Clinical Features

Some children with generalized tonic-clonic seizures, or their parents, are aware of the impending seizure, hours or days before it occurs. The child may have a headache, insomnia, irritability, or a change in appetite. This prodrome is to be distinguished from an aura, which is a simple partial seizure that may occur before generalization of the seizure. Unlike the aura, the prodrome is not associated with any EEG epileptiform activity.

As indicated by the name, generalized tonic-clonic seizures have two distinct phases: tonic and clonic [Gastaut and Broughton, 1972]. Loss of consciousness usually occurs simultaneously with the onset of a generalized stiffening of flexor or extensor muscles – the tonic phase. The loss of consciousness usually is complete, and it is rare for patients to have any partial awareness of what happened during the seizure. During the tonic phase, prolonged extension of the back, neck, and all limbs often occurs. The eyes remain open, and a cry or yell is common. The tonic phase typically lasts 10–30 seconds and is followed by the clonic phase, which usually starts with a rapid tremor and then slows to massive jerks of the extremities and trunk. A decrescendo pattern to the frequency (although not necessarily the strength) of the jerks is seen as the seizure ceases. The clonic phase typically lasts 30–60 seconds.

Cyanosis is common and results from the arrest of ventilation during the tonic phase and insufficient short breaths during the following clonic phase. Pupillary dilatation, salivation, sweating, hyperthermia, and incontinence are common.

A postictal state always follows the clonic phase. The duration is quite variable. Some patients, even after a severe and prolonged seizure, respond within a minute or so, whereas other patients may be difficult to arouse for 20–30 minutes. Although the postictal phase initially consists of stupor, it may be followed by confusion or agitation.

In a number of syndromes, generalized seizures are a predominant feature. Epilepsy with so-called grand mal seizures on awakening is a syndrome in which the generalized tonic-clonic seizures occur only on awakening [Betting et al., 2006; Unterberger et al., 2001; Beghi et al., 2006]. In generalized epilepsy with febrile seizures plus, patients initially have febrile seizures; later, as the condition evolves, they experience afebrile generalized tonic-clonic or other types of generalized seizures [Abou-Khalil et al., 2001; Baulac et al., 2004; Scheffer and Berkovic, 1997; Wallace et al., 2001, 2002]. Generalized tonic-clonic or clonic-tonic-clonic seizures often can be a prominent component of juvenile myoclonic epilepsy, a condition discussed in Chapter 56. Children with Lennox–Gastaut syndrome may have generalized tonic-clonic seizures, although tonic seizures are the core seizure type in this syndrome.

Although their disorder currently is not classified as a syndrome, a distinct group of patients with photosensitive epilepsy have seizures provoked by flickering lights and have a photoconvulsive response to strobe light on EEG. The photoconvulsive response is characterized by spike-and-wave and multiple spike-and-wave complexes that are bilaterally synchronous, symmetric, and widespread (Figure 53-1). These should be contrasted with spikes that are time-linked with the photic stimulation and confined to the occipital region, which in children are normal. The photoconvulsive response may be self-limited and cease during stimulation or continue beyond the stimulation [Reilly and Peters, 1973]. The most effective frequency of the flash is 10–20 Hz.

The seizures evoked by photic stimulation usually are primary generalized in type: generalized tonic-clonic, absence, or myoclonic seizures. Although patients with partial seizures may have photoconvulsive responses during an EEG study, it is unusual for a partial seizure to be precipitated by photic stimulation [Jayakar and Chiappa, 1990]. Generalized epileptiform discharges during photic stimulation correlate with generalized seizures, whereas focal discharges are more commonly associated with partial seizures [Gilliam and Chiappa, 1995].

Photosensitive epilepsy can be classified into two major groups: (1) pure photosensitive epilepsy, in which clinical seizures occur only when the patient is exposed to the photic stimulus, and (2) photosensitive epilepsy, in which spontaneous seizures occur in addition to those induced by light stimulation [Binnie and Jeavons, 1992]. Precipitating stimuli that can produce a seizure include sunlight reflected from water, sunlight viewed through leaves of trees in a breeze or while driving along tree-lined streets, discotheque lighting, faulty fluorescent lamp (“nervous ballast”), television, and video games. Photosensitive epilepsy usually appears around puberty, with a mean age at onset of 14 years and a higher incidence in girls than in boys [Jeavons, 1982].

Differential Diagnosis

Difficulty is rarely encountered in correctly diagnosing generalized tonic-clonic seizures (formerly termed grand mal seizures). Generalized tonic-clonic seizures can be divided into those that are primarily generalized from onset and those that begin as partial seizures and then secondarily generalize [Schmidt et al., 1983; Jobst et al., 2001]. Differentiating features are listed in Table 53-1. On very rare occasions, generalized tonic-clonic seizures begin as another generalized seizure type such as absence [Niedermeyer, 1976] before evolving into tonic-clonic activity.

Table 53-1 Comparison of Primary and Secondary Generalized Tonic-Clonic Seizures

	Primary GTC	Secondary GTC
Prodrome	Occasionally	Occasionally
Aura	Never	Frequently
Usual duration	1–3 min	1–3 min
Family history for seizures	Frequently	Occasionally
Acquired lesions	Rarely	Frequently
EEG Interictal Photoconvulsive response Hyperventilation	Normal or generalized spike-wave Frequently May activate spike-wave discharges	Normal or focal or multifocal spikes Rarely Usually does not activate epileptiform discharges

Breath-holding attacks, pseudoseizures (nonepileptic events), and syncope occasionally may resemble generalized tonic-clonic seizures. These are discussed in Chapters 64 and 65.

Electroencephalographic Findings

In patients with partial seizures with secondary generalization, the interictal EEG features are similar to those described for partial seizures. Patients with primary generalized tonic-clonic seizures typically have either normal interictal EEG activity or bursts of generalized spike-and-wave discharges. As with absence seizures, spike-and-wave or polyspike-and-wave activity can occur with photic stimulation and hyperventilation. Normal EEG activity, however, can be observed in patients with generalized tonic-clonic seizures.

The ictal EEG features begin suddenly and are widespread. The tonic phase usually begins as loss of background frequencies, with sudden generalized suppression of the background activity (flattening or attenuation of the EEG signal), followed by a gradual build-up of low-voltage fast spikes, usually starting at 20–40 Hz and then decreasing to 10 Hz, lasting up to 10 seconds, with a progressive increase in amplitude and decrease in frequency – the so-called “epileptic recruiting rhythm.” This is followed by the clonic phase, with slow waves following the spikes. The spike-and-wave complexes gradually slow in frequency before stopping.

During the postictal phase, the EEG shows either suppression of background activity or diffuse slowing. The duration of the postictal changes is variable, with background abnormalities lasting minutes to even days following the seizure. Focal slowing during the postictal phase suggests that the seizure had a partial onset. The absence of any slowing during the postictal phase should raise the question of nonepileptic seizures.

Etiology

The etiology of seizures in children who have secondary generalized tonic-clonic seizures is the same as those described for partial seizures. Patients with primary generalized tonic-clonic seizures usually do not have structural lesions and often have a familial disorder, such as juvenile myoclonic epilepsy. The genetics of generalized tonic-clonic seizures are discussed in Chapter 52.

Initial Evaluation

The initial steps in the evaluation depend to a major degree on the patient’s clinical status on first presentation to the physician. For example, the patient who arrives at the emergency department following a generalized seizure with fever and confusion is evaluated differently from the otherwise normal child who presents several hours after a generalized seizure. The former needs an urgent evaluation to look for an infectious etiology, such as meningitis or encephalitis, whereas the latter can be managed less hastily. This chapter deals with the evaluation and treatment indicated for patients with generalized seizures as their only presenting clinical sign.

In all children with their first seizure, a careful history should be obtained, with particular attention to whether the seizure was preceded by an aura or if the seizure had any focal features. An aura, focal onset to the seizures, or Todd’s paralysis would suggest that the seizure had a partial onset. A review of potential precipitating factors, such as sleep deprivation or photic stimulation, may be useful in counseling the patient and the parents. A past medical history of birth asphyxia or trauma, head injury, prolonged febrile seizures, meningitis, or encephalitis may offer etiologic clues indicating that the seizures have a partial onset. A history of other neurologic symptoms should be sought. Headaches, especially those associated with vomiting or occurring at night, should raise the possibility of a structural lesion.

Although neuroimaging appears to have reduced the importance of the neurologic examination, abnormal findings, even if subtle, may provide clues to the location of seizure onset and etiology of the seizures. For example, asymmetries in facial expression or strength may indicate focal deficits, even in the presence of normal neuroimaging findings.

Diagnostic studies ordered depend on findings during the history and neurologic examination. Children with an unremarkable history other than for the seizures and with normal findings on neurologic examination typically require only an EEG and neuroimaging. An EEG should always be obtained because it may help differentiate partial from generalized seizures. Focal epileptiform activity or slowing would raise the possibility of a structural lesion.

Neuroimaging is recommended in all patients presenting with their first unexplained generalized tonic-clonic seizure, with the recognition that, in patients with normal neurologic examinations, the chance of finding a treatable lesion is quite low. Because generalized tonic-clonic may have a partial onset with subsequent rapid generalization, however, the seizure may be incorrectly diagnosed as primary generalized in type. In nonemergency settings, the imaging test of choice is a magnetic resonance imaging (MRI) scan. Computed tomography (CT) scans can be used in acute situations to determine whether a mass lesion and hemorrhage is present.

The need for further diagnostic testing, such as metabolic screening and cerebrospinal fluid examination, depends on the clinical presentation. In the absence of mental retardation, developmental regression, or abnormalities on neurologic examination, these studies usually are not indicated following the initial seizure.

Comorbidities Associated with Generalized Seizures

While a major goal in the treatment of epilepsy is stopping the seizures, it is not the only treatment goal. Patients with epilepsy are a risk for a number of comorbidities. Comorbidity refers to the co-occurrence of two supposedly separate conditions that occur together more than by chance (also see Chapter 62). Depression occurs more frequently in patients with epilepsy than in the normal population, so that epilepsy and depression are comorbidities. Comorbidities are not necessarily causal. For example, because epilepsy and depression are comorbidities does not mean that epilepsy caused the depression or depression caused the epilepsy. Rather, it is possible that both conditions have a common biological substrate or that another independent variable triggers one of the comorbidities. For example, epilepsy often leads to drug therapy, which could cause depression independently of the epilepsy.

Comorbidities associated with epilepsy include depression [Camfield and Camfield, 2009; Dunn et al., 1999], suicidality [Bridge et al., 2007; Tellez-Zenteno et al., 2007; Donner et al., 2001; McGregor and Wheless, 2006], attention-deficit hyperactivity disorder (ADHD) [Dunn and Kronenberger, 2005], conduct disorders [Dunn et al., 2009], anxiety [Caplan et al., 2005], cognitive impairment and learning disabilities [Fastenau et al., 2004; Aldenkamp et al., 2005], and migraine [Pellock, 2004].

Being aware of the comorbidities frequently associated with childhood epilepsy may influence the choice of antiepileptic drug (AED) used to treat the seizures. For example, lamotrigine and valproate may be helpful in treating both the primary generalized seizures and mood disturbance. Likewise, topiramate and valproate can treat both seizures and migraine. On the other hand, AEDs may exacerbate the comorbid condition. Topiramate can have adverse cognitive effects, while benzodiazepines and barbiturates can exacerbate ADHD and conduct disorders.

Medical Treatment

The medical treatment of generalized seizures that have a partial onset and secondarily generalize is, in general, the same as for the treatment of partial seizures. It is generally assumed that an AED that reduces the likelihood of partial seizures would also prevent partial seizures that secondarily generalize. However, it is possible that there may be a difference in the ability of an AED to prevent secondary generalization following the partial onset.

One of the issues is that, in many studies, partial seizures with secondary generalization are included along with primary generalized tonic-clonic seizures. In the United States, AEDs that have an indication for monotherapy or adjunctive therapy of generalized seizures include phenytoin and carbamazepine. However, while both drugs are effective in partial seizures, they can exacerbate primary generalized seizures [Perucca et al., 1998; Guerrini et al., 1998]. Studies examining efficacy and safety of AEDs in children with primary generalized epilepsy are very limited. Although a number of the newer AEDs are being used for the treatment of primary generalized tonic-clonic seizures, even in adults definitive evidence for their effectiveness is lacking [Faught, 2003; French et al., 2004]. In addition, data for adults and children often are combined when studies are reported. Antiepileptic drug studies done solely in children with primary generalized tonic-clonic seizures are limited. Although most of the newer antiepileptic drugs have been used in the treatment of generalized tonic-clonic seizures, their usefulness in children has not yet been established [Holmes, 2003; Jarrar and Buchhalter, 2003].

The major drugs typically used to treat primary generalized tonic-clonic seizures include valproate [Murphy and Delanty, 2000; Ramsay and DeToledo, 1997; Marson et al., 2007], lamotrigine [Mikati and Holmes, 1997; Trevathan et al., 2006; Marson et al., 2007], levetiracetam [Rosenfeld et al., 2009;Noachtar et al., 2008;Wheless, 2007], and topiramate [Biton et al., 1999; Marson et al., 2007]. Although phenobarbital is effective in the treatment of primary generalized tonic-clonic seizures, the adverse side effects profile has reduced its use as initial therapy for primary generalized tonic-clonic seizures [Taylor et al., 2001].

The four drugs most commonly used for primary generalized tonic-clonic seizures are reviewed briefly here. Additional information about AEDs is available in Chapter 59.

Clinical Features

Absence seizures, formerly termed petit mal seizures, are characterized by an abrupt cessation of activity, change in facial expression, and impairment of consciousness [Browne et al., 1974; Pearl and Holmes, 2008; Porter et al., 1973]. Absence seizures are not common, accounting for less than 10 percent of all seizure types [Hauser and Hersdorffer, 1990; Hauser and Kurland, 1975; Sofijanov, 1982]. Absence seizures may be the most common seizure type to go undetected. The prevalence of absence seizures is highest during the first 10 years of life and then drops dramatically to a very low level [Hauser and Kurland, 1975; Hertoft, 1963; Sato et al., 1976]. Absence seizures are more common in girls than in boys [Hertoft, 1963; Sato et al., 1976]. Typical absence seizures rarely start before the age of 2 years or after the teenage years [Sato et al., 1983; Sato, 1983]. In a study of 83 patients with absence seizures, Sato and co-workers [Sato et al., 1983] found the average age at onset was 3.8 years.

Absence seizures are classified as typical or atypical in type (Table 53-3). Typical absence seizures are short, rarely lasting over 30 seconds; as with other generalized seizures, they are never associated with an aura or postictal impairment. The sudden onset of impaired consciousness, usually associated with a blank facial appearance without other motor or behavioral phenomena, is characteristic. The degree of impairment of consciousness is variable. Some children remember virtually everything that is said during the seizure, whereas for others, the entire duration of the seizure is “time lost.”

Table 53-3 Classification of Absence Seizures

Clinical Seizure Type	EEG – Interictal	EEG – Ictal
Typical absence a. Impairment of consciousness only b. With mild clonic components c. With tonic components d. With automatisms e. With autonomic components

Normal background; short bursts of regular and symmetrical 2.5–4-Hz spike wave; rare frontal or multifocal spikes, sharp waves; photoconvulsive response Regular and symmetrical 2.5–4-Hz spike wave; often induced by hyperventilation or photic stimulation Atypical absence Abnormal background; short bursts of irregular, asymmetrical <2.5-Hz spike wave; multifocal spikes, sharp waves; photoconvulsive response rare Bursts of irregular, asymmetrical <2.5-Hz spike wave; rarely induced by hyperventilation or photic stimulation

Although the absence seizure is commonly thought to consist only of staring, in fact the behavioral changes associated with the seizure type usually are more complex. Most absence seizures are accompanied by motor, behavioral, or autonomic phenomena, and seizures characterized by only staring and altered consciousness are unusual. Penry et al. [1975] reviewed 374 absence seizures recorded on videotape from 48 patients and found simple absences, characterized by staring and cessation of activities, to constitute only 9.4 percent of the seizures. A majority of the patients had other clinical manifestations.

Automatisms, semipurposeful behaviors of which the patient is unaware and subsequently cannot recall, are very common with absence seizures [Holmes et al., 1987; Penry et al., 1975]. They either may be perseverative, reflecting continuation of preictal activities, or may arise de novo. Simple behaviors, such as rubbing the face or hands, licking the lips, chewing, grimacing, scratching, or fumbling with clothes, tend to be de novo automatisms. Complex activities, such as dealing cards, moving a chess piece, or handling a toy, are generally perseverative. Speech, if it occurs during the seizure, usually is perseverative and may be slow and slurred, but also may be totally normal [McKeever et al., 1983]. The longer the absence seizure lasts, the more likely automatisms are to occur [Penry et al., 1975].