CHAPTER 54

Seizure Disorders

Henry Cohen, MS, PharmD, FCCM, BCPP, CGP • Samantha M. Smalley, PharmD, BCPS

Seizures are the clinical manifestations of excessive and hypersynchronous, usually self-limiting, abnormal activity of neurons in the cerebral cortex. The behavioral features of a seizure reflect the cerebral cortical areas where the abnormal neuronal activity originates and spreads (Engel, 1989). A convulsion implies a violent, involuntary contraction or series of contractions of voluntary muscles. Epilepsy is a chronic condition characterized by two or more unprovoked recurrent seizures. Epilepsy implies a periodic recurrence of seizures with or without convulsions (Engel, 1989).

ANATOMY, PHYSIOLOGY, AND PATHOLOGY

The excitability of the neuronal cell membrane depends on the maintenance of an electrical charge, or potential difference, between the intracellular and extracellular environments, analogous to the cardiac cell. This is achieved through the maintenance of different concentrations of negatively charged ions on either side of the membrane in the resting state, with the outside having a net positive charge relative to the inside.

The membrane is thus polarized in its resting state, usually with a membrane potential of –60 to at least –80 mV. During depolarization, the permeability of the membrane changes to allow positive ions to flow in, eliminating the potential difference. The membrane is subsequently repolarized when the ions that flowed in are pumped back out. The movement of ions during these phases is extremely complex and involves many different channels that are governed by various influences and are operative at different phases of the process (Engel, 1989).

Excitatory postsynaptic potentials generally are caused by excitatory neurotransmitters, which include the excitatory amino acids glutamate and aspartate, acetylcholine, and the less-potent histamine and corticotropin-releasing factor (Engel, 1989; Meldrum, 1992). These substances modify Na⁺, K⁺, or Ca⁺⁺ channels to reduce the potential difference across the membrane and facilitate rapid depolarization (Figure 54.1). Inhibitory postsynaptic potentials are caused by inhibitory neurotransmitters, primarily gamma-aminobutyric acid (GABA) and glycine, and the less-potent dopamine, norepinephrine, and serotonin. These substances move K⁺ out of the cell or Cl^– into the cell, increasing the relative intracellular negativity and hyperpolarizing the membrane, making rapid depolarization less likely.

Any imbalance in excitatory or inhibitory influence may lead to hypersynchronous neuronal firing. The action potential spreads to neighboring cells, causing them to fire at the same time and to have concurrent refractory periods. All the neurons emerge from refractoriness simultaneously and are susceptible to firing simultaneously again; the process is thus repeated and perpetuated (Engel, 1989). This coordinated firing spreads until a critical mass is reached and a seizure ensues. The term “seizure threshold” corresponds to the limit beyond which the patient can be made to seize, when subjected to a sufficient number of epileptogenic factors.

During a generalized tonic-clonic seizure, there is a 300% increase in cerebral oxygen consumption and a 900% increase in cerebral blood flow. The increased brain blood flow is necessary to supply neurons with oxygen, glucose, and other necessary nutrients while removing the enormous amounts of carbon dioxide and metabolic waste products. Since the brain has a limited capacity to increase brain blood flow, a state of sequential neuronal hypoxia, anoxia, ischemia, and impending necrosis develops. Hypoxia-induced lactate synthesis causes the production of free radicals (e.g., superoxides, peroxides), damaging and destroying the neuronal cells. In patients with status epilepticus (a convulsive seizure or series of seizures lasting longer than 5 minutes), cardiac collapse and rhabdomyolysis may occur with renal failure as a consequence of prolonged ictal activity (DeLorenzo, Towne, Pellock, & Ko, 1992; Dodson et al., 1993).

EPIDEMIOLOGY

Epilepsy and seizures are among the most prevalent neurological disorders. Currently, epilepsy ranks as the fourth most common neurological disorder, behind migraine, stroke, and Alzheimer’s disease (Hirtz et al., 2007). The prevalence of epilepsy across the United States is approximately 2.2 million people, while worldwide up to 65 million people are affected (Institute of Medicine, 2012). More than 1% of the general population will have at least one seizure in a lifetime (Sander, 2003). An estimated 1 in 100 people experience either a single unprovoked seizure or are diagnosed with epilepsy every year (Institute of Medicine [IOM], 2012). The annual incidence of epilepsy in the U.S. population is about 50 per 100,000 people (Sander, 2003). Although epilepsy affects all age groups, the incidence is bimodal. Those in early childhood and the elderly have the highest frequency of new-onset seizures (Thurman, Beghi, & Begley, 2011). Annual costs of epilepsy may be as high as $12.5 billion depending on the resources measured, for example, lost productivity (Yoon, Frick, Carr, & Austin, 2009).

FIGURE 54.1
These graphs shows the phases of the Na⁺ action potential after hyperpolarization as recorded at the neuronal cell body (soma); a shows the resting membrane potential of approximately 85 mV; b shows the phase of graded Na⁺-mediated depolarization, during which a slow–moderate inward flow of Na⁺ ions begins to reduce the membrane potential; c indicates the level of the threshold (approximately 65 mV) at which “explosive” or rapid depolarization d occurs; this is also known as the rising phase of the all-or-none regenerative spike; e is the repolarization phase, during which the Na⁺ current g and voltage-dependent K⁺ current h reestablish the resting membrane potential; in fact, the potential transiently becomes greater than the resting potential, in the phase known as after hyperpolarization f. i indicates the absolute refractory period, and j indicates the relative refractory period, during which an appropriate change in the electrophysiological environment can induce a depolarization to occur prematurely.

HISTORY AND PHYSICAL EXAMINATION

The diagnosis of epilepsy is clinical and is based on a detailed description of events experienced by the patient before, during, and after a seizure and, more importantly, on an eyewitness account. Three questions need to be answered when the provider is evaluating a patient with possible epileptic seizures:

Is it epilepsy?

What type of epilepsy?

What is the etiology?

DIAGNOSTIC TESTS

The EEG provides supportive evidence for the clinical diagnosis of epilepsy by demonstrating epileptiform discharges; however, normal studies do not exclude seizures. The EEG aids in the classification of seizures, the selection of appropriate antiepileptic drugs (AEDs), and the analysis of the patient’s response to therapy.

MRI and CT of the brain can complement electrophysiological studies by identifying structural brain lesions that may be causally related to the development of epilepsy. MRI is more sensitive than CT in detecting cerebral lesions related to epilepsy, such as cortical heterotopias or mesial temporal sclerosis, and hamartomas. Some abnormalities, such as calcified or bony abnormalities, may be easier to interpret on CT than MRI. Positron emission tomography and single photon emission CT are less readily obtainable. These techniques can identify areas of cerebral hypometabolism interictally in patients with partial epilepsy, even when MRI and CT have been normal (Engel, 1989).

DIFFERENTIAL DIAGNOSIS

Differentiating epileptic seizures from other paroxysmal non-epileptic events is a common problem. Not all paroxysmal behaviors that include shaking, stiffening, or staring are epileptic seizures. Paroxysmal behavioral changes can result from many different medical, neurological, and psychiatric disorders. In some cases, these disorders coexist, further confounding the diagnosis and therapy.

Non-epileptic seizures are common and are reported to occur in approximately 5% to 20% of epileptic outpatients (Commission, 1989; Gates, Luciano, & Devinsky, 1991). Patients whose non-epileptic episodes are mistaken for epilepsy face a variety of potential iatrogenic hazards. Patients with undiagnosed non-epileptic seizures usually receive AEDs, whose behavioral toxicity may actually exacerbate non-epileptic seizures (Gates et al., 1991). Physiological non-epileptic seizures such as syncope are commonly misdiagnosed as epilepsy (Table 54.1). One of the most common misdiagnoses of refractory epilepsy is psychogenic non-epileptic seizures (PNES), which accounts for approximately 30% of cases seen at epilepsy centers today. PNES is a paroxysmal episode that is exacerbated by a psychological event (e.g., a stressful situation; LaFrance & Benbadis, 2006).

Syncope is defined as a sudden transient loss of consciousness resulting from a reduction of cerebral blood flow. It is associated with a loss of postural tone and spontaneous recovery. The diagnosis of syncope is supported if episodes:

TABLE 54.1

Non-Epileptic Seizures Presenting as Syncope

I.	Syncope of cardiac origin
	A.	Dysrhythmias
		1.	Supraventricular dysrhythmias
		2.	Atrial flutter/fibrillation
		3.	Paroxysmal atrial tachycardia
		4.	Sick sinus syndrome
		5.	Ventricular dysrhythmias
		6.	Paroxysmal bradycardia or tachycardia
		7.	Heart block or asystole
	B.	Congenital heart disease
	C.	Cardiomyopathy
	D.	Drug-induced cardiac abnormalities
II.	Syncope of noncardiac origin, from diminished cerebral perfusion
	A.	Vasovagal
		1.	Micturition
		2.	Cough
		3.	Carotid sinus disturbance
	B.	Valsalva maneuver
	C.	Drug-induced (decreased systemic vascular resistance)
		1.	Antipsychotics
		2.	Tricyclic antidepressants
		3.	Antihypertensives
	D.	Orthostatic
		1.	Antihypertensive agents
		2.	Hypovolemia
		3.	Parkinson’s disease
		4.	Shy-Drager syndrome
		5.	Autonomic dysfunction
			a. Diabetes
			b. Amyloidosis
			c. Porphyria
	E.	Benign paroxysmal vertigo
	F.	Breath holding
	G.	Hyperventilation
	H.	Migraine headaches
	I.	Cerebrovascular disease
		1.	Stroke
		2.	Transient ischemic attack

Are precipitated by anxiety or pain (e.g., venipuncture) or assumption of the upright position

Exclusively occur while standing or sitting

Are associated with pallor and diaphoresis

Are not associated with sustained tonic or clonic movements, bladder incontinence, or tongue or cheek bites

Are not followed by post-episode confusion, lethargy, muscle soreness, and headache.

Although incontinence strongly suggests an epileptic seizure, if the bladder is overdistended when syncope occurs, there also may be incontinence. Prodromal symptoms such as abdominal sensations (e.g., “butterflies” or nausea), flushing and warmth, dizziness and lightheadedness, bilateral paresthesia, and a feeling of fear and unreality occur with both syncope and epileptic seizures. Symptoms such as formed visual or auditory hallucinations, olfactory hallucinations, déjà vu, or focal sensory or motor phenomena strongly suggest partial seizures.

A prodrome lasting several seconds, followed by loss of consciousness for 15 to 60 seconds, followed by a rapid return to a normal level of attentiveness, is typical of syncope. The greatest source of error in distinguishing seizures from syncope is failure to recognize that brief tonic or clonic movements often occur in syncope (convulsive syncope), especially when the patient is maintained in the upright or sitting position (Pacia, Devinsky, Luciano, & Vazquez, 1994; Ziegler, Lin, & Bayer, 1978).

The physical examination of patients with possible syncope includes a brief survey of general medical and neurological systems, specifically palpation of the pulse and measurement of orthostatic heart rate and blood pressure. An electrocardiogram may help detect abnormalities such as arrhythmias, conduction blocks, and prolonged Q-T syndrome (Pacia et al., 1994).

Classification of Seizures

A seizure is not a diagnosis; it is a series of signs and symptoms. Similar seizures can result from multiple underlying cerebral processes. In some cases, seizures are the sole manifestation of the disorder; in others, they are only one of several signs and symptoms present. Certain seizures affect patients of a selected age group and produce a characteristic clinical and EEG profile but are idiopathic. The International League Against Epilepsy (ILAE) classifies epileptic seizures based on clinical symptoms and EEG features (Tables 54.2A, B, and 54.3; Berg et al., 2010). Previously, epileptic seizures were divided into two major categories: partial and generalized. However, more recently, this classification scheme was modified to simplify the epilepsy classification scheme. The new classification maintains the distinction between generalized and focal onset, however, has replaced partial with focal. Most noticeably, partial seizures are no longer subcategorized as simple and complex based on loss of consciousness. Focal seizures are defined to originate from one hemisphere, but can be either localized to one discrete area or widely spread throughout central nervous system (CNS) networks. Additionally, the terms simple, complex, and secondarily generalized partial seizures are all now defunct. Since the Food and Drug Administration (FDA) indications for antiepileptic agents do include the traditional epilepsy classifications, it is important to be cognizant of both classifications. Defining the seizure type and epilepsy syndrome helps determine whether medication is necessary, the likelihood of complete response to AED treatment, and the potential duration of treatment.

TABLE 54.2A

International Classification of Epileptic Seizures (New Classification, Commission, 2005–2009)

Generalized seizures

Tonic–clonic (in any combination)

Absence

Typical

Absence with special features

Myoclonic absence

Eyelid myoclonia

Myoclonic

Myoclonic atonic

Myoclonic tonic

Clonic

Tonic

Atonic

Focal seizures

Unknown

Epileptic spasms

TABLE 54.2B

International Classification of Epileptic Seizures (Traditional Classification Scheme, Commission, 1989)

I.	Partial seizures (focal or local onset)
	A.	Simple partial seizures (consciousness is preserved)
		1.	With motor signs
		2.	With special sensory or somatosensory symptoms
		3.	With autonomic symptoms or signs
		4.	With psychic symptoms
	B.	Complex partial seizures (consciousness is impaired)
		1.	Simple partial onset followed by impairment of consciousness
		2.	With impairment of consciousness at onset
	C.	Partial seizures evolving to secondarily generalized seizures
		1.	Simple partial seizures evolving to generalized seizures
		2.	Complex partial seizures evolving to generalized seizures
		3.	Simple partial seizures evolving to complex partial seizures evolving to generalized seizures
II.	Generalized seizures (bilateral symmetric onset; convulsive or nonconvulsive)
	A.	Absence seizures
		1.	Typical absences (no motor involvement)
		2.	Atypical absences (motor involvement)
		3.	Myoclonic seizures
	B.	Clonic seizures
	C.	Tonic seizures
	D.	Tonic–clonic seizures
	E.	Atonic seizures (static seizures)
III.	Unclassified epileptic seizures