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Management of generalized seizures in childhood
Original Articles
Management of Generalized Seizures in Childhood Lawrence A. Lockman, biD The management of generalized seizures, the most
in childhood, depends upon accurate diagnosis, choice of appropriate antiepileptic drug, and attention to detail in the choice of diagnostic and therapeutic modalities. Most patients with generalized seizures can achieve control but the long-term prognosis may be less favorable than is widely believed. common
Lockman LA. Management of generalized seizures in childhood. Pediat Neurol 1985:1: 265-73.
Introduction Generalized seizures, the most common type occurring in childhood, are distinguished by epileptiform activity that does not appear to have lateralized or localized onset. The generalized seizures, as classified by the International League Against Epilepsy (ILAE), are listed in Table 1 [1]. More recently the ILAE has proposed a classification of the epilepsies and epileptic syndromes (Table 2) [2], many of which occur in the pediatric age range. These two classification schemes allow better assignment of the individual patient for purposes of diagnosis, choice of antiepileptic drug, and understanding of the natual history of the disorder. Absence Seizures
The term, absence, refers to a constellation of primary generalized seizures in which loss of consciousness is the most prominent feature (Table 1) [1]. Absence seizures and several variants share a number of characteristics: onset within a relatively narrow age range; a strong familial (genetic) propensity; bilaterally synchronous spike-and-wave or multiple spike-andwave activity electroncephalographically, either during the seizure or interictally. These seizures are unlikely to respond favorably to
Table 1.
International Classification of Epileptic Seizures and Generalized Seizures*
Clinical Seizure Type A. Absence seizures 1. Typical a. Impairment of consciousness only b. With mild clonic components c. With atonic components d. With tonic components e. With automatisms f. With autonomic components (b through fmay be used alone or in combination) 2. Atypical may have the following: a. Changes in tone that are more pronounced than in A. 1 b. Onset and/or cessation that is not abrupt B. Myoclonic seizures, myoclonic jerks (single or multiple) C. Clonic seizures D. Tonic seizures E. Tonic-clonic seizures F. Atonic (Astatic) seizures (Combinations may occur.) *Modified from [1]
treatment with barbiturates, hydantoins, or carbamazepine and may, in some instances, worsen [3, 4]. Ethosuximide and valproate are considered the medications of choice. In the typical simple absence attack, the patient suddenly loses consciousness; ongoing activity ceases without significant alteration in postural tone and without movement except, perhaps, for some subtle eyelid fluttering. After a few seconds, consciousness and activity are abruptly resumed without any post-ictal confusion or drowsiness. Multiple seizures may occur in a single day. During the seizure, the electroencephalogram exhibits bilaterally synchronous, frontally predominant, 3 Hz spike-and-slow-wave activity. The electroencephalogram usually consists of normal background activity without paroxysmal
Communications should be addressed to: Dr. Lockman; Division of Pediatric Neurology; University of Minnesota Medical School; Box 445 Mayo Memorial Building; 420 Delaware Street SE; Minneapolis, MN 55455.Received July 25, 1985; accepted August 16, 1985 Lockman: Generalized Seizures
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Table 2.
Generalized epilepsies and epileptic syndromes*
Idiopathic, with age-related onset, listed in order of age Benign neonatal familial convulsions Benign neonatal convulsions Benign myoclonic epilepsy in infancy Childhood absence epilepsy (pyknolepsy) Juvenile absence epilepsy Juvenile myoclonic epilepsy (impulsive petit real) Epilepsy with grand real seizures (GTCS) on awakening Other generalized idiopatihic epilepsies, if they do not belong to one of the above syndromes can still be classified as generalized idiopathic epilepsies. Idiopathic and/or symptomatic, in order of age of appearance Infantile spasms Lennox-Gastaut syndrome Epilepsy with myoclonic-astatic seizures Epilepsy with myclonic absences Symptomatic Nonspecific etiology Early myoclonic encephalopathy Specific syndromes Epileptic seizures may complicate many disease states. Included under this heading are those diseases in which seizures are a presenting or predominant feature. Epilepsies and syndromes undetermined as to whether they are focal or generalized With both generalized and focal seizures Neonatal seizures Severe myoclonic epilepsy in infancy Epilepsy with continuous spike-waves during slow wave sleep Acquired epileptic aphasia (Landau-Kleffner syndrome) Without unequivocal generalized or focal features. This heading covers all cases with GTCS where clinical and EEG findings do not permit classification as clearly generalized or localization-related, such as in many cases of sleep grand mal.
*Modified from [3]
features between these bursts. Atypical absence seizures differ in several respects from the simple absence seizure. Changes in muscle tone are more pronounced or the onset or the cessation is not abrupt. During the seizure the electroencephalogram is more heterogeneous and may manifest fast activity, irregular spike-and-slow-wave complexes, or other paroxysmal features. Symmetry is not regularly seen, although bilaterality is the rule. However, variations in all of these features do not preclude the diagnosis of absencle seizures. Thus the seizures may consist of impairment of consciousness only. The frequency of the electroencephalographic (EEG) paroxysm may vary from about 2.5 to 4 Hz, and there may be multiple spike-and-slow-wave complexes. Additionally, the EEG background may be abnormal, with the presence of paroxysmal activity, such as spikes or spike-and-slow-wave complexes. The essential features of absence seizures are, thus, only the loss of 266
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consciousness and the symmetrical ictal spike-and-wave discharges at 2.5 to 4 Hz. If additional clinical features are seen, the term complex absence is applied. In absence with mild clonic components, the clonic movements may include eyelid blinking, mouth twitching, and finger, arm, or shoulder movements. Posture is not disturbed but objects may be dropped. In absence with increase in postural tone, the increase may be either symmetrical or asymmetrical. If there is a decrease in postural tone there may be head drooping or mild slumping but the patient does not fall. Absence with automatisms was described by Penry and Dreifuss [5] in a videotelemetry study of 93 absence seizures in 12 patients. Both complex and simple automatisms occurred in these patients, often relating to the pre-ictal activity of the child or to the environmental stimuli. More than 50 % of seizures lasting longer than 7 seconds were accompanied by automatisms. Therefore the differentiation of complex absence from partial complex seizures may be impossible on purely clinical grounds and necessitates ictal EEG analysis with activation techniques (i.e., hyperventilation) to precipitate a seizure. Hyperventilation has been found more effective than prolonged monitoring in predicting clinical seizure frequency [6] and prolonged monitoring is more effective than parent or teacher observation [7]. Hyperventilation is also useful in clinically assessing the efficacy of pharmacotherapy. In absence with autonomic phenomena, alterations in pupil size, skin color, and heart rate suggest sympathetic nervous system involvement. Urinary incontinence can also occur. In the 374 absence seizures analyzed by Penry et al. [8] only 35 (9.4%) were simple whereas 90.6% were complex, with automatisms occurring during 63.1%, mild clonic components occurring in 45.5%, and decreased postural tone occurring in 22.5% of the seizures. Brain tumors have been discovered in some patients with generalized seizures; they are virtually unheard of in patients with primary generalized seizures [9], generalized non-convulsive seizures [10], or in patients whose seizure disorder did not begin with [11] or progress to [12] focal clinical or electrographic abnormalities. Absence seizures affect cognitive function. Porter, Penry, and Dreifuss [13] studied 14 patients with absence seizures using a computer-assisted reaction-
time measurement triggered by the onset of EEG paroxysms. Of the reaction times measured, 56% were distinctly abnormal. Later onset stimuli yielded even more abnormal reaction times. In another study of 26 patients [14], 413 auditory reaction times were determined. They were normal during the 1 second before the EEG paroxysms. At the onset of the paroxysms, 43% of the auditory reaction times were normal; 20% were normal after a delay of 0.5 seconds into the paroxysm. The authors concluded that regardless of duration, the spike-wave paroxysm impaired consciousness and therefore treatment should attempt to control all spike-wave paroxysms. Whether or not to pursue further diagnostic studies or treatment in the asymptomatic patient with 3 Hz spike-and-wave activity found incidentally on EEG has not been directly studied. One of the striking features of absence seizures is the enormous number of seizures that can occur in a single day, often ranging into the hundreds. Clearly these events interfere with normal scholastic performance and can jeopardize the patient's safety. Treatment with a single antiepileptic drug (monotherapy) is preferred. Ethosuximide has been the drug of choice for 20 years [15]. More recently, valproate has been shown to be equally effective [16], but the higher incidence of minor and serious side effects, the rare occurrence of fatal hepatic toxicity, and the need to monitor hematologic and liver function make it a second choice for absence seizures. About half of the patients with absence seizures become seizure free and may be withdrawn from medication after two to four years. For the remainder, either the absence seizures persist or the patient goes on to develop tonic-clonic seizures. In a prospective study of 48 patients [17], 90% of absence patients without tonic-clonic seizures, with normal or better intelligence, and a negative family history of seizure disorders became seizure free. In a prospective study of 90 patients with typical absence seizures [18] and followup for up to 15 years, patients with myoclonic or atonic absence had a poor prognosis. Patients with simple absence or absence with automatisms often remitted. Overall remission rate with absence was only 57.5%. Thirty-six per cent of patients developed tonic
neurologic examination, and without hyperventilationinduced spikes-and-waves [19]. Seizures stopped in more than 90% of the patients who had three or more of these findings. Relapse is most likely to occur in the first year after treatment is discontinued [20]. Thus, simple absence and absence with automatisms are not always benign disorders of childhood and the prognosis is guarded. Current pharmacological management, while often effective in controlling the clinical seizures, does not seem to have influenced the long-term outcome in a significant fashion. Other Forms of Absence Seizures Delgado-Escueta et al. [21] and Janz et al. [22] described several other varieties of absence: Juvenile absence clinically is identical to classical absence but has an EEG signature of 8 to 12 Hz "diffuse rhythms." Myoclonic absence is characterized by brief unconsciousness with staring, stereotyped automatisms, and bilateral symmetrical clonic jerks. Myoclonus absence differs in that the clonic jerks are asymmetrical and the automatisms are reactive. These seizures are all said to respond to valproate. Impulsive petit mal, described in 1955 by Janz and Christian [23], is a specific syndrome of epileptic seizures which occurs in the second decade of life. It has probably been reported under many different names including juvenile myoclonic seizures, bilateral massive myoclonic jerks, generalized epilepsy with myoclonia during adolescence and late childhood, and myoclonic petit mal. Said to occur in 4 % of patients with epilepsy [23, 24], its importance is related not only to the frequency of occurrence, but also to its ready confusion with tonic-clonic seizures (grand mal) leading to the use of ineffective antiepileptic drugs [25]. The myoclonic jerks occur shortly after awakening (morning myoclonus), are mild, and are not accompanied by loss of consciousness. The interictal EEG signature of this seizure is fast (4-6 Hz), multiple, spike-and-slow-wave complexes. Fast, diffuse spikes (16-24 Hz) are seen in both hemispheres during the myoclonic jerks [26]. Photic stimulation leads to a photoconvulsive response or even photoconvulsive seizures. These patients often have a variety of other seizure types and 50% of them also have absence [21]. The disorder is often progressive. The patients, particularly if the myoclonic attacks become more frequent, develop either clonic seizures or clonic-tonicclonic seizures (sometimes misdiagnosed as tonic-clonic seizures). During the clonic seizures consciousness is
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lost; the patient falls to the floor, either forcefully, resulting from a massive myoclonic jerk, or because of a sudden loss of muscle tone. Rapid clonic jerking of the face and extremities and autonomic changes ensue. Consciousness returns quickly and there is little postictal depression. Additionally, the patient may have a tonic phase separating the initial and terminal clonic phases leading to a clonic-tonic-clonic seizure. Tsuboi and Christian [27] reported a high family incidence of myoclonic events. About 41% of relatives of probands had these abnormalities with a peculiar propensity among female relatives; 15 % of relatives without clinical myoclonus manifested the EEG findings. The treatment of choice is valproate, to which the seizures are said to be very responsive [26], and the prognosis is excellent, in part because of the age -limited nature of the disorder. However, long-term medication may be necessary [25]. Tonic-Clonic Seizures Tonic-clonic convulsions are among the most common seizures affecting children and may account for 75 % of seizures of childhood. Three major features of the generalized tonic-clonic seizure are the immediate loss of consciousness, an initial motor phase consisting of tonic contractions of all of the muscles, often with opisthotonus, and a second phase consisting of clonic contractions of the muscles. These contractions are forceful, and as the seizure runs its course, the forcefulness does not diminish although the time between these contractions gradually lengthens. Cyanosis, drooling, and urinary incontinence are common. Since seizures that are generalized from the onset begin with loss of consciousness, it is questionable if an aura can be part of the ictus. It seems more likely the aura, that portion of the seizure that occurs before the patient loses awareness, is the sign of a partial seizure with rapid generalization. This distinction is important not only for consideration of possible causes of the epilepsy, but also in considering optimal pharmacologic management. Tonic-clonic seizures may be precipitated by a number of triggering events, most commonly vasovagal syncope, but also flashing lights, music, or sudden startle, and the decreased cerebral blood flow which occurs with breathholding spells. Seizures which occur following decreased cerebral perfusion should not be considered to be epilepsy and, while antiepileptic drugs may decrease or even abolish the convulsive event, 268
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therapy is more appropriately directed toward preventing the disruption of blood flow. In reflex epilepsy, efforts are directed toward reducing the exposure to precipitating stimuli. Low dose atropine is effective in preventing the decrease in cardiac output that occurs with breathholding spells, and its use can be considered when these episodes occur frequently enough to cause disruption of a child's activities. The patient with a single generalized tonic-clonic convulsion poses a special problem. Since the diagnosis of epilepsy depends on the occurrence of repeated seizures, such a label is not appropriate in these cases. A cause for the seizure should be sought utilizing detailed history, physical and neurological examinations, laboratory investigation of possible abnormalities of electrolytes, glucose, calcium, and renal function. It also seems reasonable to obtain brain imaging, utilizing either CT or MRI, to evaluate possible structural abnormalities of the brain. If no precipitating cause is elucidated, then seizures will recur in only about 50% of patients and antiepileptic drugs should be withheld. The tonic-clonic convulsion is socially devastating because of the drama of the event and the associated incontinence. From a life-quality point of view, one tonic-clonic seizure per month is probably more restricting than 50 absence seizures per day. Therefore moderate medication side-effects may be tolerated in the quest for control. The prognosis is generally good if the tonic-clonic seizures begin after age five and before puberty [28]. Many antiepileptic drugs have been used; carbamazepine, phenobarbital, phenytoin, and valproate are often effective. Only ethosuximide, of the commonly used antiepileptic drugs, seems to lack efficacy against this seizure type. Clonic-Tonic-Clonic Seizures Clonic-tonic-clonic seizures, well described by Delgado-Escueta et al. [21], may be confused with tonic-clonic seizures. The former often occur on awakening and are exacerbated by fatigue and sleep deprivation. Interictally, there are 4- to 6-Hz EEG bursts. During the seizure there are diffuse multiple spike discharges of 14 to 24 Hz. The seizure begins with clonic flexor spasms; there is a 20 to 30 second period of tonic extension which is then followed by another episode of clonus. Myoclonic-Astatic Seizures (The Lennox-Gastaut Syndrome) The essential features of the Lennox-Gastaut syn-
drome are early onset of epilepsy; multiple seizure types in the same patient, including absence, myoclonic jerks, and atonic or astatic seizures; impaired development and intellect; and generalized slow spikeand-wave discharges on EEG. Other terms which have been used for the Lennox-Gastaut syndrome are astatic seizures, akinetic epilepsy, minor motor epilepsy, propulsive petit mal, akinetic petit mal, and severe myokinetic epilepsy of early childhood with slow spikeand -wave. The slow spike-and-wave discharges are an interictal EEG phenomenon [29]. They are activated by sleep [29]. Ictally the same discharge may be seen during an atypical absence attack, one in which these is less abrupt and complete loss of consciousness. During seizures other findings may supervene such as desynchronization of the record [30-33] especially associated with tonic seizures [29], and brief bursts of polyspikes or rapid spikes [34]. This lack of a one-to-one relationship between the epileptiform discharges and the clinical seizures is in marked contrast with other generalized seizures, especially simple absence. On the other hand, Dreifuss [35] stated that some of these children are in absence status for years at a time, suggesting that the slow spike-and-wave discharge may correlate with a clinical seizure state. Many patients have periods of relative freedom from seizures interspersed with periods of distressingly frequent seizures, and sometimes even absence status. The frequent, often forceful, falls are a cause of recurrent injury, particularly to the face and head, and result in lacerations, with subsequent, often disfiguring scars. Football helmets, and more recently hockey helmets, are of some benefit in reducing the severity of injury. In contradistinction to generalized absence and impulsive petit mal, in which genetics probably plays a major role, patients with myoclonic-astatic epilepsy are much more likely to have a specific etiology found, ranging from 50 to 90% of cases [29, 36]. The most commonly attributed cause is perinatal neurological insult. A significant number of patients have a prior history of infantile spasms. There is a much higher incidence of epilepsy in the families of patients with myoclonic-astatic epilepsy than in the general population, but the seizures in the relatives are rarely of the myoclonic-astatic type. Males predominate in most series, comprising up to 71% of patients. A variety of other etiologies have been implicated in individual patients including tuberous sclerosis, lipid
storage diseases, and aminoacidopathies. There is a high frequency of cerebral atrophy, particularly subcortical, on CT scans [37]. A rare form of myoclonic-astatic epilepsy with male preponderance and normal intelligence occurring in 1 to 5 year olds, was described by Doose [38]. Tonic seizures are not usually seen. There may be a genetic predisposition and the prognosis is much better than in the Lennox-Gastaut syndrome. No other group of seizure patients is more challenging and frustrating to manage. Every antiepileptic drug, alone and in combination, has been used in these patients, often with no success whatsoever. Most of these patients are subjected to polypharmaceutical assaults with no detectable difference in seizure frequency or severity. Indeed, some agents may make the seizures worse, or if not, then may make the patient worse [4]. Sedative antiepileptic drugs probably should be avoided. Phenobarbital almost never influences the seizures and may cause cognitive and behavioral aberrations. Papini et al. [39] found in a study of 16 patients for prolonged periods of time that the average number of seizures per day was 25. About 31% of the seizures occurred during drowsiness and 54% occurred during inactive wakefulness. Only 6% occurred during sleep and 1% during active wakefulness. The authors suggest that secondary effects of sedative antiepileptic drugs may increase seizure frequency by decreasing active alertness in these patients. Clonazepam, originally thought to be effective in these seizures, often exhibits tolerance, necessitating dosage increase and eventual sedation. Monotherapy with valproate is as likely to benefit the patient as any other therapy, and ea~:ly reports of its efficacy and the ability of so,axe pai~ient.a to discard their helmets, has turned out to he only slightly over-enthusiastic. The ketogenic diet, origi~lally proposed by Wilder, and later modified by Hutte:a!ocher et al. [40, 41] to permit a more normal nutritional state, has been extraordinarily effective in an occasional otherwise intractable patient. More recently, Trauner et al. [42] found that adequate growth could be maintained by increasing the total daily caloric intake to as high as 150% of normal for age and size. Unpalatability, expense, and the social isolation imposed by such a stringent diet are the major drawbacks to its use. More recently, ACTH has been found effective for seizure control in up to 80% of the patients in an uncontrolled study [43].
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Drugs With accurate diagnosis and careful selection of the appropriate medication, control can be achieved in the primary generalized seizures in most (75 to 86%) of patients [26].
dose-related rise in transaminases and serum ammonia have also been seen, but are not harbingers of the acute fatal hepatic syndrome. The hyperammonemia is related in some patients to decreased alertness or even coma.
Ethosuximide (ETH)
Clonazepam
For thirty years, ethosuximide has been the drug of choice for the treatment of absence accompanied by 3 Hz spike-and-wave. The drug is remarkably free from serious side-effects; even minor side effects are not common. At higher doses singultus is occasionally seen, often in relationship to the presumed peak blood levels of the drug. Gastric distress is relatively common and minimized by giving the ETH with food. Doses up to 40 mg/kg/day are recommended with target blood levels of 50 to 100 ~g/ml; in the absence of side-effects, much higher blood levels can be achieved accompanied by better seizure control in some patients. Levels of up to 150 p,g/ml are often tolerated.
Widely used in the treatment of generalized seizures in children, particularly atypical absence and the seizures occurring as part of the Lennox-Gastaut syndrome, it has become clear that the early seizure control is only transient, that frequent dosage increases are required, and that eventually further benefit is precluded by the appearance of dose-related side effects including lethargy, irritability, and drooling. Furthermore, attempts to wean the patient from a no longer effective drug frequently leads to worsening of the underlying seizures and the emergence of generalized tonic-clonic seizures. Alterations of the dosage regimen of clonazepam and other benzodiazepine drugs may lead to longer lasting efficacy
Valpmic acid (VPA) Heralded as a major advance in the drug therapy of epilepsy, VPA has earned a special place in the armamentarium. VPA is the drug of choice for absence associated with tonic-clonic seizures or myoclonus. It is also a clear choice for the single drug treatment of clonic-tonic-clonic and myoclonic-astatic seizures. It is also effective in tonic-clonic seizures but other agents may be chosen because of safety considerations. VPA is the clear drug of choice for juvenile myoclonic epilepsy which is often misdiagnosed as grand mal epilepsy. In atonic seizures (e.g., Lennox-Gastaut syndrome) VPA is more likely to be of benefit than any other single drug. The liquid and capsule preparations are rapidly absorbed and peak plasma levels are achieved in about an hour. A valproic acid dimer has slower and a more variable absorption rate, particularly in children; this variability precludes the use of peak and trough levels. Strikingly effective in certain epileptic syndromes in which there were formerly no effective medications, and relatively free from minor side effects, unfortunately VPA use has been associated with a syndrome of rapidly progressive hepatic failure, characterized by microvesicular accumulation of fat and hepatic necrosis which is almost invariably fatal. It is unclear what factors predispose to this tragic event, but it is assumed that it is an idiosyncratic response to the drug, perhaps due to an unusual mode of metabolism. Lesser degrees of metabolic abnormality including a
[441.
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Phenobarbital Phenobarbital is available in a wide selection of inexpensive preparations for oral and parenteral use. The half-life is considerably longer than one day, so that once-a-day administration is not only rational but preferred. Conversely, since it takes about 5 half-lives to achieve steady state levels, optimal effects may not occur for 2 to 3 weeks. It may take this long for doserelated side effects to abate. Phenobarbital has been used against tonic-clonic, partial simple, and partial complex seizures, has demonstrated efficacy in preventing febrile seizures, and is the current drug of choice in neonatal seizures. Parenteral preparations allow consideration as a drug for the treatment of status epilepticus, but it is not now the drug of choice. The major undesirable side effects of phenobarbital are brain-mediated [45]. Sedation is frequently a problem, although this effect is said to be transient with continued use. The deleterious effect on cognitive fanction may lead to the discontinuation of the drug. In children who receive phenobarbital starting in infancy, the adverse effects on learning may not be apparent until the drug is discontinued. More obvious are the behavioral side effects of phenobarbital, including hyperactivity, distractibility, and irritability. Control seems reasonably related to blood levels.
Levels of greater than 16 vg/ml are needed for prevention of febrile seizures and neonatal seizures and similar levels are probably needed for other seizure types as well. Notable sedation occurs regularly with levels above 40 v.g/ml leading to the usual recommended therapeutic range of blood levels of 20 to 40 gg/ml. There is little justification for the use of the alcoholic elixir. The ethanol content is responsible for the postdose lethargy in some infants, which, considering the rate of absorption and the half-life, can not be due to the phenobarbital. Tablets as small as 8 mg are now readily available for use even in tiny infants.
usual dose requirement for children is from 10 to 30 mg/kg/day and therapeutic blood levels of 5 to 12 #g/ml are the rule, akhough the relationship between dose and blood level are only approximate. At higher dosages, transient diplopia and ataxia may occur at the time of peak blood levels; these side effects can be minimized by further dividing the daily dose. Side effects may be partially due to carbamazepine-10,11epoxide, a metabolite [48]. The percent of drug present as carbamazepine-10,11-epoxide is increased in the presence of other antiepileptic drugs [49]. Toxic levels of CBZ (and perhaps epoxide, also) occur when erythromycin is used for intercurrent infections.
Phenymin (PHT) Still a drug of choice for adults, particularly with generalized tonic-clonic seizures and also partial seizures, its role in the treatment of children with generalized seizures is less secure. Phenytoin is known to exacerbate simple absence as well as several of the seizure types seen in Lennox-Gastaut syndrome. It remains a very effective agent for the control of generalized tonic-clonic seizures. However, there are several drawbacks in using PHT in children. The effects on hair and gum growth as well as the coarsening of facial features are unacceptable to most patients and their families. PHT has also been shown to have significant deleterious effects on learning, a major consideration in the school-aged patient [46]. While the gingival hypertrophy can largely be prevented through a vigorous program of oral hygiene, the other side effects are not now preventable.
Other Considerations Although antiepileptic drug therapy is the cornerstone of the medical management of generalized seizures, attention to environmental factors that can induce seizures may be helpful [50]. Careful reconsideration of the goals of therapy may lead to an entirely different approach to the patient [51]. Rarely, intractable seizures in infancy may respond to high-dose pyridoxine; a trial seems reasonable for any patient before instituting antiepileptic drug therapy [52]. The individual child with generalized seizures provides formidable challenges as a result of newer diagnostic techniques; more useful classification of the epileptic seizures; more effective antiepileptic drugs; better ways of precribing and monitoring antiepileptic drugs; inreased patient, family, and school awareness of epilepsy and its treatment; vigorous advocacy of local and national support groups; and increasing research efforts in basic and clinical epileptology. Thus, the clinician bears increasing responsibility for helping the child with epilepsy achieve the best possible outcome in the face of an avalanche of information, sometimes conflicting. Knowledge of the natural history of a particuar epileptic syndrome allows comparison of the individual patient's course to the natural history of the disorder and suggests reasonable (i.e., attainable) goals in the immediate and long-term management of the child.
Carbamazepine (CBZ) Carbamazepine has emerged as a drug of choice for partial seizures, both simple and complex [47]. While far from the drug of choice, occasionally CBZ is effective in treating absence refractory to other agents, presumably because of rapid generalization of a localized epileptic discharge. The availability of a 100 mg scored, chewable tablet has made it possible to use CBZ in very young children, although safety and efficacy has not been formally demonstrated in children under 6 years of age. The relatively short half-life mandates 3 or even 4 daily doses. Diplopia, dizziness, malaise, and ataxia are frequently encountered when the drug is started, but can be minimized by starting with very low doses and increasing the daily dose every 3 or 4 days. (With a half-life of about 8 to 10 hours, this represents more than 5 half-lives of the drug.) The
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venheilk 1957;176:346-86. [24] AsconapeJ, and PenryJK. Some clinical and EEG aspects of benign juvenile myoclonic epilepsy. Epilepsia 1984 ;25:108-14. [25] Delgado-Escueta AV, Enrile-Bascal FE. Juvenile myoclonic epilepsy of Janz. Neurology 1984;34:285-94. [26] Delgado-Escueta AV, Treiman DM, Walsh GO. The treatable epilepsies (first of two parts). N Eng J Med 1983; 308:1508-14. [27] Tsuboi T, Christian W. On the genetics of the primary generalized epilepsy with sporadic myoclonias of the impulsive petit mal type: A clinical and electroencephalographic study of 399 probands. Humangentik 1973; 19:155-82. [28] Ellenberg JH, Hirtz DG, Nelson KB. Age of onset of seizures in young children. Ann Neurol 1984; 15 : 127-34. [29] Markand ON. Slow spike-wave activity in EEG and associated clinical features: Often called Lennox or Lennox-Gastaut syndrome. Neurology 1977;27:746-57. [30] Gastaut H, Tassinari CA. Epilepsies. In Remond A, ed: Handbook of electroencephalography and clinical neurophysiology. Amsterdam: Elsevier 1975;13A:3-104. [31] Gibbs FA, Gibbs EL. Atlas of electroencephalography; Vol II, Epilepsy. Reading, MA: Addison-Wesley, 1952. [32] Gastaut H, Roger J, Suolayrol R, et al. Childhood epileptic encephalopathy with diffuse slow spike-waves (otherwise known as "petit mal variant' ') or Lennox syndrome. Epilepsia 1966;7:139-79. [33] Blume WT, David RB, Gomez MR. Generalized sharp and slow wave complexes. Brain 1973;96:289-306. [34] Niedermeyer E. The generalized epilepsies. Springfield, IL: CC Thomas, 1972. [35] Dreifuss FE. Pediatric Epileptology: Classification and management of seizures in the child. Boston: John Wright-PSG, 1983. [36] Kurokawa T, Goya N, Fukuyama Y, et al. West syndrome and Lennox-Gastaut syndrome: A survey of natural history. Pediatrics 1980;65:81-8. [37] Gastaut H, Pinsard N, Genton P. Electroclinical correlations of CT scans in secondary generalized epilepsies. In: Canger R, Angeleri F, Penry JK, eds. Advances in epileptology: XIth Epilepsy international symposium. New York: Academic Press, 1980. [38] Doose H, Gerken H, Leonhardt R. Centrencephalic myoclonic-astatic petit real: Clinical and genetic investigations. Neuropaediatr 1970;2:59-78. [39] Papini M, Pasquinelli A, Armellini M, et al. Alertness and incidence of seizures in patients with Lennox-Gastaut syndrome. Epilepsia 1984;25:161-7. [40] Huttenlocher PR. Ketonemia and seizures: Metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy. Pediatr Res 1976; 10:536-40. [41] Huttenlocher PR, Wilboum AJ, SignoreJM. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology 1971 ;21 : 1097-1110. [42] Trauner DA. Medium-chain triglyceride (MCT) diet in intractable seizure disorders. Neurology 1985; 35:237-8. [43] Snead OC, BentonJW, Myers GJ. ACTH and prednisone in childhood seizure disorders. Neurology 1983;33:966-70. [44] Sher PH. Alternate day clonazepam treatment of intractable seizures. Arch Neurol 1985;42:787-8
[45] Tfimble MR, Reynolds EH. Anticonvulsant drugs and mental symptoms. Psychol Med 1976;6:169-78. [46] Stores G. Behavioral effects of anti-epileptic drugs. Devel Med Child Neurol 1975,17:647-58. [47] Mattson RH et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N EnglJ Med 1985;313:145-5 I. [48] Schoeman JF, Elyas AA, Brett EM, LascellesPT. Correlation between plasma carbamazepine-lO-11-epoxide concentration and drug side-effects in children with epilepsy. Dev Med Child Neurol 1984;26:756-64.
[49] Schoeman JF, Elyas AA, Brett EM, Lascelles FT. Altered ratio of carbamazepine-lO,11-epoxide/carbamazepine in plasma of children: Evidence of anticonvulsant drug interaction. Dev Med Child Neurol 1984;26:749-55. [50] Aird RB. The importance of seizure-inducing factors in the control of refractory forms of epilepsy. Epilepsia 1983;24: 567-83. [51] Taylor DC, McKinlay I. When not to treat epilepsy with drugs. Dev Med Child Neurol 1984;26:822-33. [52] Goutieres F, Aicardi J. Atypical presentations of pyridoxinedependent seizures: A treatable cause of intractable epilepsy in infants. Ann Neurol 1985;17:117-20.
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Management of Generalized Seizures in Childhood Lawrence A. Lockman, biD The management of generalized seizures, the most
in childhood, depends upon accurate diagnosis, choice of appropriate antiepileptic drug, and attention to detail in the choice of diagnostic and therapeutic modalities. Most patients with generalized seizures can achieve control but the long-term prognosis may be less favorable than is widely believed. common
Lockman LA. Management of generalized seizures in childhood. Pediat Neurol 1985:1: 265-73.
Introduction Generalized seizures, the most common type occurring in childhood, are distinguished by epileptiform activity that does not appear to have lateralized or localized onset. The generalized seizures, as classified by the International League Against Epilepsy (ILAE), are listed in Table 1 [1]. More recently the ILAE has proposed a classification of the epilepsies and epileptic syndromes (Table 2) [2], many of which occur in the pediatric age range. These two classification schemes allow better assignment of the individual patient for purposes of diagnosis, choice of antiepileptic drug, and understanding of the natual history of the disorder. Absence Seizures
The term, absence, refers to a constellation of primary generalized seizures in which loss of consciousness is the most prominent feature (Table 1) [1]. Absence seizures and several variants share a number of characteristics: onset within a relatively narrow age range; a strong familial (genetic) propensity; bilaterally synchronous spike-and-wave or multiple spike-andwave activity electroncephalographically, either during the seizure or interictally. These seizures are unlikely to respond favorably to
Table 1.
International Classification of Epileptic Seizures and Generalized Seizures*
Clinical Seizure Type A. Absence seizures 1. Typical a. Impairment of consciousness only b. With mild clonic components c. With atonic components d. With tonic components e. With automatisms f. With autonomic components (b through fmay be used alone or in combination) 2. Atypical may have the following: a. Changes in tone that are more pronounced than in A. 1 b. Onset and/or cessation that is not abrupt B. Myoclonic seizures, myoclonic jerks (single or multiple) C. Clonic seizures D. Tonic seizures E. Tonic-clonic seizures F. Atonic (Astatic) seizures (Combinations may occur.) *Modified from [1]
treatment with barbiturates, hydantoins, or carbamazepine and may, in some instances, worsen [3, 4]. Ethosuximide and valproate are considered the medications of choice. In the typical simple absence attack, the patient suddenly loses consciousness; ongoing activity ceases without significant alteration in postural tone and without movement except, perhaps, for some subtle eyelid fluttering. After a few seconds, consciousness and activity are abruptly resumed without any post-ictal confusion or drowsiness. Multiple seizures may occur in a single day. During the seizure, the electroencephalogram exhibits bilaterally synchronous, frontally predominant, 3 Hz spike-and-slow-wave activity. The electroencephalogram usually consists of normal background activity without paroxysmal
Communications should be addressed to: Dr. Lockman; Division of Pediatric Neurology; University of Minnesota Medical School; Box 445 Mayo Memorial Building; 420 Delaware Street SE; Minneapolis, MN 55455.Received July 25, 1985; accepted August 16, 1985 Lockman: Generalized Seizures
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Table 2.
Generalized epilepsies and epileptic syndromes*
Idiopathic, with age-related onset, listed in order of age Benign neonatal familial convulsions Benign neonatal convulsions Benign myoclonic epilepsy in infancy Childhood absence epilepsy (pyknolepsy) Juvenile absence epilepsy Juvenile myoclonic epilepsy (impulsive petit real) Epilepsy with grand real seizures (GTCS) on awakening Other generalized idiopatihic epilepsies, if they do not belong to one of the above syndromes can still be classified as generalized idiopathic epilepsies. Idiopathic and/or symptomatic, in order of age of appearance Infantile spasms Lennox-Gastaut syndrome Epilepsy with myoclonic-astatic seizures Epilepsy with myclonic absences Symptomatic Nonspecific etiology Early myoclonic encephalopathy Specific syndromes Epileptic seizures may complicate many disease states. Included under this heading are those diseases in which seizures are a presenting or predominant feature. Epilepsies and syndromes undetermined as to whether they are focal or generalized With both generalized and focal seizures Neonatal seizures Severe myoclonic epilepsy in infancy Epilepsy with continuous spike-waves during slow wave sleep Acquired epileptic aphasia (Landau-Kleffner syndrome) Without unequivocal generalized or focal features. This heading covers all cases with GTCS where clinical and EEG findings do not permit classification as clearly generalized or localization-related, such as in many cases of sleep grand mal.
*Modified from [3]
features between these bursts. Atypical absence seizures differ in several respects from the simple absence seizure. Changes in muscle tone are more pronounced or the onset or the cessation is not abrupt. During the seizure the electroencephalogram is more heterogeneous and may manifest fast activity, irregular spike-and-slow-wave complexes, or other paroxysmal features. Symmetry is not regularly seen, although bilaterality is the rule. However, variations in all of these features do not preclude the diagnosis of absencle seizures. Thus the seizures may consist of impairment of consciousness only. The frequency of the electroencephalographic (EEG) paroxysm may vary from about 2.5 to 4 Hz, and there may be multiple spike-and-slow-wave complexes. Additionally, the EEG background may be abnormal, with the presence of paroxysmal activity, such as spikes or spike-and-slow-wave complexes. The essential features of absence seizures are, thus, only the loss of 266
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consciousness and the symmetrical ictal spike-and-wave discharges at 2.5 to 4 Hz. If additional clinical features are seen, the term complex absence is applied. In absence with mild clonic components, the clonic movements may include eyelid blinking, mouth twitching, and finger, arm, or shoulder movements. Posture is not disturbed but objects may be dropped. In absence with increase in postural tone, the increase may be either symmetrical or asymmetrical. If there is a decrease in postural tone there may be head drooping or mild slumping but the patient does not fall. Absence with automatisms was described by Penry and Dreifuss [5] in a videotelemetry study of 93 absence seizures in 12 patients. Both complex and simple automatisms occurred in these patients, often relating to the pre-ictal activity of the child or to the environmental stimuli. More than 50 % of seizures lasting longer than 7 seconds were accompanied by automatisms. Therefore the differentiation of complex absence from partial complex seizures may be impossible on purely clinical grounds and necessitates ictal EEG analysis with activation techniques (i.e., hyperventilation) to precipitate a seizure. Hyperventilation has been found more effective than prolonged monitoring in predicting clinical seizure frequency [6] and prolonged monitoring is more effective than parent or teacher observation [7]. Hyperventilation is also useful in clinically assessing the efficacy of pharmacotherapy. In absence with autonomic phenomena, alterations in pupil size, skin color, and heart rate suggest sympathetic nervous system involvement. Urinary incontinence can also occur. In the 374 absence seizures analyzed by Penry et al. [8] only 35 (9.4%) were simple whereas 90.6% were complex, with automatisms occurring during 63.1%, mild clonic components occurring in 45.5%, and decreased postural tone occurring in 22.5% of the seizures. Brain tumors have been discovered in some patients with generalized seizures; they are virtually unheard of in patients with primary generalized seizures [9], generalized non-convulsive seizures [10], or in patients whose seizure disorder did not begin with [11] or progress to [12] focal clinical or electrographic abnormalities. Absence seizures affect cognitive function. Porter, Penry, and Dreifuss [13] studied 14 patients with absence seizures using a computer-assisted reaction-
time measurement triggered by the onset of EEG paroxysms. Of the reaction times measured, 56% were distinctly abnormal. Later onset stimuli yielded even more abnormal reaction times. In another study of 26 patients [14], 413 auditory reaction times were determined. They were normal during the 1 second before the EEG paroxysms. At the onset of the paroxysms, 43% of the auditory reaction times were normal; 20% were normal after a delay of 0.5 seconds into the paroxysm. The authors concluded that regardless of duration, the spike-wave paroxysm impaired consciousness and therefore treatment should attempt to control all spike-wave paroxysms. Whether or not to pursue further diagnostic studies or treatment in the asymptomatic patient with 3 Hz spike-and-wave activity found incidentally on EEG has not been directly studied. One of the striking features of absence seizures is the enormous number of seizures that can occur in a single day, often ranging into the hundreds. Clearly these events interfere with normal scholastic performance and can jeopardize the patient's safety. Treatment with a single antiepileptic drug (monotherapy) is preferred. Ethosuximide has been the drug of choice for 20 years [15]. More recently, valproate has been shown to be equally effective [16], but the higher incidence of minor and serious side effects, the rare occurrence of fatal hepatic toxicity, and the need to monitor hematologic and liver function make it a second choice for absence seizures. About half of the patients with absence seizures become seizure free and may be withdrawn from medication after two to four years. For the remainder, either the absence seizures persist or the patient goes on to develop tonic-clonic seizures. In a prospective study of 48 patients [17], 90% of absence patients without tonic-clonic seizures, with normal or better intelligence, and a negative family history of seizure disorders became seizure free. In a prospective study of 90 patients with typical absence seizures [18] and followup for up to 15 years, patients with myoclonic or atonic absence had a poor prognosis. Patients with simple absence or absence with automatisms often remitted. Overall remission rate with absence was only 57.5%. Thirty-six per cent of patients developed tonic
neurologic examination, and without hyperventilationinduced spikes-and-waves [19]. Seizures stopped in more than 90% of the patients who had three or more of these findings. Relapse is most likely to occur in the first year after treatment is discontinued [20]. Thus, simple absence and absence with automatisms are not always benign disorders of childhood and the prognosis is guarded. Current pharmacological management, while often effective in controlling the clinical seizures, does not seem to have influenced the long-term outcome in a significant fashion. Other Forms of Absence Seizures Delgado-Escueta et al. [21] and Janz et al. [22] described several other varieties of absence: Juvenile absence clinically is identical to classical absence but has an EEG signature of 8 to 12 Hz "diffuse rhythms." Myoclonic absence is characterized by brief unconsciousness with staring, stereotyped automatisms, and bilateral symmetrical clonic jerks. Myoclonus absence differs in that the clonic jerks are asymmetrical and the automatisms are reactive. These seizures are all said to respond to valproate. Impulsive petit mal, described in 1955 by Janz and Christian [23], is a specific syndrome of epileptic seizures which occurs in the second decade of life. It has probably been reported under many different names including juvenile myoclonic seizures, bilateral massive myoclonic jerks, generalized epilepsy with myoclonia during adolescence and late childhood, and myoclonic petit mal. Said to occur in 4 % of patients with epilepsy [23, 24], its importance is related not only to the frequency of occurrence, but also to its ready confusion with tonic-clonic seizures (grand mal) leading to the use of ineffective antiepileptic drugs [25]. The myoclonic jerks occur shortly after awakening (morning myoclonus), are mild, and are not accompanied by loss of consciousness. The interictal EEG signature of this seizure is fast (4-6 Hz), multiple, spike-and-slow-wave complexes. Fast, diffuse spikes (16-24 Hz) are seen in both hemispheres during the myoclonic jerks [26]. Photic stimulation leads to a photoconvulsive response or even photoconvulsive seizures. These patients often have a variety of other seizure types and 50% of them also have absence [21]. The disorder is often progressive. The patients, particularly if the myoclonic attacks become more frequent, develop either clonic seizures or clonic-tonicclonic seizures (sometimes misdiagnosed as tonic-clonic seizures). During the clonic seizures consciousness is
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lost; the patient falls to the floor, either forcefully, resulting from a massive myoclonic jerk, or because of a sudden loss of muscle tone. Rapid clonic jerking of the face and extremities and autonomic changes ensue. Consciousness returns quickly and there is little postictal depression. Additionally, the patient may have a tonic phase separating the initial and terminal clonic phases leading to a clonic-tonic-clonic seizure. Tsuboi and Christian [27] reported a high family incidence of myoclonic events. About 41% of relatives of probands had these abnormalities with a peculiar propensity among female relatives; 15 % of relatives without clinical myoclonus manifested the EEG findings. The treatment of choice is valproate, to which the seizures are said to be very responsive [26], and the prognosis is excellent, in part because of the age -limited nature of the disorder. However, long-term medication may be necessary [25]. Tonic-Clonic Seizures Tonic-clonic convulsions are among the most common seizures affecting children and may account for 75 % of seizures of childhood. Three major features of the generalized tonic-clonic seizure are the immediate loss of consciousness, an initial motor phase consisting of tonic contractions of all of the muscles, often with opisthotonus, and a second phase consisting of clonic contractions of the muscles. These contractions are forceful, and as the seizure runs its course, the forcefulness does not diminish although the time between these contractions gradually lengthens. Cyanosis, drooling, and urinary incontinence are common. Since seizures that are generalized from the onset begin with loss of consciousness, it is questionable if an aura can be part of the ictus. It seems more likely the aura, that portion of the seizure that occurs before the patient loses awareness, is the sign of a partial seizure with rapid generalization. This distinction is important not only for consideration of possible causes of the epilepsy, but also in considering optimal pharmacologic management. Tonic-clonic seizures may be precipitated by a number of triggering events, most commonly vasovagal syncope, but also flashing lights, music, or sudden startle, and the decreased cerebral blood flow which occurs with breathholding spells. Seizures which occur following decreased cerebral perfusion should not be considered to be epilepsy and, while antiepileptic drugs may decrease or even abolish the convulsive event, 268
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therapy is more appropriately directed toward preventing the disruption of blood flow. In reflex epilepsy, efforts are directed toward reducing the exposure to precipitating stimuli. Low dose atropine is effective in preventing the decrease in cardiac output that occurs with breathholding spells, and its use can be considered when these episodes occur frequently enough to cause disruption of a child's activities. The patient with a single generalized tonic-clonic convulsion poses a special problem. Since the diagnosis of epilepsy depends on the occurrence of repeated seizures, such a label is not appropriate in these cases. A cause for the seizure should be sought utilizing detailed history, physical and neurological examinations, laboratory investigation of possible abnormalities of electrolytes, glucose, calcium, and renal function. It also seems reasonable to obtain brain imaging, utilizing either CT or MRI, to evaluate possible structural abnormalities of the brain. If no precipitating cause is elucidated, then seizures will recur in only about 50% of patients and antiepileptic drugs should be withheld. The tonic-clonic convulsion is socially devastating because of the drama of the event and the associated incontinence. From a life-quality point of view, one tonic-clonic seizure per month is probably more restricting than 50 absence seizures per day. Therefore moderate medication side-effects may be tolerated in the quest for control. The prognosis is generally good if the tonic-clonic seizures begin after age five and before puberty [28]. Many antiepileptic drugs have been used; carbamazepine, phenobarbital, phenytoin, and valproate are often effective. Only ethosuximide, of the commonly used antiepileptic drugs, seems to lack efficacy against this seizure type. Clonic-Tonic-Clonic Seizures Clonic-tonic-clonic seizures, well described by Delgado-Escueta et al. [21], may be confused with tonic-clonic seizures. The former often occur on awakening and are exacerbated by fatigue and sleep deprivation. Interictally, there are 4- to 6-Hz EEG bursts. During the seizure there are diffuse multiple spike discharges of 14 to 24 Hz. The seizure begins with clonic flexor spasms; there is a 20 to 30 second period of tonic extension which is then followed by another episode of clonus. Myoclonic-Astatic Seizures (The Lennox-Gastaut Syndrome) The essential features of the Lennox-Gastaut syn-
drome are early onset of epilepsy; multiple seizure types in the same patient, including absence, myoclonic jerks, and atonic or astatic seizures; impaired development and intellect; and generalized slow spikeand-wave discharges on EEG. Other terms which have been used for the Lennox-Gastaut syndrome are astatic seizures, akinetic epilepsy, minor motor epilepsy, propulsive petit mal, akinetic petit mal, and severe myokinetic epilepsy of early childhood with slow spikeand -wave. The slow spike-and-wave discharges are an interictal EEG phenomenon [29]. They are activated by sleep [29]. Ictally the same discharge may be seen during an atypical absence attack, one in which these is less abrupt and complete loss of consciousness. During seizures other findings may supervene such as desynchronization of the record [30-33] especially associated with tonic seizures [29], and brief bursts of polyspikes or rapid spikes [34]. This lack of a one-to-one relationship between the epileptiform discharges and the clinical seizures is in marked contrast with other generalized seizures, especially simple absence. On the other hand, Dreifuss [35] stated that some of these children are in absence status for years at a time, suggesting that the slow spike-and-wave discharge may correlate with a clinical seizure state. Many patients have periods of relative freedom from seizures interspersed with periods of distressingly frequent seizures, and sometimes even absence status. The frequent, often forceful, falls are a cause of recurrent injury, particularly to the face and head, and result in lacerations, with subsequent, often disfiguring scars. Football helmets, and more recently hockey helmets, are of some benefit in reducing the severity of injury. In contradistinction to generalized absence and impulsive petit mal, in which genetics probably plays a major role, patients with myoclonic-astatic epilepsy are much more likely to have a specific etiology found, ranging from 50 to 90% of cases [29, 36]. The most commonly attributed cause is perinatal neurological insult. A significant number of patients have a prior history of infantile spasms. There is a much higher incidence of epilepsy in the families of patients with myoclonic-astatic epilepsy than in the general population, but the seizures in the relatives are rarely of the myoclonic-astatic type. Males predominate in most series, comprising up to 71% of patients. A variety of other etiologies have been implicated in individual patients including tuberous sclerosis, lipid
storage diseases, and aminoacidopathies. There is a high frequency of cerebral atrophy, particularly subcortical, on CT scans [37]. A rare form of myoclonic-astatic epilepsy with male preponderance and normal intelligence occurring in 1 to 5 year olds, was described by Doose [38]. Tonic seizures are not usually seen. There may be a genetic predisposition and the prognosis is much better than in the Lennox-Gastaut syndrome. No other group of seizure patients is more challenging and frustrating to manage. Every antiepileptic drug, alone and in combination, has been used in these patients, often with no success whatsoever. Most of these patients are subjected to polypharmaceutical assaults with no detectable difference in seizure frequency or severity. Indeed, some agents may make the seizures worse, or if not, then may make the patient worse [4]. Sedative antiepileptic drugs probably should be avoided. Phenobarbital almost never influences the seizures and may cause cognitive and behavioral aberrations. Papini et al. [39] found in a study of 16 patients for prolonged periods of time that the average number of seizures per day was 25. About 31% of the seizures occurred during drowsiness and 54% occurred during inactive wakefulness. Only 6% occurred during sleep and 1% during active wakefulness. The authors suggest that secondary effects of sedative antiepileptic drugs may increase seizure frequency by decreasing active alertness in these patients. Clonazepam, originally thought to be effective in these seizures, often exhibits tolerance, necessitating dosage increase and eventual sedation. Monotherapy with valproate is as likely to benefit the patient as any other therapy, and ea~:ly reports of its efficacy and the ability of so,axe pai~ient.a to discard their helmets, has turned out to he only slightly over-enthusiastic. The ketogenic diet, origi~lally proposed by Wilder, and later modified by Hutte:a!ocher et al. [40, 41] to permit a more normal nutritional state, has been extraordinarily effective in an occasional otherwise intractable patient. More recently, Trauner et al. [42] found that adequate growth could be maintained by increasing the total daily caloric intake to as high as 150% of normal for age and size. Unpalatability, expense, and the social isolation imposed by such a stringent diet are the major drawbacks to its use. More recently, ACTH has been found effective for seizure control in up to 80% of the patients in an uncontrolled study [43].
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Drugs With accurate diagnosis and careful selection of the appropriate medication, control can be achieved in the primary generalized seizures in most (75 to 86%) of patients [26].
dose-related rise in transaminases and serum ammonia have also been seen, but are not harbingers of the acute fatal hepatic syndrome. The hyperammonemia is related in some patients to decreased alertness or even coma.
Ethosuximide (ETH)
Clonazepam
For thirty years, ethosuximide has been the drug of choice for the treatment of absence accompanied by 3 Hz spike-and-wave. The drug is remarkably free from serious side-effects; even minor side effects are not common. At higher doses singultus is occasionally seen, often in relationship to the presumed peak blood levels of the drug. Gastric distress is relatively common and minimized by giving the ETH with food. Doses up to 40 mg/kg/day are recommended with target blood levels of 50 to 100 ~g/ml; in the absence of side-effects, much higher blood levels can be achieved accompanied by better seizure control in some patients. Levels of up to 150 p,g/ml are often tolerated.
Widely used in the treatment of generalized seizures in children, particularly atypical absence and the seizures occurring as part of the Lennox-Gastaut syndrome, it has become clear that the early seizure control is only transient, that frequent dosage increases are required, and that eventually further benefit is precluded by the appearance of dose-related side effects including lethargy, irritability, and drooling. Furthermore, attempts to wean the patient from a no longer effective drug frequently leads to worsening of the underlying seizures and the emergence of generalized tonic-clonic seizures. Alterations of the dosage regimen of clonazepam and other benzodiazepine drugs may lead to longer lasting efficacy
Valpmic acid (VPA) Heralded as a major advance in the drug therapy of epilepsy, VPA has earned a special place in the armamentarium. VPA is the drug of choice for absence associated with tonic-clonic seizures or myoclonus. It is also a clear choice for the single drug treatment of clonic-tonic-clonic and myoclonic-astatic seizures. It is also effective in tonic-clonic seizures but other agents may be chosen because of safety considerations. VPA is the clear drug of choice for juvenile myoclonic epilepsy which is often misdiagnosed as grand mal epilepsy. In atonic seizures (e.g., Lennox-Gastaut syndrome) VPA is more likely to be of benefit than any other single drug. The liquid and capsule preparations are rapidly absorbed and peak plasma levels are achieved in about an hour. A valproic acid dimer has slower and a more variable absorption rate, particularly in children; this variability precludes the use of peak and trough levels. Strikingly effective in certain epileptic syndromes in which there were formerly no effective medications, and relatively free from minor side effects, unfortunately VPA use has been associated with a syndrome of rapidly progressive hepatic failure, characterized by microvesicular accumulation of fat and hepatic necrosis which is almost invariably fatal. It is unclear what factors predispose to this tragic event, but it is assumed that it is an idiosyncratic response to the drug, perhaps due to an unusual mode of metabolism. Lesser degrees of metabolic abnormality including a
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Phenobarbital Phenobarbital is available in a wide selection of inexpensive preparations for oral and parenteral use. The half-life is considerably longer than one day, so that once-a-day administration is not only rational but preferred. Conversely, since it takes about 5 half-lives to achieve steady state levels, optimal effects may not occur for 2 to 3 weeks. It may take this long for doserelated side effects to abate. Phenobarbital has been used against tonic-clonic, partial simple, and partial complex seizures, has demonstrated efficacy in preventing febrile seizures, and is the current drug of choice in neonatal seizures. Parenteral preparations allow consideration as a drug for the treatment of status epilepticus, but it is not now the drug of choice. The major undesirable side effects of phenobarbital are brain-mediated [45]. Sedation is frequently a problem, although this effect is said to be transient with continued use. The deleterious effect on cognitive fanction may lead to the discontinuation of the drug. In children who receive phenobarbital starting in infancy, the adverse effects on learning may not be apparent until the drug is discontinued. More obvious are the behavioral side effects of phenobarbital, including hyperactivity, distractibility, and irritability. Control seems reasonably related to blood levels.
Levels of greater than 16 vg/ml are needed for prevention of febrile seizures and neonatal seizures and similar levels are probably needed for other seizure types as well. Notable sedation occurs regularly with levels above 40 v.g/ml leading to the usual recommended therapeutic range of blood levels of 20 to 40 gg/ml. There is little justification for the use of the alcoholic elixir. The ethanol content is responsible for the postdose lethargy in some infants, which, considering the rate of absorption and the half-life, can not be due to the phenobarbital. Tablets as small as 8 mg are now readily available for use even in tiny infants.
usual dose requirement for children is from 10 to 30 mg/kg/day and therapeutic blood levels of 5 to 12 #g/ml are the rule, akhough the relationship between dose and blood level are only approximate. At higher dosages, transient diplopia and ataxia may occur at the time of peak blood levels; these side effects can be minimized by further dividing the daily dose. Side effects may be partially due to carbamazepine-10,11epoxide, a metabolite [48]. The percent of drug present as carbamazepine-10,11-epoxide is increased in the presence of other antiepileptic drugs [49]. Toxic levels of CBZ (and perhaps epoxide, also) occur when erythromycin is used for intercurrent infections.
Phenymin (PHT) Still a drug of choice for adults, particularly with generalized tonic-clonic seizures and also partial seizures, its role in the treatment of children with generalized seizures is less secure. Phenytoin is known to exacerbate simple absence as well as several of the seizure types seen in Lennox-Gastaut syndrome. It remains a very effective agent for the control of generalized tonic-clonic seizures. However, there are several drawbacks in using PHT in children. The effects on hair and gum growth as well as the coarsening of facial features are unacceptable to most patients and their families. PHT has also been shown to have significant deleterious effects on learning, a major consideration in the school-aged patient [46]. While the gingival hypertrophy can largely be prevented through a vigorous program of oral hygiene, the other side effects are not now preventable.
Other Considerations Although antiepileptic drug therapy is the cornerstone of the medical management of generalized seizures, attention to environmental factors that can induce seizures may be helpful [50]. Careful reconsideration of the goals of therapy may lead to an entirely different approach to the patient [51]. Rarely, intractable seizures in infancy may respond to high-dose pyridoxine; a trial seems reasonable for any patient before instituting antiepileptic drug therapy [52]. The individual child with generalized seizures provides formidable challenges as a result of newer diagnostic techniques; more useful classification of the epileptic seizures; more effective antiepileptic drugs; better ways of precribing and monitoring antiepileptic drugs; inreased patient, family, and school awareness of epilepsy and its treatment; vigorous advocacy of local and national support groups; and increasing research efforts in basic and clinical epileptology. Thus, the clinician bears increasing responsibility for helping the child with epilepsy achieve the best possible outcome in the face of an avalanche of information, sometimes conflicting. Knowledge of the natural history of a particuar epileptic syndrome allows comparison of the individual patient's course to the natural history of the disorder and suggests reasonable (i.e., attainable) goals in the immediate and long-term management of the child.
Carbamazepine (CBZ) Carbamazepine has emerged as a drug of choice for partial seizures, both simple and complex [47]. While far from the drug of choice, occasionally CBZ is effective in treating absence refractory to other agents, presumably because of rapid generalization of a localized epileptic discharge. The availability of a 100 mg scored, chewable tablet has made it possible to use CBZ in very young children, although safety and efficacy has not been formally demonstrated in children under 6 years of age. The relatively short half-life mandates 3 or even 4 daily doses. Diplopia, dizziness, malaise, and ataxia are frequently encountered when the drug is started, but can be minimized by starting with very low doses and increasing the daily dose every 3 or 4 days. (With a half-life of about 8 to 10 hours, this represents more than 5 half-lives of the drug.) The
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