINICAL MANIFESTATIONS OF PARTIAL SEIZURES

SUBTYPE	CLINICAL MANIFESTATIONS
Motor	Versive movements (turning of head or eyes in one direction) Posturing Clonic movements of a muscle group Automatisms (coordinated, repetitive involuntary movements)
Somatosensory	Abnormal tastes Abnormal smells Abnormal visual phenomena
Sensory	Paresthesias (pins-and-needles sensations)
Autonomic	Pupillary changes Diaphoresis Epigastric rising sensation Piloerection Heart rate change Heart rhythm change Blood pressure change
Psychic	Dysphasia Fear Anxiety Depression Distortions of memory (déjà vu or jamais vu) Autoscopy Derealization Depersonalization

Generalized Seizures

Generalized seizures are subdivided into several types (Table 14.1). In tonic-clonic seizures there is loss of consciousness, with a tonic phase characterized by rigidity and contraction of body musculature followed by a clonic phase characterized by alternating muscle contraction and relaxation with resultant synchronous jerking limb movements for several minutes. Associated signs include loss of bowel or bladder continence, tongue biting, and postictal confusion or lethargy. Absence seizures consist of a brief (usually less than 10 seconds) lapse in consciousness with arrest of ongoing activity. The impairment in consciousness can be so brief that the patient may be unaware of it. Typical absence seizures have a rapid onset and offset and a characteristic 3-Hz generalized spike-and-wave electroencephalogram (EEG) pattern. Other generalized seizures include the myoclonic, atonic, tonic, and clonic seizure subtypes.

▪ ETIOLOGY

Seizures of new onset can occur as the result of a primary neurological disorder or as the symptomatic result of an underlying systemic dysfunction, such as a metabolic derangement or organ dysfunction (Table 14.3). The International League Against Epilepsy (ILAE) further classifies seizure etiology based on whether there is an identifiable precipitating cause. Symptomatic seizures are the consequence of a known or suspected cerebral dysfunction. Acute symptomatic (provoked) seizures are those occurring in close association with an acute toxic or metabolic insult or with an acute central nervous system (CNS) insult such as infection, tumor, trauma, ischemic stroke, or hemorrhage. Acute symptomatic seizures usually remit with resolution of the underlying illness. Remote symptomatic seizures are those that occur in relation to a well-demonstrated antecedent condition such as earlier head injury, stroke, or infection that causes a static lesion. Such remote symptomatic causes are not likely to resolve and may explain ongoing epilepsy. The term idiopathic is reserved for partial or generalized epileptic seizures occurring with particular clinical characteristics and EEG findings that define clear individual syndromes; most are genetic in origin. Cryptogenic seizures are those for which no cause can be identified. Identification of symptoms and signs consistent with an epileptic syndrome can help clarify appropriate treatments as well as prognosis.

TABLE 14.3 COMMON CAUSES OF NEW ONSET SEIZURES

*Primary CNS disorder*
	Stroke or vascular insult
	CNS infection (e.g., meningitis, encephalitis, cysticercosis)
	Head injury or trauma
	Mass lesion
	Idiopathic epilepsy
*Systemic disorder*
	Hypoglycemia or hyperglycemia
	Hyperosmolar state
	Hyponatremia
	Hypocalcemia
	Hepatic encephalopathy
	Uremic encephalopathy
	Diffuse cerebral ischemia
	Hypertensive encephalopathy
	Eclampsia
	Drug intoxication
	Drug withdrawal
CNS, central nervous system.

▪ PATHOPHYSIOLOGY

Current evidence suggests the likelihood that partial and generalized epilepsies originate from different pathophysiological mechanisms. Partial epilepsies presumably arise from a focal lesion, with spread resulting from recruitment of other brain areas. Clinically, there may be an interval between the neurological insult causing the lesion and the development of recurrent seizures. Generalized epilepsies, on the other hand, have been found to arise from abnormalities in the neurons themselves or within an aggregate of neurons fashioned into a network.

▪ DIAGNOSTIC APPROACH

History

After an episode of altered consciousness or behavior, the first step is to determine whether the event was truly an epileptic seizure. Paroxysmal disorders that may mimic seizures include syncope, transient ischemic attack, breath-holding spells, hyperventilation syndrome, episodic dyscontrol syndrome, migraine, movement disorders, sleep disorders, and psychogenic nonepileptic seizures (Table 14.4). Misdiagnosis can have adverse effects. There may be delays in initiating the appropriate medical care for underlying medical or psychiatric conditions. In many states, there are restrictions placed on driving after a seizure episode.

Definitive diagnosis can be made only if a seizure occurs during a period of EEG recording and if the electrographic discharges can be correlated with the patient’s signs and symptoms. Therefore the diagnosis of seizure remains primarily a clinical one. The history, both from the patient and from witnesses, is paramount. It is also important to ensure that this was, indeed, the patient’s first seizure. Sometimes, the first reported seizure is actually the latest in a series of events such as staring spells or myoclonic jerks that were not previously recognized as seizures. History should be obtained about prior possible neurological insults, such as head trauma, birth injury, history of meningitis or intracranial infection, and stroke, because these can lead to static lesions from which acquired seizures can develop.

TABLE 14.4 DIFFERENTIAL DIAGNOSIS OF SEIZURE

DIAGNOSIS	KEY FEATURES
Partial seizure	Often preceded by positive symptoms Symptoms evolve over seconds Recurrent events stereotyped
Generalized seizure	Onset in any position Loss of consciousness of minutes Tonic phase with increased tone Can be associated with incontinence,tongue biting Minutes in duration Postictal confusion or lethargy Recurrent events stereotyped
Syncope	Onset while standing or during postural change, straining Loss of consciousness is brief Preceded by pallor, nausea, sweating, visual changes such as dimming Flaccid tone typical, but can have brief convulsive activity Recovery usually rapid if recumbent
Transient ischemic attack	Seconds to hours in duration Negative symptoms (loss of motor function or sensation)
Breath-holding spell	Common in children Frequently provoked by frustration or anger Associated with pallor and/or cyanosis, bradycardia If prolonged, may result in loss of consciousness
Hyperventilation syndrome	More common in females More common in patients with underlying anxiety disorder Associated with dyspnea, tachycardia, lightheadedness, circumoral paresthesias
Episodic dyscontrol (rage attack)	More common in males Often situational Goal-directed aggressive behaviors predominate May be amnestic for event
Migraine	Often preceded by positive symptoms Symptoms evolve over minutes Rarely progress to loss of consciousness
Psychogenic nonepileptic seizure	May be precipitated by emotional stressors Recurrent events often not stereotyped May exhibit goal-directed behaviors Can be prolonged (>5 minutes)

The other important historical piece of information is whether the seizure was generalized or partial in onset. This information is garnered from both patient and witness reports. Was there an aura, such as an abnormal taste, smell, vision, déjà vu, jamais vu, or other psychic sensation? The aura is actually the result of simple partial seizure activity, implying a partial onset. Was there head or eye version or limb shaking first on one side of the body? Partial-onset seizures suggest an underlying focal structural abnormality and portend a higher rate of seizure recurrence. Therapy can differ depending on the type of seizure; thus it is important to identify the type of seizure.

Seizures can occur unpredictably, but in some cases may be precipitated by sleep deprivation, alcohol intake or withdrawal, hormonal changes, or stress. Concomitant infection or missed medications are common precipitants for breakthrough seizures in patients with known epilepsy. In a few seizure types, seizures can be provoked by hyperventilation or photic stimulation.

Physical Examination

After determining, based on clinical history, that a seizure likely occurred, the next step in the evaluation is looking for an underlying symptomatic cause. Initial workup should include a general physical examination to look for signs of infection, such as fever, ear infection, meningeal signs, or evidence of head trauma. Detailed and complete neurological examination is essential, looking particularly for focal or lateralizing signs or deficits.

Laboratory Studies

Blood tests should be performed to screen for toxic or metabolic disturbances, such as hyperglycemia or hypoglycemia, hyponatremia, hypocalcemia, renal or hepatic dysfunction, and alcohol or drug intoxication. Lumbar puncture should be performed if fever, meningismus, or infectious prodrome are present.

Neuroimaging

Computed tomography (CT) or magnetic resonance imaging (MRI) of the head should be performed immediately in patients with suspected structural lesions. Specifically, it should be performed in those with focal deficits on examination, altered mental status, history of trauma, fever or other infection, and headache and in those with a history of malignancy, immunosuppression, or anticoagulation. In most other cases, neuroimaging should be considered urgent. Most providers prefer MRI over contrast-enhanced CT given the superior resolution and resultant structural detail provided by MRI.

Electroencephalography

Electroencephalogram is helpful in that approximately 50% of people who have epilepsy have epileptiform EEG discharges between seizures (interictally). Epileptiform discharges include abnormal spikes, polyspike discharges, sharp waves, and spike-and-wave complexes. Because the other 50% do not have an abnormal interictal EEG, a single normal EEG does not rule out seizure. If a routine EEG is normal but suspicion of epilepsy is high, the EEG can be repeated under stress conditions, such as sleep deprivation or by employing additional electrode arrays. Other options include prolonged or long-term EEG monitoring to capture and record the clinical events in question. This can take the form of outpatient ambulatory EEG or inpatient video-EEG monitoring. In addition to confirming the presence of paroxysmal abnormal discharges, long-term EEG can provide information on whether discharges are focal or generalized, help determine the focus of seizure activity, can help quantify frequency of events, and allow for characterization of specific epilepsy syndromes (Table 14.5). Ultimately, though, the EEG is not failsafe; the diagnosis of seizure remains a clinical one, combining and interpreting the information gathered via history, physical examination, and the EEG findings.

KEY POINTS

1. New-onset seizure must first be distinguished from other mimicking conditions to avoid delays in appropriate treatment.

2. Seizure is primarily a clinical diagnosis based on careful history from both patient and observers.

3. Physical examination should focus on possible signs of infection, trauma, or lateralizing deficits.

4. Urgent MRI or head CT is indicated when a CNS insult is suspected from examination or history.

5. EEG may be helpful in characterizing seizure or capturing epileptiform discharge between seizures, but does not rule out a seizure disorder if negative.

TABLE 14.5 INDICATIONS FOR LONG-TERM EEG MONITORING

Characterize paroxysmal events as epileptic or nonepileptic

Quantify seizure frequency

Presurgical localization of epileptic focus

Diagnose epilepsy syndrome

▪ MANAGEMENT

The decision to initiate antiepileptic drug (AED) therapy after a single seizure is based on several factors, including the validity of the diagnosis, risk of recurrence, and patient preference. For most patients with unprovoked seizures, the risk of recurrence is under 50% over 2 years, and immediate AED therapy to prevent seizure recurrence does not alter the development of epilepsy or its natural history. Thus AEDs are usually not recommended after a single unprovoked seizure. On the other hand, patients with substantial risks for recurrence, such as focal deficits, presence of an underlying incorrectable cause, or EEG abnormalities, warrant treatment after a single seizure because risk of recurrence is increased in these groups. Patient preferences on risk may affect these recommendations. If a second seizure occurs, the 2-year risk of recurrence increases to approximately 75% and AEDs should be started.

Antiepileptic Medications

Goals of pharmacotherapy include reduction or elimination of seizures while minimizing adverse effects of treatment. Monotherapy is the preferred goal, with the choice of AED based on seizure type or underlying epilepsy syndrome (Table 14.6). In general, carbamazepine, oxcarbazepine, and phenytoin are the preferred first-line medications in cases of partial-onset seizures. Valproic acid and phenytoin are the preferred first-line medications for generalized-onset seizures. Lamotrigine, topiramate, zonisamide, and levetiracetam are effective against both partial-onset and generalized seizures. Side effects, cost, and dosing schedule can play a role in medication selection as well. An adequate trial of antiepileptic medication involves increasing the medication until seizures are controlled or until adverse effects occur. Although serum drug levels are available for most medications, published therapeutic ranges are based on a broad population of patients. Treatment efficacy or toxicity should be used for endpoints in place of a desired therapeutic serum level. Seizure control is achieved at different serum drug levels in different patients. If seizures are not well controlled on the first-choice AED, a second AED is started, followed by gradual taper and discontinuation of the first agent. If seizures are not well controlled after adequate trials of two antiepileptic medications, it is highly likely that seizures will remain refractory to medical therapy. At this point, referral to an epilepsy specialist is warranted.

Side Effects of Antiepileptic Drugs

Commonly reported adverse effects for all of the AEDs include sedation, concentration and memory difficulties, dizziness, and dyspepsia. Adverse effects may be dose related, noted when a drug is first initiated or after dosage increases. Dose-related effects can be minimized by lowering the dosage or by discontinuing the medication. Idiosyncratic reactions are not dose related, but instead may be immune mediated or based on individual factors specific to the patient. Idiosyncratic reactions tend to be more serious and at times even life threatening (Table 14.7). Skin rash can occur with all of the AEDs. Rarely, this can result in severe Stevens-Johnson syndrome, particularly with phenobarbital, phenytoin, carbamazepine, and lamotrigine. Psychiatric side effects are common and will be discussed in a later section.

TABLE 14.6 ANTIEPILEPTIC DRUGS AND TREATED SEIZURE TYPES^a

	TYPE OF SEIZURES
MEDICATION	PARTIAL ONSET	SECONDARILY GENERALIZED	GENERALIZED TONIC-CLONIC	ABSENCE	MYOCLONIC	TONIC
Phenobarbital	[check mark]	[check mark]	[check mark]
Primidone	[check mark]	[check mark]	[check mark]
Tiagabine	[check mark]	[check mark]
Vigabatrin^b	[check mark]	[check mark]
Phenytoin	[check mark]	[check mark]	[check mark]
Valproic acid	[check mark]	[check mark]	[check mark]	[check mark]	[check mark]	[check mark]
Carbamazepine	[check mark]	[check mark]	[check mark]
Oxcarbazepine	[check mark]	[check mark]
Lamotrigine	[check mark]	[check mark]	[check mark]	[check mark]
Topiramate	[check mark]	[check mark]	[check mark]			[check mark]
Zonisamide	[check mark]	[check mark]	[check mark]	[check mark]
Ethosuximide				[check mark]
Levetiracetam	[check mark]	[check mark]			[check mark]
Gabapentin	[check mark]	[check mark]
Felbamate						[check mark]
^aRecommendations based on literature review. ^bVigabatrin not approved by U.S. Food and Drug Administration.