Chapter 22. Epilepsy
Epilepsy is "an occasional, an excessive and a disorderly discharge of nervous tissue" induced by any process involving the cerebral cortex that pathologically increases the likelihood of depolarization and synchronized firing of groups of neurons (John Hughlings Jackson, 1889). There are many potential underlying causes such as metabolic disorders of nerve cells or virtually any disorder that damages cortical tissue including trauma, hemorrhage, ischemia, anoxia, infection, hyperthermia, or the presence of scar tissue relating to prior injury.
All neurons in the nervous system are capable of excessive firing when damaged; however, the threshold for this abnormality varies considerably in different areas. The cerebral cortex is the only area from which epileptiform activity arises with any frequency. Even still, not all areas of the cerebral cortex have the same tendency to epileptic activity: most of the neocortex is relatively resistant, while the temporal lobes and frontal lobes (particularly the limbic areas) are highly susceptible.
Electrodes applied to the scalp (the electroencephalogram; EEG) are often able to detect abnormal activity of a seizure. The excessive electroencephalographic discharge recorded can be useful in localizing the source of the seizure activity and, occasionally, by its pattern can delineate the type of seizure disorder. It is unusual to have the opportunity to record an EEG during the actual clinical seizure. However, up to 2/3 of patients have abnormal electrical discharges that can be recorded between clinical events. A normal EEG in a person suspected of having epilepsy does not rule out the possibility since inter-seizure (interictal) electric activity is frequently normal.
It is important to note the distinction between seizures and "epilepsy" (often called a "seizure disorder"). A seizure is an event. All human cerebral cortices have the potential to generate seizures given enough of a stimulus. In fact, nearly 10 percent of people will have one at some time in their life. However, the term epilepsy implies an abnormally heightened tendency to have seizures such that the person is likely to have them from time-to-time in the course of normal life. This can range from one a decade to many in a day.
There are several types of seizures. Broadly, they can be divided into primary generalized seizures and focal onset (localization-related) seizures. In primary generalized seizures, the seizure involves all of the cerebral cortex simultaneously. In focal onset seizures, it involves a localized cluster of neurons having epileptiform activity. Table 22-1 presents a simplified functional-anatomical categorization of seizure types. It is not exhaustive but it does give the spectrum of major seizure categories. While most seizures present with motor correlates, some can present with mainly inhibitory phenomena. The blank, staring episodes of petit mal, the common childhood seizure disorder, are a good example.
Seizures are not only recognized by the activity during the main portion of the seizure but also by phenomena that lead up to the clinical seizure (often termed an "aura"), and the condition of the patient after the event (the "post-ictal" state).
The etiology of epilepsy is different at different ages. In very young children the most common causes include intrauterine and perinatal brain damage. Metabolic defects and congenital malformations also tend to present in childhood. Genetic epilepsies often present in later childhood through adolescence (basically school ages), while brain tumors and strokes are usually a cause of epilepsy in adulthood. Some conditions can affect any age, including trauma or infections (such as encephalitis). Some syndromes are quite characteristic in age of onset, including petit mal epilepsy in early school age children, temporal lobe epilepsy developing in late adolescence or early adulthood (often in patients with a history of prolonged, severe febrile seizures as a young child), or juvenile myoclonic epilepsy (JME) in adolescence.
The following discussion will consider those epilepsies that involve the entire brain from the outset (generalized epilepsies) and then consider those of focal onset and then the medical emergency of “status epilepticus”.
Generalized seizures involve abnormal electrical activity in all of the cerebral cortex simultaneously. Therefore, it is presumed that the triggers and signals for these seizures are arising outside of the cortex (reticular formation of the upper brain stem or thalamus). In any event, some signal recruits all of the cerebral cortex to depolarize synchronously and, therefore, results in sudden loss of consciousness and massive synchronous motor activity. This is manifested initially by tonic contraction of all muscles of the body. The individual assumes a rigid extended posture due to extensor muscles overpowering the flexors. Respiration is arrested and air is expelled from the lungs through a closed glottis (resulting in a guttural "cry"). This is followed in seconds (up to one minute) by synchronous intermittent contraction and relaxation (clonic activity) of the limbs and trunk, and then complete relaxation as the electrical seizure dies (Figure 22-1). The clonic phase and the postictal phase probably result from massive activation of inhibitory neurons in the brain. Usually the seizure is exhausted within several minutes but rarely may continue for hours or days as "status epilepticus". Autonomic motor overflow frequently occurs simultaneously, manifested clinically by emptying of the bladder and, less often, the bowel. The pupils are large during the ictal phase and blood pressure and pulse are erratic (usually elevated). A variable postseizure (postictal) period of depressed consciousness and confusion ensues. The length of this period probably depends on the length of the seizure and to some degree the general health of the brain. For example, it is likely to be much longer in the elderly and in those with a background of diffuse brain dysfunction.
"Spike-wave" electric activity is seen 0n the EEG during the clonic phase of generalized-motor seizures. The "spike," which represents massive and synchronous depolarization, manifests itself clinically as the clonic, flexion motor jerk. This is followed by a phase of relaxation, which electrically is seen as the "wave," and which reflects massive inhibition. A train of spike-wave discharges can go on for many minutes during the active phase of a seizure.
Grand mal seizures were considered the most prevalent type of adult seizure until recently when it was realized that many seizure types were being overlooked. Many patients with localization-related (focal) epilepsy have the event culminate in what has been termed a "secondarily generalized seizure." This secondary generalization either occurs through activation of the upper brain stem or by direct cortico-cortical spread through the commissures (corpus callosum, hippocampal commissure or anterior commissure). Clues to the fact that this seizure is not a primary generalized seizure may be found either in a premonitory "aura" (usually visceral or emotional symptoms leading up to the seizure) or reports from observers of unusual motor events (such as blinking, twitching, sniffing, picking at the clothes or lip smacking) immediately prior to losing consciousness. These symptoms are the result of electrical activity in the focal area prior to generalization.
Most individuals with primary generalized epilepsy begin with seizures in childhood that are often the result of an abnormal sensitivity of neurons (some conditions have clear abnormalities in ion channels and a definite inheritance). The most common syndrome of epilepsy (representing 5-10% of epilepsy) is juvenile myoclonic epilepsy (JME). This is a syndrome because there are several genetic abnormalities that result in a common clinical picture. Typically, the child is normal or only has absence seizures when young. In late child hood or early adolescence, the patient develops involuntary jerking movements that are particular common in the morning. These myoclonic events may result in dropping or throwing things, or sudden falls. These are often overlooked or thought to be “clumsiness”. Some months or years later the patient has a primary generalized convulsion (sometimes following a flurry of myoclonic events). This often leads to diagnosis since the EEG is characteristically abnormal even in between episodes. There are at least six different genes that are involved, all of which are related in one way or another to ion channel function. Interestingly, JME patients respond to a very specific anticonvulsants regardless of the specific genetics, and don’t improve with other common anticonvulsants. As we learn more about other idiopathic epilepsies we are very likely to find that many are associated with specific abnormalities of neuronal excitability.
In addition to these genetic and “idiopathic” epilepsies, many metabolically induced seizures fit the grand mal category. The main categories of metabolic seizures include ionic abnormalities (Na, K, Ca, Mg, BUN, pH, etc.), sedative withdrawal in addicts (alcohol, barbiturates, benzodiazepines), hypoglycemia, hypoxia, and hyperthermia (especially before the age of 4). There are some uncommon toxins that can also generate seizures. Remember, seizures of this type do not necessarily indicate epilepsy unless there is an abnormal tendency to have seizures without the severe metabolic insult.
These are generally seizures of childhood that are thought also to originate in the upper brain stem. Clinically, patients show many short episodes (a few seconds) of blank staring (absence) for which the patient has no memory. The EEG is highly specific (showing 3 per second spike/wave activity that can almost always be brought on by hyperventilation) (Figure 22-2).
Although the seizure is usually characterized by staring and “blankness”, there may be eyelid fluttering or chewing movements. The seizure is usually very brief (usually less than 15 seconds) and the patient “snaps out of it” suddenly and without any evident postictal period. However, they will have no awareness of anything that happened during the episode.
You might ask why the petit mal seizure is predominantly a negative (absence) phenomenon when there is diffuse electrical synchronization of the cortex. Several reasons for this are suggested, and one of these is reflected in the spike-wave electroencephalographic pattern. The spike represents diffuse depolarization (excitation) of cortical neurons, whereas the wave is considered to represent diffuse inhibition (hyperpolarization). This postexcitatory inhibition is presumably adequate to prevent behavioral manifestations (e.g., overt convulsions) from being initiated by the massive depolarization. Another reason for lack of convulsive movements is that the immature motor cortex of children may be more resistant to excitatory recruitment. Children with petit mal usually maintain their posture during the short (seconds) absence attacks. This is presumed to be because the seizure activity does not spread to involve more resistant brain stem postural mechanisms.
Most children with absence seizures have spontaneous remission from their seizures later in childhood or early adolescence. Neuronal maturation presumably increases the capability of the cerebral cortex to spontaneously inhibit excessive synchronous activity. Of the remaining children who continue to have seizures the great majority have generalized seizures of a tonic-clonic, tonic, atonic or myoclonic nature. One interpretation for this is that there are common subcortical mechanisms for the production of the generalized, rhythmic spike-wave pattern of activity seen in petit mal seizures and other primary generalized convulsions.
Seizures of Focal Nature (Partial Seizures) With or Without Secondary Spread to Generalized Motor Manifestation
Partial (focal) seizures begin in a particular part of the cerebral cortex. They are categorized by their initial manifestations and whether they result in a secondary generalized convulsion. The initial manifestations of these seizures are based on the function of the tissue in which the epileptiform activity begins. These seizures can have a rather simple presentation if the cortex in which they begin has a well-defined sensory or motor function. When this involves sensory cortex there is usually a positive phenomenon (i.e., a presence of the sensation) rather than initial loss of sensation. For example, paresthesias, flashing lights or smells may be perceived if the postcentral gyrus, calcarine cortex or uncus regions are involved in the seizure activity. If the primary motor cortex is involved, local tonic and/or clonic motor phenomena may be seen. So-called "complex partial seizures" involve the association cortices of the frontal, temporal or parietal lobes. These are characterized by more complicated emotions, feelings or perceptions, along with a "clouding of consciousness". The patient is not fully in tune with their environment and responds to internal cues. Memory for the event is usually partial, at best. A good history of the symptoms right at the onset of the seizure may give important clues as to the origin.
After the focal seizure, the area of cortex that is most involved can have postictal depression of function lasting from minutes to hours. This can result in paralysis ("Todd paralysis") if the motor cortex is involved. Patients can have the appearance of focal deficit during this period and it may be difficult to distinguish from a patient with stroke. The history of seizure and the gradual recovery of function is critical to this differentiation.
If the focal seizure is not contained by normal inhibitory processes in the brain, it can spread to involve both hemispheres via the corpus callosum and/or the reticular formation of the mesodiencephalon and a generalized motor clinical seizure results. This may be tonic, tonic-clonic or just clonic in nature and is termed a "secondarily generalized seizure".
Seizures arising in or adjacent to the motor cortex appear simply as clonic jerking of the motor structures (muscle groups) innervated by the cortex involved (on the contralateral side). If the seizure spreads from the focus, the clinical seizure progresses to involve contiguous areas of the body (Figure 22-3). The progression appears as a march of activity over the body (and over the cortex; the Jacksonian march) from the upper extremity to the face, trunk, and lower limb. As with any partial seizure, it may subsequently generalize either via the corpus callosum or the rostral brain stem.
Seizures arising in the somatosensory cortex produce paresthesia on the contralateral side that can spread (in a manner similar to the "march" of motor symptoms) over the body. After the focal seizure, there may be diminished sensations in the region.
The patient with rapid onset of transient sensory symptoms can represent a particular diagnostic difficulty. The differential diagnostic possibilities for this presentation include transient ischemic attacks (TIA), migraine transient dysfunction, and simple partial seizures of a somatosensory type. There are some factors that would favor a diagnosis of TIA, such as older age, clinically evident cervical vessel stenotic disease, lack of a "march" (see above), previous history of cerebrovascular disease, changes in the retinal blood vessels (e.g., residual cholesterol emboli) and additional involvement of motor systems (see, Chapter 27). Migraine would be suspected if the sensory symptoms were followed by headache, usually unilateral (see Chapter 18). However, it must be kept in mind that headache may be a rare manifestation of seizure (usually during the postictal period), and may also be seen with transient ischemic attacks on occasion. It is helpful to note that the sensory symptoms of migraine spread ("march") over the body in a period of minutes, while those of seizure usually march over seconds. On the other hand, symptoms of transient ischemia appear suddenly. Of course, if the focal seizure is followed by a secondarily generalized seizure, the diagnosis of seizure disorder is almost assured since it is very rare that transient ischemia initiates a focal seizure.
Auditory-vestibular cortex involvement appears as a hallucination of sound (tinnitus) and vertigo with or without generalization. This may be mistaken for inner ear disease (such as Meniere syndrome) if a generalized convulsion does not occur. Audiometric tests are very useful and will almost always show abnormality in Meniere syndrome but not in simple partial seizures. Of course, an EEG may be helpful by showing focal abnormality in the posterior temporal region. However, the EEG is frequently normal between seizures.
Visual cortex involvement is manifested as hallucinations in the contralateral visual field. Foci in the primary visual cortex (calcarine cortex) appear as unformed flashes, spots, and zig-zags of light, colored or white, whereas foci in the visual association cortex cause more formed hallucinations such as floating balloons, stars, and polygons. Yet more anterior in the visual association areas (in posterior temporal or parietal lobes) more complex sensory hallucinations may occur (e.g., people talking, occasionally described as something like a flashback).
Focal seizures arising in the olfactory cortex (near the uncus of the rostral medial temporal lobe) may give rise to hallucinations of smell and taste, most often described as acrid and unpleasant. Spread to adjacent cortex is common, and complex partial seizure results.
Complex focal (partial) seizures result from partial seizures beginning in the frontal, temporal or (less often) parietal association cortex. These manifest with behavioral, visceral and affective (emotional) phenomena. The limbic cortex has the lowest cortical threshold for initiating and sustaining seizure activity. Additionally, the limbic cortex, which includes the hippocampus, parahippocampal temporal cortex, retro-splenial-cingulate-subcallosal cortex, orbito-frontal cortex, and insula - is the cortex most susceptible to metabolic injury. This is particularly true of the hippocampus, where "sclerosis" (a process of neuron loss with associated gliosis) is a relatively common result of early life or prenatal insult to the brain. It is not surprising then that complex partial epilepsy is quite common - probably the most common form of seizure disorder.
If this seizure does not generalize rapidly, it can remain as a partial seizure for a prolonged period. The visceral and affective (psychomotor) components of the seizure dominate the clinical picture. Simple and/or complex visceral, sensory and emotional phenomena dominate the picture. There may be peculiar and unpleasant smells and tastes, bizarre abdominal sensations, fear, anxiety, rarely rage, and excessive sexual appetite. These may be combined with some visceral and behavioral phenomena such as sniffing, chewing, lip smacking, salivation, excessive bowel sounds, belching, penile erection, feeding, or running. Rarely, a seizure completely isolates the limbic system from the neocortex and reticular formation, which continue to function normally. The patient may carry out complex functions (e.g., drive a car), and because the memory functions of the hippocampus are not functioning normally, they may have no idea of what transpired. This type of behavior, associated with amnesia, is more often caused by transient ischemia, head trauma or migraine phenomena involving the hippocampal regions than by seizure activity.
You may wonder why focal cortical seizures do not all generalize and why focal epileptiform activity seen on the EEG is not always manifested as a clinical seizure. It appears that this results from collateral inhibition that is present in normal brain to prevent just such excessive excitation. Of course, this can be overcome if the region of brain that is involved is too great, if inhibition is exhausted or if the excitatory activity overwhelms the inhibition.
Generalized and focal seizures may on occasion become continuous with very little or no interictal period. The usual definition is continuous or recurrent seizures over a 30-minute period without return to normal over the period. Presumably, in status, the normal brain inhibitory mechanisms for terminating seizures are not sufficient to stop the activity.
Circumstances that predispose to status epilepticus are similar to those that result in recurrence of single or multiple seizures in individuals who are otherwise medically or physiologically well controlled. An example is acute termination of anticonvulsant medication, which results in temporarily heightened seizure susceptibility. This appears to result in rebound hyperexcitability similar to that seen in patients who are dependent on sedative medications or alcohol. Although withdrawal of medication is the most common cause of status epilepticus, any circumstance that increases central nervous system excitability may lead to seizure recurrence or less commonly status epilepticus. Emotional excess (e.g., fright or anger), fever, or other hypermetabolic states, hypoglycemia, hypocalcemia, hypomagnesemia, hypoxemia, and toxic states (e.g., tetanus, uremia, exogenous, excitatory agents such as amphetamine, aminophyline, lidocaine, penicillin) are a few examples.
Continuous generalized motor seizures (status epilepticus) are a medical emergency. If they are not terminated, the chance of dying is very high and many survivors are left with brain damage. The massive muscle activity of the seizures leads to hyperthermia with temperatures as high as 106 degrees Fahrenheit or more, which if sustained, causes irreversible damage to neurons. Hypoxia from inadequate pulmonary ventilation also causes brain damage. Severe lactic acidosis from shock and tissue hypoxia, amplified by excessive muscle activity, probably contributes to neuron deterioration. Death is usually not from brain dysfunction directly, but from overtaxation of cardiopulmonary reserve by the combination of massive continuous exercise, hypoxia, lactic acidosis, shock, and possibly also hyperthermia. Additionally, massive autonomic activity can result in severe blood pressure changes and arrhythmia. Though somewhat controversial, it is possible that brain damage can also be caused by continued seizure activity alone. Therefore, even the person who is paralyzed by a neuromuscular blocking agent (curariform drug), intubated and mechanically ventilated, and whose blood pressure and temperature are controlled within normal range needs to have their seizure activity terminated as soon as possible.
Continuous partial (focal) seizure activity (epilepsia partialis continua) is less life threatening but may, if prolonged, lead to focal neuronal damage. Its tendency to generalize into major motor status epilepticus also makes it important to terminate the seizures as soon as possible. The etiologic factors are similar to those initiating seizure recurrence and status epilepticus. Occasionally epilepsia partialis continua is the presenting manifestation of a seizure focus. This is most common in adults, and neoplasm or ischemia-infarction of the brain is the most frequent cause followed by less common causes such as stimulant toxicity and hyperglycemia.
Initial treatment of epilepsy is based on medical suppression of the excitable focus. Much has been learned about the pharmacologic effects of antiepileptic drugs, but their exact modes of action remain unclear.
Seizures that are symptomatic of systemic or localized central nervous system metabolic disorders, such as infection, disorders of fluid and electrolyte balance, exogenous and endogenous toxicities, and renal failure, are best treated by ameliorating the underlying condition, if possible, and the concomitant use of anticonvulsant medications where indicated.
Some anticonvulsant drugs suppress neuronal membrane excitability, probably by hyperpolarization, which possibly reflects a decreased intracellular sodium or calcium concentration. Some appear to depress excitatory synaptic transmission or increase inhibitory neurotransmission. Many anticonvulsants affect the activity of ion channels (particularly fast sodium channels) that are important in seizure generation and propagation. All these mechanisms could increase neuronal resistance to excessive discharge or protect normal neurons from recruitment by neighboring excessive discharge.
An ideal anticonvulsant decreases abnormal excitability, has a minimal sedating effect, and is free of other significant and deleterious side effects. No medication achieves these goals. Fortunately, phenytoin, carbamazepine, valproic acid and phenobarbital, mainstays of epilepsy therapy, approach these criteria while a host of newer agents (e.g., gabapentin, lamotrigine, topiramate, etc.) may have fewer side effects and be at least as effective for some seizure types. Some drugs have effectiveness against only one seizure type (ethosuximide for absence seizures) while most have a variable effect on generalized versus partial seizures.
A special case is the emergent treatment of status epilepticus, where is it an urgent matter to stop the seizure in the minimum amount of time, using parenteral medications even at the expense of sedation. In this situation, intravenous benzodiazepines (such as diazepam or lorazepam), phenytoin and phenobarbital are the drugs of choice. Of course, intubation and even general anesthesia may be necessary while exploring the reason for the status epilepticus.
Medical therapy is successful in decreasing seizures in almost 80% of epileptics. 50% have their seizures reduced to a negligible level. Approximately 30% gain complete arrest of their seizures. If one anticonvulsant is not successful, a second is attempted. If two have been tried unsuccessfully, the likelihood of successful medical control of seizures declines substantially (even if multiple anticonvulsants are used simultaneously).
If medical therapy does not adequately control the seizures, surgical removal or isolation of the seizure focus can be considered. The focus must be localized by imaging and/or electrodiagnostic study, and, if localized, must be surgically approachable. The most common operations carried out today are temporal lobectomy and, less often, local corticectomy. Surgical isolation of seizure foci in one hemisphere by corpus callosum section is successful in some resistant cases; the major aim of this type of surgery is to decrease the seizure generalization. Seizures that spread via the brain stem would be unlikely to be affected by corpus callosum section. Fortunately, this appears to be a more resistant and less common path of generalization.
Of course, if seizures are symptomatic of a treatable medical condition, that condition must be addressed, where possible. Approximately 10% of persons with focal epilepsy have a tumor, for example. The older the patient, the more likely that seizures are to be the result of tumor or scarring from prior cerebrovascular disease. This agrees with the age-incidence spectrum of neoplasm and stroke. Therefore, patients with clearly focal seizures merit more extensive neurologic evaluation, including magnetic resonance imaging (see Chapter 11). MRI is preferred to CT scanning since it provides a much better view of the inferior frontal lobes and the anteromedial temporal lobes that are often obscured by bone in the CT scan. It is preferred that the imaging be performed without and then with contrast media due to the fact that some small tumors may be overlooked unless their tendency to enhance with contrast is recognized.
- Gastaut, H. Broughton, R.: Epileptic Seizures. Springfield, IL, Charles C. Thomas, Publisher. 1972.
- Laidlaw, J., Richens, A.: A Textbook of Epilepsy. Edinburgh, Churchill and Livingston. 1976.
- Schmidt, R.P., Wilder, B.J.: Epilepsy. Philadelphia, F.A. Davis Co., 1968.
- Sutherland, J.M., Eadie, M.J.: The Epilepsies. London, Churchill Livingstone, 1980.
- Woodbury, D.M., Penry, J.K., Pippenger, C.E. (Eds): Antiepileptic Drugs. 2nd Ed., New York, Raven Press, 1982.
- Reeves, A.G.: Epilepsy and the Corpus Callosum. New York, Plenum Press, 1995.
- Engel, J.: Surgical Treatment of Epilepsy. New York, Raven Press, 1987.
Define the following terms:epilepsy, primary generalized seizure, complex partial seizure, myoclonic seizure, petit mal seizure, simple partial seizure, focal seizure, secondary generalization, status epilepticus, postictal period, interictal, Todd's paralysis, hippocampal sclerosis, temporal lobe epilepsy, seizure focus.
22-1. What is epilepsy?
22-2. What are primarily generalized seizures?
22-3. What are potential causes of primary generalized seizures?
22-4. Does epilepsy last a lifetime?
22-5. What is the usual description of a generalized seizure?
22-6. What is a petit mal (absence) seizure?
22-7. What is a myoclonic seizure?
22-8. What are partial seizures?
22-9. What is a simple partial seizure?
22-10. What is a complex partial seizure?
22-11. What are common auras of complex partial seizures arising in the temporal lobes?
22-12. What is secondary generalization?
22-13. What is status epilepticus?
22-14. What are common causes of status epilepticus?
22-15. Why is status epilepticus an emergency?
22-16. What can be done in order to evaluate epilepsy?
22-17. What are "non-epileptic" seizures?
22-18. What are the available therapies for epilepsy?