The earliest descriptions of tonic-clonic seizures appear in Egyptian hieroglyphics prior to 700 BC. Indeed, until the time of Hippocrates (400 BC), all seizures were considered “a convulsion of the whole body together with an impairment of leading functions” (3). From that time forward, a clear distinction between unilateral and generalized convulsive seizures is present in medical literature. Remarkably, another 2000 years passed before nonconvulsive (“de petits”) seizures were widely recognized as epileptic events separate from convulsive (“grand acces”) seizures (4). In the early 19th century, tonic-clonic seizures were grouped with other convulsive attacks, all referred to as “le grand mal” (5).

The preferred description, generalized tonic-clonic seizure, is based on observations documented by closed-circuit television or cinematography with electroencephalographic monitoring (6). Although still used frequently, the term grand mal is now discouraged; it does not imply the presence or absence of a sequence of events that could help to distinguish clinically between primary and secondary generalized seizures or between GTCSs and other types of convulsive seizures. Other similarly ambiguous designations are “generalized convulsion” and “major motor seizure.” Even “tonic-clonic” warrants further qualification, because a tonic-clonic sequence of motor events may be generalized, asymmetrical, unilateral, or focal.

The Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) (6) defines seizures according to clinical and electroencephalographic criteria. Because GTCSs are described simply as a tonic phase followed by a clonic phase, future revisions likely will focus on the clinical description. For example, GTCSs are often preceded by one or more myoclonic jerks or a brief clonic seizure and may be followed by a prominent postictal phase of tonic contraction (7). The classification also describes known patterns of progression (e.g., a partial seizure secondarily generalizing to a tonic-clonic seizure). Further distinctions based on the precise sequence of clinical ictal events may be useful in the future for differentiating primary from secondary generalization, identifying specific epilepsy syndromes (8), or predicting therapeutic response.

According to the Commission on Classification and Terminology of the ILAE (9), epilepsy syndromes with bilateral tonic-clonic seizures are divided into idiopathic (cryptogenic, essential, primary) and symptomatic (secondary) categories. This distinction is further discussed in Chapters 14 and 22. Symptomatic epilepsy syndromes have a presumed cause based on a known disturbance of brain function. Those syndromes currently classified as idiopathic that have the greatest number of specific defining criteria (e.g., age of onset, characteristic electroencephalographic expression, provoking factors) are now assumed to be specific genetic disorders.

As noted by Aicardi (10), GTCSs occur in so many different types of epilepsy that their diagnostic value is limited. However, other types of coexisting seizures are often useful for syndrome classification. The generalized idiopathic epilepsies (9) in which GTCSs occur along with other seizure types include benign myoclonic epilepsy in infancy (GTCSs in adolescence), childhood absence epilepsy (pyknoepilepsy; GTCSs in 40% to 60% of cases), juvenile absence epilepsy (GTCSs in 80% of cases), Lennox-Gastaut syndrome (idiopathic in 30% of patients; GTCSs are infrequent), myoclonic astatic epilepsy (Doose syndrome; GTCS is the initial seizure type in >50% of cases), juvenile myoclonic epilepsy (impulsive petit mal; GTCSs in >90% of cases), and epilepsy with myoclonicastatic seizures (which may also be symptomatic in some patients) (9). Partial idiopathic epilepsies (idiopathic focal epilepsies) in which GTCSs occur secondarily include benign childhood epilepsy with centrotemporal spikes and childhood epilepsy with occipital paroxysms (benign epilepsy of childhood with occipital spike-and-wave complexes) (11). In addition, there are some epilepsy syndromes in which GTCSs never occur, such as early infantile epileptic encephalopathy (Ohtahara syndrome) and early myoclonic encephalopathy, as well as those in which GTCSs are usually the only seizure type, such as grand mal seizures upon awakening. Seizures in otherwise normal individuals in which GTCSs are triggered by photic stimulation are almost always indicative of primary generalized epilepsy. Some epilepsy syndromes, such as Dravet syndrome, are typically associated with multiple seizure types, but occasionally with only GTCSs (12). Hot-water exposure and fever may trigger a variety of seizure types, particularly partial seizures. Hot-water exposure may also trigger seizures in patients with Dravet syndrome.

Some proposed syndromes of idiopathic epilepsy with GTCSs emphasize the presence, absence, or degree of associated generalized myoclonus (8) (see also juvenile myoclonic epilepsy versus epilepsy with GTCSs upon awakening). Although some syndromes are more widely accepted than others, evidence for each has been difficult to obtain for six reasons:

The number of clinical and electroencephalographic features that overlap among some proposed syndromes with GTCSs, the limited number of diagnostic features for
certain proposed syndromes, the phenotypic variation in seizure types that can occur with the same genetic abnormality, and the existence of patients who apparently have more than one syndrome all continue to make the electroclinical classification of some patients with GTCSs highly problematic. Although phenotypic classifications have necessarily preceded the development of genetic classifications, dramatic advances in molecular genetics promise to revolutionize the classification of the epilepsies. Currently, idiopathic epilepsies that are presumed to have a genetic basis are thought to account for up to 60% of all epilepsies (16).

Eisner and colleagues (17,18) provided early evidence for a genetic factor in GTCSs by demonstrating a significant familial aggregation in individuals whose seizures began before age 15 years, 6 months; this effect was even stronger among those whose seizures began before the age of 4 years. Tonic-clonic seizures occurred in 8.3% of probands’ relatives, in contrast to 2.2% of relatives of the control population. Tsuboi and Endo (19) also found a clear genetic basis for idiopathic grand mal epilepsy. In their study, individuals with idiopathic GTCSs had the highest rate of offspring with either febrile or afebrile seizures (16.8%); a healthy control population was not studied. Genetic linkage studies by Greenberg and colleagues (20) and Durner and associates (21) showed a strong link between the seizures of juvenile myoclonic epilepsy and human leukocyte antigen (HLA) factors on chromosome 6 (see Chapters 7 and 25). Their work also supports the notion that generalized epileptiform activity on EEG readings is a subclinical electroencephalographic marker of the disorder in unaffected family members. More recently, Cossette and coworkers (22) described an Ala322Asp mutation in the γ-aminobutyric acid receptor α₁ subunit in a single pedigree with recognized juvenile myoclonic epilepsy. Indeed, it is now known that a variety of geneticbased abnormalities can give rise to epilepsy. These include abnormal ion channel function, neuronal nicotinic acetylcholine receptor (nAChR) site abnormalities, disordered brain development, progressive neurodegeneration, and disturbances of cerebral energy metabolism (23).

Idiopathic epilepsies inherited in a mendelian fashion in which GTCSs may occur include autosomal dominant nocturnal frontal lobe epilepsy mapped to chromosome 20q13-q13.3 with mutations in CHRNA4 (the gene encoding the α₄ subunit of the nAChR), benign familial neonatal convulsions (BFNC), generalized epilepsy with febrile seizures plus (GEFS+), and other rare disorders (23). BFNC is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 (EBN1) and 8q24 (EBN2) (24,25). BFNC is characterized by GTCSs starting on the second or third postnatal day and is considered a prototypic model of monogenic idiopathic generalized epilepsy (IGE) (26,27). Mutations in the voltage-gated potassium channel gene KCNQ2 and the homologous gene KCNQ3 have been found in cases linked to chromosome 20q13.3 (28,29).

GEFS+ is a genetic syndrome with heterogeneous phenotypes (30,31). The most common phenotype was described by the authors as “febrile seizures plus” (FS+), with febrile seizures occurring after 6 years of age with or without associated afebrile tonic-clonic seizures. The GEFS+ spectrum includes other seizure types, such as absence, myoclonic, and atonic, as well as myoclonic-astatic epilepsy. Inheritance is autosomal-dominant with linkage to chromosome 19q. A mutation has been identified in the α₁ subunit of the neuronal sodium channel in one family (SCNB1) (32). Recently, Baulac and colleagues (33) reported a GEFS+ family with the locus mapped to chromosome 2q21-q33, with genes coding for three isoforms of the brain sodium channel α subunit (SCN1A, SCN2A, and SCN3A) being strong candidates. Temporal lobe epilepsy may be an occasional late consequence of the GEFS+ syndrome (31). Two loci responsible for febrile seizures, FEB1 and FEB2, have been mapped on chromosomes 18q and 19p, respectively (33).

Idiopathic epilepsies with a complex mode of inheritance in which GTCSs occur are rarely, if ever, monogenic. Hoping to find one gene common to all IGEs, Durner and associates (34) performed a genome scan in 89 families chosen because a proband had adolescent-onset IGE. They found the strongest evidence for linkage to chromosome 18 when all families were analyzed together. In patients with juvenile myoclonic epilepsy, there was strong linkage on chromosome 6 near the HLA region. According to Sander and coworkers (35), three tentative loci predisposing individuals to juvenile myoclonic epilepsy have been mapped to the chromosomal segments 6p21.3, 6p11, and 15q14, but replication studies have failed to establish unequivocal linkage relationships. Other IGE families without myoclonus provide evidence for linkage to chromosome 8 in the area that encompasses the locus for the β₃ subunit of the nAChR (CHRNB3) (36,37). However, Sander and associates (35) failed to replicate evidence of a major locus for common familial IGEs in chromosome region 8q24. Furthermore, Durner and associates (34) found that if a family member had absence seizures (irrespective of the syndrome), there was strong linkage to two areas on chromosome 5. The investigators concluded that the most likely genetic model for IGE is oligogenic, with strong evidence for a locus common to all IGEs on chromosome 18 and differentiating loci for specific seizure types on chromosomes 5, 6, and 8. They recommended that further investigations be aimed at identifying individual genes for specific seizure types rather than epilepsy syndromes.

Genetic mapping of the progressive myoclonic epilepsies (see also discussion of zonisamide in “Therapy” below) now includes epilepsy of the Unverricht-Lundborg type (EPM1) mapped to the cystatin B gene on chromosome 21 band q22.3 and Lafora disease (EPM2) mapped to 6q23-q25 (38,39). Rapid progress has also been made in establishing the genetic basis of neuronal ceroid lipofuscinoses (40) and determining the mitochondrial abnormalities
responsible for myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), and Leigh disease (41).

Neuronal migration disorders associated with tonic-clonic seizures that have a known genetic basis include X-linked lissencephaly (X-linked dominant, male) and subcortical band heterotopia/double cortex (X-linked dominant, female), both of which are associated with a double cortin gene on chromosome Xq21-24 (23). Periventricular nodular heterotopia (X-linked dominant with male lethality) is ascribed to the defect of a gene coding for a filamin-1 actin-binding protein on chromosome Xq28 (23).

A variety of symptoms may precede GTCSs by hours or even days (Table 18.1). These are thought to arise either directly from heightened cortical excitability (e.g., myoclonus or difficulty concentrating) or indirectly from the physiologic changes that alter the seizure threshold (e.g., mood change or headache). The physician should not be misled into thinking that these symptoms represent the auras of partial seizures, particularly in individuals who can reliably predict their seizures because of the regularity with which the symptoms occur. For the majority of patients with GTCSs, however, premonitory symptoms are absent.

The coexistence of generalized myoclonus supports a diagnosis of primarily generalized, as opposed to secondarily generalized, tonic-clonic seizures. Myoclonus of the arms and trunk occurs in approximately 10% to 50% of all patients with generalized convulsions (14), and myoclonus on awakening is a key feature in juvenile myoclonic epilepsy (impulsive petit mal). In addition to premonitory symptoms, some seizures may be anticipated on the basis of known precipitating factors, such as sleep or photic stimulation (82). Nocturnal idiopathic GTCSs usually take place near the beginning or the end of sleep and only rarely during rapid eye movement (REM) sleep (83,84). Light-sensitive seizures are facilitated by sleep deprivation. Abrupt withdrawal of antiepileptic drugs (AEDs) in patients with established epilepsy may be more likely to trigger an isolated GTCS or, occasionally, life-threatening GTCS status epilepticus than other kinds of seizures. Malow and colleagues (85) found that rapid withdrawal of AEDs during monitoring resulted in the occurrence of significantly more GTCSs than did gradual tapering, whereas no apparent differential effect on the rate of complex partial seizures was reported. Fortunately, life-threatening status epilepticus is rare in epilepsy-monitoring units in which AEDs are routinely withdrawn, perhaps because of the dramatic reduction in the patient’s level of activity produced by bed rest. If the purpose of monitoring is to localize seizure onset, it is preferable to record partial seizures (with or without secondary GTCSs) rather than rapidly evolving secondary GTCSs. In such circumstances, gradual withdrawal of AEDs before and during monitoring may reduce the likelihood of GTCSs.

Idiopathic GTCSs may evolve directly from typical absence (86), clonic, or tonic seizures (7). Secondary GTCSs may evolve from partial seizures in individuals with idiopathic epilepsy (e.g., benign epilepsy with centrotemporal spikes) or symptomatic epilepsy. Generalization occurs during a brief period (up to 40 seconds) (2) between the end of the partial seizure and the beginning of the GTCS. This phase is often marked by versive (turning) head movements, body movements, or vocalization.

Clonic activity is the most common immediate precursor to the tonic-clonic phase. As Gastaut and Broughton (7) observed, idiopathic GTCSs are frequently preceded by several myoclonic jerks or a brief clonic seizure. Myoclonic or clonic activity also may occur during the transition from partial seizures to GTCSs (2,74). Analyzing videotapes of 32
secondary GTCSs in which all phases of GTCS (including generalization) were present, Theodore and coworkers (2) found that antecedent clonic activity lasted from 3 to 21 seconds. Our own experience indicates that generalized myoclonus at the onset of an unprovoked tonic-clonic seizure is practically pathognomonic for primary generalization.

Although GTCSs typically involve both sides of the body symmetrically, they may begin with versive movements of the head and eyes (87). The significance of these movements is controversial. In two studies (88,89), initial conjugate eye and head turning was noted in patients with either partial (e.g., frontal or temporal foci) or primary generalized seizures; in those with partial-onset seizures, ipsilateral head turning was as common as contralateral head turning. We have also observed head and eye deviation at the onset of primary generalized seizures evolving out of 3- to 4-Hz spike-and-wave activity. However, in a third study, Wyllie and associates (90) found that strongly versive head and eye movements consistently occurred in patients with secondary GTCSs arising from the contralateral hemisphere. Kernan and colleagues (91) also observed that forced head turning was contralateral to seizure onset greater than 85% of the time if it consisted of sustained, unnatural tonic or clonic movements that either occurred during the 10 seconds prior to generalization or continued through it. In this study, ipsilateral head turning almost always appeared to be volitional and ended before secondary generalization in more than 90% of cases. Although all authors noted exceptions to the localizing value of versive head movements, we agree with the latter two studies (90,91) that forceful involuntary movements at seizure onset with greater than 45 degrees of rotation, as distinguished from volitional movements or brief automatisms, have lateralizing value.

The tonic-clonic convulsion begins with brief tonic flexion of the axial musculature, accompanied by upward eye deviation and pupillary dilatation. The tonic muscle contraction spreads quickly, elevating and abducting the arms. The elbows semiflex and the hands rotate with the palms forward. The lower extremities simultaneously assume a position of flexion, adduction, and external rotation. Muscular contraction in the limbs is greatest proximally. The mouth is characteristically held rigid and half open.

This brief flexor spasm is followed by a longer period of tonic extension, also beginning in the axial musculature; the tonic extension phase is heralded by forced closure of the mouth, which sometimes produces oral trauma. It also causes a forced expiration of air, sometimes resulting in a 2- to 12-second “epileptic cry.” The arms then become semiflexed and abducted, with the forearms partially crossed in front of the chest. At the same time, the legs are adducted, extended, and fixed in internal rotation with the feet and toes in extension. During the tonic phase, heart rate and blood pressure may more than double, and intravesicular bladder pressure may increase to five times the normal value. Sweating is a regular occurrence and leads to a measurable drop in skin resistance (Fig. 18.1). The tonic phase may be as brief as 1 to 3 seconds or as long as 20 seconds (2,7). The transition from the tonic to the clonic phase is gradual. Referred to by Gastaut and Broughton (7) as the “intermediate vibratory period,” it emerges from the tonic phase as an approximately 8-Hz diffuse tremor that
gradually slows to 4 Hz as the clonic phase becomes established. This early clonic, or tremulous, phase lasts from 3 to 17 seconds (2).

When each recurrent inhibition of tetanic contraction produces complete atonia, the clonic phase appears as repeated, violent flexor spasms, each accompanied by pupillary contraction and dilatation. The intervals of atonia gradually become more prolonged and somewhat irregular until a final spasm occurs. The lengthening of the atonic intervals is independent of the absolute number of clonic contractions (75). Contraction of sphincter muscles blocks enuresis until the end of the clonic phase. In secondary generalized seizures, in which the frequency and duration of clonic jerking are uninterrupted, there is almost always a regular, gradual slowing of clonic jerks. In an uncomplicated secondary generalized seizure, the duration of clonic activity ranges widely from 3 to 65 seconds (2). Near the end of this phase, jerking slows to approximately 1 Hz.

In human electroconvulsive therapy-induced GTCSs, it has not been possible to dissociate the contribution of postictal hypometabolism from that of ictal hypermetabolism through the use of fluorodeoxyglucose positron emission tomography (PET) because of limitations in time resolution; however, the increase in cerebral blood flow during GTCSs is likely a result of increased cerebral glucose metabolism (Fig. 18.2).

Gastaut and Broughton (7) suggested that when convulsive activity on the two sides of the body is clearly asynchronous, the convulsion may be viewed as two independent unilateral seizures rather than as a single generalized one. Whether such seizures are more typical of secondary generalization is unclear.

Following the last clonic jerk, respiration returns within several seconds, and there is sustained pupillary dilatation. In many cases, tonic activity returns, lasting from several seconds to minutes. Occasionally, postictal tonic activity is as intense as the initial tonic contraction and results in opisthotonos and trismus, which may cause tongue laceration. The activity usually has a rostral predominance, which in its most limited form appears only as jaw tetany (92), and may selectively affect the arms, the legs, or both. Because the tonic contraction involves predominantly extensor muscles and coexists with profound metabolic depression of cortical function, Ajmone-Marsan and Ralston (92) hypothesized that it represents a functional decerebrate state. This view is supported by postictal PET findings that show hypometabolism predominating in cortical structures (Fig. 18.2) (86,93). In approximately 50% of GTCSs, extensor plantar responses can be elicited postictally (94); in secondary generalized seizures, these are likely to be found contralateral to the hemisphere of onset. Incontinence occurs between the end of the clonic phase and the beginning of the postictal tonic phase. Ejaculation and fecal incontinence are rare in the immediate postictal period.

As the patient gradually awakens, a confusional state with automatic behavior may ensue. Often, the individual falls asleep directly and awakens feeling tired. Complaints of generalized muscle soreness and headache are common. Diffuse ictal skin color changes (probably from venous congestion as a result of impaired venous return or cyanosis caused by apnea-induced hypoxia) disappear quickly. Piloerection and petechial hemorrhages occasionally are seen. The actual ictus lasts 1 to 2 minutes, but patients often measure seizure duration through the initial part of the postictal period as lasting 5 to 15 minutes. During this time, cerebral hypometabolism resolves gradually (Fig. 18.2). In one of only a few studies of the postictal recovery of cognitive function, Helmstaedter and
colleagues (95) found that complete reorientation (to person, location, and time) occurred at an average of 18 minutes following secondarily generalized seizures (range, 4 to 45 minutes; 1 standard deviation, 15 minutes; 18 seizures studied). This contrasted with an orientation recovery time of 1 to 10 minutes for complex partial seizures (1 standard deviation, 3 minutes; 13 seizures studied).

Immediately following the seizure, the arterial pH level is decreased to 7.14±0.06 (rarely to <7.0). Changes in mean levels of CO₂ (17.1±1.1) and venous lactate (12.7±1.0 mEq/L) also occur. The acid-base equilibrium is restored to normal within 60 minutes by the metabolism of lactic acid (96). Serum glucose increases transiently (usually <200 mg/dL) (97), although with recurrent seizures (status epilepticus), hypoglycemia is the rule. Cerebrospinal fluid (CSF) cell counts are usually normal following a single, uncomplicated GTCS, but in patients with idiopathic status epilepticus, a minor pleocytosis (5 to 30 cells/mm³) is not unusual (98), and counts of up to 80 cells/mm³ are seen occasionally (99). Regardless of the number of seizures, a cell count greater than 10 cells/mm³ should be considered evidence of an intracranial inflammatory process until proven otherwise (17).

Transient fluctuations in endocrine function always follow a GTCS (Table 18.2; for review, see ref. 99). Most consistent and easily observable is an increase in prolactin level (present in >90% of GTCSs; Fig. 18.3) (100). Prolactin increases within 5 minutes, reaches a peak of 5 to 30 times baseline levels in 19 to 20 minutes, and remains significantly elevated for 1 hour postictally (101,102). In multiple GTCSs, each successive seizure elicits a lower rise in prolactin level. In GTCS status epilepticus, the serum prolactin level is usually within normal range. This failure of prolactin to rise does not appear to be the result of simple depletion, because the injection of thyrotropin-releasing hormone under such conditions still results in a significant (twofold) increase (103). Although other hormones also may increase following GTCSs (Table 18.2), the relatively limited circadian variation of serum prolactin and the consistency of its increase make it the most useful clinical marker for sporadic seizures.

Prolactin elevation also may help to distinguish GTCSs from psychogenic pseudoseizures or other nonepileptic events. For diagnostic purposes, a prolactin level should be measured within 60 minutes of the seizure, and a second level, to be used as a baseline for comparison, should be obtained at least 24 hours later. False-negative results have been reported in the settings of both electroconvulsive and spontaneous tonic-clonic seizures, although they are far more likely with simple or complex partial seizures (100,101,104,105). With the exception of one case report (106), psychogenic pseudoseizures have not been found to significantly increase prolactin levels in patients classified according to closed-circuit television /electroencephalographic findings (102,107). Absence and myoclonic seizures and absence status do not cause significant elevations in prolactin levels (108). Minor increases may occur during periods of stress (e.g., seriously ill patients in the emergency department) (109), but not of the magnitude seen with GTCSs.