Generalized tonic-clonic (GTC) seizures may be either primary or secondary in onset.¹ Although the older terms grand mal, convulsion, and fit are still widely used by patients, the preferred terminology of tonic-clonic seizure derives from intensive correlative analysis of GTC clinical seizure semiology with simultaneous ictal electroencephalography (EEG), and implies a usual prototypical progressive sequence of clinical movements that often help distinguish this seizure type from other predominantly motor, primarily generalized, or partial-onset seizure types (i.e., myoclonic, tonic, and extratemporal partial seizures) and from psychogenic or physiologic nonepileptic spells.¹

Primary generalized tonic-clonic (PGTC) seizures arise from bisynchronous ictal behavioral and EEG onset simultaneously from both cerebral hemispheres. They are a chief seizure type within the rubric of generalized seizure types occurring in primary (idiopathic) generalized epilepsy syndromes,² but they could occur as isolated single spontaneous seizures or as acute provoked symptomatic seizures unassociated with the development of epilepsy.³ In contrast, secondarily generalized tonic-clonic (SGTC) seizures are the final common pathway of seizure propagation from focal seizures. An SGTC may be the sole or predominant seizure phenotype and presenting clinical expression of a partial-onset seizure and focal epilepsy syndrome. Diagnostic confusion between PGTC and SGTC seizures occurs frequently, given their overall similar clinical appearance, especially in new-onset epilepsy, when patients have had relatively few seizures, limiting opportunities for direct observation and accurate description.^3,4

Because PGTC and SGTC seizures often have very similar clinical manifestations, careful consideration must be given prior to assigning a diagnosis of a PGTC seizure type when a patient initially presents with a clinical history of a GTC. In practice, differentiating PGTCs from SGTCs may be quite difficult. The distinction between PGTCs and SGTCs in clinical outpatient practice most often relies on indirect evidence, such as neuroimaging and interictal EEG data, or clinical history features, such as described ictal behavior, patient age, family history, seizure periodicity, known aggravating factors, and the presence of other known partial or primary generalized seizure types, including auras. Confident determination of the seizure type and underlying epilepsy syndrome is enabled in children with newly diagnosed epilepsy, given higher seizure burden and more frequently diagnostic interictal EEGs in that patient population, whereas in adults, corroborative investigations are frequently frustratingly negative in new-onset epilepsy, leading to uncertainty regarding the appropriate seizure type and syndromic epilepsy diagnosis in many patients.^5,6 Uncertain epilepsy syndrome diagnosis can hamper appropriate tailoring of antiepileptic drug (AED) treatment in refractory epilepsy.

When diagnostic uncertainty persists, and accurate seizure type diagnosis is necessary to direct further empiric AED therapies and consideration of a surgical approach in refractory patients, ictal video-EEG monitoring (VEM) is necessary to distinguish PGTCs from SGTCs.^7–9 VEM has been found to significantly increase accurate diagnosis of idiopathic generalized epilepsy (IGE).¹⁰ It has a particularly high yield (88%) in identifying diagnostic interictal or ictal EEG manifestations consistent with juvenile myoclonic epilepsy (JME) of Janz, a prototypical primary IGE syndrome, and is especially valuable for demonstrating diagnostic findings within a period of 1 or 2 days for 90% of JME patients having previously negative laboratory interictal EEGs.¹¹ Prompt diagnosis and effective treatment of PGTCs are important, given the association of GTC seizure types with an increased risk of injury and death.^12,13

This chapter reviews the epidemiology and etiologic factors underlying PGTCs, presents typical and atypical interictal and ictal behavioral and EEG manifestations of PGTCs that inform proper diagnosis of seizure type in epilepsy monitoring practice, and concludes with a brief overview of treatment considerations for PGTCs. Further information on SGTCs can be found in Chapter 11.

The epidemiology of PGTCs is not well delineated. Population-based epidemiologic studies usually rely on history alone or, at best, corroborative interictal EEG data, and are thus necessarily limited in precise distinction of PGTCs from SGTCs. However, considerable epidemiologic data concerning GTCs overall is available.

Incidence Rate

PGTCs account for approximately 6% of first (solitary, single) seizure presentations.¹⁴ The annual incidence for all GTC seizures in those with epilepsy in the general population is ~23 to 26%.^15–17

Age of Onset

PGTCs are typically first seen in older children, adolescents, and young adults commensurate with the usual ages of onset for the common IGE syndromes involving PGTCs, including childhood and juvenile absence epilepsies and JME. PGTCs may also be seen in younger children but are rare prior to 3 years of age, given immaturity within the developing brain in cortical neuronal and synaptic functioning and incomplete myelination along key propagation pathways.^18–25 Overall, adults more commonly manifest SGTCs than PGTCs.²⁶

Gender Distribution

PGTCs are generally considered to be evenly distributed between male and female populations, but gender distribution of PGTCs may vary according to the underlying epilepsy syndrome. There is heterogeneity between predominant gender in the IGE subsyndromes of early childhood. Childhood absence epilepsy more often affects girls than boys, and in benign myoclonic epilepsy of infancy and the later evolving myoclonic-astatic epilepsy of childhood (Doose syndrome, in which PGTCs may occasionally be seen), there is a clear male predominance.^16,28–30 In adolescence and adulthood, the principal epilepsy syndrome associated with PGTC occurrence is JME, in which there also appears to be a slight female predominance.³¹

Prevalence Rates within Epilepsy and within the General Population

The prevalence of GTCs in those with epilepsy is approximately 21%.¹⁶ Between 25 and 50% of children and adults with epilepsy experience GTCs,¹⁷ and about 39% of those with epilepsy have an electroclinical epilepsy syndromic diagnosis of IGE.³² In various studies, a wide range of epilepsy outpatients (11–87%) with primary IGE experience only PGTCs as their sole seizure type during longitudinal follow-up.³³ PGTCs are relatively more common among children than adults overall.^27,34

Associated Epilepsy Syndromes and Natural History

PGTCs are a principal seizure type in several IGE syndromes.^3,35 Table 13-1 outlines IGE syndromes in which PGTCs commonly occur. Idiopathic (also called essential or primary) generalized epilepsies are presumed to be independent of any other brain abnormality, distinguished from symptomatic (i.e., secondary) generalized epilepsies, which are associated with other neurologic abnormalities.³ Regardless of subsyndrome, IGEs share the following qualities: (1) genetic predisposition, with frequent clinical seizures or subclinical genetic EEG patterns in first-degree relatives; (2) essentially otherwise normal interictal patterns, with a normal developmental history and neurologic examination; (3) primary generalized seizure types of absence, myoclonic, astatic, or myoclonic-astatic, and PGTCs without a history of tonic seizures or tonic-astatic seizure types; and (4) generalized interictal and ictal EEG patterns, often with photosensitivity.

IGEs include a variety of refined subsyndromic diagnoses further delineated below. Although the International League Against Epilepsy recognizes several distinct subsyndromes of IGEs, in practice, clinical phenotypes are often less distinct, and within single IGE kindreds, different individuals may manifest different subsyndromes.^36,37 Distinguishing which overall syndromic classification and subsyndromic category into which a patient with PGTC belongs involves consideration of other historically reported seizure types, interictal and/or ictal EEG, neuroimaging characteristics, and other key clinical variables, including age of onset, provocative factors, presence or absence of an underlying known brain disorder, and interictal cognitive or developmental sequelae. Current estimates predict 60% or more of idiopathic epilepsies may be eventually recognized as genetic in nature.³⁸ In the future, increasing availability of genetic testing may play a role in defining specific genetically determined epilepsy syndromes, but currently genotyping is not routinely used in clinical practice.

PGTCs are common in IGE. IGE syndromes manifesting PGTCs include benign familial neonatal convulsions (BFNC), generalized epilepsy with febrile seizures plus (GEFS+), benign myoclonic epilepsy in infancy (BMEI), myoclonic-astatic epilepsy of childhood (Doose syndrome), epilepsy with myoclonic absences, childhood absence epilepsy (CAE, or pyknolepsy), juvenile absence epilepsy (JAE), and JME.³⁵ Adolescents and adults with PGTCs are typically associated with JAE, JME, or generalized tonic-clonic seizures on awakening (GTCOA).

During infancy, PGTCs may be seen in BFNC, GEFS+, and BMEI. BFNC is a rare syndrome with generalized tonic-clonic or focal seizures often presenting during the first week of life (but as late as the seventh month), remitting by 12 months of age, although approximately 15% of patients develop seizures later in life as well.^39,40 Benign familial neonatal-infantile seizures (BFNIS) is a closely related clinical phenotype that is genetically distinct.⁴¹ GEFS+ is another autosomal dominant disorder presenting in infancy or early childhood, characterized by initial febrile seizures between 6 months and 6 years of age, and variable association of an ensuing epilepsy involving febrile and afebrile PGTCs and a mixture of other seizure types.⁴²

BMEI begins between 6 months and 4 years of age and predominantly affects boys. It is characterized by brief generalized myoclonic jerks involving axial musculature and limbs, either singular or clustering, with or without febrile or afebrile PGTCs. A family history of epilepsy or febrile seizures is seen in 30%. BMEI most often remits within 1 year of onset and may be followed by later life/adolescent PGTCs.^28,29 A subset of BMEI patients is prominently photosensitive and may have light-sensitive seizures, especially at the onset of their epilepsy.^2,43

Myoclonic-astatic epilepsy of childhood (Doose syndrome) affects infants and children with onset between 6 months and 6 years of age, peaking between the ages of 2 and 4 years. Doose syndrome presents with febrile or afebrile PGTCs in approximately 50% of patients, usually occurring months or years prior to the hallmark myoclonic-astatic seizure type, and are most often solely or predominantly nocturnal in occurrence. Myoclonic-astatic seizures involve myoclonic upper extremity and axial jerks with an immediately ensuing astatic/atonic component that can cause sudden falls, head nods, or knee buckling. There are clustered episodes of frequent absence seizures and absence status epilepticus in one third of patients, as well as nocturnally predominant PGTCs. A family history is frequently present. Two thirds of those with Doose syndrome are boys. Although cognition and development are normal prior to the onset of seizures, cognitive impairment, linguistic and motoric developmental delay, and ataxia may unfold, correlated with refractory seizures and underlying symptomatic causes. Doose syndrome must be differentiated from other presentations involving prominent myoclonic and astatic seizure types; the presence of tonic seizures instead indicates an epileptic encephalopathy and is correlated with an underlying symptomatic or cryptogenic epileptic syndrome, such as progressive myoclonus epilepsy, Dravet syndrome, or Lennox-Gastaut syndrome.^30,44

PGTCs are more commonly seen in the later childhood and adolescent onset IGE subsyndromes of JAE, JME, and GTCOA.⁴⁵ Differentiation between these epilepsy syndromes depends chiefly on the age of onset, types of predominant seizure expression in an individual patient, and interictal and ictal EEG patterns. Absence, clonic, and myoclonic seizures are also frequent in each of these syndromes except GTCOA, which has PGTCs alone by definition.

CAE presents between the ages of 4 and 12, with predominant or exclusive absence seizures. Eyelid or oral myoclonia and prominent independent axial or limb myoclonic seizures are rarely seen (some consider these exclusionary for CAE), but automatisms and minor facial myoclonus during absence seizures are frequent. PGTC seizures occur in 40 to 60% of CAE patients.^46–50 Developmental and neurologic examinations are normal. Typically, CAE remits by the early teenage years.

JAE is more often an enduring disorder that presents toward the end of the first decade of life with a mixture of absence, myoclonic, and PGTC seizure types. Absences are less frequent and less responsive to medication than in CAE. PGTCs may be the presenting manifestation of JAE, seen in 80 to 90% of patients and often persisting into adulthood.^50,51

JME instead has more frequent and prominent myoclonic and PGTCs seen in 90% of patients, especially during early morning hours within the first 15 to 60 minutes after awakening for the day. Although seizures remit readily with medication in most patients, sleep deprivation and alcohol binges are frequent seizure precipitants in JME, and an enduring lifelong epileptic potential with rare remission off medication is typical. GTCOA is a closely related variant of JME and by definition is limited to PGTCs that usually occur shortly after awakening, but seizure occurrence later in the day is possible. PGTCs and other primary generalized seizure types have a diurnally predominant periodicity with a morning peak in occurrence.⁵²

Causes or Risk Factors

PGTCs may constitute a portion of acute symptomatic provoked GTCs in the context of a systemic illness or exposure, but correlative neurophysiology distinguishing PGTCs from SGTCs in these settings is lacking. Most PGTCs are associated with an underlying IGE syndrome. IGEs are presumed to have an underlying genetic cause, and the last decade has seen a dramatic expansion in documented genotypes for IGE subsyndromes, especially for those in infancy and early childhood. Prognosis for eventual remission varies by syndrome, but the presence of prominent afebrile PGTCs in a patient implies a high likelihood of an enduring heightened epileptic potential, particularly in older children, adolescents, and adults. First-degree relatives of those with IGE also frequently manifest both febrile seizures and unclassified GTCs, suggesting that unaffected kindred members of probands with diagnosed IGE frequently harbor an underlying nonspecific genetic seizure susceptibility expressed predominantly as clinically overt PGTCs.³⁷

Pathologic Substrates

Although IGEs have been presumed to have underlying genetic etiologies, multiple genotypes of the IGEs have been explicitly defined only over recent years. Several IGE syndromes have proven to be genetically determined channelopathies having known chromosomal loci, and downstream translational functional consequences causing specific epileptogenic neuronal dysfunction have been increasingly elucidated. Table 13-2 summarizes the currently known genetically determined channelopathies identified in IGE syndromes in children and adults.

IGEs may exhibit either straightforward Mendelian genetics or complex genetic inheritance patterns. Of the monogenic idiopathic epilepsies, genes encoding over 15 voltage-dependent and ligand-gated ion channels have been identified already in this burgeoning field of research, most having clinical onset of seizures in childhood and adolescence.^53,54 Currently defined genetic channelopathies have considerable heterogeneity of associated clinical IGE phenotypes, particularly well exemplified by GEFS+ kindreds, in which the spectrum of earlier and later life febrile and afebrile seizures seen may in part explain the epidemiologic link between early life febrile seizures and later life generalized epilepsies.^55,56

In infancy, BFNC, an autosomal dominant disorder with linkage mapping to 20q13.3 (EBN1) and 8q24 (EBN2), has been well characterized, with mutations in the M-type potassium channel genes KCNQ2 and KCNQ3.^42,57–63 KCNQ2, KCNQ3, and KCNQ5 heteromers play a role in neuronal M-current generation, which modulates neuronal excitability.⁶⁴ Functional consequences of specific mutations continue to be defined; a missense mutation of KCNQ2 showed significantly reduced potassium current amplitude, whereas two KCNQ3mutations did not show similar functional consequences.⁶⁵ BFNS/BFNIS has also been shown to be a channelopathy involving the SCN2A sodium channel subunit gene.⁴¹

GEFS+, another autosomal dominant disorder with incomplete penetrance, has been associated with several known loci, including the voltage-gated sodium channel beta-1 subunit gene (SCN1B,at 19q13.1),⁶⁶ the sodium channel alpha-1 subunit gene (SCN1A, at 2q21-q33),⁶⁷ the gamma-2 GABA (gamma-aminobutyric acid) receptor subunit gene (GABRG2, at 5q34,^68,69 and as yet unidentified genes at 2p24 and 21q22.^70,71 Curiously, more severe dysfunction of SCN1Aleads to the more refractory symptomatic epilepsy syndrome of severe myoclonic epilepsy of infancy (Dravet syndrome).⁷² A slightly different but overlapping group of febrile seizure-plus patients has been mapped to loci including the febrile convulsions 1 gene (FEB1) on chromosome 8q13-q21,⁷³ the gene FEB2 on 19p13,⁷⁴ and FEB5 on 6q22-q24.⁷⁵

The complex genetic inheritance of IGE syndromes affecting older children and adults has proven even more challenging to define than the monogenic disorders causing IGE in infancy, except for a few kindreds having clear autosomal dominant inheritance patterns. JME is one prototypical example of applied translational molecular neuroscience toward the genetic mapping of a well-defined clinical epileptic syndrome. JME can be inherited as either a Mendelian autosomal dominant or autosomal recessive trait or as a non-Mendelian complex genetic trait. Several kindreds have now demonstrated precise linkages to various loci, including 3q26,⁷⁶ the gene EFHC1 on 6p12 encoding a EF-hand motif protein affected by heterozygous or doubly heterozygous missense mutations,^77–84 and various mutations impacting the alpha-1 subunit of the GABA receptor encoded by 5q34.^85–88 Because the causality of single genes in Mendelian inheritance patterns of JME has been well established, the influence of single nucleotide polymorphisms (SNPs) upon JME with complex genetics has become an emerging field of inquiry, as yet without proven identification for influence of any well-defined SNPs.^89,90

Linkage analyses and candidate gene screening have facilitated identification of specific channelopathies associated with other IGE syndromes. CAE with febrile seizures has been associated with GABRG2. Mutations in the gene encoding the alpha-1 subunit of the GABA-A receptor (GABRA1) have been identified in CAE and JME.^85,91,92 Mutations in a gene encoding a neuronal voltage-gated Cl⁻ channel (CLCN2)are also seen in IGE; CLCN2is thought to participate in neuronal inhibition by maintenance of low intracellular chloride concentration, which facilitates GABA-A receptor functioning.^76,93 Although overlap and comingling of various IGE subsyndrome phenotypes (i.e., CAE, JAE, and JME) are well known even within single kindreds, CAE and JAE were recently shown to share a likely genetic link, and JME was distinct from either subsyndrome.³⁷ Other IGE kindreds have been mapped to chromosomes 5, 6, 8, and 18, with inconsistent linkage patterns.^94–96 A complex underlying polygenic basis is suspected for the IGE subsyndromes of BMEI, Doose syndrome, and epilepsy with myoclonic absences, but the genetic basis for these disorders has not yet been demonstrated.^97,98

The genetics of epileptic disorders will very likely continue to be elegantly defined. However, gene mapping in epilepsy has thus far failed to translate into a tangible practical clinical impact, such as development of more specific and effective AED therapies or widely applicable prognostic gene tests with utility to meaningfully alter the clinical management and counseling of IGE patients.^99,100

The role of the genetically determined channelopathies in activating or perpetuating the pathophysiology of PGTC seizure generation remains poorly understood. PGTCs and other generalized seizures in IGEs are presumed to be generated by reverberatory thalamocortical neuronal networks. Converging evidence from recent quantitative EEG and functional and structural neuroimaging studies has been consistent with a prominent role of both the frontal cortex and the thalamus in the pathophysiology of IGE seizures, and white matter loss in frontal-thalamic circuitry has been correlated with PGTC frequency.^101–105 Although a generalized epileptic network involving the bilateral cortex and thalamus is favored to cause PGTCs and other IGE seizure types, focal regions of frontal lobe cortical hyperexcitability could function as partial seizure generators with rapid secondary bilateral synchrony, either activated by normal ascending thalamocortical projections or with primary localized cortical seizure onset that subsequently entrains the thalamus and subcortical structures, as implied by IGE patients having consistently focal features seen in ictal semiology, interictal and ictal EEG recordings, neuroimaging, and neuropsychometric testing.^106,107

Ictal Behavior

PGTCs have somewhat variable ictal behaviors. They may begin without a preceding seizure (truly primary), but they can also arise directly following another generalized seizure type, including absence, clonic, astatic, or myoclonic seizures.^4,108–110 Even among PGTCs without another generalized seizure at onset, the initial clinical features may vary substantially, but most often PGTCs follow a clonic-tonic-clonic (C-T-C) progression of limb movements. (Videos 13-1, 13-2, and 13-3).²⁶ When seen in this classic sequence, a C-T-C seizure progression has been suggested to be pathognomonic of a PGTC. However, the sequence may also be tonic-clonic, lacking the initial clonic manifestations, or progress from iterative myoclonic and clonic movements directly without an intervening tonic phase (Video 13-4).^26,108 Initial and ensuing arm and leg movements may be symmetrical or asymmetrical, synchronous or asynchronous. Although consistent asymmetries in the ictal behavior always beg the question as to whether the seizure is an SGTC with focal onset, focal manifestations can clearly occur in PGTCs as well (Videos 13-2 and 13-3). The diagnostic sine qua non of the PGTC ictal behavior is bilateral clonic and/or tonic-clonic limb movements.²⁶

PGTCs may be subdivided and analyzed by several relatively discrete, yet continuously and sequentially evolving, prototypical phases (yet PGTCs do not invariably contain each phase): (1) subjective premonitory symptoms, (2) pre-tonic-clonic, (3) brief clonic, (4) tonic, (5) major clonic, and (6) postictal.^{26,108,111,112} The initial subjective premonitory symptoms phase (also called a prodrome) is variable and may include headache, difficulty concentrating, disturbed sleep, dizziness, lethargy, and mood or personality disturbances occurring minutes to hours prior to onset of consciousness impairment and discrete motor phenomena.¹¹³

Consciousness impairment is an invariable feature during the course of a PGTC. Although the phase for loss of consciousness within a PGTC seizure varies and is difficult to objectify, lost consciousness probably occurs within the pre-tonic-clonic phase. The pre-tonic-clonic phase involves repetitive vocalizations thought to arise from clonic pharyngeal and laryngeal contractions (Video 13-2).^110,114

The brief clonic phaseis distinguished by brief clonic facial and limb movements. In a substantial minority of patients, this initial clonic phase is more prominent and prolonged, evolving to larger amplitude sustained clonic limb movements typical of a CTC ictal semiology (Videos 13-1, 13-2, and 13-3).¹¹⁰

The tonic phaseis characterized by head, arm, truncal, and leg flexion posturing with eventual arm abduction, accompanied by leg adduction with ensuing external rotation. The mouth is held half-open, with vocalization related to forced expiration against a closed glottis, associated with upward eye deviation and an accompanying sympathetic storm manifested by pupillary dilation, tachycardia, hypertension, and increased intravesicular pressure and hypoventilation mediated by tonic diaphragmatic and respiratory muscle contraction that results in cyanosis.

The major clonic phasefollows and includes forced mouth closure that may result in tongue, buccal mucosa, or lip laceration. Initial rapid tremulous movements subsequently organize into repetitive large amplitude clonic limb jerking that progressively slows in frequency. Evidence from human subdural EEG recordings in focal clonic seizures found a coinciding polyspike-wave burst recorded from the precentral gyrus, in which iterative muscular clonic movements resulted from cortical polyspike activity preceding muscular agonist-antagonist co-contraction by 17 to 50 msec, while ensuing cortical inhibitory slow waves mediated brief intervening muscular relaxation and atonia between the clonic contractions.¹¹⁵ Inhibitory influences eventually predominate and terminate the seizure, resulting in postictal exhaustion and paresis that characterize the final postictal phase. During the major clonic phase, the pupils may alternately contract and dilate simultaneously with the limb clonic movements. Arms are typically in a semiflexed abducted posture, and legs are usually extended, adducted, and internally rotated with plantar flexion of the ankles, feet, and toes. Clonic limb movements are most often initially symmetrical and synchronous in PGTCs. Although focal onset SGTCs may remain synchronous throughout the seizure, recent evidence suggests that clonic movements of SGTCs progressively dephase toward the end of the seizure, and that seizure resolution in SGTCs may be characterized by a “last arm twitching” sign that is most often ipsilateral to the side of initial seizure onset, and thus contralateral to the hemisphere receiving the seizure through propagation.^110,116 This sign has been validated as a localizing sign for partial seizures of temporal lobe origin in two independent studies.^117,118 Thus, the “last arm twitching” sign may be helpful in distinguishing focal onset SGTCs from PGTCs, which in contrast usually have symmetrical arm clonic movements at seizure terminus.

The final, postictal,phase is characterized by initial flaccid areflexic quadriparesis, sustained pupillary dilation, apnea with ensuing slow regular respiratory rate, and variable occurrence of urinary and/or bowel incontinence due to sphincter relaxation following terminus of the clinical convulsion, as bladder and bowel sphincters remain contracted until the end of the preceding major clonic phase (Videos 13-1, 13-4, and 13-2). The postictal phase may last minutes to an hour or longer. Patients may be extremely sleepy and difficult to sustainably arouse during this period and later awaken with headache, myalgias, confusion, and, more rarely, psychosis. Focal neurologic deficits, such as aphasia, Todd paralysis, or unilateral Babinski signs, may occur following PGTCs, but these focal signs are strongly suggestive of partial seizure onset. Bilateral Babinski signs are often seen after PGTCs, but in contrast, focal plantar extension may be noted contralateral to the side of ictal onset in SGTCs.^119,120 Todd paralysis, a hemiparesis contralateral to the side of seizure onset, is seen in ~13% of patients with focal epilepsies, and when present, should always raise consideration for an alternative diagnosis of an SGTC seizure type.¹²¹

Although oral trauma usually occurs during the major clonic seizure phase, it is most often noted by the patient or caregivers in the postictal period. Oral trauma from biting is more frequently on the side(s) of the tongue. In SGTCs, lateralized trauma has been described either contralateral or ipsilateral to the side of seizure onset, but biting on the tongue tip or of the cheek or lip may also occur.¹²² Oral trauma and a history of incontinence are frequently given by both patients with organic epilepsy and those with psychogenic events, but actual physical evidence of these phenomena appears to be more specific to true epilepsy.¹²² Rarely, postictal tetany with opisthotonos, jaw trismus, and tongue laceration have also been reported.¹²³

PGTCs are briefer on average than SGTCs. PGTCs are ~1 minute in duration, whereas SGTCs are somewhat longer.^26,110Simple partial seizures (including auras) at onset and consistently focal limb movements or posturing are also suggestive of SGTCs rather than PGTCs. Sustained head and body version and version occurring immediately prior to the major clonic phase are particularly reliable signs distinguishing SGTCs from PGTCs, occurring in ~25% of SGTCs overall.^{110,116,124–127} However, focal version should not be considered incontrovertible evidence of partial onset, given that these features may also be found in PGTCs (Video 13-2).^106,128,129 The “figure 4” sign, though rarely reported in PGTCs, occurs almost invariably in SGTCs, with the extended arm contralateral and flexed arm ipsilateral to the seizure focus (Video 13-3).^{26,124,130,131}

Ancillary laboratory tests are sometimes useful in the distinction of PGTCs from psychogenic seizures and may include serum hormonal measures and creatinine kinase. Prolactin elevation is seen in 90% of GTCs overall, peaking at up to 30-fold over baseline values within 20 minutes postically and remaining elevated for 1 hour following the ictus.^132–134 For assessment of prolactin, a postictal level drawn within 1 hour of the ictus may be compared against that of a subsequently obtained presumed baseline value drawn 24 hours later. Similarly, postictal serum creatinine kinase is sometimes useful in distinguishing GTCs from psychogenic seizures.^135,136 However, such tests are rarely necessary when VEM has been performed because it provides the gold standard for electroclinical seizure type classification.

Ictal Electroencephalography

PGTCs generally show diffuse or generalized ictal onset patterns on EEG, either generalized rhythmic activity or generalized spike-wave or polyspike-wave complexes (Figure 13-1). If the PGTC starts with a generalized absence or myoclonic seizure, the ictal EEG pattern will reflect the typical electrographic accompaniment of that seizure type, showing typical generalized 3 Hz spike-wave discharges, atypical generalized spike-wave discharges within the frequency range of 4 to 6 Hz, or polyspike discharges (Figure 13-2). PGTCs beginning primarily without another antecedent generalized seizure type usually show background attenuation, followed by generalized 10 Hz rhythmic activity and polyspikes and subsequent spike-wave complexes that progressively slow in frequency (Figure 13-1). The spike component is coincident with a clinical flexion spasm, and the wave component mirrors clinical relaxation and inhibited tone. Ictal epileptiform EEG activity is most often completely obscured by muscle and movement artifacts after the first few seconds of seizure onset. The pattern of muscle artifact evident in all EEG channels is in itself very characteristic in PGTCs and can sometimes be exploited to diagnostic advantage, given that the full pattern of ictal EEG spike-wave pattern with overriding accompanying muscle activation obliterates the screen, then synchronously and progressively slows in frequency with intervening slow-wave discharges, an inimitable sequence not seen in psychogenic episodes.¹³⁷ To best visualize the underlying ictal EEG, one may pragmatically consider reducing the high-frequency filter setting to 35 or 15 Hz to enable partial revelation of the underlying EEG activity (although cautious interpretation and avoidance of overreading are recommended because filtered muscle activity can be easily mistaken for epileptiform EEG waveforms) (Figure 13-3). The generalized spike-wave activity progressively slows in frequency until termination, with ensuing generalized background voltage attenuation or frank suppression then seen, often several minutes in duration. Previous research of primary generalized seizures has suggested subtle hemispheric asynchrony at seizure outset that may persist variably throughout the seizure.^138,139 Future applications of frequency evolution in PGTCs could be helpful in distinguishing organic epileptic PGTCs from psychogenic events, but currently available techniques such as Gabor or short time Fourier transforms remain investigational.^140,141

Even when seizures are not recorded during VEM, careful analysis of the interictal EEG recording may yield diagnostic information.^142–144 Although the interictal EEG is usually normal in patients with PGTCs and IGE, interictal epileptiform discharges (IEDs) are often present. These may not be obvious as epileptic by appearing as intermittent rhythmic frontal or occipital delta activity (essentially, rhythmic focal spike-wave complexes without the spike component) and rhythmic parietal theta activity.¹⁴⁵ IEDs usually are typical or atypical generalized spike-wave complexes, or polyspike and/or polyspike-wave discharges (Figure 13-4). They are seen in roughly 50% of patients with GTCs overall, but they have been reported to occur in 1 to 2% of normal individuals; if there is a first-degree relative with generalized epilepsy, as many as 10 to 13% of individuals without recognized clinical seizures may demonstrate interictal epileptiform activity on EEG.^142,144Focal spike-wave discharges may also be seen in those with PGTCs and should not be mistaken as definitive evidence for an underlying epileptogenic focus unless consistent and persistently focal discharges are seen (Figure 13-5).¹⁴⁵