The prevalence and importance of epilepsy, recurrent unprovoked seizures, can hardly be overstated. From the epidemiologic studies of Hauser and colleagues, one may extrapolate an incidence of approximately 2 million individuals in the United States who have epilepsy and predict about 44 new cases per 100,000 persons each year. These figures are exclusive of patients in whom seizures transiently complicate febrile and other illnesses or injuries. It has also been estimated that slightly less than 1 percent of persons in the United States will have epilepsy by the age of 20 years (Hauser and Annegers). Over two-thirds of all epileptic seizures begin in childhood (most in the first year of life), and this is the period when seizures assume the widest array of forms. In the practice of pediatric neurology, epilepsy is one of the most common disorders, and the chronicity of childhood forms adds to their importance. The incidence increases again after age 60 years. For all these reasons, physicians should know something of the nature of seizure disorders and their treatment. It is notable that, in striking contrast to the many treatments available for epilepsy, as pointed out by J. Engel, 80 to 90 percent of persons with epilepsy in the developing world never receive medical attention.
The word epilepsy is derived from Greek words meaning “to seize upon” or a “taking hold of.” Our predecessors referred to it as the “falling sickness” or the “falling evil.” Although a useful medical term to denote recurrent seizures, the words epilepsy and epileptic may still have unpleasant connotations and should be used advisedly in dealing with patients. In 1870, Hughlings Jackson, the eminent British neurologist, postulated that seizures were due to “an excessive and disorderly discharge of cerebral nervous tissue on muscles.” The discharge may result in an almost instantaneous loss of consciousness, alteration of perception or impairment of psychic function, convulsive movements, disturbance of sensation, or some combination thereof.
Terminologic difficulty arises from the diversity of the clinical manifestations of seizures. The term convulsion, referring as it does to an intense paroxysm of involuntary repetitive muscular contractions, does not fully capture the range of disorders resulting from abnormal electrical discharges, or seizures, that may consist only of an alteration of sensation or consciousness. Seizure is preferable as a generic term because it embraces all paroxysmal electrical discharges of the brain, and also because it lends itself to qualification. The term motor or convulsive seizure, therefore, is not tautologic, and one may likewise speak of a sensory seizure or psychic seizure. There is also an entity of “nonconvulsive seizure” that may impair consciousness, but not manifest any abnormal convulsive movement. This represents an important and potentially treatable form of an encephalopathy or confusional state.
A first solitary seizure or brief outburst of seizures may occur during the course of many medical illnesses. It indicates that the cerebral cortex has been affected by disease, either primarily or secondarily. If prolonged or repeated every few minutes, the condition termed status epilepticus, it may threaten life. Equally important, a seizure or a series of seizures may be the manifestation of an ongoing neurologic disease that requires special diagnostic and therapeutic measures. Status epilepticus may be of the nonconvulsive type, and continuously impair consciousness and is difficult to detect clinically because of the absence of characteristic movements.
A more common and less-grave circumstance is for a seizure to be but one in an extensive series recurring over a long period of time, with most of the attacks being more or less similar in type. In this instance, they may be the result of an inactive lesion that remains as a scar in the cerebral cortex. The original disease may have passed unnoticed, or perhaps had occurred in utero, at birth, in infancy, or in parts of the brain inaccessible for examination or too immature to manifest signs. The increasingly refined techniques of MRI now also reveal small zones of developmental cortical dysplasia and hippocampal sclerosis, both of which tend to be epileptogenic. Patients with such long-standing but subtle lesions probably make up a large portion of those with recurrent seizures. If there is no underlying lesion, the condition is classified as idiopathic or primary, but in the modern era, this is come to be almost synonymous with a genetic cause. In this category, there are a large number of important types of epilepsy for which no pathologic basis has been established, and for which there is no apparent underlying cause except a genetic disorder of ion channel function. Included here are special hereditary forms such as generalized tonic-clonic (grand mal), and “absence” seizure states as suggested in classifications many years ago by Lennox and Forster. Persistent seizures, regardless of cause, can secondarily damage cortical tissue by several mechanisms that include excitotoxicity and, in the setting of prolonged tonic seizures, systemic hypoxia.
CLASSIFICATION OF SEIZURES AND EPILEPSIES
Seizures have been grouped in several ways: according to their presumed etiology, that is, idiopathic (primary) or symptomatic (secondary); their site of origin; their clinical form (generalized or focal); their frequency (isolated, cyclic, or repetitive, or the closely spaced sequence of status epilepticus); or by special electroencephalographic (EEG) patterns. A distinction must be made between the classification of seizures: generalized tonic clonic (grand mal), absence (petit mal), myoclonic, partial, and others, and the classification of the epilepsies, or epileptic syndromes, which are specific diseases, many of which may manifest several seizure types. These are discussed later in the chapter. A further distinction is made by clinical and EEG features. This approach allows for the reasonable predictability of response to specific medications and to some extent, in prognosis.
Basically, this classification divides seizures into two types—focal (formerly termed partial), in which a focal or localized onset can be discerned clinically or by EEG, or generalized, in which the seizures appear to begin bilaterally. Generalized seizures are of two types—convulsive and nonconvulsive. The common convulsive type is the tonic-clonic (grand mal) seizure. Less common is a purely tonic, purely clonic, atonic, and myoclonic. The typical nonconvulsive generalized seizure is the brief lapse of consciousness or absence (petit mal); included also under this heading are minor motor phenomena. Focal seizures can also be convulsive or uncommonly, nonconvulsive. Furthermore, focal seizures can secondarily generalize into any of the types listed above.
The classification followed here was first proposed by Gastaut et al in 1970 and has been refined repeatedly by the Commission on Classification and Terminology of the International League against Epilepsy. This nomenclature, based mainly on the clinical form of the seizure, and its EEG features, has been adopted worldwide and is generally referred to as the “International Classification.” A modified version of it is reproduced in Table 15-1.
Table 15-1INTERNATIONAL CLASSIFICATION OF EPILEPTIC SEIZURES ||Download (.pdf) Table 15-1INTERNATIONAL CLASSIFICATION OF EPILEPTIC SEIZURES
Generalized seizures (bilaterally symmetrical and without focal onset)
Tonic, clonic, or tonic-clonic (grand mal)
Absence (petit mal)
Myoclonic including atonic and tonic types
Focal (formerly “partial”); characterized by main feature(s). (See Table 15-2)
Simple (without loss of consciousness or alteration in psychic function)
Aura; somatosensory or special sensory (visual, auditory, olfactory, gustatory, vertiginous)
Awareness retained (formerly “simple”) or impaired (formerly “complex”)
Unclassifiable; cannot be characterized as focal, generalized or both, including epileptic spasms
Focal seizures are further classified according to their additional features such as a specific subjective experience (aura), motor, autonomic, and most importantly, whether awareness or consciousness is disturbed; the latter was formerly called partial complex seizure, now termed focal seizures with dyscognitive features. In reality, an aura represents the initial phase of a focal seizure; in some instances, it may constitute the entire epileptic attack.
A complementary classification is provided by considering the epilepsy syndromes, a group of somewhat diverse, age-dependent and usually genetically determined entities that arise without underlying structural abnormalities. The syndromes are characterized the age of onset, type of seizure, and often, by a particular EEG pattern. By contrast, epilepsies manifesting as seizures that begin locally and may evolve into generalized tonic-clonic seizures, termed secondarily generalized tonic clonic seizures (termed bilateral convulsive in Fig. 15-1), generally have no such genetic component and are usually the result of underlying brain disease, either acquired or a result of congenital malformations or metabolic defects. Quite often, the initial focal phase is not appreciated, leading to misdiagnosis. An increasing frequency and severity of this group of disorders with age reflects the accumulation of focal cerebral damage from trauma, strokes, and other damage.
We begin our discussion with a practical approximation of the classification shown in Fig. 15-1, followed by consideration of a number of well-defined epilepsies and epileptic syndromes.
A proposed current classification of epileptic syndromes based on the age of onset of the seizure disorder is shown in Fig. 15-2, and the distribution of the seizure types for each age epoch, obtained and aggregated from several sources is shown in Fig. 15-3. There has been substantial progress in defining the molecular basis of familial and hereditary epilepsies over the last decade; it is likely that these insights will lead to modification of both the clinical classifications and management of the epilepsies.
The distribution of the main types of epilepsy by age. The overrepresentation of absence and myoclonic seizures in childhood and of complex partial seizures in older individuals is evident. Complex partial=focal with dyscognitive features; simple partial=focal without dyscognitive features. (Adapted from Hauser and Annegers and the texts of Engel and of Pedley.)
Generalized Convulsive Seizures (Tonic-Clonic, Grand Mal)
In the common primary type of seizure, most often a convulsion starts with little or no warning. Sometimes the patient senses the approach of a seizure by several subjective phenomena (prodrome) even prior to an epileptic aura, which represents a focal seizure. For some hours, the patient may feel apathetic, depressed, irritable, or, rarely, the opposite—ecstatic. In a patient with generalized epilepsy (juvenile myoclonic epilepsy being one typical type), one or more myoclonic jerks of the trunk or limbs on awakening may herald a seizure later in the day. Abdominal pains or cramps, a sinking, rising, or gripping feeling in the epigastrium, pallor or redness of the face, throbbing headache, constipation, or diarrhea have been given prodromal status, but they do not occur consistently enough to be predictive of an oncoming seizure.
Most often, generalized seizure strikes without warning, beginning with a sudden loss of consciousness and a fall to the ground that may lead to facial and other injuries. In some cases of generalized seizure there may be momentary movement of one part of the body before consciousness is lost (turning of the head and eyes or whole body or intermittent jerking of a limb), although the patient often fails to form a memory of this and such information is obtained only from an observer. At times, this movement represents a focal onset of a seizure and, as has already been pointed out, it is useful to distinguish between a primary (generalized) type of seizure with widespread EEG abnormalities at the onset, and a secondarily generalized type. The secondary generalized type implicates a focal brain lesion.
The initial motor signs are typically a brief flexion of the trunk, an opening of the mouth and eyelids, and upward deviation of the eyes. The arms are elevated and abducted, the elbows semiflexed, and the hands pronated. These are followed by a more protracted extension (tonic) phase, involving first the back and neck, then the arms and legs. There may be a piercing cry as the whole musculature is seized in a spasm with biting of the lateral margin of the tongue, and air is forcibly emitted through the closed vocal cords. Because the respiratory muscles are caught up in the tonic spasm, breathing is suspended and after some seconds the skin and lips may become cyanotic. The pupils are dilated and unreactive to light. The bladder may empty at this stage or later, during the postictal coma. This is the tonic phase of the seizure and lasts for 10 to 20 s.
There then occurs a transition from the tonic to the clonic phase of the convulsion. At first, there is a mild generalized tremor, which is, in effect, a repetitive relaxation of the tonic contraction. It begins at a rate of approximately 8 per second and coarsens to 4 per second; then it rapidly gives way to brief, violent flexor spasms that come in rhythmic salvos and agitate the entire body. If prolonged, the face becomes violaceous and contorted by a series of grimaces. Autonomic signs are prominent: the pulse is rapid, blood pressure is elevated, pupils are dilated, and salivation and sweating are prominent; bladder pressure may increase sixfold during this phase. The clonic jerks decrease in amplitude and frequency over a period of about 30 s. The patient remains apneic until the end of the clonic phase, which is often marked by a deep inspiration. Instead of the whole dramatic sequence described above, the seizures may be abbreviated or limited in scope by medications.
In the terminal phase of the seizure, all movements end and the patient is motionless and limp in a deep coma. The pupils begin to contract to light. Breathing may be quiet or stertorous. This state persists for several minutes, after which the patient opens his eyes, begins to look about, and appears bewildered and is confused and may be quite agitated. The patient may speak and later not remember anything that has been said and undisturbed becomes drowsy and falls asleep, sometimes for several hours, then often awakens with a pulsatile headache. When fully recovered, such a patient has no memory of any part of the spell but knows that something has happened because of the strange surroundings (in ambulance or hospital), the obvious concern of those around him, and often, a sore, bitten tongue and aching muscles from the violent movements. The convulsive contractions, if violent enough, may crush a vertebral body or result in a serious injury; a fracture, periorbital hemorrhages, subdural hematoma, posterior shoulder dislocation, or burn may have been sustained in the fall.
Each of these phases of the generalized tonic-clonic seizure has characteristic EEG accompaniments. Initially, movement artifacts obscure the EEG tracing; sometimes there are repetitive spikes or spike-wave discharges lasting a few seconds, followed by an approximately 10-s period of 10-Hz spikes. As the clonic phase asserts itself, the spikes become mixed with slow waves and then the EEG slowly assumes a polyspike-and-wave pattern. When all movements have ceased, the EEG tracing is nearly isoelectric for a variable time, and then the brain waves gradually resume their preseizure pattern.
Severe seizures may be accompanied by a systemic lactic acidosis with a fall in arterial pH, reduction in arterial oxygen saturation, and rise in PCO2. These effects are secondary to the respiratory arrest and excessive muscular activity. If prolonged, they may cause hypoxic-ischemic damage to remote areas in the cerebrum, basal ganglia, and cerebellum. In paralyzed and artificially ventilated subjects receiving electroconvulsive therapy, these changes are less marked and the oxygen tension in cerebral venous blood may actually rise. Heart rate, blood pressure, and particularly CSF pressure rise briskly during an ECT-induced seizure. According to Plum and colleagues, the rise in blood pressure evoked by a seizure usually causes a sufficient increase in cerebral blood flow to meet the increased metabolic needs of the brain.
Convulsions of this type ordinarily come singly or in groups of two or three and may occur when the patient is awake and active or during sleep, or when falling asleep or awakening. It is useful to know that seizures on awakening usually signify a generalized type, whereas those occurring during the period of sleep are more often focal in nature. Some 5 to 8 percent of such patients will at some time have a prolonged series of such seizures without resumption of consciousness between them; this is status epilepticus and demands urgent treatment. The first outburst of seizures in an individual may take the form of status epilepticus.
Aside from psychogenic episodes that imitate seizures, few clinical states simulate a generalized tonic-clonic seizure, but several are worthy of mention. One is a clonic jerking of the extended limbs (usually less severe than those of a grand mal seizure) that occurs with vasodepressor syncope or a Stokes-Adams hypotensive attack. In contrast to an epileptic type of EEG, the brain waves are slow in frequency and low in amplitude during the jerking movements. A rarer phenomenon that may be indistinguishable from a generalized convulsion occurs as part of the syndrome of basilar artery occlusion. This presumably has its basis in ischemia of the corticospinal tracts in the pons (Ropper); a similar ischemic mechanism in the cortex has been invoked for “limb-shaking TIAs” (transient ischemic attacks), in which there are clonic movements of one limb or one side of the body during an episode of cerebral ischemia. Clonic limb movements occur immediately after a traumatic concussion and an observer who arrives at this moment will be unable to determine if the inciting event was a seizure causing a fall with head injury, or a collision causing a concussion and convulsive movements. In infants, a breath-holding spell may closely simulate the tonic phase of a generalized seizure. Another disorder that simulates a seizure, albeit self-induced, is the fainting lark (or in the British, the “mess trick”). By hyperventilating in a squatting position and standing rapidly combined with a Valsalva maneuver, a syncopal episode is induced that ends with generalized convulsive movements (see Lempert et al).
Absence (Petit Mal) Seizures
In contrast to major generalized seizures, absence seizures (formerly referred to as petit mal or pyknoepilepsy) are notable for their brevity, rapid onset and cessation, and frequency and the paucity of motor activity. Indeed, they may be so brief that the patients themselves are sometimes not aware of them; to an onlooker, they resemble a moment of absentmindedness or daydreaming. The attack, coming without warning, consists of a sudden interruption of consciousness, for which the French word absence (“not present,” “not in attendance”) has been retained. The patient stares and briefly stops talking or ceases to respond. Only about 10 percent of such patients are completely motionless during the attack; in the remainder, one observes a brief burst of fine clonic (myoclonic) movements of the eyelids, facial muscles, or fingers or small synchronous movements of both arms, all at a rate of 3 per second as shown many years ago by Penry and colleagues. This rate corresponds to that of the EEG abnormality, which takes the form of a generalized 3-per-second spike-and-wave pattern (see Fig. 2-7I). Absence seizures are said to be “typical” if they have a rapid onset and offset, typical three per second spike and wave, and complete loss of awareness.
Minor automatisms—in the form of lip-smacking, chewing, and fumbling movements of the fingers—are common during an attack but may be subtle. Postural tone may be slightly decreased or increased, and occasionally there is a mild vasomotor disorder. As a rule, such patients do not fall; they may even continue complex acts such as walking or riding a bicycle. After 2 to 10 s, occasionally longer, the patient reestablishes full contact with the environment and resumes his preseizure activity. Only a loss of the thread of conversation or the place in reading betrays the occurrence of the momentary “blank” period (the absence). In many such patients, voluntary hyperventilation for 2 to 3 min is an effective way of inducing absence attacks.
Typical absence seizures constitute the most characteristic epilepsy of childhood (“childhood absence”); rarely do the seizures begin before 4 years of age or after puberty. Another attribute is their great frequency (hence, the old term pykno, meaning “compact” or “dense”). As many as several hundred may occur in a single day, sometimes in bursts at certain consistent times of the day. They produce periods of inattention and may appear in the classroom when the child is sitting quietly rather than participating actively in his lessons. If frequent, they disturb attention and thinking to the point that the child’s performance in school is impaired. Less frequently, such attacks may last for hours with no interval of normal mental activity between them—so-called absence or petit mal status. Absence epilepsy of adolescent onset (“juvenile absence”) does not have the very high seizure frequency of the childhood type. Cases of absence status have also been described in adults with frontal lobe epilepsy (see in the following text). In contrast to childhood absence seizures, the disorder may last well into adulthood and be punctuated by generalized tonic-clonic seizures or a burst of seizures. Akinesia (motionlessness) is not unique to any seizure type.
The typical absence, with or without myoclonic jerks, rarely causes the patient to fall. Absence should be considered a separate entity because of its relative benignity. It may be the only type of seizure during childhood. The attacks tend to diminish in frequency in adolescence and then often disappear, only to be replaced in many instances by major generalized seizures. About one-third of children with absence attacks will, in addition, display symmetrical or asymmetrical myoclonic jerks without loss of consciousness, and about half will at some time have major generalized (tonic-clonic) convulsions.
Distinguished from typical absence seizures are variants in which the loss of consciousness is less complete or in which myoclonus is prominent, and others in which the EEG abnormalities are less regularly of a 3-per-second spike-and-wave type (they may occur at the rate of 2 to 2.5 per second or take the form of irregular 4- to 6-Hz polyspike-and-wave complexes). Atypical absence is a term that was introduced to describe long runs of slow spike-and-wave activity, usually with no apparent loss of consciousness. External stimuli, such as asking the patient to answer a question or to count, interrupt the run of abnormal EEG activity. The current classification (Fig. 15-1) separates the disorder into groups that are identified as typical, atypical, and having special features, namely, myoclonic jerks or eyelid myoclonus.
In sharp contrast to the typical absence epilepsies, is a form that has its onset between 2 and 6 years of age and is characterized by atonic, or astatic, seizures (i.e., falling attacks), often succeeded by various combinations of minor motor, tonic-clonic, and partial seizures and by progressive intellectual impairment in association with a distinctive, slow (1- to 2-Hz) spike-and-wave EEG pattern. This is the Lennox-Gastaut syndrome. Often it is preceded in earlier life by infantile spasms, a characteristic high-amplitude chaotic EEG picture (hypsarrhythmia), and an arrest in mental development, a triad sometimes referred to as the West syndrome (see further on). The early onset of atonic seizures with abrupt falls, injuries, and associated abnormalities nearly always has a grave implication—namely, the presence of serious neurologic disease. Prematurity, perinatal injury and metabolic diseases of infancy are the most common underlying conditions. This is essentially a form of symptomatic generalized epilepsy, in contrast to the foregoing idiopathic types such as typical absence epilepsy (petit mal). The Lennox-Gastaut syndrome may persist into adult life and is one of the most difficult forms of epilepsy to treat.
The phenomenon of myoclonus was discussed in Chap. 4, where the relationship to seizures was emphasized. Characterized by a brusque, brief, muscular contraction, some myoclonic jerks may be so small as to involve only one muscle or part of a muscle; others are so large as to displace a limb on one or both sides of the body or the entire trunk musculature. Many are brief, lasting 50 to 100 ms; they may occur intermittently and unpredictably or present as a single jerk or a brief salvo.
As mentioned earlier, a series of several small, rhythmic myoclonic jerks may appear with varying frequency as part of atypical absence seizures, and as isolated events in patients with generalized clonic-tonic-clonic or tonic-clonic seizures. As a rule, seizure-associated myoclonus, when occurring in isolation, is relatively common, signifies nothing more than the seizure disorder, and usually responds well to antiepileptic medication. In contrast, there are diseases in which myoclonus is progressive in severity or very frequent. These disorders have their onset in childhood and raise the suspicion of entities such as the myoclonus-opsoclonus-ataxia syndrome, lithium or other drug toxicity or, if lasting a few weeks, subacute sclerosing panencephalitis. Chronic progressive polymyoclonus with dementia characterizes the group of juvenile lipidosis (see Chap. 36), Lafora-type familial myoclonic epilepsy, certain mitochondrial disorders, and other chronic familial degenerative diseases of undefined type (paramyoclonus multiplex of Friedreich) as noted further on in Table 15-3. The large number of adult diseases causative of myoclonus and seizure disorders are discussed in later chapters. Myoclonus as a phenomenon is further described in Chap. 4.
Juvenile Myoclonic Epilepsy
This is the most common form of idiopathic generalized epilepsy in older children and young adults. It begins in adolescence, typically around age 15 years, with a range that essentially spans all of the teenage years. The patient comes to attention because of a generalized tonic-clonic seizure, often upon awakening or because of myoclonic jerks in the morning that involve the entire body; sometimes absence seizures are prominent. The family reports that the patient has occasional myoclonic jerks of the arm and upper trunk that is brought out with fatigue, early stages of sleep, or alcohol ingestion. A few patients in our experience have had only the myoclonic phenomena and rare absence or tonic-clonic seizures that persisted unnoticed for years. The EEG shows characteristic bursts of 4- to 6-Hz irregular polyspike activity. A linkage has been established to several loci, mainly of ion channels and of GABA-related receptors.
The disorder does not impair intelligence and tends not to be progressive, for which reason it has been called “benign,” but a proclivity to infrequent seizures usually continues throughout life. A report by Baykan and colleagues has indicated that, over an average of two decades, the majority of patients have long seizure-free periods and a large reduction in myoclonic seizures by the fourth decade but only one-fifth become virtually seizure free. Valproic acid in particular and some other antiepileptic drugs are highly effective in eliminating the seizures and myoclonus but they should be continued indefinitely as discontinuation of medication is associated with a high rate of relapse. Owing to the potential teratogenicity of valproate, women of childbearing age are often given levitiracetam or lamotrigine, acknowledging that they may not be as effective as the first choice of drug. It has been observed that carbamazepine and phenytoin may exaggerate the seizures.
As indicated earlier, the International Classification divides all seizures into two types—generalized, in which the clinical and EEG manifestations indicate bilateral and diffuse cerebral cortical involvement from the onset, and focal, in which the seizure is often the product of a demonstrable focal lesion or EEG abnormality in some part of the cerebral cortex. The manifestations of focal seizures reflect the locale of the lesion. In the past focal seizures were classified by whether consciousness was retained (partial) or impaired (complex), but are now subsumed under the term “dyscognitive” if awareness is altered. Focal seizures with sensory or motor features at the onset most often arise from foci in the sensorimotor cortex. Those with impairment of consciousness, which occurs in many forms, most often have their focus in the limbic and autonomic areas or in the temporal lobe, but a frontal localization is also known. Table 15-2 lists the common sites of the lesions and the corresponding types of seizures.
Table 15-2COMMON FOCAL SEIZURE PATTERNS ||Download (.pdf) Table 15-2COMMON FOCAL SEIZURE PATTERNS
|CLINICAL TYPE ||LOCALIZATION |
|Somatic Motor |
|Jacksonian (focal motor) ||Prerolandic gyrus |
|Masticatory, salivation, speech arrest ||Amygdaloid nuclei, opercular |
|Simple contraversive ||Frontal |
|Head and eye turning associated with arm movement or athetoid-dystonic postures ||Supplementary motor cortex |
|Somatic and Special Sensory (Auras) |
|Somatosensory ||Contralateral postrolandic |
|Unformed images, lights, patterns ||Occipital |
|Auditory ||Heschl gyri |
|Vertiginous ||Superior temporal |
|Olfactory ||Mesial temporal |
|Gustatory ||Insula |
|Visceral: autonomic ||Insular-orbital-frontal cortex |
|Focal Seizure with Altered Consciousness |
|Formed hallucinations ||Temporal neocortex or amygdaloid–hippocampal complex |
|Illusions ||— |
|Dyscognitive experiences (déjà vu, dreamy states, depersonalization) ||— |
|Affective states (fear, depression, or elation) ||Temporal |
|Automatism (ictal and postictal) ||Temporal and frontal |
|Staring ||Frontal cortex, amygdaloid–hippocampal complex, reticular–cortical system |
Relatively few focal seizures can be localized precisely from clinical data alone. However, when combined with scalp and intracranial EEG recording and MRI, the localization is reasonably accurate.
Frontal Lobe Seizures (Focal Motor and Jacksonian Seizures)
Focal motor seizures are attributable to a discharging lesion of the frontal lobe. A common type, originating in the supplementary motor area, takes the form of a turning movement of the head and eyes to the side opposite the irritative focus, often associated with a tonic extension of limbs, also on the side contralateral to the affected hemisphere. This may constitute the entire seizure, or it may be followed by generalized clonic movements. The extension of the limbs may occur just before or simultaneously with loss of consciousness but a lesion in one frontal lobe may give rise to a major generalized convulsion without an initial turning of the head and eyes. It has been postulated that, if there is loss of consciousness, it is the result of a rapid spread of the discharge from the frontal lobe to integrating centers in the thalamic or high midbrain reticular formation.
One form of focal frontal convulsion is the Jacksonian motor seizure, which begins with tonic and then clonic contraction of the fingers of one hand, the face on one side, or the muscles of one foot. Sometimes a series of clonic movements of increasing frequency build up to a tonic contraction. The characteristic feature is that the movements spread (march) from the part first affected to other contiguous muscles on the same side of the body. In its typical form, the seizure spreads from the hand, up the arm, to the face, and down the leg; or if the first movement is in the foot, the seizure marches up the leg, down the arm, and to the face, usually in a matter of 20 to 30 s. Rarely, the first muscular contraction is in the abdomen, thorax, or neck. In some cases, the one-sided seizure activity is followed by turning of the head and eyes to the convulsing side, occasionally to the opposite side, and then by a generalized seizure with loss of consciousness. Consciousness is not lost if the sensorimotor symptoms remain confined to one side.
The frontal lobe, being so large, can give rise to numerous forms of seizure including the typical Jacksonian type described above, but also adversive (contralateral turning of the body or of a body part), speech arrest, frontal, absence types, and a number of unusual disorders related to discharges from the supplementary motor area including hyperkinetic and postural tonic varieties. In practice, it is often difficult to distinguish such seizures from parasomnic (sleep related) events (see Chap. 18).
Focal motor seizures may begin with forceful, sustained deviation of the head and eyes, and sometimes of the entire body, are referred to as versive or adversive. The turning movements are usually to the side opposite the electrical focus but sometimes, to the same side. The same is true for the head and eye turning that occurs at the end of the generalized tonic-clonic phase of seizures (Wylie et al). In seizures of temporal lobe origin, early in the seizure, there may be head turning ipsilaterally followed by forceful, contraversive head (and body) turning. These head and body movements, if they occur, may be preceded by quiet staring or automatisms. Nonforceful, unsustained, or seemingly random lateral head movements during the ictus do not have localizing value and suggest that the phenomena are epileptic.
Following convulsions that have a prominent focal motor signature, there is often a transient paralysis of the affected limbs. This “Todd paralysis” persists for minutes or at times for hours after the seizure, usually in proportion to the duration of the convulsion. Continued focal paralysis beyond this time usually indicates the presence of a focal brain lesion as the underlying cause of the seizure or persisting seizures in a nonconvulsive form. A similar Todd phenomenon is found in cases of focal epilepsy that involve the language, somesthetic, or visual areas; here the persistent deficit corresponds to the region of brain affected.
The high incidence of focal motor epilepsy that originates with movements in the face, hands, and toes is probably related to the disproportionately large cortical representation of these parts. Contraversive deviation of only the head and eyes can be induced most consistently by electrical stimulation of the superolateral frontal region (area 8), just anterior to area 6 (see Figs. 21-1 and 21-2). The disease process or focus of excitation is usually in or near the rolandic (motor) cortex, that is, area 4 of Brodmann (see Figs. 3-3 and 22-2); in some cases, and especially if there is a sensory accompaniment, it has been found in the postrolandic convolution.
Lesions confined to the motor cortex are reported to assume the form of clonic contractions, and those confined to the premotor cortex (area 6), tonic contractions of the contralateral arm, face, neck, or all of one side of the body. Tonic elevation and extension of the contralateral arm and flexion of the ipsilateral arm (fencing posture) and choreoathetotic and dystonic postures have been associated with high medial frontal lesions (area 8 and supplementary motor cortex), as have complex, bizarre, and flailing movements of a contralateral limb, but this always raises the suspicion of a nonepileptic phenomenon. Perspiration and piloerection occur occasionally in parts of the body involved in a focal motor seizure, suggesting that these autonomic functions have a cortical representation in or adjacent to the rolandic area. Focal motor and Jacksonian seizures have essentially the same localizing significance.
Seizure discharges arising from the cortical language areas may give rise to a brief aphasic disturbance (ictal aphasia) and ejaculation of a word or loud sound or, more frequently, a vocal arrest. Ictal aphasia is usually succeeded by other focal or generalized seizure activity but may occur in isolation, without loss of consciousness, in which case it can later be described by the patient. Postictal aphasia is more common than ictal aphasia. Verbalization at the onset of a seizure has no consistent lateralizing significance and, paradoxically, is usually associated with an origin in the nondominant hemisphere. These disturbances should be distinguished from the stereotyped repetition of words or phrases or the garbled speech that characterizes some complex partial seizures or the postictal confusional state and, of course, Wernicke aphasia.
Somatosensory, Visual, and Other Types of Sensory Seizures
Somatosensory seizures, either focal or “marching” to other parts of the body on one side, are nearly always indicative of a focus in or near the postrolandic convolution of the opposite cerebral hemisphere. Penfield and Kristiansen found the seizure focus in the postcentral or precentral convolution in 49 of 55 such cases. The sensory disorder is usually described as numbness, tingling, or a “pins-and-needles” feeling and occasionally as a sensation of crawling (formication), electricity, or movement of the part. Pain and thermal sensations may occur but are exceedingly rare. In the majority of cases, the onset of the sensory seizure is in the lips, fingers, or toes, and the spread to adjacent parts of the body follows a pattern determined by sensory arrangements in the postcentral (postrolandic) convolution of the parietal lobe see Salanova et al). If the sensory symptoms are localized to the head, the focus is in or adjacent to the lowest part of the convolution, near the sylvian fissure; if the symptoms are in the leg or foot, the upper part of the convolution, near the superior sagittal sinus or on the medial surface of the hemisphere, is involved.
Olfactory hallucinations, perhaps the most important of the sensory seizures because they signify a particular localization, are associated with disease of the inferior and medial parts of the temporal lobe, usually in the region of the parahippocampal convolution or the uncus [hence Jackson’s term uncinate seizures (see also Chap. 11)]. Usually the perceived odor is exteriorized, that is, projected to someplace in the environment, and is described as disagreeable or foul, though otherwise unidentifiable. Gustatory hallucinations also have been recorded in proven cases of temporal lobe disease and less often with lesions of the insula and parietal operculum; salivation and a sensation of thirst may be associated. Electrical stimulation in the depths of the sylvian fissure, extending into the insular region, has produced peculiar sensations of taste.
Visual seizures are relatively rare but also have localizing significance. Lesions in or near the striate cortex of the occipital lobe usually produce elemental visual sensations of darkness or sparks and flashes of light, which may be stationary or moving and colorless or colored. According to Gowers, red is the most frequently reported color, followed by blue, green, and yellow. These images may be referred to the visual field on the side opposite of the lesion or may appear straight ahead. If they occur on one side of the visual field, patients perceive that only one eye is affected (the one opposite the lesion), probably because most persons are aware of only the temporal half of a homonymous field defect. Curiously, a seizure arising in one occipital lobe may cause momentary blindness in both fields. It has been noted that lesions on the lateral surface of the occipital lobe (Brodmann areas 18 and 19) are likely to cause a sensation of twinkling or pulsating lights. More complex or formed visual hallucinations are usually caused by a focus in the posterior part of the temporal lobe, near its junction with the occipital lobe, and may be associated with auditory hallucinations. The localizing value of visual auras has been confirmed by Bien and colleagues (2000) in a group of 20 surgically treated patients with intractable seizures. They found that elementary visual hallucinations and visual loss were typical of occipital lobe epilepsy but could also occur with seizure foci in the anteromedial temporal and occipitotemporal regions. Reference is made here to the childhood occipital seizure disorder described by Panayiotopoulos, discussed further on. These patients experience rudimentary visual hallucinations. One interesting feature that we have observed is of extreme turning of the head and eyes toward the visual images.
Auditory hallucinations are infrequent as an initial manifestation of a seizure and usually represent a psychotic disorder or one of several more benign conditions. Occasionally, a patient with a focus in one superior temporal convolution will report a buzzing or roaring in the ears. A human voice, sometimes repeating unrecognizable words, or the sound of music has been noted a few times with lesions in the more posterior part of one temporal lobe. Some people with epilepsy and a strong family history of seizures with auditory auras, may have normal imaging but turn out to have mutations in the LGI1 gene.
Vertiginous sensations of a type suggesting a vestibular origin may on rare occasions be the first symptom of a seizure. The lesion is usually located in the superoposterior temporal region or the junction between parietal and temporal lobes. In one of the cases reported by Penfield and Jasper, a sensation of vertigo was evoked by stimulating the cortex at the junction of the parietal and occipital lobes. Occasionally with a temporal focus, the vertigo is followed by an auditory sensation. Giddiness, or light-headedness, is a frequent prelude to a seizure, but this symptom, as discussed in Chap. 14, has so many different connotations that it is of little diagnostic value.
Vague and often indefinable visceral sensations arising in the thorax, epigastrium, and abdomen are among the most frequent of auras, as already indicated. Most often they have a temporal lobe origin, although in several such cases the seizure discharge has been localized to the upper bank of the sylvian fissure, in the upper or middle frontal gyrus, or in the medial frontal area near the cingulate gyrus. Palpitation and acceleration of the heart rate at the beginning of the attack have also been related mainly to a temporal lobe focus.
Temporal Lobe Seizures (Characterized by Altered Responsiveness, Complex Partial Seizures, Psychomotor Seizures)
These differ from the major generalized and absence seizures discussed above in that (1) they signify a focal onset in the temporal lobe as reflected by an aura that may be a hallucination or perceptual illusion, or (2) a period of altered behavior and incomplete impairment of consciousness, a dyscognitive state, in contrast to the loss of connection to the environment typical of absence epilepsy.
Although it is difficult to enumerate all the psychic experiences that may occur during these types of seizures, they may be categorized as illusions, hallucinations, depersonalization states, and affective experiences. Among the altered psychic states are a feeling of intense perception of familiarity in an unfamiliar circumstance or place (déjà vu) or, conversely, of strangeness or unfamiliarity (jamais vu) in a previously known place or circumstance. There may be the experience of autoscopy, a type of depersonalization, or dream-like state in which the patient views himself as an external observer. Fragments of certain old memories or scenes may insert themselves into the patient’s mind and recur with striking clarity, or there may be an abrupt interruption of memory. (See Gloor for a more detailed description of the experiential phenomena of temporal lobe epilepsy.) Sensory illusions, or distortions of ongoing perceptions, are the most common. Objects or persons in the environment may shrink or recede into the distance, or they may enlarge (micropsia and macropsia), or perseverate as the head is moved (palinopsia). Tilting of the visual environment has been reported. Hallucinations are most often visual or auditory, consisting of formed or unformed visual images, sounds, and voices; less frequently, they may be olfactory (usually unpleasant, unidentifiable sensations of smell), gustatory, or vertiginous. Associated epigastric and abdominal sensations have been alluded to above and likely have their origin in autonomic and limbic structures.
Emotional experiences as a result of seizure, while less common, may be dramatic—fear, anxiety, sadness, anger, happiness, ecstasy, and sexual excitement have all been recorded. Fear and anxiety are the most common affective experiences, while occasionally the patient describes a feeling of rage or intense anger as part of a temporal lobe seizure.
Each of these subjective psychic states may constitute the entire seizure or some combination may occur and immediately precedes a period of altered awareness. These “auras” represent electrical seizures as already mentioned and have the same localizing significance as motor convulsions do for the frontal cortex. All the temporal lobe ictal experiences have no apparent connection to objective circumstances and are generally not related to the situation in which the patient finds himself during the seizure.
The motor components of a focal temporal lobe or limbic seizure, if they occur, arise during the later phase of the seizure and take the form of automatisms such as lip-smacking, chewing or swallowing movements, salivation, fumbling of the hands, or shuffling of the feet. Patients may walk around in a daze or act inappropriately. Complex acts that were initiated before the loss of consciousness—such as walking, chewing food, turning the pages of a book, or even driving—may continue. However, when asked a specific question or given a command, the patients are obviously out of contact with their surroundings. There may be no response at all, or the patient may look toward the examiner in a perplexed way or utter a few stereotyped phrases. The patient may walk repetitively in small circles (volvular epilepsy), run (epilepsia procursiva), or simply wander aimlessly, either as an ictal or postictal phenomenon (poriomania). These forms of seizure, according to some epileptologists, are actually more common with frontal lobe than with temporal lobe foci of origin. Dystonic stiffness of the arm and leg contralateral to the seizure focus is found to be an accompaniment of temporal lobe seizures (more often this is from the supplementary motor of the frontal than the temporal lobes).
In a small number of patients with temporal lobe seizures (7 of 123 patients studied by Ebner et al), some degree of responsiveness (to simple questions and motor commands) is preserved in the presence of prominent automatisms such as lip-smacking and swallowing. Interestingly, the seizures originate in the right temporal lobe. That consciousness should be altered with temporal lobe epilepsy is not at all self-evident. Several mechanisms have been studied, particularly by Blumenfeld’s group, and converge on the effects of temporal lobe discharge on deep structures such as the medial thalamus and the septal nuclei. Amnesia is an important component of the alteration in the state of consciousness in temporal lobe epilepsy but does not explain the entire syndrome.
The patient, in a confused and irritable state, may resist or strike out at the examiner. These types of behaviors, which occur in a limited number of patients with temporal lobe or frontal seizures, usually take the form of nondirected oppositional resistance to restraint. These behaviors manifest during a period of automatic behavior (so called because the patient presumably acts like an automaton) or, more often, in the postictal period. Unprovoked assault or outbursts of intense rage or blind fury are very unusual; Currie and associates found such outbursts in only 16 of 666 patients (2.4 percent) with temporal lobe epilepsy. Penfield once commented that he had never observed a rage state as a result of temporal lobe stimulation. It is exceedingly unlikely that an organized violent act requiring several sequential steps in its performance, such as obtaining a weapon and using it in a directed manner, could represent a temporal lobe seizure.
Rarely, laughter may be the most striking feature of a seizure (gelastic epilepsy). A particular combination of gelastic seizures and precocious puberty has been traced to a hamartoma of the hypothalamus. Crying, or dacrystic epilepsy, on the other hand, while demonstrated in children, is very infrequent and more often indicates a psychogenically induced episode.
The patient with temporal lobe seizures may exhibit only one of the foregoing manifestations of seizure activity or various combinations. In a series of 414 patients studied by Lennox, 43 percent displayed some of the motor changes; 32 percent, automatic behavior; and 25 percent, alterations in psychic function. Because of the frequent concurrence of these symptom complexes, he referred to them as the psycho-motor triad. Probably the clinical pattern varies with the precise locality of the lesion and the direction and extent of spread of the electrical discharge.
After the attack, the patient usually has no memory or only fragments of recall for what was said or done. Any type of complex partial seizures may proceed to other forms of secondary generalized seizures. The tendency to generalization holds true for all types of partial or focal epilepsy.
Temporal lobe seizures are not peculiar to any period of life, but they do show an increased incidence in adolescence and the adult years and have an uncertain relationship to childhood febrile seizures. The topic of febrile seizures is broader than this association suggests; it is taken up in a later section of the chapter. Neonatal convulsions, head trauma, and various other nonprogressive perinatal neurologic disorders are other antecedents that place a child at risk of developing complex partial seizures (Rocca et al). Two-thirds of patients with temporal lobe seizures also have generalized tonic-clonic seizures or have had them in early childhood, and it has been theorized that the generalized seizures may have led to secondary excitotoxic damage to the hippocampal portions of the temporal lobes. In the latter cases, carefully performed and quantitated MRI in the coronal plane may disclose a loss of volume and gliosis in the hippocampi and adjacent gyri on one or both sides—that is, medial (or mesial) temporal sclerosis, discussed later in the chapter (Fig. 15-4).
Medial temporal sclerosis. A. T1-weighted MRI in the coronal plane, showing reduced volume of the left hippocampus (shown by arrow) and secondary enlargement of the adjacent temporal horn of the lateral ventricle. B. Coronal T2-FLAIR image showing abnormal hyperintense signal within the left hippocampus (shown by arrow).
Temporal lobe seizures are highly variable in duration. Behavioral automatisms rarely last longer than a minute or two, although postictal confusion and amnesia may persist for a considerably longer time. Some consist only of a momentary change in facial expression and a blank spell, resembling an absence. Almost always, however, temporal lobe events are characterized by distinct ictal and postictal phases, whereas patients with absence attacks usually have an instantaneous return of full consciousness following the ictus.
Postictal behavior after temporal lobe seizures is often accompanied by widespread or focal slowing in the EEG. Prolonged disorientation for time and place suggests a right-sided source. Automatisms in the postictal period have no lateralizing connotation (Devinsky et al). However, postictal posturing and paresis of an arm (Todd’s paralysis) or an aphasic difficulty are helpful in determining the side of the lesion (Cascino). Postictal nose wiping, which is reported on video recording to occur in half of patients with temporal lobe seizures, is carried out by the hand ipsilateral to the seizure focus according to Leutzmezer and colleagues.
Amnesic Seizures (Transient Epileptic Amnesia)
Rarely, recurrent attacks of transient amnesia are the only manifestations of temporal lobe epilepsy, although it is unclear whether the amnesia in such patients represents an ictal or postictal phenomenon. These attacks of pure amnesia have been referred to as transient epileptic amnesia (TEA; Palmini et al; Zeman et al). If the patient functions at a fairly high level during the attack, as may happen, there is a resemblance to transient global amnesia (described in Chap. 20). However, in contrast to transient global amnesia, the relative brevity and frequency of the amnesic spells, their tendency to occur on awakening, the impaired performance on complex cognitive tasks, and the absence of repetitive stereotyped questions help to make the distinction.
MEDICAL AND PSYCHIATRIC ASPECTS OF EPILEPSY
Behavioral and Psychiatric Disorders With Epilepsy
Some comments are in order concerning the issues of behavioral and psychiatric disorders in patients who have seizures. Data as to prevalence of these disorders have been derived mainly from studies of selected groups of patients attending specialty clinics that tend to treat the most difficult and complicated cases. In one such study (Victoroff), approximately one-third of epileptic patients had a history of major depressive illness, and an equal number had symptoms of anxiety disorder; psychotic symptoms were found in 10 percent. Similar figures, also from a university-based epilepsy center, have been reported by Blumer et al. It must be emphasized that these remarkably high rates of psychiatric morbidity do not reflect the prevalence in the entire population of patients with epilepsy. Epidemiologic studies provide only limited evidence of an association with psychosis in the overall population of epileptics (see Trimble and the review by Trimble for a critical discussion of this subject). Furthermore, it should be borne in mind that many chronic medical conditions are associated with psychiatric reactions. On the other hand, the unpredictability and stigma of the epileptic disorders may contribute to depression and anxiety.
The postictal state in patients with temporal lobe epilepsy rarely incorporates a protracted paranoid-delusional or amnesic psychosis lasting for days or weeks. The EEG during this period may show no seizure discharge, although this does not exclude repeated seizures in temporal lobe structures that are remote from the recording electrodes. This disorder, virtually indistinguishable from psychosis, may also present in the interictal period.
It had been observed that some patients with temporal lobe seizures may exhibit a number of personal peculiarities. It was stated that they are slow and rigid in their thinking, verbose, circumstantial and tedious in conversation, inclined to mysticism, and preoccupied with rather naive religious and philosophical ideas. Obsessionalism, humorless sobriety, emotionality (mood swings, sadness, and anger), and a tendency to paranoia are other frequently described traits. Diminished sexual interest and potency in men and menstrual problems in women, not readily attributable to antiepileptic drugs, are common among patients with complex partial seizures of temporal lobe origin. Geschwind proposed that a triad of behavioral abnormalities—hyposexuality, hypergraphia, and hyperreligiosity—constitutes a characteristic syndrome but this has been disputed.
Bear and Fedio suggested that certain personality traits were more common with right temporal lesions, and that anger, paranoia, and cosmologic or religious conceptualizing are more characteristic of left temporal lesions. However, Rodin and Schmaltz found no features that would distinguish foci on either side and they found no behavioral changes that would distinguish patients with temporal lobe epilepsy from other groups of epileptics. The problem of personality disturbances in epilepsy has not been clarified and many modern clinicians no longer identify these traits as parts of the epileptic syndrome, having in the past been imputed to these patients by societal and medical biases (see review by Trimble) but even this is open to other interpretation.
Sudden Unexplained Death in Epilepsy
In the past few decades, sudden death has been emphasized as an underappreciated problem in the epileptic population. Certainly, the mortality in individuals with epilepsy is increased ostensibly from accidents, suicide, and the underlying cause of seizures. However, the main contributor to the increased mortality rate in otherwise healthy people with epilepsy is unexpected death outside of circumstances such as drowning, trauma from a fall, myocardial infarction, and automobile accidents during the seizure. It is to this group that the acronym “SUDEP,” or sudden unexplained death in epilepsy, has been applied. Surprisingly, unexpected death is predominantly an issue of adulthood more than of childhood. The rate of unexpected death increases with the duration and severity of epilepsy and several population studies suggest that the rate may be as high as several-fold higher than in age matched individuals in the general population. The rate of this entity is generally given as approximately 0.35 cases per 1,000 person years but with severe epilepsy, and as high as 3 to 9 per 1,000 person years, as summarized by Leestma and colleagues. Most patients affected have a history of generalized tonic-clonic seizures and die in bed. In children, those with treatment resistant epilepsy, developmental delay and several syndromes such as tuberous sclerosis are at particular risk.
Several factors have emerged as risks from population-based and cohort case controlled studies; the postictal period immediately after a tonic clonic seizure, increasing seizure frequency (including three generalized seizures in the preceding year), lack of successful treatment (i.e., patients not in remission as documented in a 40-year follow-up of childhood epilepsy by Sillanpää and Shinnar), or subtherapeutic levels of antiepileptic drugs, the period of early adulthood, long-standing epilepsy, and mental retardation.
Most instances of SUDEP occur when the patient is unattended or during sleep. Although respiratory difficulty and cardiac changes including asystole and ventricular arrhythmias are known to occur during and immediately after seizures, none of these has been a consistent factor and usually, the precise mechanism of death has been difficult to determine. A postictal “shutdown” of brainstem activity resulting in hypercapnia or hypoxemia has been suggested but there may be various causes operative in different cases.
One approach to preventing sudden death is adequate treatment with antiepileptic drugs. The risk of sudden death is as high as 20 times greater for untreated patients. Some specialists in the field of epilepsy have suggested that an open conversation be undertaken about the problem with patients and their families. More often, neurologists raise the issue only in high risk patients or when specifically asked. A review of this subject has been provided by Devinsky.
SPECIAL EPILEPTIC SYNDROMES
There remain to be considered several epileptic syndromes and other seizure states that cannot be readily classified with the usual types of generalized or partial seizures. Many of these, particularly the first four entities discussed below, have been found to have a genetic basis, typically involving an ion channel disorder.
Benign Epilepsy of Childhood With Centrotemporal Spikes (Rolandic Epilepsy, Sylvian Epilepsy)
This common focal motor epilepsy is unique among the focal epilepsies of childhood in that it is self-limiting despite a very abnormal EEG pattern. It is usually transmitted in families as an autosomal dominant trait and begins between 5 and 9 years of age. It typically announces itself by a nocturnal tonic-clonic seizure with focal onset. Thereafter, the seizures take the form of clonic contractions of one side of the face, less often of one arm or leg, and the interictal EEG shows high-voltage spikes in the contralateral lower rolandic or centrotemporal area. Seizures are readily controlled by a single anticonvulsant drug and gradually disappear during adolescence. The relation of this syndrome to developmental dyslexia is unsettled.
Epilepsy with Occipital Spikes (Panayiotopoulos Syndrome)
A similar type of epilepsy, usually benign in the sense that there is no intellectual deterioration and the seizures often cease in adolescence, has been associated with spike activity over the occipital lobes as identified by Panayiotopoulos. Visual hallucinations, while not invariable, are the most common clinical feature, according to the review by Taylor and colleagues; sensations of movements of the eyes, tinnitus, or vertigo are also reported in cases of occipital epilepsy. These authors point out symptomatic causes of the syndrome, mainly cortical heterotopias. Autonomic overactivity is prominent with the seizures in some children. In both of these types of childhood epilepsy the observation that spikes are greatly accentuated by sleep is a useful diagnostic feature.
Infantile Spasms (West Syndrome)
This term is applied to a special and particularly dramatic form of epilepsy of infancy and early childhood. West, in the mid-nineteenth century, described the condition in his son in great detail. This disorder, which in most cases appears during the first year of life, is characterized by recurrent, single or brief episodes of gross flexion movements of the trunk and limbs and, less frequently, by extension movements (hence the alternative terms infantile spasms or salaam or jackknife seizures). Most but not all patients with this disorder show major EEG abnormalities consisting of continuous multifocal spikes and slow waves of large amplitude. However, this pattern, named by Gibbs and Gibbs as hypsarrhythmia (“mountainous” dysrhythmia), is not specific for infantile spasms, being frequently associated with other developmental or acquired abnormalities of the brain. As the child matures, the seizures diminish and usually disappear by the fourth to fifth year. If MRI and CT scans are more or less normal, the usual pathologic findings according to Jellinger are cortical dysgeneses. Both the seizures and the EEG abnormalities may respond dramatically to treatment with adrenocorticotropic hormone (ACTH), corticosteroids, or the benzodiazepine drugs, of which clonazepam is probably the most widely used. A type of West syndrome that is caused by tuberous sclerosis also responds dramatically to gamma-aminobutyric acid (GABA)-inhibiting drugs such as vigabatrin, as noted below. However, most patients, even those who were apparently normal when the seizures appeared, are left mentally impaired. Infantile spasms may later progress to the Lennox-Gastaut syndrome, a seizure disorder of early childhood of graver prognosis as discussed in a previous section.
The well-known uncomplicated febrile seizure, specific to infants and children between 6 months and 5 years of age (peak incidence ages 9 to 20 months) and with a strong inherited tendency, is generally regarded as a benign condition. The frequency has been estimated to be approximately 4 per 1,000 children under the age of 5 but reportedly twice as high in Japanese children. It usually takes the form of a single, generalized motor seizure occurring as the patient’s core temperature rises or reaches its peak. Seldom does the seizure last longer than a few minutes and by the time an EEG can be obtained, there is no abnormality and recovery is complete. The seizures do not recur during the same episode of fever. The temperature is usually above 38°C (100.4°F).
Any viral or bacterial illness, or, rarely, an immunization, may be the precipitant of the fever; herpesvirus 6 is one of the common precipitants, probably because of its tendency to cause high fever. Prophylactic antiepileptic drugs have not been found to be helpful in preventing febrile seizures. Except for a presumed genetic relationship with benign epilepsy of childhood (Luders et al), which in itself is transient in nature, these patients’ risk of developing epilepsy in later life is only slightly greater than that of the general population. In some families, such as those studied by Nabbout and colleagues, febrile seizures alone, without generalized epilepsy, have been associated with a particular gene by linkage analysis. Presumably, when the gene products are identified, some insight into the nature of defects that lower the seizure threshold will be forthcoming.
This benign type of febrile seizure should not be confused with more serious illnesses in which a febrile acute encephalitic or encephalopathic state causes focal or prolonged seizures, generalized or focal EEG abnormalities, and repeated episodes of febrile convulsions during a febrile illness (complex febrile seizures). In these cases, these seizures may recur not only with infections but also at other times. When patients with both types are combined together under the rubric of febrile convulsions, it is not surprising that a high percentage are complicated by later atypical petit mal, atonic, and astatic spells followed by tonic seizures, mental retardation, and partial complex epilepsy. In a study of 67 patients with medial temporal lobe epilepsy by French and colleagues, 70 percent had a history of complex febrile seizures during the first 5 years of life, although many did not again develop seizures until their teens. Bacterial meningitis was an important risk factor; head and birth trauma were less-common factors. Epidemiologic studies have substantiated this clinical point of view. Annegers and colleagues observed a cohort of 687 children for an average of 18 years after their initial febrile convulsion. Overall, these children had a fivefold excess of unprovoked seizures in later life. Among the children with simple febrile convulsions, the risk was only 2.4 percent. By contrast, children with what Annegers and colleagues called complex febrile convulsions (focal, prolonged, or repeated episodes of febrile seizures) had a greatly increased risk—8, 17, or 49 percent, depending on the association of one, two, or three of the complicating features.
It has been appreciated for a long time that seizures can be evoked in certain individuals by a discrete physiologic or psychologic stimulus. The term reflex epilepsy is reserved for this small subgroup. Forster classified these seizures in accordance with their evocative stimuli into five types: (1) visual—flickering light, visual patterns, and specific colors (especially red), leading to rapid blinking or eye closure; (2) auditory—sudden unexpected noise (startle), specific sounds, musical themes, and voices; (3) somatosensory—either a brisk unexpected tap or sudden movement after sitting or lying still, or a prolonged tactile or thermal stimulus to a certain part of the body; (4) writing or reading of words or numbers; and (5) eating.
Visually induced seizures are by far the most common type. The seizures are usually myoclonic but may be generalized and triggered by the photic stimulation of television or an EEG examination or by the photic or pattern stimulation of video games. In other types of reflex epilepsy, the evoked seizure may be focal (beginning often in the part of the body that was stimulated) or generalized and may take the form of one or a series of myoclonic jerks or of an absence or tonic-clonic seizure. Seizures induced by reading, voices, or eating are most often of the complex partial type; seizures induced by music are usually myoclonic, simple, or complex partial. A few such instances of reflex epilepsy have been caused by focal cerebral disease, particularly occipital lesions.
Many of the antiepileptic drugs are effective in controlling individual instances of reflex epilepsy. Some patients learn to avert the seizure by undertaking a mental task, for example, thinking about some distracting subject, counting, or by initiating some type of physical activity. Forster demonstrated that in certain types of reflex epilepsy, the repeated presentation of the stimulus may eventually render the trigger innocuous but this requires a great deal of time and reinforcement, which limits its therapeutic value.
Epilepsia Partialis Continua
This is a special type of focal motor epilepsy characterized by persistent rhythmic clonic movements of one muscle group—usually of the face, arm, or leg—which are repeated at fairly regular intervals every few seconds and continue for hours, days, weeks, or months without spreading to other parts of the body. Thus epilepsia partialis continua is, in effect, a highly restricted and very persistent focal motor status epilepticus. The distal muscles of the leg and arm, especially the flexors of the hand and fingers, are affected more frequently than the proximal ones. In the face, the recurrent contractions involve either the corner of the mouth or one or both eyelids. Occasionally, isolated muscles of the neck or trunk are affected on one side. The clonic activity may be accentuated by active or passive movement of the involved muscles and may be reduced in severity but not abolished during sleep.
First described by Kozhevnikov in patients with Russian spring-summer encephalitis, these ongoing partial seizures may be induced by a variety of acute or chronic cerebral lesions. In some cases the underlying disease is not apparent, and the clonic movements may be mistaken for some type of slow tremor or extrapyramidal movement disorder. Most patients with epilepsia partialis continua show focal EEG abnormalities, either repetitive slow-wave abnormalities or sharp waves or spikes over the central areas of the contralateral hemisphere. In some cases, the spike activity can be related precisely in location and time to the clonic movements (Thomas et al). In the series collected by Obeso and colleagues, there were various combinations of epilepsia partialis continua and cutaneous reflex myoclonus (cortical myoclonus occurring only in response to a variety of afferent stimuli).
As would be expected, a wide range of causative lesions has been implicated—developmental anomalies, encephalitis, demyelinative diseases, tumors, metabolic abnormalities, particularly hyperosmolarity, and degenerative diseases. Epilepsia partialis continua is particularly common in patients with the rare condition, Rasmussen encephalitis (see further on).
Whether cortical or subcortical mechanisms are responsible for epilepsia partialis continua is an unresolved question. The electrophysiologic evidence adduced by Thomas and colleagues favors a cortical origin; the pathologic evidence is less definite. In each of eight cases in which the brain was examined postmortem, they found some degree of involvement of the motor cortex or adjacent cortical area contralateral to the affected limbs. However, all but one of these patients also had some involvement of deeper structures on the same side as the cortical lesion, on the opposite side, or on both sides.
It is characteristic of the disorder to be resistant to treatment, often leading to the use of several antiepileptic drugs and still finding them to be ineffectual. At times, it is preferable to reduce the medications and their number in favor of producing fewer side effects. These judgments must be made in view of the disruption of daily life. Although exceptional cases may persist for a year or more, most resolve, leaving variable neurologic defects.
In 1958, Rasmussen described three children in whom the clinical problem consisted of intractable focal epilepsy (the epilepsia partialis continua described above) in association with a progressive hemiparesis. The cerebral cortex disclosed a mild meningeal infiltration of inflammatory cells and an encephalitic process marked by neuronal destruction, gliosis, neuronophagia, some degree of tissue necrosis, and perivascular cuffing. Many additional cases were soon uncovered and Rasmussen was able to summarize the natural history of 48 personally observed patients (see the often cited monograph by Andermann and the more recent review by Bien and colleagues 2005). Adult cases are known and they tend to have a milder and more protracted course as noted by Villani and coworkers. Some have focal cortical myoclonus.
An expanded view of the syndrome has added several interesting features. The affected children are typically ages 3 to 15 years, more girls than boys. Half of them have epilepsia partialis continua. The progression of the disease leads to hemiplegia or other deficits and focal brain atrophy, and even total hemiatrophy, in most cases. The neuropathology of five cases revealed extensive destruction of the cortex and white matter with intense gliosis and lingering inflammatory reactions.
The CSF shows a pleocytosis and sometimes oligoclonal bands but these are not uniform findings. Focal cortical and subcortical lesions are usually visualized by MRI and are bilateral in some cases. The finding of antibodies to glutamate receptors (GluR3) in a proportion of patients with Rasmussen encephalitis has raised interest in an immune causation (see review by Antel and Rasmussen). The autoimmune hypothesis has been supported by the findings of Twyman and colleagues that these antibodies cause seizures in rabbits and lead to the release of the neurotoxin kainate in cell cultures. However, Wendl’s group and others have found these antibodies and many others various types of focal epilepsy and have questioned their specificity.
The unrelenting course of the disease had in the past defied medical therapy. In some patients the process eventually burns out, but in those with continuous focal epilepsy the seizures continued despite all antiepileptic drugs. The use of high doses of corticosteroids, when started within the first year of the disease, proved beneficial in 5 of the 8 patients treated by Chinchilla and colleagues. Repeated plasma exchanges and immune globulin have also been tried, but the results are difficult to interpret. When the disease is extensive and unilateral, neurosurgeons have resorted to partial hemispherectomy.
PSYCHOGENIC NONEPILEPTIC SEIZURES (PNES, PSEUDOSEIZURES)
These common episodes, which simulate convulsive or nonconvulsive seizures, are not the result of a paroxysmal neuronal discharge. They are termed psychogenic nonepileptic seizures (PNES) and comprise a heterogeneous group of disorders that are easily mistaken for epileptic spells. Moreover, they comprise a large proportion of treatment resistant epilepsy and often are treated with multiple antiepileptic drugs, to which they are unresponsive. It has been estimated that 70 percent of people diagnosed with PNES have been previously diagnosed and treated for epilepsy. In large series, nonepileptic seizures comprise 4 percent of cases of transient loss of consciousness, 20 percent of referrals to specialist epilepsy services, and 50 percent of apparent status epilepticus. It should be emphasized that patients with true epileptic seizures can exhibit psychogenic ones as well, making the distinction between the two particularly difficult. It is this population that proves most vexing (and common) in specialty epilepsy services.
Our current conceptualization is that the condition arises as a behavioral response to underlying emotional or psychological distress. Episodes may be derived from traumatic experiences in early life, particularly physical, sexual, and mental abuse during childhood but such is not always the case. Many experts consider them to be allied with hysteria (Briquet disease, conversion disorder, as discussed in Chap. 47) or malingering. Recent studies suggest that a conversion-hysterical disorder accounts for most cases, and that malingering is rare but this is difficult to prove.
Three broad categories of psychogenic states seem to generate pseudoseizures: (1) panic disorder that is itself common in people with epilepsy; (2) dissociative disorders, in which convulsions are typically prolonged, resembling generalized tonic-clonic seizures, or alternatively, swooning as in a faint or presyncopal spell, or blank spells that closely simulate absence seizure; and (3) malingering, the deliberate feigning of seizures to avoid certain situations, for example, imprisonment.
Usually, the unconventional motor display in the course of a nonepileptic seizure is sufficient to identify it as such: completely asynchronous thrashing of the limbs and repeated side-to-side movements of the head; striking out at a person who is trying to restrain the patient; hand-biting, kicking, trembling, and quivering; pelvic thrusting and opisthotonic arching postures; and screaming or talking during the ictus. It is helpful to observe that the eyes are kept quietly or forcefully closed in pseudoseizure whereas the lids are open or show clonic movement in epilepsy. Psychogenic spells are likely if attacks are prolonged (many minutes, even hours), if there is rapid breathing (whereas apnea is typical during and after a seizure), or if there is tearfulness after an episode. Psychogenic seizures tend to occur in the presence of observers, to be precipitated by emotional factors. With few exceptions, tongue-biting, incontinence, hurtful falls, or postictal confusion are lacking but if the tongue is bitten in one of these spells it is usually the front, compared to the lateral tongue injury that is characteristic of an epileptic attack. Incontinence does not assist in making a clear distinction from epileptic seizures.
Another clue to nonepileptic seizures has been highly resistant epilepsy in an individual with normal cognitive function and normal brain imaging. Sometimes there has been a background of unexplained medical problems, previous psychological problems (depression, panic disorder, overdose, self harm, addiction), and a life story that includes intense emotional trauma. Prolonged fugue states usually prove to be manifestations of hysteria or a psychopathy, that is, a dissociative state, even in a known epileptic.
The serum creatine kinase levels are normal after nonepileptic seizures; this may be helpful in distinguishing them from epilepsy. Where doubt remains, a recording of the ictal or postictal EEG or prolonged combined video and EEG recording of an attack may settle the issue. The treatment of these patients requires a patient, nonjudgmental and multidisciplinary approach with the goal of reducing disability and hospital admission and eliminating unnecessary medications.
THE NATURE OF THE ELECTRICAL DISCHARGE LESION IN EPILEPSY
Physiologically, the epileptic seizure has been defined as a sudden alteration of central nervous system (CNS) function resulting from a paroxysmal high-frequency or synchronous low-frequency, high-voltage electrical discharge. This discharge arises from an assemblage of excitable neurons in any part of the cerebral cortex and possibly in secondarily involved subcortical structures as well. In the proper circumstances, a seizure discharge can be initiated in an entirely normal cerebral cortex, as when the cortex is activated by ingestion of drugs, or by withdrawal from alcohol or other sedative drugs. A special mechanism that ostensibly creates a secondary seizure focus, “kindling,” is the result of repeated stimulation with subconvulsive electrical pulses from an established focus elsewhere; it is known to occur in animal models but is a controversial entity in humans.
Viewed from a larger physiologic perspective, seizures require three conditions: (1) a population of pathologically excitable neurons; (2) an increase in excitatory, mainly glutaminergic, activity through recurrent connections in order to spread the discharge; and (3) a reduction in the activity of the normally inhibitory GABAergic projections. Each of these has been challenged but is supported by considerable data and together they serve as a reasonable model, as noted below. Understanding of the initial discharges and their spread has been advanced by the identification of several rare forms of familial epilepsy that are the result of mutations in sodium, potassium, acetylcholine receptor, or GABA channels on neurons. These are discussed further on under “Role of Genetics.”
Just why the neurons in or near a focal cortical lesion discharge spontaneously and synchronously is not fully understood. Some of the electrical properties of a cortical epileptogenic focus suggest that its neurons have been deafferented. Neurons in these circumstances are hyperexcitable, and they may chronically remain in a state of partial depolarization, able to fire irregularly at rates as high as 700 to 1,000 per second. The cytoplasmic membranes of such cells have an increased ionic permeability, which renders them susceptible to activation by hyperthermia, hypoxia, hypoglycemia, hypocalcemia, and hyponatremia, as well as by repeated sensory (e.g., photic) stimulation and during certain phases of sleep (where hypersynchrony of neurons occurs).
As a model of spontaneous discharges, epileptic foci induced in the animal cortex by the application of penicillin are characterized by spontaneous interictal discharges, during which the neurons of the discharging focus exhibit large, calcium-mediated paroxysmal depolarizations (depolarizing shifts), followed by prolonged after-hyperpolarizations. The latter are caused in part by calcium-dependent potassium currents, but enhanced synaptic inhibition also plays a role. The depolarizing shifts occur synchronously in the penicillin focus and summate to produce surface-recorded interictal EEG spikes; the after-polarizations correspond to the slow wave of the EEG spike-and-wave complex (see Engel). The neurons surrounding an experimental epileptogenic focus are hyperpolarized and release inhibitory GABA. The spread of seizures depends on factors that activate neurons in the focus or inhibit those surrounding it. Beyond this, the precise mechanism that governs the transition from a circumscribed interictal discharge to a widespread seizure state is not understood.
Biochemical studies of neurons from a seizure focus have not greatly clarified the problem. Levels of extracellular potassium are elevated in glial scars near epileptic foci, and a defect in voltage-sensitive calcium channels has also been postulated. Epileptic foci are known to be sensitive to acetylcholine and to be slow in binding and removal of the neurotransmitter. A deficiency of the inhibitory neurotransmitter GABA, increased glycine, decreased taurine, and either decreased or increased glutamic acid have been variously reported in excised human epileptogenic tissue, but whether these changes are the cause or result of seizure activity has not been determined. The interpretation of reported abnormalities of GABA, biogenic amines, and acetylcholine in the cerebrospinal fluid (CSF) of epileptic patients poses similarly great difficulties.
Concurrent EEG recordings from an epileptogenic cortical focus and subcortical, thalamic, and brainstem centers in the animal model have enabled investigators to construct a sequence of electrical and clinical events that characterize an evolving focal seizure. Firing of the involved neurons in the cortical focus is reflected in the EEG as a series of periodic spike discharges, which increase progressively in amplitude and frequency. Once the intensity of the seizure discharge exceeds a certain point, it overcomes the inhibitory influence of surrounding neurons and spreads to neighboring cortical regions via short corticocortical synaptic connections.
A provocative finding, based on sophisticated mathematical analysis of EEG tracings, indicates that subtle electrographic changes arise several minutes before the ictal discharge (see LeVan Quyen et al). This suggests that seizures could be triggered either by a change in central thalamic rhythm generators or a subtle alteration in the electrical activity in the region of a focal lesion. Of interest are the findings by Litt and colleagues that in a small number of patients there are prolonged bursts of seizure-like activity detected by sophisticated techniques even days before the onset of temporal lobe seizures. Their proposal is that these events cause a cascade of electrophysiologic changes that very gradually culminate in a seizure.
If unchecked, cortical excitation spreads to the adjacent cortex and to the contralateral cortex via interhemispheric pathways, and also to anatomically and functionally related pathways in subcortical nuclei (basal ganglionic, thalamic, and brainstem reticular nuclei). It is at this time that the clinical manifestations of the seizure begin. The excitatory activity from the subcortical nuclei is conceived to feed back to the original focus and to other parts of the cerebrum, a mechanism that serves to amplify their excitatory activity and to give rise to the characteristic high-voltage polyspike discharge in the EEG. The spread of excitation to the subcortical, thalamic, and brainstem centers corresponds to the tonic phase of the seizure and to loss of consciousness as well as to the signs of autonomic nervous system overactivity (mydriasis, tachycardia, hypertension) and to arrest or respiration. The development of unconsciousness and the generalized tonic contraction of muscles are reflected in the EEG by a diffuse high-voltage discharge pattern appearing simultaneously over the entire cortex. There is little evidence to support the conjecture made by Penfield that seizure activity originates in the thalamus; thus his term centrencephalic seizure is no longer used.
Soon after the spread of excitation, a diencephalic inhibition begins and intermittently interrupts the seizure discharge, changing it from the persistent tonic phase to the intermittent bursts of the clonic phase. In the surface EEG, a transition occurs from a continuous polyspike to a spike-and-wave pattern. The intermittent clonic bursts become decreasingly frequent and finally cease altogether, leaving in their wake an “exhaustion” (paralysis) of the neurons of the epileptogenic focus and a regional increase in permeability of the blood–brain barrier and regional edema in magnetic resonance images. An excess of these inhibitory mechanisms and metabolic exhaustion are thought to be the basis of Todd’s postepileptic paralysis and of postictal stupor, sensory loss, aphasia, hemianopia, headache, and diffuse slow waves in the EEG. Plum and associates observed a two- to threefold increase in cerebral glucose utilization during seizure discharges and suggested that the paralysis that follows might be a result of neuronal depletion of glucose and an increase in lactic acid. The exact roles played by each of these factors in postictal paralysis of function are not settled.
Insights to absence seizures have been obtained from animal models of bilaterally synchronous 3-per-second high-voltage spike-and-wave discharges. The spike-and-wave complex, which represents brief excitation followed by slow-wave inhibition, is the type of EEG pattern that characterizes the clonic (inhibitory) phase of the focal motor or grand mal seizure. By contrast, this strong element of inhibition is present diffusely throughout an “absence” attack, a feature that perhaps accounts for the failure of excitation to spread to lower brainstem and spinal structures (tonic-clonic movements do not occur). Earlier mentioned is the work by Blumenfeld’s group, suggesting that the interruption of consciousness in this syndrome can be linked with electrophysiologic changes in the thalamus, comparable to what is described for types of generalized seizure.
Of theoretical importance is the observation that a seizure focus may establish, via commissural connections, a persistent secondary focus in the corresponding cortical area of the opposite hemisphere (mirror focus). The nature of this phenomenon is obscure; it may be similar to the “kindling” phenomenon mentioned earlier in animals, where a repeated nonconvulsive electrical stimulation of normal cortex induces a permanent epileptic focus. No morphologic change is visible in the mirror focus, at least by light microscopy. The mirror focus may be a source of confusion when trying to identify the side of the primary discharging lesion by EEG. However, there is only limited evidence that mirror foci related to the kindling phenomenon produce seizures in humans (see Goldensohn).
EEG AND LABORATORY TESTING IN EPILEPSY
The origins of EEG activity of an epileptic focus and the generalization of seizures are discussed in Chap. 2 and earlier in this chapter. The EEG provides confirmation of Hughlings Jackson’s concept of epilepsy—that it represents a recurrent, sudden, excessive discharge of cortical neurons. The EEG is the most sensitive, indeed indispensable, tool for the diagnosis of epilepsy; but like other ancillary tests, it must be used in conjunction with clinical data. In patients with idiopathic generalized seizures, and in a high proportion of their relatives, interictal spike-and-wave abnormalities without any clinical seizure activity are common, especially if the EEG is repeated several times or taken over long periods. By contrast, a proportion of epileptic patients have a perfectly normal interictal EEG. Using standard methods of scalp recording, the EEG may even be normal during the experiential aura of a simple or complex partial seizure. Furthermore, interpretation of EEG abnormalities must take into account that a small number of healthy persons (approximately 2 to 3 percent) show paroxysmal EEG abnormalities.
A single EEG tracing obtained during the interictal state is abnormal to some degree in 30 to 50 percent of epileptic patients; this figure rises to 60 to 70 percent if patients are subjected to several recordings. Many EEG patterns are possible in seizures. One consistent observation, however, has been that the region of earliest spike activity corresponds best to the epileptogenic focus, a rule that has come to guide epilepsy surgery. The postseizure or postictal state also has an EEG correlate, taking the form of random generalized slow waves after generalized seizures and focal slowing following partial seizures. With clinical recovery, the EEG returns to normal or to the preseizure state.
A higher yield of abnormalities and a more precise definition of seizure types can be obtained by the use of several special EEG procedures, as described in Chap. 2. Here it is restated that activating procedures such as hyperventilation, photic stroboscopic stimulation, and sleep increase the yield of EEG recordings. EEG recording during sleep is particularly helpful because focal abnormalities, particularly in the temporal lobes, may become prominent in slow-wave and stage II sleep. Sphenoidal leads have been used to detect inferomedial temporal seizure activity, but they are uncomfortable and probably add little more information than can be obtained by the placement of additional subtemporal scalp electrodes. Nasopharyngeal electrode recordings are too contaminated by artifact to be clinically useful.
Beyond dependably identifying artifacts in the EEG recording, one of the main challenges for the electroencephalographer is to differentiate between normal patterns that simulate seizures and true epileptic or interictal discharges. These paroxysmal but ostensibly normal patterns appear mostly during sleep, each with a highly characteristic morphology. These include small sharp spikes, “14 and 6” polyspike activity, lambda and posterior occipital mu rhythm, and occipital sharp transients. These are pictured in most standard textbooks on the subject of EEG and discussed in Chap 2.
Several methods of long-term EEG monitoring are now in common use and are of particular value in the investigation of patients with surgically removable epileptogenic foci and of nonepileptic spells. The most common of these makes use of telemetry systems, in which the patient is attached to the EEG machine by cable or radio transmitter without unduly limiting freedom of movement. The telemetry system is joined to an audiovisual recording system, making it possible to record seizure phenomena (even at night, under dim or infrared light) and to synchronize them with the EEG abnormalities. An alternative is the use of a small digital recording device that is attached to a miniature EEG machine worn by the patient at home and at work (“ambulatory EEG”). The patient is instructed to push a button if he experiences an “event,” which can later be correlated with EEG activity.
Imaging and Laboratory Abnormalities Associated With Seizures
Cerebral imaging has come to play a major role in the diagnosis of seizures. CT is able to demonstrate many of the typical underlying causes of seizures in adults but MRI is more sensitive for the detection of small structural abnormalities underlying epilepsy including tumor, stroke and traumatic lesions. Furthermore, more subtle abnormalities such as medial temporal sclerosis, heterotopias and other disorders of neuronal migration, and small glial scars can be clearly visualized with MRI. Advances in MRI field strength and techniques such as thin slice acquisition, continue to expose structural lesions in what were previously called cryptogenic cases and some of these lesions may be surgically remediable.
After a seizure, particularly one with a focal component, MRI sometimes discloses subtle focal cortical swelling and signal change in the FLAIR (fluid-attenuated inversion recovery) and diffusion-weighted sequences, or, if a contrast agent is administered, an ill-defined cortical blush may be visible. These changes are transient and are the effect of, rather than cause of, seizure and are thought to reflect disruption of the blood–brain barrier and metabolic changes in the cortex. There is an approximate relationship between the duration of seizure activity and the intensity and extent of these changes but they rarely persist for more than a day or two. Likewise, angiography or perfusion imaging performed soon after a seizure may show a focal area of enhanced blood flow or elevated blood volume. Less-well understood is the findings on MRI of increased T2 signal or restricted diffusion in the hippocampi and posterior thalamus after a prolonged seizure or status epilepticus. There are also imaging changes in the white matter, particularly the splenium of the corpus callosum that may occur soon after the withdrawal of certain antiepileptic medications as discussed in the later section on the use of these drugs and by Gürtler and colleagues.
The CSF after a seizure occasionally contains a small number of white blood cells (most often in the range of 10/mm3) in about 5 percent of patients. In a series of 309 individuals, Tumani and colleagues found up to 24 white blood cells but the median was far lower. A slight increase in protein is also possible. Like the imaging abnormalities these findings may lead to spurious conclusions about the presence of an active intracranial lesion, particularly if polymorphonuclear leukocytes predominate; a larger pleocytosis should always be construed as a sign of inflammatory or infectious disease.
Systemic (lactic) acidosis is a common result of convulsive seizures, and it is not unusual for the serum pH to reach levels near or below 7 if taken immediately after a convulsion. Of more practical value is the fact that almost all generalized convulsions produce a rise in serum creatine kinase activity that persists for hours, a finding that could be used to greater advantage in emergency departments to assist in distinguishing seizures from fainting. Of course, extensive muscle injury from a fall or prolonged compression during a period of unconsciousness can produce the same abnormality.
Concentrations of serum prolactin, like those of other hypothalamic hormones, rise for 10 to 20 min after all types of generalized seizures, including complex partial types, but not in absence or myoclonic types. An elevation may help differentiate a psychogenic seizure from a genuine one; however, serum prolactin may also be slightly elevated after a syncopal episode (Fisher et al). There is also a postictal rise in ACTH and serum cortisol, but these changes have a longer latency and briefer duration. If elevations in these hormonal levels are used as diagnostic tests, one must have information about normal baseline levels, diurnal variations, and the effects of concurrent medications. Changes in body temperature, which are said to sometimes precede a seizure, may reflect hypothalamic changes but are far less consistent and difficult to use in clinical work.
In most autopsied cases of primary generalized epilepsy of the genetic variety, the CNS is grossly and microscopically normal. Not surprisingly, there are also no visible lesions in the seizure states complicating drug intoxication and withdrawal, transient hyper- and hyponatremia, and hyper- and hypoglycemia, which presumably represent derangements at the cellular level.
In contrast, symptomatic epilepsies have definable lesions. MRI, which has been used as a surrogate for pathology, has improved matters by exposing some cortical heterotopias that had been previously difficult to detect, and to highlight the frequency of gliosis in the medial temporal lobes. Other lesions include zones of neuronal loss and gliosis (scars) or other lesions such as heterotopia, dysgenic cortex, hamartoma, vascular malformation, porencephaly, and tumor. Vascular malformations, hamartomas, ganglioneuromas and related dysembryoplastic neuroectodermal tumors (DNET), which are important causes of drug resistant epilepsy, and low-grade astrocytomas were less frequent; again, in a small number, no abnormalities could be found. Certainly the focal epilepsies are associated with the highest incidence of structural abnormalities, although in certain cases no morphologic change is visible.
It has not been possible to determine which component of the lesion is responsible for the seizures. Gliosis, fibrosis, vascularization, and meningocerebral cicatrix have all been incriminated, but they are found in nonepileptic foci as well. The Scheibels’ Golgi studies of neurons from epileptic foci in the temporal lobe showed distortions of dendrites, loss of dendritic spines, and disorientation of neurons near the scars, but these findings have dubious status because they were not usually compared with similar nonepileptic lesions. Once a gliotic focus of whatever cause becomes epileptogenic, it may remain so throughout the patient’s lifetime.
Medial (Mesial) Temporal Sclerosis
In several series of cases of temporal lobe excisions in prior decades, such as the often cited one described by Falconer, a specific pattern of neuronal loss with gliosis (sclerosis) in the hippocampal and amygdaloid region was found in the majority, and this abnormality is being increasingly recognized with MRI, as already noted (medial temporal sclerosis; see Fig. 15-4). The most common associated histologic finding is loss of neurons in the CA1 segment (Sommer sector) of the pyramidal cell layer of the hippocampus, often unilateral, extending into contiguous regions of both the pyramidal layer and the underlying dentate gyrus. It is still undetermined whether this neuronal loss is primary or secondary and, if the latter, whether it was incurred at birth or happened later as the consequence of recurrent seizures.
However, early life head trauma, infections, and a variety of less-common perturbations may also cause the combination of neuron loss and mild gliosis of medial temporal sclerosis. The cessation of seizures in many patients following surgical resection of the medial temporal lobe favors the first interpretation that the pathologic change is primary in most cases (see further on under “Surgical Treatment of Epilepsy”). Attesting to the uncertainty of cause or effect are numerous surgical series that favor one view or the other (see editorial by Sutula and Pitkänen).
Most primary epilepsies have a genetic basis and, as in many other diseases such as diabetes and atherosclerosis, the mode of inheritance is complex, that is, some are likely to be polygenic but increasingly, single mutations are being found. That a genetic factor is operative in the primary generalized epilepsies is suggested by a familial incidence in 5 to 10 percent of such patients and, in certain families, the inheritance of a seizure disorder through specific genes (Afawi et al). The importance of genetic factors in the primary epilepsies is also underscored by evidence from twin registries; the overall concordance rate has been up to 70 percent for monozygotic twins and, 30 percent for dizygotic pairs (Vadlamudi et al).
Of course, epilepsy is a component of many genetic syndromes that are defined by their dysmorphic appearance, neurocutaneous disorder, or maldevelopment of the cerebra with or without mental retardation. What we consider first the few idiopathic seizure disorders that are inherited by a simple (mendelian) pattern. These include a subgroup of benign neonatal familial convulsions inherited as an autosomal dominant trait (Leppert et al), and a similar disorder of infantile onset and a benign myoclonic epilepsy of childhood (autosomal recessive). Particularly informative are a special group of epileptic disorders in which monogenic genetic defects are related to abnormalities of ion channels or neurotransmitter receptors (Table 15-3). These were mentioned earlier in the discussion of the physiology of seizures and despite their rarity they suggest that idiopathic epilepsy may be caused by a disruption in the function of these same channels.
Table 15-3MONOGENIC EPILEPTIC DISORDERS ||Download (.pdf) Table 15-3MONOGENIC EPILEPTIC DISORDERS
| ||GENE ||PROTEIN INVOLVED |
|Sodium channels || || |
| Familial generalized seizures with febrile seizures “plus”; see text ||SCN1A,B (GABAA) ||Sodium channel subunits; less often, GABA receptor |
| Benign familial neonatal convulsions ||SCN2A ||Sodium channel subunits |
| Dravet syndrome (severe myoclonic epilepsy of infancy) ||SCN1A ||Sodium channel α-subunit |
|Potassium channels || || |
| Benign infantile epilepsy ||KCNQ2,3 ||Potassium channel subunits |
| Episodic ataxia type 1 with partial epilepsy ||KCNA1 || |
|Ligand-gated channels || || |
| Autosomal dominant nocturnal frontal seizures ||CHRNA 2,4 ||Nicotinic acetylcholine receptor subunits |
| Familial generalized and febrile seizures ||GABRG2 ||GABAA receptor subunit |
| Juvenile myoclonic epilepsy ||GABRA1 (CACNB4) ||GABAA receptor subunit; less often, calcium channel subunit |
| Glucose transporter-1 deficiency ||SLC2A1 ||GLUT1 (responsive to ketogenic diet) |
|Calcium channels || || |
| Episodic ataxia type 2 with spike-wave seizures ||CACNA1A ||Calcium channel subunit |
|Malformations of Cortical Development |
| Holoprosencephaly, generalized epilepsy ||SHH, PTCH, ZIC2, SIX3, TGIF ||Sonic hedgehog, SHH receptor, transcription factors |
| Schizencephaly, generalized epilepsy ||EMX2 ||Homeodomain protein |
| Tuberous sclerosis, generalized epilepsy ||TSC1, 2 ||Hamartin, tuberin |
| Lissencephaly, generalized epilepsy ||LIS1 ||Platelet-activating factor acid hydrolase |
| Double-cortex syndrome, generalized epilepsy ||DCX ||Doublecortin |
| Heterotopia, focal epilepsy ||FLN1 ||Filamin1 |
| Fukuyama muscular dystrophy, lissencephaly, generalized epilepsy ||FCMD ||Fukutin |
| Walker-Warburg syndrome, generalized epilepsy ||POMT1 ||O-mannosyl transferase |
| Muscle-eye-brain disease, generalized epilepsy ||MEB ||Glycosyltransferase, PMGnT1 |
| Angelman syndrome: myoclonic, tonic-clonic, atonic seizures ||UBE3A ||Ubiquitin-protein ligase |
|Progressive Myoclonic Epilepsies (PME) |
| Unverricht-Lundborg disease with PME ||EPM1 ||Cystatin B |
| Lafora body disease with PME ||EPM2A ||Laforin, protein tyrosine phosphatase |
| Myoclonic epilepsy with ragged red fibers ||tRNAlys ||Mitochondrial lysine tRNA |
| Dentatorubro-pallidoluysian atrophy with PME ||DRPLA ||Atrophin-1 |
| Gaucher disease ||PSAP ||β-Glucocerebrosidase |
| Sialidosis type I ||NEU1 ||Sialidase |
| Ceroid lipofuscinosis (CLN) and PME ||CLN ||CLN2, CLN3, CLN5, CLN6 also cause generalized, atonic and atypical absence seizures |
|Mixed Seizure Types |
| Lipoid proteinosis and temporal lobe epilepsy ||ECM1 ||Extracellular matrix protein 1 |
| Autosomal dominant lateral temporal lobe epilepsy ||LGI1 ||Leucine-rich glioma inactivated protein |
| CLN8; progressive nonmyoclonic epilepsy with retardation ||CLN8 ||Membrane protein in endoplasmic reticulum |
| Pyridoxine deficiency ||ALDH7A1 ||Antiquitin (ATQ-1) |
The consequences of almost all of these mutations are to enhance overall neuronal excitability. Examples include autosomal dominant nocturnal frontal lobe epilepsy, which may present as a partial seizure (in which the offending mutations are in subunits of the nicotinic acetylcholine receptor subunit); so-called “generalized epilepsy with febrile seizures plus” (subunits of a neuronal sodium channel associated with various combinations of uncomplicated febrile seizures, febrile seizures persisting beyond childhood, generalized, absence, myoclonic, atonic, and complex partial seizures); benign familial neonatal convulsions (two different potassium channels); and forms of juvenile myoclonic epilepsy and childhood absence epilepsy (subunits of the brain GABAA receptor).
Some of these are summarized in Table 15-3, and their number will almost certainly expand in the next few years. As with numerous other genetic neurologic disorders, a single mutation may produce different epilepsy and seizure types, and a single type may be the result of one of several different mutations. Also notable is the low penetrance of some monogenic epileptic disorders, particularly the autosomal dominant one associated with nocturnal frontal seizures.
Another group of epilepsies with mendelian inheritance has been ascribed to genetic defects that do not implicate ion channels. Most of these are primarily myoclonic disorders in which the epilepsy is one component. Two forms of progressive myoclonic epilepsy, Unverricht-Lundborg disease and Lafora body disease, are the result, respectively, of mutations in genes encoding cystatin B and tyrosine phosphatase. To these inherited forms of epilepsy may be added diseases such as tuberous sclerosis and ceroid lipofuscinosis (Chap. 36), which have a strong proclivity to cause seizures and genetically determined heterotopias such as FLN1 (this and other developmental aberrations are discussed in Chap. 37).
More complex genetic elements are identified in several childhood seizure disorders—absence epilepsy with 3-per-second spike-and-wave discharges and benign epilepsy of childhood with centrotemporal spikes—both of which are transmitted as autosomal dominant traits with incomplete penetrance or perhaps in a more complicated manner. In the partial, or focal, epilepsies the role of heredity is not nearly so clear. Yet in numerous studies there has been a greater-than-expected incidence of seizures, EEG abnormalities, or both among first-degree relatives. Among the familial cortical epilepsies, both a temporal and frontal lobe type, are inherited in a polygenic fashion or in an autosomal dominant pattern. Undoubtedly also inherited, is the tendency to develop simple febrile convulsions, though the mode of inheritance is uncertain. Finally, copy number variations probably play a role in approximately 5 percent of cases according to Olsen and colleagues.
CLINICAL APPROACH TO EPILEPSY
The physician faced with a patient who seeks advice about an episodic disorder of nervous function must determine first, whether the episode in question is a seizure. In the diagnosis of epilepsy, history is the key; in many adult cases the physical examination is unrevealing. The examination in infants and children is of greater value, as the finding of dysmorphic and cutaneous abnormalities allow the diagnosis of a number of highly characteristic cerebral diseases that give rise to epilepsy.
Paramount in establishing that there has been a seizure is a description from a witness. A detailed account of the event is required and in particular, the type and duration of bodily movements, level of alertness and responsiveness during and immediately after the episode, skin color and breathing, and incontinence. If a witness is not available, then a telephone call to observers and family may give more information than does sophisticated laboratory testing. From the patient, information can be obtained regarding tongue biting, incontinence, and recollection of the event of the immediately preceding epoch. If the patient is able to provide information, previous events that may have been misinterpreted as other than a seizure, for example, brief losses of consciousness, myoclonic jerks, rumpled bedsheets with incontinence, unexplained falls with injury and so forth, may hint at preceding seizures. The family history, developmental milestones, neonatal events and the circumstances of birth are useful additional aspects of the evaluation of epilepsy.
In the category of genuine seizures, the diagnosis of temporal lobe epilepsy may be difficult to distinguish from imitators of epilepsy. These attacks are so variable and so often induce disturbances of behavior and psychic function—rather than overt interruptions or loss of consciousness—that they may be mistaken for temper tantrums in children, drug ingestion, hysteria, panic attacks, or acute psychosis. These seizures may include verbalizations that cannot be remembered, walking aimlessly, repetitive olfactory and gustatory hallucinations, stereotyped hand movements or automatism such as lip smacking. The nature of the patient’s report of a psychic experience is often helpful in distinguishing seizures from psychogenic events. In the former, patients attempt to focus with great effort on the description of the experience, although the term “indescribable” is often included in the report, whereas vague and imprecise descriptions of “something being wrong” or resorting to a friend or family member to describe the event usually implicates a psychogenic seizure. We place emphasis on amnesia for the events of at least part of the seizure as an important criterion for the diagnosis of temporal lobe epilepsy. Hysterical fugues can cause substantial difficulty in diagnosis. They may be recognized by the loss of personal identity and by episodes that are longer than typical of seizures, sometimes up to a few days.
Absence attacks may be similarly difficult to distinguish from other brief disorders of consciousness. Helpful maneuvers are to have the patient hyperventilate to evoke an attack or to observe the patient counting aloud for several minutes. Those with frequent absence attacks will pause or skip one or two numbers.
The conditions most likely to simulate an epileptic seizure are psychogenic nonepileptic seizures and other paroxysmal events such as panic attack and syncope but also, unexplained falls (drop attacks), transient ischemic attacks, particularly those associated with limb shaking, rapid eye movement (REM) sleep behavior disorder, subarachnoid hemorrhage, migraine, hypoglycemia, cataplexy, paroxysmal ataxia and choreoathetosis, and transient global amnesia. In emergency departments it is often difficult to differentiate the postictal effects of an unwitnessed seizure from the confusion and amnesia following cerebral concussion.
The clinical differences between a seizure and a syncopal attack are considered in Chap. 17; there it was emphasized that no single criterion stands inviolate. Particularly emphasized because of their potential gravity are episodes of cardiac syncope from a serious arrhythmia, especially ventricular tachycardia. Cardiac arrhythmias may present as episodes of unheralded loss of consciousness, sometimes with associated convulsive movements that simulate epileptic disorders and the failure to pursue the diagnosis of arrhythmia may have important consequences. Palpitations, previous myocardial infarction, ECG abnormalities, valvular disease, and thoracic trauma may direct attention to the proper diagnosis.
Migraine may be mistaken for a seizure. One feature of the focal neurologic disorder of typical migraine is particularly helpful—namely, the pace of the sequence of cerebral malfunction over a period of minutes rather than seconds, as in focal epilepsy. Even this criterion may fail occasionally, especially if both migraine and partial seizures are joined, for example, as expressions of a vascular malformation of the brain.
Identification of a TIA and its separation from focal epilepsy are aided by considering that most paroxysmal vascular disorders are characterized by loss of function that can be attributed to one area of the cortex such as paralysis, blindness, diplopia, or aphasia. If the ischemic attack is marked by an evolution of symptoms, they tend to develop more slowly than those of a seizure. The patient’s age and presence of vascular risk factors, evidence of disease of the heart and carotid arteries, and the lack of disorder of consciousness or amnesia may be supportive of the diagnosis of vascular disease. However, a “limb-shaking” TIA and convulsive phenomena at the outset of basilar artery occlusion may be nearly impossible to distinguish from epilepsy.
Regarding the distinction of seizures from odd disorders such as cataplexy, paroxysmal ataxia or choreoathetosis, transient global amnesia, it is sufficient to be aware of the diagnostic features for each of these conditions. REM sleep behavior disorder tend to occur later in the sleep cycle, as they require REM, whereas frontal epileptic seizures with violent motions or acts that might be mistaken for REM sleep behavior disorder, can occur at any time of the night and tend to be briefer than the sleep disorder. Drop attacks (falling to the ground without loss of consciousness as discussed in Chap. 6) remain an enigma. In most cases, it has not been possible to substantiate an association with circulatory disturbances of the vertebrobasilar system and seldom have we observed drop attacks to be an expression of atonic or myoclonic epilepsy.
Several laboratory studies are usually included in the initial diagnostic evaluation—complete blood count (CBC), blood chemistries, ECG, EEG, and imaging of the brain, preferably MRI. CT gives some information on major problems that may underlie epilepsy but MRI is superior in detecting the various structural causes of epilepsy. If blood is tested after the episode in question, elevation in creatine kinase (persistent for hours) and formerly, elevation of prolactin (for up to 10 min) may occur after an unwitnessed convulsive seizure but the test is not specific enough to be useful in general practice. Other forms of testing—for example, cardiac stress tests, Holter monitor, tilt-table testing, long-term cardiac rhythm monitors, and sleep studies—are sometimes indicated in order to exclude some of the nonepileptic disorders listed earlier. Some patients may need prolonged EEG monitoring, either in the hospital or with portable equipment at home. In all forms of epilepsy, prolonged EEG and video monitoring in a hospital unit may prove diagnostic.
Seizures in Each Age Period
Having concluded that the neurologic disturbance under consideration is one of seizure, the next issue is to identify its type (Table 15-4 and Fig. 15-5). Indeed, in most cases this determines the nature of treatment. Because there are so many seizure types, especially in childhood and adolescence, each one tending to predominate in a certain age period, a clinical advantage accrues to considering seizures from just this point of view. A broader approach includes consideration of the neurologic and EEG findings, the response to drugs, etiology, and prognosis.
Table 15-4CAUSES OF RECURRENT SEIZURES IN DIFFERENT AGE GROUPS ||Download (.pdf) Table 15-4CAUSES OF RECURRENT SEIZURES IN DIFFERENT AGE GROUPS
|AGE OF ONSET ||PROBABLE CAUSEa |
|Neonatal ||Congenital maldevelopment, birth injury, anoxia, metabolic disorders (hypocalcemia, hypoglycemia, vitamin B6 deficiency, biotinidase deficiency, phenylketonuria, and others) |
|Infancy (1–6 months) ||As above; infantile spasms (West syndrome) |
|Early childhood (6 months–3 years) ||Infantile spasms, febrile convulsions, birth injury and anoxia, infections, trauma, metabolic disorders, cortical dysgenesis, accidental drug poisoning |
|Childhood (3–10 years) ||Perinatal anoxia, injury at birth or later, infections, thrombosis of cerebral arteries or veins, metabolic disorders, cortical malformations, Lennox-Gastaut syndrome, “idiopathic,” probably inherited, epilepsy (Rolandic epilepsy) |
|Adolescence (10–18 years) ||Idiopathic epilepsy, including genetically transmitted types, juvenile myoclonic epilepsy, trauma, drugs |
|Early adulthood (18–25 years) ||Idiopathic epilepsy, trauma, neoplasm, withdrawal from alcohol or other sedative drugs |
|Middle age (35–60 years) ||Trauma, neoplasm, vascular disease, alcohol or other drug withdrawal |
|Late life (older than 60 years) ||Vascular disease (usually postinfarction), tumor, abscess, degenerative disease, trauma |
Distribution of the main causes of epilepsy at different ages. Evident is the prevalence of congenital causes in childhood and the emergence of cerebrovascular disease in older patients. (Adapted from several sources including Hauser and Annegers and the texts of Engel and Pedley.)
Figure 15-5 displays the frequency of each seizure type and the main causes of seizures by age group. These data are assembled from various sources and are approximate, but they highlight several points of clinical importance.
The neonatologist is often confronted by an infant who begins to convulse in the first days of life. In most instances, the seizures are fragmentary—an abrupt movement or posturing of a limb, stiffening of the body, rolling up of the eyes, a pause in respirations, lip-smacking, chewing, or bicycling movements of the legs. Even the experienced observer may have difficulty at times in distinguishing seizure activity from the normal movements of the neonate. If manifest seizures are frequent and stereotyped, the diagnosis is less difficult. The seizures correlate with focal or multifocal cortical discharges; however, as is the case with most EEG changes in neonates, these are poorly formed and less distinct than seizure discharges in later life. Presumably the immaturity of the cerebrum prevents the development of a fully organized seizure pattern, and the incomplete corticocortical myelination prevents bihemispheric spread. The EEG is nonetheless helpful in diagnosis. For example, periods of EEG suppression may alternate with sharp or slow waves, or there may be discontinuous theta activity that represents electrographic seizure activity. Conversely, electrical seizure activity in the neonate may be unattended by clinical manifestations.
An early onset of myoclonic jerks, either fragmentary or massive, with an EEG pattern of alternating suppression and complex bursts of activity is particularly ominous. Ohtahara described another unfavorable form of neonatal seizure evolving in infancy into infantile spasms (West syndrome) and Lennox-Gastaut syndrome and leaving in its wake severe brain damage. Most reported patients have been left developmentally delayed.
Neonatal seizures occurring within 24 to 48 h of a difficult birth are usually indicative of severe cerebral damage, usually anoxic, either antenatal or parturitional. Such infants often succumb, and about half of the survivors are seriously handicapped. Seizures having their onset several days or weeks after birth are more often an expression of acquired or hereditary metabolic disease. In the latter group, hypoglycemia is the most frequent cause; another, hypocalcemia with tetany, has become infrequent. A hereditary form of pyridoxine deficiency is a rare but treatable cause, sometimes also inducing seizures in utero and characteristically responding promptly to massive doses (100 mg) of vitamin B6 given intravenously. Biotinidase deficiency is another rare but correctable cause. Nonketotic hyperglycemia, maple syrup urine disease, as well as other metabolic disorders may lead to seizures in the first week or two of life and are expressive of a more diffuse encephalopathy.
In contrast, benign forms of neonatal seizures have also been identified. For example, Plouin described a form of benign neonatal clonic convulsions beginning on days 2 and 3, up to day 7, (“fifth day seizures”) in which there were no specific EEG changes. The seizures then remit and have a good prognosis. The inheritance is autosomal dominant. There are other nonfamilial cases with onset on days 4 to 6, wherein the partial seizures may even increase to status epilepticus; the EEG consists of discontinuous theta activity. In both these groups, the outlook for normal development is good and seizures seldom recur later in life. There are also benign forms of polymyoclonus without seizures or EEG abnormality in this age period. Some occur only with slow-wave sleep or feeding. They disappear after a few months and require no treatment. A form of benign nocturnal myoclonus in the neonate is also well known.
Neonatal seizures may continue into the infantile period, or seizures may begin in an infant who seemed to be normal up to the time of the first convulsive attack. While the most common type of convulsion is the febrile seizure, not strictly a type of epilepsy, the most characteristic epilepsy at this age is the massive sudden myoclonic jerk of head and arms leading to flexion or, less often, to extension of the body (infantile spasms, salaam spasms). This form, which characterizes the West syndrome as described earlier, has many underlying causes. The same seizure type occurs in infants with tuberous sclerosis (diagnosed in infancy by the presence of hypopigmentated macules, or “ash-leaf spots”), phenylketonuria, or Sturge-Weber angiomatosis, but most often it is associated with other diseases beginning in this age period. Infantile spasms cease by the end of the second year and are replaced by focal and secondarily generalized seizures. They do not respond well to the usual antiepileptic medications. Some instances of infantile spasms may be due to a metabolic encephalopathy of unknown type or, a cortical dysgenesis (Jellinger). West syndrome is characterized by an EEG picture of large bilateral slow waves and multifocal spikes (hypsarrhythmia).
The Dravet syndrome, which includes myoclonic and focal seizures, occurs in this age group but is also relevant to adult practice as patients are recognized with persistence of resistant epilepsy of several types. In the past this form of epilepsy and developmental delay were attributed to a febrile illness or vaccination in infancy but it has become clear that the syndrome is the result of a loss of function mutation in a sodium channel gene (SCN1A in most cases). The initial seizures in these cases have been bought forward by a febrile episode or other neonatal event but they are subsequently characterized by unprovoked and treatment resistant episodes.
Febrile seizures represent a challenging problem in this age period. When febrile seizures are prolonged, focal, or accompanied by a neurologic deficit, they are referred to as complicated febrile seizure. These are distinguished from the benign familial febrile seizure syndrome discussed earlier in the chapter. While myoclonic activity with seizures in this age group raises concern of a serious condition, there is a common benign form with a heritable component and does not lead to developmental delay.
Seizures Presenting in Early Childhood
A number of focal epilepsies may appear for the first time during this age period and carry a good prognosis, that is, the neurologic and intellectual capacities remain relatively unimpaired and seizures may cease in adolescence. These disorders begin between 3 and 13 years of age and there is often a familial predisposition. Most are marked by distinctive focal spike activity that is accentuated by sleep (see earlier, in reference to benign childhood epilepsy with centrotemporal or occipital spikes). Several of these have been discussed earlier under the “Special Epileptic Syndromes.” In one form, benign childhood epilepsy with centrotemporal spikes, unilateral tonic or clonic contractions of the face and limbs recur repeatedly with or without paresthesia; anarthria may follow the seizure. There are central and temporal spikes in the EEG interictally. Less commonly, the focus originates in an occipital lobe with EEG spiking on eye closure. An acquired aphasia characterizes another disorder that was described by Landau and Kleffner to mark the beginning of an illness in which there are partial or generalized motor seizures and multifocal spike or spike-and-wave discharges in the EEG and deterioration of language function.
As in any age group, there are structural causes of seizures that include medial temporal sclerosis, described in several places in this chapter, tumor and arteriovenous malformation. The special case of Rasmussen encephalitis and intractable seizures has already been discussed under the “Special Epileptic Syndromes.”
Among the generalized idiopathic epilepsies, the typical absence disorder, with its regularly recurring 3-per-second spike-and-wave EEG abnormality, begins in this age period (rarely before age 4 years) and carries a good prognosis. This seizure disorder responds well to medications, as indicated further on. Its features are fully described in “Absence Variants.”
Convulsions in this age group may present around the age of 4 years as focal myoclonus with or without astatic seizures, atypical absence, or generalized tonic-clonic seizures. The EEG, repeated if initially normal, is most helpful in diagnosis; it reveals a paroxysmal 2- to 2.5-per-second spike-and-wave pattern on a background of predominant 4- to 7-Hz slow waves. Many of these cases qualify as the Lennox-Gastaut syndrome, are difficult to treat, and are likely to be associated with developmental delay. At this age, perhaps more than any other, the first burst of seizures may take the form of status epilepticus and, if not successfully controlled, may end fatally.
Seizures in Later Childhood and Adolescence
These represent a common problem in practice but present a special difficulty because this is the age at which syncope and psychogenic seizures begin to occur and alcohol and drug abuse may begin. In this age period in particular, as the adolescent strives for independence, the social disruption caused by seizures are likely to take a toll on the relationships and educational progress of the emerging adult. Here, we also face the frequent issue relating to the nature and management of the first seizure in an otherwise normal young person. As in other age groups, the history often discloses the likely provocation of seizures, as for example, in young person has been sleep deprived or imbibing alcohol or one of many abused drugs and has a first seizure. A search for a cause of the first seizure in this age group is necessary by MRI, ECG, and EEG but these tests less frequently disclose an underlying lesion than in other age groups. Often, there has only been a single event and no clinical or EEG features to define the nature of the seizure disorder. However, the type of seizure that first brings the child or adolescent to medical attention is most likely to be a generalized tonic-clonic convulsion and may mark the beginning of idiopathic generalized epilepsy or juvenile myoclonic epilepsy, as described earlier sections.
A few patients have had a history of absence in which the EEG shows a characteristic polyspike pattern, about one-third with a photomyoclonic response. When the seizures are an expression of a congenital epileptic focus that is associated with developmental delay or scholastic failure, the diagnostic and therapeutic problem becomes demanding. In the special group of younger individuals with long-standing seizures, nearly half have temporal lobe epilepsy. Huttenlocher and Hapke, in a follow-up study of 145 infants and children with intractable epilepsy, found that the majority had developmental delay.
Opinion is divided on whether treatment is required for the older child or adolescent who comes to medical attention because of a first seizure that appears to be idiopathic. Age, sex, and the circumstances of the seizure (withdrawal from drugs or alcohol, myoclonic episodes, family history) all figure into the risk of subsequent seizures. What is apparent is that the early use of antiepileptic drugs has little effect on the occurrence of later seizures, as summarized in guidelines authored by Krumholz and colleagues as discussed further on. When such cases have been observed without treatment, such as in the series reported by Hesdorfer and colleagues, the risk of another seizure over 10 years was 13 percent unless the first episode was status epilepticus, in which case the risk was 41 percent. Attention is given to regularizing sleep and minimizing alcohol and stimulants.
Seizures in Late Adult Life
Hauser and Kurland reported an increase in the incidence of seizures as the population ages—from 11.9 per 100,000 in the 40- to 60-year-old age group to 82 per 100,000 in those 60 years of age or older. Often, these individuals live alone so there is no witness to the event, they have multiple medical problems, they may have cognitive difficulty that impedes an accurate history, multiple medications are almost the rule, and cerebral imaging is likely to show abnormalities that may not be referable to the problem at hand.
A person in this age group who begins to have seizures of either focal or generalized type may harbor a primary or secondary tumor, a past cerebral infarct, or a traumatic cortical scar that had not declared itself clinically. For example, according to Sung and Chu, previous infarcts are by far the most common lesions underlying status epilepticus in late adult life. Probably the nature of the population in a given clinic determines the relative frequency of underlying causes. In any case, cerebral imaging usually settles the issue.
However, many seizure-like events in this age group are the result of a cardiac arrhythmia, particularly ventricular tachycardia but also cardiac disorders not related to rhythm such as aortic stenosis. Therefore, ECG and long-term monitoring of heart rhythm are useful ancillary tests if the episode remains unexplained.
Cortical and subcortical lesions, the result of previous traumatic contusions, are a particularly important cause of seizures; the lesions are revealed by brain imaging and are typically located in the anterior frontal and temporal lobes. Brain abscess and other inflammatory and infectious illnesses remain common causes of adult seizures in tropical regions. In the elderly, seizures as a result of advanced Alzheimer and other degenerative diseases occur in up to 10 percent of cases; moreover, these patients are subject to falls, subdural hematoma, and all other illnesses of old age, such as cancer, that secondarily affect the brain. In individuals with cancer, cerebral metastasis is certainly a common cause of a first seizure.
In the common case of an adult with a first unexplained seizure, it has been our practice not to administer an antiepileptic medication unless there is an underlying structural lesion or an abnormality on a single EEG or with prolonged monitoring and to reevaluate the situation in 6 to 12 months. The decision regarding starting treatment in an older adult is informed by a number of factors including occupation, need for driving, safety of home environment, use of alcohol and other sedatives, anticipated compliance, and drug interactions. Usually, a second MRI and EEG are performed to exclude focal abnormalities that were not appreciated during the initial evaluation, but often these studies are again unrevealing. This approach has been prompted by data such as those of Hauser and colleagues, who found that about one-third of patients with a single unprovoked seizure will have another seizure within 5 years; the risk is even greater if there is a history of seizures in a sibling, a complex febrile convulsion in childhood, or a spike-and-wave abnormality in the EEG. Moreover, the risk of recurrence is greatest in the first 24 months. In patients with two or three unexplained seizures, a far higher proportion, about 75 percent, have further seizures in the subsequent 4 years.
Seizures due to Underlying Medical Disease
Several diseases announce themselves by an acute convulsion. Here we focus on generalized medical disorders as causes of single and episodic seizures, in contrast to structural lesions of the brain that cause focal or generalized epilepsy.
The possibility of abstinence seizures in patients who abuse alcohol or use benzodiazepine and related sedative drugs, must be considered when seizures occur for the first time in adult life or in adolescence. Suspicion is raised by the stigmata of alcohol abuse or a history of prolonged anxiety requiring sedative drugs. Also, sleep disturbance, tremulousness, disorientation, illusions, and hallucinations can be associated with the convulsive phase of the withdrawal syndrome. Seizures in this setting may occur singly, but as often, in a brief flurry, the entire convulsive period lasting for several hours and rarely for a day or longer, during which time the patient may display twitchiness or myoclonus and be unduly sensitive to photic stimulation. Chapter 41 discusses alcohol and other drug-related seizures in detail.
Infections and Inflammatory-Immune Conditions
An outburst of seizures is also a prominent feature of all varieties of bacterial meningitis, more so in children than in adults. Fever, headache, and stiff neck provide the clues to diagnosis, and lumbar puncture yields the salient data. In endemic areas and in individuals who have traveled from these areas, cysticercosis and tuberculous granulomas of the brain are very common causes of epilepsy. Myoclonic jerking and seizures may appear early in acute herpes simplex encephalitis and other forms of viral, treponemal, and parasitic encephalitis, including those derived from HIV infection, both directly and indirectly such as toxoplasmosis and brain lymphoma; and in subacute sclerosing panencephalitis. Seizure(s) without fever or stiff neck may be the initial manifestation of syphilitic meningitis, a fact worth noting as this process reemerges in AIDS patients.
A variety of autoimmune encephalitides may cause seizures as, for example, with the anti-NMDA receptor antibody that is associated with ovarian and other teratomas and other paraneoplastic conditions such as the antibody syndrome directed at the voltage-gated potassium channel complex (see Chap. 30).
Seizures in Metabolic Encephalopathy
Uremia has a strong tendency to produce convulsions. Of interest is the relation of seizures to the development of acute anuric renal failure, generally from acute tubular necrosis but occasionally due to glomerular disease. Total anuria may be tolerated for several days without the appearance of neurologic signs, and then there is an abrupt onset of twitching, trembling, myoclonic jerks, and brief generalized motor seizures; acute hypertension probably plays a role. The entire motor constellation, one of the most dramatic in medicine, lasts several days until the patient sinks into terminal coma or recovers by dialysis. When this twitch-convulsive syndrome accompanies lupus erythematosus, seizures of undetermined cause, or generalized neoplasia, one should suspect its basis in renal failure.
Other acute metabolic illnesses and electrolytic disorders complicated by generalized and multifocal motor seizures are hyponatremia and its opposite, the hypernatremic, hyperglycemic and other hyperosmolar states, hypoglycemia, thyrotoxicity, porphyria, hypomagnesemia, and hypocalcemia. In all these cases, rapidly evolving electrolyte abnormalities are more likely to cause seizures than those occurring gradually. For this reason it is not possible to assign absolute levels of sodium, blood urea nitrogen (BUN), osmolarity, or glucose concentrations above or below which seizures are likely to occur. Lead (in children) and mercury (in children and adults) are the most frequent of the metallic poisons, still rare as a group, that cause convulsions. The presence of these heavy metals in homeopathic treatments should not be overlooked.
Generalized seizures, with or without twitching, occur in the advanced stages of many other illnesses, such as hypertensive encephalopathy, the posterior reversible encephalopathy syndrome from various drugs (PRES, as discussed in Chap. 33), sepsis—especially gram-negative septicemia with shock—and hepatic coma. Usually, seizures in these circumstances can be traced to an associated metabolic abnormality and are revealed by appropriate studies of the blood. Seizures are a central feature of the eclamptic syndrome as discussed in a separate section below.
In most cases of seizures caused by metabolic and withdrawal states, treatment with antiepileptic drugs is not necessary as long as the underlying disturbance is rectified. Indeed, antiepileptic drugs are usually ineffective in halting the seizures if the metabolic disorder persists.
Medications and Other Drugs as Causes of Seizures
In addition to the withdrawal states, a large number of medications are themselves capable of causing seizures, usually when toxic blood levels are attained. The antibiotic imipenem and excessive doses of other penicillin congeners as well as linezolid may be responsible, particularly if renal failure leads to drug accumulation. Cefepime, a fourth-generation cephalosporin, widely used for the treatment of gram-negative sepsis, can result in status epilepticus, if given in excessive dosage (Dixit et al). Renal dysfunction, preexisting brain lesions and previous epilepsy have been emphasized as features associated with antibiotic-induced seizures in a review by Sutter and colleagues (2015), and they emphasize that the evidence for associations between seizures and specific antibiotics are often based on limited evidence.
The tricyclic antidepressants, bupropion, and lithium may cause seizures, particularly in the presence of a structural brain lesion. Lidocaine and aminophylline are known to induce an unheralded single convulsion if administered too quickly or in excessive doses. The use of the analgesic tramadol has also been associated with seizures. Curiously, the anesthetic propofol, which is discussed further on as a potent anticonvulsant in the treatment of status epilepticus, has caused marked myoclonic phenomena in some patients and, rarely, seizures. These may occur during induction or emergence from anesthesia or as a delayed effect (Walder et al).
The list of medications that at one time or another have been associated with a convulsion is long and, if no other explanation for a single seizure is evident, the physician is advised to look up in standard references the side effects of the drugs being administered to the patient. In a few of our otherwise healthy adult patients, extreme sleep deprivation coupled with ingestion of large doses of antibiotics or adrenergic medications or other remedies that are used indiscriminately for the symptomatic relief of colds has been the only plausible explanation for a single or doublet seizure.
Furthermore, many illicit drugs of several varieties may cause seizures. Among the most prominent are cocaine, high-potency synthetic cannabinoids, abuse of amphetamines, phencyclidine, psilocibin, lysergic acid and related compounds. Some of these cause convulsions through an intermediate of extreme hypertension of vasculopathy but others seem to have a direct neurotoxic effect.
Global Arrest of Circulation
Cardiac arrest, suffocation or respiratory failure, carbon monoxide poisoning, or other causes of hypoxic encephalopathy tend to induce diffuse myoclonic jerking and generalized seizures as cardiac function resumes. The myoclonic-convulsive phase of this condition may last only a few hours or days, in association with coma, stupor, and confusion; or it may persist indefinitely as an intention myoclonus state (Lance-Adams syndrome). These movements are to be distinguished from the convulsive movements of syncope discussed earlier in the chapter and in Chap. 17.
Convulsive seizures are quite uncommon in the acute or evolving phases of an arterial stroke. The ischemic convulsive phenomena of a “limb-shaking TIA” and a burst of generalized clonic motor activity during basilar artery occlusion have been mentioned earlier, but are uncommon and are not truly epileptic phenomena. Embolic infarcts involving the cortex become epileptogenic in fewer than 10 percent of cases and only after an interval of several months or longer. It has been stated in texts that thrombotic infarcts involving the cortex are almost never convulsive at their onset. Lacunar infarction, being deep and not involving the cortical surface, of course, does not produce convulsions.
In contrast, cortical venous thrombosis with underlying ischemia and infarction acts as a highly epileptogenic lesion (see Chap. 33). The same is true for hypertensive encephalopathy [including the above mentioned posterior reversible encephalopathy (PRES) and eclampsia] and thrombotic thrombocytopenic purpura (TTP), which has a strong tendency to cause nonconvulsive status epilepticus. The rupture of a saccular aneurysm is sometimes marked by one or two generalized convulsions that are not epileptic in nature and are probably predicated on the arrest of cerebral circulation. Cerebral hemorrhages, spontaneous or traumatic, that extend near the cortex, also may present with seizures acutely or become sources of recurrent focal seizures as a delayed consequence.
The use of anticonvulsants as prophylaxis for seizures after a typical cortical stroke of embolic or thrombotic type or nontraumatic cerebral hemorrhage is not necessary. The rate of such seizures has been estimated to be 3 percent or less in the first year. This subject is addressed further in Chap. 33.
Seizures With Acute Head Injury
It is not uncommon for severe concussion to be attended by brief convulsive movements (see Chap. 34). The appearance is in most cases of clonic twitching but may include a momentary tonic phase. Rarely, a prolonged clonic convulsion occurs. The nature of this event, whether originating in the reticular formation as a component of concussion, or from some disruption of cortical activity, is not clear. Almost invariably in our experience, the EEG recorded hours or a day later is normal, and imaging studies are likewise normal or show a small contusion. There is little to guide one in treatment of these patients; we tend to give a course of antiepileptic medications for several weeks but it is not established if this is the correct approach. Aside from penetrating brain trauma, the risk of delayed seizures is low. Further details on this subject, particularly seizures that occur as a late effect of traumatic brain injury can be found in Chap. 34.
Seizures During Pregnancy
Here one contends with two scenarios: the woman with epilepsy who becomes pregnant and the woman who has her first seizure during pregnancy. According to the extensive EURAP study, about two-thirds of epileptic women who become pregnant have no change in seizure frequency or severity (the majority remain seizure free); the remainder are evenly split between those in whom the frequency increases and in an equal number, it lessens. A systematic review has indicated that almost 90 percent of women who were seizure-free for a year before becoming pregnant, have no seizures during pregnancy.
Many antiepileptic medications also seem to be safe for the baby during breast-feeding in that only small amounts are excreted in lactated milk. The degree of penetration into breast milk is dependent on the extent of protein binding. Highly bound drugs do not appear in substantial concentrations and the converse is true. Relatively safe agents include carbamazepine, which is found to be 40 percent of the mother’s serum concentration, resulting in a neonatal blood level that is below the conventionally detectable amount. Phenytoin is excreted at 15 percent of maternal serum concentration, and valproate, being highly protein bound, is virtually absent in breast milk. No adverse effects have been attributed to these small amounts of these drugs. Those that appear in intermediate concentrations include levetiracetam, oxcarbazepine, tiagabine, vigabatrin, gabapentin, and topiramate. Drugs considered risky for the infant because of high concentrations in breast milk include phenobarbital, primidone, ethosuximide, zonisamide, and benzodiazepines. The risks of using this last group of drugs in the postpartum period must be weighed against the sedating effects of the medication on the neonate.
In the past, issues regarding a coagulopathy in the fetus exposed to phenobarbital (now infrequently used for adult seizure disorders) and certain of the other drugs are well known to obstetricians and pediatric specialists and are treated with the oral administration of vitamin K, 20 mg/d during the eighth month or 10 mg IV 4 h before birth and 1 mg IM to the neonate.
Teratogenic Effects of Antiepileptic Medications
Because it is important to prevent major convulsions in the pregnant epileptic woman, antiepileptic medication should not be discontinued or arbitrarily reduced, particularly if there have been recent convulsions. The conventional drugs (phenytoin, carbamazepine, levetiracetam, lamotrigine) are all tolerated in pregnancy comparably to their use before pregnancy. Plasma levels of most of these drugs, both the free and protein-bound fractions, fall slightly in pregnancy in part because they are cleared more rapidly from the blood but there is considerable inter-individual variability. It is important to monitor the drug levels so that adjustments can be made. The main issue, however, pertains to the potential teratogenicity of most of the drugs with valproate having more risk than the others, and a slight reduction in verbal IQ in children born of mothers who had been exposed to valproate during pregnancy.
The most common teratogenic effects have been cleft lip and cleft palate, but infrequently also a subtle facial dysmorphism (“fetal anticonvulsant syndrome”), similar to the fetal alcohol syndrome. In general, the risk of major congenital defects is low; it increases to 4 to 5 percent in women taking antiepileptic drugs during pregnancy, in comparison to 2 to 3 percent in the overall population of pregnant women. These statistics have been essentially confirmed in the large study by Holmes and colleagues, conducted among several Boston hospitals. When all types of malformations were included, both major and minor, 20 percent of infants born to mothers who took antiepileptics during pregnancy showed abnormalities, compared to 9 percent of mothers who had not taken medications. These authors identified “midface hypoplasia” (shortened nose, philtrum, or inner canthal distance) and finger hypoplasia as characteristic of anticonvulsant exposure; these changes were found in 13 and 8 percent of exposed infants, respectively. However, it should be emphasized that in large surveys, major malformations have occurred in only 5 percent of infants exposed to antiepileptic drugs. The infants born of a group of women with epilepsy who had not taken anticonvulsants during pregnancy showed an overall rate of dysmorphic features comparable to that in control infants, but there was still a 2 to 3 percent rate of facial and finger hypoplasia. This risk is shared more or less equally by all the major antiepileptics again, with valproate associated with a higher rate. Aggregating eight databases, Jetnik and colleagues found a number of malformations of the nervous and somatic systems to be increased in comparison to other antiepileptic drugs.
Of equal or greater concern has been the findings by Meador and colleagues that in utero exposure to valproate was associated with lower IQs (by 9 points) compared to lamotrigine in children at the age of 4. It is not clear if the effect persists after this age. Children who had been exposed to phenytoin or to carbamazepine also had slightly lower IQs but this difference was ostensibly accounted for by lower maternal IQ. Some studies, including the one by Meador and colleagues suggest that folate may have an ameliorating effect on this detrimental effect at age 3, whereas there is an uncertain benefit of folate in preventing fetal malformations due to the drugs.
The risk of neural tube defects is also slightly increased by anticonvulsants during pregnancy, and greatest for the use of valproate. It had been considered to be reduced by giving folate before pregnancy has begun (it is not clear if this is true for valproate), but epilepsy experts avoid the use of valproate during pregnancy altogether. These risks are greater in women taking more than one anticonvulsant, so that monotherapy is a desirable goal. Furthermore, the risk is disproportionately increased in families with a history of these defects. Some of the newer anticonvulsants should probably be used cautiously until greater experience has been obtained. As each new drug has been introduced over the years, there has usually been a tentative claim of reduced teratogenic effects, often proven later to be incorrect. Claims have been made of safety in this regard for lamotrigine, causing many specialists to change from the more conventional drugs to this one in women who anticipate becoming pregnant, but lamotrigine levels tend to fall precipitously during pregnancy. A report by Cunnington and colleagues using registry information suggests that the incidence of major birth defects in the fetuses exposed to lamotrigine during the first trimester is just under 3 percent, similar to risk estimates for the general population but also close to the 3 to 4 percent risk derived from most registries of women on anticonvulsants. Polytherapy with lamotrigine and valproate raised the estimate of risk to 12 percent. For all the drugs, polytherapy has the highest risk and there is a significant dose effect for an individual drug on the likelihood of fetal malformation.
If a woman with epilepsy has not required medications for a time before getting pregnant and has a seizure during pregnancy, the best choice of medication may be phenytoin for its advantage in rapid seizure control, or levetiracetam. Exposure of the fetus late in gestation poses few teratogenic risks. If a woman discovers she is pregnant while on an antiepileptic drug, changing medications is unlikely to reduce the chances of birth defects, even for valproate, but this drug retains the risk of lower IQ in the child. The special case of eclamptic seizures is managed by infusion of magnesium as noted below.
Epileptic women of childbearing age who are on an antiepileptic medication, particularly those which induce cytochrome P450, should be advised that higher doses of the estradiol component of birth control agents are required or they may be exposed to the issues of becoming pregnant while antiepileptic medications. Phenytoin, carbamazepine, and topiramate induce hepatic enzymes and most other medications do not have this effect.
This syndrome appears during the last trimester of pregnancy or soon after delivery and may announce itself by hypertension and convulsions; the latter are generalized and tend to occur in clusters (See Also Chap. 33). The standard practice is to induce labor or perform a cesarean section and manage the seizures as one would manage those of hypertensive encephalopathy (of which this is one type). The administration of magnesium sulfate continues to be the favored treatment by obstetricians for the prevention of eclamptic seizures; two randomized trials have reestablished its value in preventing seizures in preeclamptic women (Lucas et al) and in avoiding a second convulsion once one had occurred (Eclampsia Trial Collaborative Group). Magnesium sulfate, 10 g IM, followed by 5 g every 4 h, proved comparable to standard doses of phenytoin as prophylaxis for seizures. Our colleagues use a regimen of 4 g IV more than 5 to 10 min followed by a maintenance dose of 5 g every 4 h IM or 1 to 2 g/h IV. In nontoxic gestational epilepsy, approximately 25 percent of patients are found to have some disease (neoplastic, vascular, or traumatic) that will persist.
The treatment of epilepsy of all types can be divided into four parts: the use of antiepileptic drugs, the surgical excision of epileptic foci and other surgical measures, the removal of causative and precipitating factors, and the regulation of physical and mental activity.
Antiepileptic Drugs—General Principles
The goal of drug treatment is to create a seizure-free state if possible and with the fewest side effects. In the past, a few seizures a year had been considered adequate control but with numerous newer medications it is reasonable to eliminate seizures. On the other hand, it is equivalently deleterious to make a patient so mentally dull as to interfere with function at work or school. The choice and dose of medication depends on many factors including sex, age, other medications, and renal or hepatic dysfunction or other medical conditions and psychiatric conditions that might be favorably influenced by a particular agent. As a general rule, starting in the lower dose range and attempting to provide twice daily or daily administration are favored.
In approximately 70 percent of all patients with epilepsy, the seizures are controlled completely or almost completely by medications; in an additional 20 to 25 percent, the attacks are significantly reduced in number and severity. In a series reported by Kwan and Brodie approximately 20 years ago but probably still reflecting current circumstances almost half of patients with a new seizure disorder were controlled with first agent tried, another approximately 15 percent respond to a second as monotherapy, and the third choice controls very few instances—the remaining cases are considered treatment-resistant. In more modern series, such as the one reported by Bonnett and colleagues, the response to a first agent of a newer class was similar but subsequent agent cumulatively was somewhat more successful, achieving 75 percent control. More importantly, the simultaneous use of medications presents special problems and the rates of suppression of seizures with each additional drug are low and generally not additive. This approach, however, may not apply to combinations of some of the newer drugs.
An additional question regards whether to start treatment immediately in an adult with a first unprovoked seizure. The MESS trial, which randomized large groups of patients after a first unprovoked seizure to either immediate treatment or none (Marson and colleagues) concluded that the treated group had fewer subsequent seizures at 6 months (18 vs 26 percent), 2 years (32 vs 39 percent), and 5 years (42 vs 51 percent) and the differences were larger for those who had multiple seizures before randomization and the time to the next seizure was delayed. However, the differences became less significant over time and the side effects of the medications, as judged by practical factors such as keeping a job, were no different between groups. The death rates were comparable. Therefore, factors such as tolerance of the medications, patient preferences, and nature of work must be taken into account when making decisions regarding antiepileptic medicines. Guidelines from the American Academy of Neurology generally accord with these views (Krumholz et al).
Table 15-5 lists the most commonly used drugs along with their dosages, effective blood levels, and serum half-lives. Because of the long half-lives of phenytoin, phenobarbital, and ethosuximide, these drugs need be taken only once daily, preferably at bedtime. Valproate and carbamazepine have shorter half-lives, and their administration should be spaced during the day. It is useful to be familiar with the serum protein-binding characteristics of antiepileptic drugs and the interactions among these drugs, and between antiepileptic and other drugs.
Table 15-5MECHANISMS AND USES OF THE MAIN ANTIEPILEPTIC DRUGS ||Download (.pdf) Table 15-5MECHANISMS AND USES OF THE MAIN ANTIEPILEPTIC DRUGS
|GENERIC NAME ||MECHANISM OF ACTION ||PRINCIPLE INDICATIONS ||MAJOR LIMITATIONS |
|Major Antiepileptic Used as Monotherapy |
|Valproic acid ||multiple, including GABA potentiation, NMDA inhibition, sodium channel inhibition, T-type calcium channel inhibition ||Focal and generalized seizures, absence seizures ||Hepatic enzyme inhibitor, teratogenicity, weight gain |
|Phenytoin ||Sodium channel inhibitor ||Focal and generalized seizures ||Hepatic enzyme inducer, nonlinear pharmacokinetics, skin hypersensitivity |
|Carbamazepine ||Sodium channel inhibitor ||Focal and generalized seizures ||Hepatic enzyme inducer, skin hypersensitivity, hyponatremia |
|Oxcarbazepine ||Sodium channel inhibitor ||Focal seizures ||Hepatic enzyme inducer, hyponatremia |
|Eslicarbazepine ||Sodium channel inhibitor ||Focal seizures, adjunctive use only ||Hepatic enzyme inducer, hyponatremia |
|Phenobarbital ||GABA potentiation ||Focal and generalized seizures ||Hepatic enzyme inducer, skin sensitivity |
|Lamotrigine ||Sodium channel inhibitor ||Focal and generalized seizures ||Hepatic enzyme inducer, skin hypersensitivity |
|Levetiracetam ||SV2A modulation ||Focal and generalized seizures ||Mood disturbance, psychosis |
|Brivaracetam ||SV2A modulation ||Focal and generalized seizures ||Less mood disturbance and psychosis than levetiracetam |
|Topiramate ||Multiple, including GABA potentiation, AMPA inhibition, sodium channel inhibition, calcium channel inhibition ||Focal and generalized seizures ||Nephrolithiasis, cognitive impairment, weight loss |
|Lacosamide ||Sodium channel inhibition ||Focal and generalized seizures || |
|Zonisamide ||Sodium channel inhibition ||Focal and generalized seizures ||Nephrolithiasis, cognitive impairment, weight loss |
|Ethosuximide ||T-type calcium channel inhibition ||Absence seizures ||Insomnia |
|Clobazam ||GABA potentiation ||Focal and generalized seizures, adjunctive use only ||Tolerance, sedation |
|Gabapentin ||Calcium channel inhibition ||Focal and generalized, adjunctive use only || |
|Pregabalin ||Calcium channel inhibition ||Focal and generalized, adjunctive use only ||Weight gain |
|Perampanel ||Glutamate (AMPA) inhibition ||Focal and generalized seizures, adjunctive use only || |
|Vigabatrin ||GABA potentiation ||Infantile spasms, focal and generalized seizures ||Retinal toxicity |
|Clonazepam ||GABA potentiation ||Adjunctive use only ||Tolerance, sedation |
|Diazepam ||GABA potentiation ||Adjunctive use only ||Tolerance, sedation |
|Lorazepam ||GABA potentiation ||Adjunctive use only ||Tolerance, sedation |
|Fosphenytoin ||Sodium channel inhibitor ||Focal and generalized seizures ||Skin hypersensitivity |
|Propofol ||Multiple, including GABA potentiation and NMDA inhibition ||Adjunctive use only (for refractory status epilepticus) ||Sedation, hypertriglyceridemia, hypotension |
Certain drugs are somewhat more effective in one type of seizure than in another, and it is necessary to use the proper drugs in optimum dosages for different circumstances. Initially, only one drug should be used and the dosage increased until sustained therapeutic levels have been attained. If the first drug does not control seizures, a different one should be tried, but frequent shifting of drugs is not advisable; each should be given an adequate trial before another is substituted. A general approach to the choice of drug in certain common forms of epilepsy is given in Table 15-6 for adults and Table 15-7 for children, but it must be noted that there are a number of drugs that may be appropriate in each circumstance. Furthermore, the antiepileptic drugs have approved purposes as assigned by the FDA (Federal Drug Administration) and the EMA (European Medicines Agency). These are more restrictive than are found in general use but it is worthwhile being familiar with the standing of various medications. A tabular summary of these approvals, main uses, and their dates of inception that divide the agents into three generations can be found in a review by Schmidt that is current as of 2016.
Table 15-6PHARMACOLOGIC ASPECTS OF ANTIEPILEPTIC DRUGS ||Download (.pdf) Table 15-6PHARMACOLOGIC ASPECTS OF ANTIEPILEPTIC DRUGS
| || ||USUAL DOSAGE || || |
|GENERIC NAME ||TRADE NAME ||CHILDREN, MG/KG ||ADULTS, MG/D ||SERUM HALF-LIFE, H ||EFFECTIVE BLOOD LEVEL, μG/ML |
|Valproic acid ||Depakote ||30–60 ||1,000–3,000 ||6–15 ||50–100 |
|Phenytoin ||Dilantin ||4–7 ||300–400 ||12–36 ||10–20 |
|Carbamazepine ||Tegretol ||20–30 ||600–1,200 ||14–25 ||4–12 |
|Oxcarbazepine ||Trileptal ||10–40 ||900–2,400 ||1–5 || |
|Eslicarbazepine ||Aptiom || ||400–1200 ||13–20 || |
|Phenobarbital ||Luminal ||3–5 (8 for infants) ||90–200 ||40–120 ||15–40 |
|Lamotrigine ||Lamictal ||0.5 ||300–500 ||15–60 ||2–7 |
|Levetiracetam ||Keppra ||20–60 ||500–3,000 ||6–8 || |
|Brivaracetam ||Briviact || ||50–200 ||9 || |
|Topiramate ||Topamax || ||400 ||20–30 || |
|Lacosamide ||Vimpat || || || || |
|Zonisamide ||Zonegran || || || || |
|Ethosuximide ||Zarontin ||20–40 ||750–1,500 ||20–60 ||50–100 |
|Clobazam ||Onfi || ||5–40 ||16–42 || |
|Gabapentin ||Neurontin || ||900–3,600 ||5–7 || |
|Pregabalin ||Lyrica || ||150–600 ||6 || |
|Perampanel ||Fycompa || ||2–12 ||105 || |
|Vigabatrin ||Sabril ||100–300 ||1,000–3,000 ||5–11 || |
|Clonazepam ||Klonopin ||0.01–0.2 ||2–10 ||18–50 ||0.01–0.07 |
|Diazepam ||Valium || ||2–40 ||60–72 || |
|Lorazepam ||Ativan ||0.15–2 ||2–20 ||12 || |
|Fosphenytoin ||Cerebyx ||5–20 ||10–20 mg/kg ||8–30 min || |
|Propofol ||Diprivan ||1.2–12mg/kg/h ||1.2–12 mg/kg/h ||40 minutes || |
Table 15-7CHOICES OF ANTIEPILEPTIC DRUGS IN CHILDHOOD SEIZURE DISORDERS ||Download (.pdf) Table 15-7CHOICES OF ANTIEPILEPTIC DRUGS IN CHILDHOOD SEIZURE DISORDERS
|SEIZURE TYPE ||INITIAL CHOICE ||SECOND ||THIRD |
|Generalized tonic-clonic ||Valproate, carbamazepine ||Lamotrigine, oxcarbazepine ||Phenytoin |
|Myoclonic ||Valproate, levetiracetam ||Lamotrigine ||Phenobarbital, clobazam |
|Absence ||Valproate ||Topiramate, levetiracetam, ethosuximide ||Lamotrigine |
|Focal ||Carbamazepine, phenytoin ||Valproate, levetiracetam, oxcarbazepine ||Lamotrigine, vigabatrin, topiramate |
|Infantile spasms ||ACTH, vigabatrin, ||Valproate ||Lamotrigine |
|Lennox-Gastaut ||Valproate ||Topiramate, lamotrigine ||Levetiracetam |
It is difficult to give definitive guidance on combining medications for refractory seizures. Several general principles are worth noting. First, it may seem sensible to avoid drug combinations with similar putative mechanisms because their side effects may be additive, for example, the addition of lamotrigine to carbamazepine or of phenytoin to carbamazepine may not be ideal but at the same time, it should be mentioned that the mechanism of action has little influence on clinical effectiveness and drugs of a similar class are often combined. Second, the clinician should be aware of known interactions through metabolic pathways such as valproate combined with either lamotrigine or phenobarbital as they share the cytochrome P450 degradation pathway. Third, although it is appropriate to use drugs that are known to be effective for the class of seizures under treatment, it is often necessary to extend the choices beyond these restrictions.
The therapeutic dose for any given patient must be determined, to some extent by clinical effect, guided by measurement of serum levels, as described below. Inquiry regarding seizure control and drug side effects is more valuable than adjustment of medication based solely on drug concentrations. Blood for serum levels is ideally drawn in the morning before the first dose of antiepileptic medication (“trough levels”), a practice that introduces consistency in measurement. A drug should not be discarded as being ineffective, even at the upper limits of therapeutic blood levels, when a slight increase in dosage would have led to suppression of attacks. On the other hand, drug levels can be helpful in detecting noncompliance or poor absorption in instances of inadequate seizure control. The management of seizures is facilitated by having patients chart their daily medication and the number, time, and circumstances of each episode. Furthermore, in some instances, asking the patients about seizure frequency may be unreliable. Some patients find it helpful to use a dispenser that is filled with medications with sufficient pills to last the week. This indicates to the patient whether a dose had been missed and whether the supply of medications is running low.
In general, higher serum concentrations of drugs are necessary for the control of focal seizures than for generalized ones. The usual blood level assay is of the total concentration of the drug (see Table 15-5); this is not a precise reflection of the amount of drug entering the brain, because—in the case of the most widely used antiepileptics—the large proportion of drug is bound to albumin and does not penetrate nervous tissue. Also, in patients who are malnourished or chronically ill or who have a constitutional reduction in proteins, there may be intoxication at low total serum levels. Certain antiepileptic drugs also have active metabolites that are not measured by methods ordinarily used to determine serum concentrations but nonetheless produce toxicity. This is particularly true for the epoxide of carbamazepine. The situation may be further complicated by interactions between one drug and the metabolites of another, as, for example, the inhibition of epoxide hydrolase by valproic acid, leading to toxicity through the buildup of carbamazepine epoxide. In circumstances of unexplained toxicity in the face of conventionally obtained serum levels that are normal, measurement may be undertaken of the levels of free drug and the concentration of active metabolites.
The use of saliva for measurement of free drug levels has merit but has not been adopted frequently in practice. The measurements correlate with free drug levels. It has the advantage of allowing the patient to collect a sample before breakfast and avoid venipuncture.
Finally, the pharmacokinetics of each drug plays a role in toxicity and the serum level that is achieved with each alteration in the dose. This is particularly true of phenytoin, which, as the result of saturation of liver enzymatic capacity, has nonlinear kinetics once serum concentration exceeds 10 mg/mL. For this reason, a typical increase in dose from 300 to 400 mg daily results in a disproportionate elevation of the serum level and toxic side effects. Elevations in drug concentrations are also accompanied by prolongation of the serum half-life, which increases the time to reach a steady-state concentration of phenytoin after dosage adjustments. Contrariwise, carbamazepine is known to induce its own metabolism, so that doses adequate to control seizures at the outset of therapy are no longer effective several weeks later.
Antiepileptic Drug Interactions
Antiepileptic drugs have manifold interactions with each other and with a wide variety of other drugs. Although many such interactions are known, only a few are of clinical significance and most pertain to older generations of medications, requiring adjustment of drug dosages (see Kutt).Among the interactions, valproate often leads to accumulation of active phenytoin and of phenobarbital by displacing them from serum proteins, as well as slightly elevating serum total levels. Some of the agents that alter the concentrations of antiepileptic medications are chloramphenicol, which causes the accumulation of phenytoin and phenobarbital, and erythromycin, which causes the accumulation of carbamazepine. Antacids reduce the blood phenytoin concentration, whereas histamine blockers used to reduce gastric acid output do the opposite. Salicylates reduce the total plasma levels of antiepileptic drugs but elevate the free fraction by displacing the drug from its protein carrier. More importantly, warfarin levels are decreased by the addition of phenobarbital or carbamazepine and may be increased by phenytoin although, with this last drug there may be unexpected alterations of the international normalized ratio (INR) in either direction. Enzyme-inducing drugs such as phenytoin, carbamazepine, and barbiturates can greatly increase the chance of breakthrough menstrual bleeding in women taking oral contraceptives and may lead to failure of contraceptive medications, and adjustments in the amount of estradiol must be made. These interactions are emphasized further below under the discussions of each agent.
Hepatic function greatly affects antiepileptic drug concentrations, since most of these drugs are metabolized in the liver. Serum levels must be checked more frequently than usual if there is liver failure, and with hypoalbuminemia it is advisable to obtain free drug levels for reasons just mentioned. Renal function has an indirect effect on the concentrations of the commonly used antiepileptics, but some agents, such as levetiracetam, gabapentin, and pregabalin, are excreted through the kidneys and require dosage adjustment in cases of renal failure. The main renal effects for the drugs in general are alterations in protein binding induced by uremia. In end-stage renal failure, serum levels are not an accurate guide to therapy and the goal should be to attain adequate free concentrations, typically, 1 to 2 μg/mL. In addition, uremia causes the accumulation of phenytoin metabolites, which are measured with the parent drug by enzyme-multiplied immunoassay techniques. In patients who are being dialyzed, total blood levels of phenytoin tend to be low because of decreased protein binding; in this situation it is also necessary to track free (unbound) levels as it is for other highly protein bound drugs. Because dialysis removes many drugs, particularly levetiracetam, phenobarbital, topiramate, ethosuximide, and gabapentin, dosage of these drugs may have to be increased or doses may have to be administered after dialysis.
Skin Eruptions from Antiepileptic Drugs
Rashes are the most frequent idiosyncratic reactions to the drugs used to treat epilepsy. The aromatic compounds (phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine) are the ones most often responsible. Furthermore, there is a high degree of cross-reactivity within this group, particularly between phenytoin, carbamazepine, and phenobarbital, and possibly, lamotrigine. The problem arises most often in the first month of use. The typical eruption is maculopapular, mainly on the trunk; it usually resolves within days of discontinuing the medication. More severe rashes may develop, sometimes taking the form of erythema multiforme and Stevens-Johnson syndrome, or even toxic epidermal necrolysis, especially with lamotrigine.
Certain polymorphisms in HLA genes (HLA-B*1502) have been associated with an increased risk of these types of severe skin reactions, particularly those of Asian ancestry but probably also in Caucasians, in whom this genotype is rare. Another allele HLA-A*3101 may be associated with skin eruptions in Caucasians (McCormack et al), but it (HLA-B*1502) does not seem reasonable at this time to screen non-Asian patients for such an infrequent complication. Another rare systemic hypersensitivity syndrome associated with the use of antiepileptic medications is one of high fever, rash, lymphadenopathy, and pharyngitis. Eosinophilia and hepatitis (or nephritis) may follow.
If any of these reactions require that one of the aromatic drugs be replaced, valproate, gabapentin, topiramate, or levetiracetam are reasonable substitutes, depending, of course, on the nature of the seizures.
Discontinuation of Antiepileptic Drugs
Withdrawal of medications may be undertaken in patients who have been free of seizures for a prolonged period. There are few firm rules to guide the physician in this decision. One plan, applicable to most forms of epilepsy, is to obtain an EEG whenever withdrawal of medication is contemplated. We have taken the approach that if the tracing is abnormal by way of showing paroxysmal activity, it is generally better to continue treatment. However, a normal EEG may not be helpful in making the decision to discontinue medications. A prospective study by Callaghan and colleagues showed that in patients who had been seizure-free during 2 years of treatment with a single drug, one-third relapsed after discontinuation of the drug, and this relapse rate was much the same in adults and children and whether the drug was reduced over a period of weeks or months. The relapse rate was lower in patients with absence and generalized-onset seizures than in patients with focal seizures. Another study by Specchio and colleagues gave results similar to those of the large Medical Research Council Antiepileptic Drug Withdrawal Study—namely, that after 2 years on a single anticonvulsant during which no seizures had occurred, the rate of relapse was 40 percent 2.5 years later and 50 percent at 5 years after discontinuation; this compared to a seizure recurrence rate of 20 percent for patients remaining on medication. Some have suggested that a longer seizure-free period is associated with a lesser rate of relapse.
Often in practice, the suggestion to stop medications after a lengthy seizure free period comes from the patient, for example if pregnancy is planned or there are untoward side effects but otherwise, the change is never risk free and therefore is infrequently impelled by the physician. Decisions regarding the cessation of medication are also tempered by patient’s desire to continue driving and their concern that another seizure may prevent a return to driving.
Patients with juvenile myoclonic epilepsy, even those with long seizure-free periods, should probably continue medication life-long, but there have been no thorough studies to support this dictum. In young women with this disorder who plan or a likely to become pregnant, changing from valproate to levetiracetam may be sensible. The appropriate duration of treatment for postinfarction epilepsy has not been studied, and most neurologists continue to use one drug indefinitely. Interestingly, epilepsy caused by military brain wounds tends to wane in frequency or to disappear in 20 to 30 years, thereafter no longer requiring treatment (Caveness). In contrast, childhood uncomplicated absence seizures do not require lifelong treatment.
A curious and unexplained lesion in the splenium of the corpus callosum has been detected in patients who have had their antiepileptic drug(s) withdrawn in the previous few days. A review of 16 patients by Gürtler and colleagues did not find a clinical correlate for this change. A broad range of drugs was implicated and the lesion was most prominent on FLAIR MRI. Various metabolic derangements cause similar lesions but the mechanism in all these instances has not been established as discussed Doherty and colleagues.
Specific Drugs in the Treatment of Seizures
The putative mechanisms of action of the most commonly used drugs are reasonably well known but gaps remain. A review by Bialer and White contains a schematic depiction of putative drug actions at excitatory and inhibitory synapses, as adopted in Fig. 15-6 and as summarized in Table 15-5. There it is apparent that for each of these two physiologic classes of neurons, some medications have their main effect on voltage-gated ion channels and others, on membrane receptors or intracellular vesicular activity.
Schematic depiction of sites and mechanisms of action of antiepileptic drugs on excitatory and inhibitory synapses. GABA, gamma amino butyric acid; GAD: glutamic acid decarboxylase; GATI: GABA transporter (also known as SLC6A1). (Adapted by permission of Nature Publishing Group and authors from Bialer M, White HS: Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9:68–82, 2010.)
Phenytoin, carbamazepine, levetiracetam, and valproate are representative antiepileptic drugs that may be considered “broad spectrum” and are more or less equally effective in the treatment of both generalized and focal seizures (see Table 15-6 for typical initial dosages). The first two of these drugs act by blocking sodium channels, thus preventing abnormal neuronal firing and seizure spread. Lamotrigine has become an alternative for treating focal seizures with a different side effect profile from the other three (see also Schmidt).
Because carbamazepine (or the related oxcarbazepine) and levetiracetam have somewhat fewer side effects, one or the other is preferred as the initial drug by many neurologists, though phenytoin and valproate have very similar therapeutic and side-effect profiles. In many cases, levetiracetam, phenytoin or carbamazepine alone will control seizures. If not, the use of valproate (which facilitates GABA activity) alone, or the combined use of two medications, produces better control. Levetiracetam has attained popularity largely because of its lack of interactions with other antiepileptic and other medications. Carbamazepine, levetiracetam, and valproate are probably preferable to phenytoin for children because they do not coarsen facial features and do not produce gum hypertrophy or breast enlargement. Because of the high incidence of myoclonic epilepsy in adolescence, it has been the practice of many neurologists to use valproate as the first drug in this age group. Weight gain, menstrual irregularities (see below) during the period of initiation of valproate, and its teratogenic effects also must be accounted for in the choice of initial drug for otherwise uncomplicated seizures in young women.
Most of the commonly used antiepileptic drugs cause, to varying degrees, a decrease in bone density and an increased risk of fracture from osteoporosis in older patients, particularly in women. Several mechanisms are probably active, among them, induction of the cytochrome P450 system, which enzymatically degrades vitamin D. No specific recommendations have been offered to counteract this effect of bone loss, but many practitioners have advised patients to take calcium supplements, vitamin D, or one of the bisphosphonates if there is no contraindication, and to periodically check bone density.
Finally, several reports and meta-analyses over the past decades have suggested that antiepileptic drugs taken together as a class, increase the incidence of depression and suicide, both in individuals with epilepsy and psychiatric patients. The issue may never be entirely resolved because of confounding factors but a patient level-analysis performed by Arana and colleagues showed no such relationship in epilepsy once underlying depression was accounted for. However, this assessment was contrary to an earlier FDA meta-analysis and it may not hold for certain drugs, for example, levetiracetam.
This sodium channel blocker has been used for decades for focal and generalized seizures. Its advantages are low cost, wide availability, ease of monitoring of blood levels and ability to rapidly achieve therapeutic levels with, oral, intravenous, and intramuscular preparations. Rash, fever, lymphadenopathy, eosinophilia and other blood dyscrasias, and polyarteritis are manifestations of idiosyncratic phenytoin hypersensitivity; their occurrence calls for discontinuation of the medication. Overdose with phenytoin causes ataxia, diplopia, and stupor. The prolonged use of phenytoin leads to hirsutism, enlargement of gums from hyperplasia of connective tissue and epithelium with subsequent periodontal disease, and coarsening of facial features in children. A clinical trial conducted by Arya and colleagues suggested that folate supplementation may prevent gingival hyperplasia in children. Chronic phenytoin use over several decades may occasionally be associated with peripheral neuropathy and probably with a form of cerebellar degeneration (Lindvall and Nilsson); it is not clear if these are strictly dose-related effects or idiosyncratic reactions. An antifolate effect on blood and interference with vitamin K metabolism have also been reported, for which reason pregnant women taking phenytoin (and in fact most other antiepileptic drugs) should be given folate supplementation and vitamin K before delivery and the newborn infant also should receive vitamin K to prevent bleeding. Phenytoin should not be used together with disulfiram, chloramphenicol, sulfamethizole, or cyclophosphamide, and the use of either phenobarbital or phenytoin is not advisable in patients receiving warfarin because of the undesirable interactions already described. Choreoathetosis is a rare idiosyncratic side effect. Fosphenytoin for intramuscular and intravenous administration allows somewhat faster attainment of serum levels and may have minor advantages in special circumstances, especially the availability of the IM route. Intravenous phenytoin and fosphenytoin, including their risks, are discussed further in the section on status epilepticus.
This drug, also a blocker of sodium channels like phenytoin, causes many of the same side effects as phenytoin, but to a slightly lesser degree. There is induction of hepatic enzymes and “autoindicution,” leading to declining drug levels after a few weeks of administration. Mild leukopenia is common, and there have been rare instances of pancytopenia, hepatic enzyme abnormalities, pancreatitis, hyponatremia (inappropriate antidiuretic hormone [ADH]), and, rarely, diabetes insipidus as idiosyncratic reactions. It is advisable therefore, that a complete blood count and liver function tests (some practitioners omit the latter because of the infrequency of hepatic problems) be done before or soon after treatment is instituted and that counts are rechecked regularly. Idiosyncratic rashes, some as severe as Stevens-Johnson syndrome may occur, particularly in Asian individuals carrying the HLA-B*1502 haplotype as mentioned above. It has not been considered useful to check patients for this haplotype but it may be considered in Asian patients.
Oxcarbazepine, an analogue of carbamazepine, has fewer of these side effects than the parent drug, especially marrow toxicity, but its long-term therapeutic value is not as well established. It has the advantage of being titrated upward at a more rapid rate than carbamazepine. Dose-related side effects are similar to carbamazepine but it has less hepatic enzyme induction. Some patients report weight gain after continued use. Hyponatremia has been reported in 3 percent of patients taking oxcarbazepine. Should drowsiness or increased seizure frequency occur, this complication should be suspected. Rashes occur at the same or slightly lower rate than with carbamazepine and there is considerable cross-reactivity for this side effect. Elevated cholesterol and osteoporosis are lesser effects, shared also with carbamazepine.
This drug in all its related forms is considered to be GABA-ergic, acting through glutamic acid decarboxylase, but also displaying some sodium channel blocking features. All preparations of this drug are occasionally hepatotoxic, an adverse effect that is usually (but not invariably) limited to children 2 years of age and younger. The use of valproate with hepatic enzyme-inducing drugs increases the risk of liver toxicity. However, mild elevations of serum ammonia and mild impairments of liver function tests in an adult do not require discontinuation of the drug. An increasingly emphasized problem with valproate has been weight gain during the first months of therapy. In one study there was an average addition of 5.8 kg, and even more in those disposed to obesity. In addition, menstrual irregularities and polycystic ovarian syndrome may appear in young women taking the drug, perhaps as a consequence of the aforementioned weight gain. Pancreatitis is a rare but important complication of valproate. Tremor and slight bradykinesias have been seen and they vaguely simulate parkinsonism. The major issues, however, pertain to its use in pregnancy as discussed earlier.
An intravenous form of valproate is available and may be useful in status epilepticus. The maximum recommended rate of administration is 3 mg/kg per min.
Introduced as an antiepileptic drug in 1912, it is as effective as phenytoin and carbamazepine, but because of its dose-related toxic effects—drowsiness and mental dullness, nystagmus, and staggering, as well as the availability of better alternatives—it is now infrequently used in adults. It inhibits sodium currents through the sodium channel and has been found to have some additional GABA-ergic effect. The drug strongly induces cytochrome P450 and therefore has interactions with many medications. There are infrequent disorders of connective tissue, such as frozen shoulder and Duyputren contractures that have been attributed to long-term use. The adverse effects of primidone are much the same. Both drugs may provoke behavioral problems in developmentally delayed children and they are still used to advantage as an adjunctive anticonvulsant and as primary therapy in infantile seizures. The rate of teratogenicity is increased (stated to be approximately 5.5 percent) and comparable to other main line drugs.
This drug closely resembles phenytoin in having a broad spectrum of antiseizure activity but has different features relating to toxicity. It functions by selectively blocking the slow sodium channel, thereby preventing the release of the excitatory transmitters glutamate and aspartate. It is effective as a first-line and adjunctive drug for generalized and focal seizures, and may be an alternative to valproate in young women because it does not provoke weight gain and ovarian problems. The main limitation to its use has been a serious rash in approximately 1 percent of patients, requiring discontinuation of the drug, and lesser dermatologic eruptions in 12 percent. It should be pointed out that some registries have reported considerably lower rates of these complications and the slow introduction of the medication may reduce the incidence of drug eruptions (see below). Rare cases of reversible chorea have been reported, especially with the concurrent use of phenytoin. Combined use with valproate greatly increases the serum level of lamotrigine. It has been said to have a more favorable teratogenic profile than most other drugs. Dosing depends greatly on the concurrent use of other drugs, reducing its dose and rapidity of escalation if used with other enzyme-inducing AEDs such as phenytoin or carbamazepine and particularly with valproate.
This novel drug with uncertain mechanism has been useful in the treatment of both partial and generalized seizures. The agent interacts with the SV2A synaptic vesicle protein, but how this relates to its antiepileptic properties is still being investigated. It is well tolerated if initiated slowly, but may produces considerable sleepiness and dizziness and if used at high doses. It also may produce irritability and depression or exaggerate underlying depression. A major advantage is that there are no important interactions with other antiepileptic drugs and it is renally excreted for which reason it is often chosen as a first-line agent in patients who have organ failure and require numerous medications, as well as those receiving hepatically metabolized chemotherapeutics. There are some data showing a favorable teratogenic profile.
Other antiepileptic drugs
Two other drugs, gabapentin and vigabatrin, were synthesized specifically to enhance the intrinsic inhibitory system of GABA in the brain. Gabapentin is chemically similar to GABA, but its anticonvulsant mechanism is not known; it has an apparent effect on calcium channels. It is moderately effective in partial and secondary generalized seizures and has the advantage of not being metabolized by the liver. Vigabatrin inhibits GABA transaminase. Vigabatrin is no longer used in adults because of the side effect or retinal damage. Tiagabine is considered to be an inhibitor of GABA reuptake.
Topiramate, has much the same mode of action and probably a broader effectiveness as tiagabine. It will rarely cause serious dermatologic side effects, especially if used with valproate, and appears to induce renal stones in 1.5 percent of patients, lower in women. Angle-closure glaucoma has also been reported as a complication. A minor problem has been the development of hyperchloremic metabolic acidosis. It has high teratogenicity in most studies.
Lacosamide, a potent drug for seizures that have a focal onset and generalize or remain focal, is currently used mainly as an adjunctive therapy. Like levetiracetam, its mechanism of action is not entirely known but it has been shown to modulate voltage-gated sodium channel activity. It may be titrated upward rapidly and has limited pharmacokinetic interactions but its effective range of blood levels is narrow; also like levetiracetam, it is renally excreted. The availability of an intravenous preparation is also notable. The main but infrequent side effects are headache and diplopia. The drug may prolong the P-R interval and worsen heart failure.
Ethosuximide and valproate are equally effective for the treatment of absence seizures, the former having fewer cognitive side effects according to a study by Glauser and colleagues. The use of ethosuximide is virtually limited to this indication. It is good practice, so as to avoid excessive sleepiness, to begin with a single dose of 250 mg of ethosuximide per day and to increase it every week until the optimum therapeutic effect is achieved. Methsuximide (Celontin) is useful in individual cases where ethosuximide and valproate have failed. In patients with benign absence attacks that are associated with photosensitivity, myoclonus, and clonic-tonic-clonic seizures (including juvenile myoclonic epilepsy), valproate is the drug of choice. Valproate is particularly useful in children who have both absence and grand mal attacks, as the use of this drug alone often permits the control of both types of seizures. The concurrent use of valproate and clonazepam has been known to produce absence status.
Zonisamide, similar to topiramate, seems to be useful for myoclonic epilepsy but its main use is currently as an adjuvant in al epilepsy. It is not predominantly a sodium channel blocker and can be taken in parallel with carbamazepine. Some clinicians have found it to produce fewer cognitive side effects than topiramate.
New antiepileptic medications are being introduced regularly, among the newer ones is brivaracetam that is likely to display to broad activity against seizure types and lack of interaction with other medications seen with levetiracetam. Retigabine, rufinamide, pregabalin, gabapentin, felbamate, eslicarbazepine, several in the diazepine class find special use, mostly in epilepsy clinics that treat recalcitrant seizures. The medications used in the neonatal and infant population are discussed below.
Treatment of Seizures in the Neonate and Young Child
This specialized area of neonatal seizures is discussed by Fenichel and by Volpe and in children by Guerrini. In general, phenobarbital has been preferred for seizure control in infancy. Probably the form of epilepsy that is most difficult to treat is the childhood Lennox-Gastaut syndrome. Some of these patients have as many as 50 or more seizures per day, and there may be no effective combination of anticonvulsant medications. Valproic acid (900 to 2,400 mg/d) will reduce the frequency of spells in approximately half the cases. The newer drugs—lamotrigine, topiramate, vigabatrin—are each effective in approximately 25 percent of cases. Clonazepam also has had limited success. In the special case of Dravet syndrome, a disorder of the sodium channel, antiepileptic drugs that block that same channel are avoided.
In the treatment of infantile spasms, ACTH or adrenal corticosteroids had been used, but vigabatrin is now found to be as effective, including in patients with underlying tuberous sclerosis (see Elterman et al).
Recurrent generalized convulsions at a frequency that precludes regaining of consciousness in the interval between seizures (convulsive status) constitutes the most serious problem in epilepsy, with an overall mortality of 20 to 30 percent, according to Towne and colleagues, but probably lower in recent years. It is perhaps the most common neurologic emergency. Some patients who die of epilepsy do so because of uncontrolled seizures of this type, complicated by the effects of the underlying illness or an injury sustained as a result of a convulsion. Rising temperature, acidosis, hypotension, and renal failure from myoglobinuria is a sequence of life-threatening events that may be encountered in cases of convulsive status epilepticus. Prolonged convulsive status (for longer than 30 min) also carries a risk of serious neurologic sequelae (epileptic encephalopathy). The MRI during and for days after a bout of status epilepticus may show signal abnormalities in the region of a focal seizure or in the hippocampi, most often reversible, but we have had several such patients who awakened and were left in a permanent amnesic state. The MRI changes are most evident on FLAIR and diffusion-weighted sequences and may also appear in the pulvinar of the thalamus. With regard to acute medical complications, from time to time a case of neurogenic pulmonary edema is encountered during or just after the convulsions, and some patients may become extremely hypertensive, making it difficult to distinguish the syndrome from hypertensive encephalopathy.
The etiologies of status epilepticus vary among age groups but all the fundamental causes of seizures are able to produce the syndrome. The most recalcitrant cases we have encountered in adults have been associated with viral or paraneoplastic encephalitis, old traumatic injury, and epilepsy with severe mental retardation. Stroke and brain tumor have, in contrast, been infrequent causes. More recently, several groups, for example, Gaspard and coworkers have emphasized autoimmune forms of encephalitis including the paraneoplastic variety as the most common explanations for new-onset refractory status epilepticus but add that over half of cases remain cryptogenic.
Treatment of Convulsive Status Epilepticus
The many regimens that have been proposed for the treatment of status epilepticus attest to the fact that no one of them is altogether satisfactory and none is clearly superior (Treiman et al) (Table 15-8).
Table 15-8APPROACH TO THE TREATMENT OF STATUS EPILEPTICUS IN ADULTS ||Download (.pdf) Table 15-8APPROACH TO THE TREATMENT OF STATUS EPILEPTICUS IN ADULTS
|Initial assessment |
| Ensure adequate ventilation, oxygenation, blood pressure |
| Intubate if necessary, based on low oxygen saturation and labored breathing |
| Insert intravenous line |
| Administer glucose and thiamine in appropriate circumstances |
| Send toxic screen |
| Assess quickly for cranial and cervical injury if onset of seizures is unwitnessed |
|Immediate suppression of convulsions |
| Lorazepam or diazepam, 2 to 4 mg/min IV to a total dose of 10 to 15 mg with blood pressure monitoring when higher rates or doses are used |
|Initiation or reloading with anticonvulsants |
| Phenytoin 15–20 mg/kg IV at 25–50 mg/min in normal saline or fosphenytoin at 50 to 75 mg/min |
|General anesthetic doses of medication for persistent status epilepticus |
| Midazolam 0.2 mg/kg loading dose followed by infusion at 0.1 to 0.4 mg/kg/h or propofol 2 mg/kg/h |
|Further treatment if convulsions or electrographic seizures persist after several hours |
| May add valproate or phenobarbital 10 mg/min to total dose of 20 mg/kg as additional anticonvulsants intravenously, or carbamazepine or levetiracetam by nasogastric tube if there is gastric and bowel activity |
| Consider neuromuscular paralysis with EEG monitoring if convulsions persist |
| Pentobarbital 10 mg/kg/h |
| Inhalational anesthetics (isoflurane) |
We have had the success with the following program, which reflects several published approaches. When the patient is first seen, an initial assessment of cardiorespiratory function is made and an oral airway established. As summarized by Bleck, a large-bore intravenous line is inserted; blood is drawn for glucose, BUN, electrolytes, and a metabolic and drug screen. A normal saline infusion is begun and a bolus of glucose is given (with thiamine if malnutrition and alcoholism are potential factors). To rapidly suppress the seizures, we generally use diazepam intravenously at a rate of about 2 mg/min until the seizures stop or a total of 20 mg has been given; alternatively, lorazepam, 0.1 mg/kg given by intravenous push at a rate not to exceed 2 mg/min, is now favored, being marginally more effective than diazepam because of its clinically longer duration of action (see Table 15-8).
Immediately thereafter, a loading dose (20 mg/kg) of phenytoin is administered by vein at a rate of less than 50 mg/min. More rapid administration risks hypotension and heart block; consequently, it is recommended that the blood pressure and electrocardiogram be monitored during the infusion. Phenytoin must be given through a freely running line with normal saline (it precipitates in other fluids) and should not be injected intramuscularly. A study by Treiman and colleagues has demonstrated the superiority of using lorazepam instead of phenytoin as the first drug to control status, but this is not surprising considering the longer latency of onset of phenytoin. Recently intravenous valproate 40 mg/kg or levetiracetam 60 mg/kg have been used as alternatives to phenytoin.
In the field, emergency medical technicians can administer lorazepam drug or midazolam. Attesting to the benefit of rapidly treating seizures, Silbergleit and colleagues have shown that intramuscular administration is slightly superior to the intravenous route simply because of the delay in inserting an intravenous line. Alldredge and colleagues showed that diazepines can be administered by paramedical workers in nursing homes with good effect in status epilepticus, terminating the seizures in about half of cases.
Nonetheless, a long-acting antiepileptic such as phenytoin must be given immediately after a diazepine has controlled the initial seizures. An alternative is the water-soluble drug fosphenytoin, which is administered in the same dose equivalents as phenytoin but can be injected at twice the maximum rate. Moreover, it can be given intramuscularly in cases where venous access is difficult. However, the delay in hepatic conversion of fosphenytoin to active phenytoin makes the latency of clinical effect approximately the same for both drugs.
In an epileptic patient known to be taking seizure medications chronically but in whom the serum level of drug is unknown, it is probably best to administer the full-recommended dose of phenytoin. If it can be established that the serum phenytoin is above 10 mg/mL, a lower loading dose may be advisable. If seizures continue, an additional 5 mg/kg is indicated. If this fails to suppress the seizures and status has persisted for 20 to 30 min, an endotracheal tube should be inserted and O2 administered.
Having emphasized the dangers of this syndrome, at each stage of treatment it is worthwhile considering if a refractory convulsive episode is of psychogenic, nonepileptic nature. The reader is referred to the previous section on this subject.
Several approaches have been suggested to control status epilepticus that persists after these efforts. At this stage we have resorted to the approach suggested by Kumar and Bleck of giving high doses of midazolam (0.2 mg/kg loading dose followed by an infusion of 0.1 to 0.4 mg/kg/h as determined by clinical and EEG monitoring). If seizures continue, the dose can be raised as blood pressure permits. We have used in excess of 20 mg/h because of a diminishing effect over days. This regimen of midazolam and phenytoin may be maintained for several days without major ill effect in previously healthy patients. Propofol given in a bolus of 2 mg/kg and then as an intravenous drip of 2 to 8 mg/kg/h is an effective alternative to midazolam, but after 24 h the drug behaves like a high dose of barbiturate and there may be hypotension. Prolonged use of propofol may precipitate hypertriglyceridemia-associated pancreatitis or a fatal shock and acidosis (propofol syndrome).
Valproate and levetiracetam are available as intravenous preparations, making them suitable for administration in status, but their role in this circumstance has not been extensively studied. Another dependable approach is infusion of either pentobarbital, starting with 5 mg/kg, or phenobarbital, at a rate of 100 mg/min until the seizures stop or a total dose of 20 mg/kg is reached; a long period of stupor must be anticipated after. Hypotension often limits the continued use of the barbiturates, but Parviainen and colleagues were able to manage this problem by fluid infusions, dopamine, and neosynephrine.
If none of these measures controls the seizures, a more aggressive approach is taken to subdue all brain electrical activity by the use of general anesthesia. The preferred medications for this purpose have been pentobarbital or propofol, which, despite their moderate efficacy as primary anticonvulsants, are easier to manage than the alternative inhalational anesthetic agents. An initial intravenous dose of 5 mg/kg pentobarbital or 2 mg/kg propofol is given slowly to induce an EEG burst-suppression pattern, which is then maintained by the administration of pentobarbital, 0.5 to 2 mg/kg/h, or propofol, up to 10 mg/kg/h. Every 12 to 24 h, the rate of infusion is slowed to determine whether the seizures have stopped. The experience of Lowenstein and Aldredge, like our own, is that most instances of status epilepticus that cannot be controlled with the combination of standard anticonvulsants and midazolam will respond to high doses of barbiturates or to propofol, but that these infusions cause hypotension and cannot be carried out for long periods. Even a ketogenic diet, more commonly employed in childhood epilepsy as discussed further on, has been suggested as an ancillary treatment in these difficult cases of truly refractory status epilepticus as discussed by Thakur and colleagues.
Should the seizures continue, either clinically or electrographically, despite all these medications, one is justified in the assumption that the convulsive tendency is so strong that it cannot be checked by reasonable quantities of medications. However, a few patients in this predicament have survived and awakened, even at times with minimal neurologic damage depending on the underlying cause.
The volatile anesthetic agent isoflurane has also been used in these circumstances with good effect, as we have reported (Ropper et al), but the continuous administration of inhalational anesthetic agents is impractical in most critical care units. Halothane has been relatively ineffective as an anticonvulsant, but ether, although impractical, has in the past been effective in some. In the end, in patients with truly intractable status, one usually depends on phenytoin, phenobarbital (smaller doses in infants and children than are shown in Table 15-8), and on measures that safeguard the patient’s vital functions. Ketamine infusions have been a last resort, in combination with a midazolam infusion. A few times over the years, we have also resorted to inducing ketosis in adults by manipulating the nutrition given through a nasogastric tube. As a cautionary note, a series reported by Sutter and colleagues (2014) suggested that adverse events such as infection as well as mortality are higher in patients receiving intravenous anesthetic drugs compared to those who did not receive them but the possibility of confounding by the severity of illness must be taken into account before accepting a causal relationship.
A word is added here concerning neuromuscular paralysis and continuous EEG monitoring in status epilepticus. With failure of aggressive anticonvulsant and anesthetic treatment, there may be a temptation to paralyze all muscular activity, an effect easily attained with drugs such as pancuronium, while neglecting the underlying seizures. The use of neuromuscular blocking drugs without a concomitant attempt to suppress seizure activity is inadvisable. If such measures are undertaken, continuous or frequent intermittent EEG monitoring is essential; this may also be also helpful in the early stages of status epilepticus in that it guides the dosages of anticonvulsants required to suppress the seizures.
In the related but less-serious condition of acute repetitive seizures, in which the patient awakens between convulsions, a diazepam gel, which is well absorbed if given rectally, is available and has been found useful in institutional and home care of epileptic patients, although it is quite expensive. A similar effect has been attained by the nasal or buccal (transmucosal) administration of midazolam, which is absorbed from these sites (5 mg/mL, 0.2 mg/kg nasally; 2 mL to 10 mg buccally). Midazolam may be preferred among the diazepines for transmucosal use because it produces somewhat less respiratory depression than the others in the class and has been more effective at controlling seizures according to a study by McIntyre and colleagues. Still, only half were controlled. These approaches have found their main use in children with frequent seizures who live in supervised environments, where a nurse or parent is available to administer the medication.
Absence status should be managed by intravenous lorazepam, valproic acid, or both, followed by ethosuximide. Nonconvulsive generalized status is treated along the lines of grand mal status, usually stopping short of using anesthetic agents (see Meierkord and Holtkamp). In the case of epilepsia partialis continua, typically a difficult condition to control, a balance must be found between stopping the phenomenon and the risk of overuse of medications that can produce stupor. The patient must be involved by way of determining how troubling the movements are to him.
Surgical Treatment of Epilepsy
The surgical excision of epileptic foci that have not responded to intensive and prolonged medical therapy is being used with increasing effectiveness. At these centers, it has been estimated that approximately 25 percent of all patients with epilepsy are candidates for surgical therapy and more than half of these may benefit from extirpation of the epileptic cortical focus. With increasing experience and standardized approaches, especially in patients with temporal lobe epilepsy, it has been suggested that many patients are waiting too long before the surgical option is employed. A perspective that may promote surgery in even further is the observation that approximately 60 percent of patients with focal seizures will respond to a conventional anticonvulsant, but that among the remainder, few will respond to the addition of a second or third drug.
However, considerable effort, time and technology are required to determine the site of epileptic discharge and the method of safe removal of the cortical tissue. To locate the discharging focus requires a careful analysis of clinical, imaging, and EEG findings, often including those obtained by long-term video/EEG monitoring and, sometimes, intracranial EEG recording by means of intraparenchymal depth electrodes, subdural strip electrodes, and subdural grids. Recently, functional imaging, magnetoencephalography, and specialized EEG analysis have been introduced to supplement these methods.
The most favorable candidates for surgery are those with focal seizures that induce altered consciousness and a unilateral temporal lobe focus. In this group, rates of cure and significant improvement approach 90 percent in some series but overall, are probably closer to 50 percent after 5 years. A randomized trial conducted by Wiebe and colleagues gave representative results after temporal lobectomy of 58 percent of 40 carefully studied patients remaining seizure-free after 1 year, in contrast to 8 percent on medication alone. Furthermore, as reported by Yoon and colleagues, among those patients who remain free of seizures for 1 year after surgery, more than half are still free of seizures after 10 years and most of the remainder had one or fewer episodes per year. It should be emphasized that most of the patients who underwent surgery in these studies still required anticonvulsant medication. Even in the special group of patients with temporal lobe foci who have no lesion on MRI but have subtle signal changes in the hippocampus, Bell et al report that 60 percent of patients can be made free of disabling seizures with surgery.
Excision of cortical tissue that contains a structural lesion outside of the temporal lobe accomplishes complete seizure-free states in approximately 50 percent. Taking all seizure types together, only approximately 10 percent of patients obtain no improvement at all and less than 5 percent are worse. The matter of resection of areas of focal cortical dysplasias in children is a highly specialized area. It has been indicated that the histologic features of the dysplasia are important determinants of the success of surgery (Fauser et al).
Other surgical procedures of value in highly selected cases are sectioning of the corpus callosum, which is for the most part palliative, and hemispherectomy, which may be curative in special circumstances. The most encouraging results with callosotomy have been obtained in the control of intractable partial and secondarily generalized seizures, particularly when atonic drop attacks are the most disabling seizure type. Removal of the entire cortex of one hemisphere, in addition to the amygdala and hippocampus, has been of value in children, as well as in some adults with severe and extensive unilateral cerebral disease and intractable contralateral motor seizures and hemiplegia. Rasmussen encephalitis, Sturge-Weber disease, and large porencephalic cysts at times fall into this category. Surgical, focused radiation, or endovascular reduction of arteriovenous malformations may reduce the frequency of seizures, but the results in this regard are somewhat unpredictable (see Chap. 34).
This technique has found some favor in cases of intractable partial and secondarily generalizing seizures. A pacemaker-like device is implanted in the anterior chest wall and stimulating electrodes are connected to the vagus at the left carotid bifurcation. The procedure is well tolerated except for hoarseness in some cases. Several trials have demonstrated an average of 25 percent reduction in seizure frequency among patients who were resistant to all manner of anticonvulsant drugs (see Chadwick for a discussion of clinical trials). The mechanism by which vagal stimulation produces its effects is unclear, and its role in the management of seizures is still being defined. Stimulation of the cerebellum and of other sites in the brain has also been used in the control of seizures, with no clear evidence of success. They must currently be considered to be experimental.
Since the 1920s, interest in this form of seizure control has varied, being revived periodically in centers caring for many children with intractable epilepsy. Despite the absence of controlled studies showing its efficacy or an agreed upon hypothesis for its mechanism, several trials in the first half of the twentieth century, and again more recently, demonstrated a reduction in seizures in half of the patients, including handicapped children with severe and sometimes intractable episodes. The diet is used mainly in children between the ages of 1 and 10 years. The regimen is initiated during hospitalization by starvation for a day or two in order to induce ketosis, followed by a diet in which 80 to 90 percent of the calories are derived from fat (Vining). The difficulties in making such a diet palatable leads to its abandonment by about one-third of children and their families.
A summary of experience from the numerous trials of the ketogenic diet can be found in the review by Lefevre and Aronson and in the report of its use in 58 children by Kinsman and colleagues. They both concluded that the diet is effective in refractory cases of epilepsy in childhood, reducing seizure frequency in two-thirds of children and allowing a reduction in the amount of anticonvulsant medication in many. It has also been commented that some benefit persists even after the diet has been stopped. Nephrolithiasis is a complication in somewhat less than 10 percent of children, and this risk is particularly high if topiramate is being used.
Keotgenic diet is the main treatment for children with GLUT1 deficiency syndrome, as discussed earlier.
For lack of a better place to comment, we note that cannabinoids are being introduced for the treatment of epilepsy, prominently in special cases such as Dravet syndrome, but as reviewed by Friedman and Devinsky, no firm conclusions as to their effectiveness can be made at this time.
Safety and Regulation of Physical and Mental Activity
A person with incompletely controlled epilepsy should not be allowed to drive an automobile. Only a few states in the United States and most provinces of Canada mandate that physicians report patients with seizures under their care to the state motor vehicle bureau. Nonetheless, physicians should counsel such a patient regarding the obvious danger to himself and others if a seizure should occur while driving (the same holds for the risks of swimming unattended). What few data are available suggest that accidents caused directly by a seizure are rare and, in any case, 15 percent have been the result of a first episode of seizure that could not have been anticipated. In some states where a driver’s license has been suspended on the occurrence of a seizure, there is usually some provision for its reinstatement—such as a physician’s declaration that the patient is under medical care and has been seizure-free for some period of time (usually 6 months or 1 to 2 years). The Epilepsy Foundation website can be consulted for updated information regarding restrictions on driving, and this serves as an excellent general resource for patients and their families (http://www.efa.org).
The most important factors in seizure breakthrough, next to the abandonment of medication or a natural reduction of serum levels of medication, are loss of sleep and abuse of alcohol or other drugs. The need for moderation in the use of alcohol must be stressed, as well as the need to maintain regular hours of sleep. Advice to collegians about moderating alcohol is particularly important.
With proper safeguards, even potentially more dangerous sports, such as swimming, may be permitted. However, operating unguarded machinery, climbing ladders, or taking baths behind locked doors are not advisable; such a person should swim only in the company of a good swimmer. There is concern about epileptic mothers bathing their infants without additional safety guards.
Psychosocial difficulties are common and must be identified and addressed early. The stigma of epilepsy remains an issue in society. Advice and reassurance to attempt to pursue a normal life will aid in preventing or overcoming any feelings of inferiority and self-consciousness of many younger patients with epilepsy. However, the situation is rarely so simple and patients and their families may benefit from more extensive counseling.
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