Tonic Status Epilepticus by C P Panayiotopoulos MD Phd (Dr

Home , Status epilepticus

Tonic status epilepticus By C P Panayiotopoulos MD PhD (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.) Originally released January 25, 2013; last updated January 27, 2017; expires January 27, 2020

Introduction

Overview

Tonic status epilepticus is a serious, sometimes fatal, epileptic condition that may last for days or even months and occurs mainly in children with neurocognitive impairment and severe epilepsy such as Lennox-Gastaut syndrome. Tonic status epilepticus in these children comprises repetitive frequent tonic seizures. Characteristically, as the status progresses, motor symptoms tend to lessen whereas autonomic disturbances, including respiratory depression, become more prominent. At final stages, there may be only electrographic evidence of tonic seizures. Video-EEG monitoring is usually mandated for the recognition of autonomic status epilepticus, particularly when motor manifestations are minimal. Treatment is demanding, and the intravenous administration of benzodiazepines may be of some concern because of a few reports that these may induce tonic status epilepticus; newer antiepileptic drugs such as lacosamide have been reported as effective. Unfortunately, the only systematic studies of tonic status epilepticus are dated 40 years ago. The author reviews the limited information on clinical manifestations, investigative procedures, pathophysiology, and optimal but anecdotal management of patients with tonic status epilepticus.

Key points • Tonic status epilepticus manifests with repetitive series of frequent tonic seizures that may last for weeks or months. • As the status progresses, autonomic manifestations, including respiratory depression, predominate and may lead to death. • Video-EEG monitoring may be mandatory. • This condition occurs nearly exclusively in children with neurocognitive impairment and mainly in those with Lennox-Gastaut syndrome. • Emergency treatment is anecdotal though newer antiepileptic drugs, such as lacosamide, appear promising.

Historical note and terminology

Tonic status epilepticus has been nearly exclusively studied systematically by Henri Gastaut and his Marseille School of epileptology (Gastaut et al 1963; Gastaut and Broughton 1972; Tassinari et al 1972; Roger et al 1974). Their classical work still remains the main source of information on the topic. Tonic status epilepticus. This variety is more frequent in children. The tonic spasms are repeated at a rate of four to twenty per hour and may progressively attenuate until no motor expression persists except recurrent superior conjugate deviation of the eyes. At this point, the attacks are usually recognized only if the EEG is monitored, but the autonomic phenomena continue and may even undergo progressive increase to terminate, during a period of relatively intact consciousness, in death from respiratory or cardiovascular failure (Gastaut and Broughton 1972).

The ILAE proposal of 1989 refers to status epilepticus of Lennox-Gastaut syndrome as “frequent (stuporous states with myoclonias, tonic, and atonic seizures)” (Commission on Classification and Terminology of the International League Against Epilepsy 1989). The ILAE Task Force on classification classified tonic status epilepticus with other generalized types of status epilepticus (Engel 2001) and gave the following description “Tonic status epilepticus most commonly occurs in patients with symptomatic generalized epilepsy but may occur in patients with idiopathic generalized epilepsy. In some of these patients, there appears to be an overlap of symptoms of idiopathic and symptomatic generalized epilepsy. Characteristically, when the patient is lying down, the neck is flexed, and the arms are flexed at the elbow and slightly elevated. The tonic spasms are brief and can continue at brief intervals for hours. In symptomatic generalized epilepsy the duration of the status epilepticus can be much longer” (Engel 2006). The new ILAE proposal has not dealt with status epilepticus (Berg et al 2010). However, the ILAE Task Force on the Classification of Status Epilepticus has now published its report on “a definition and classification of status epilepticus” that encompasses all types of status epilepticus, and it takes into consideration current knowledge regarding its pathophysiology and the need to address clinical treatment decision making time points, as well as the conduct of epidemiologic and clinical studies (Trinka et al 2015). Accordingly, “status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures” (Trinka et al 2015). This definition is conceptual, with 2 operational dimensions: the first is the length of the seizure and the time point (t1) at which the seizure should be regarded as an “abnormally prolonged seizure.” The second time point (t2) is the time of ongoing seizure activity beyond which there is a risk of long-term consequences. In the case of convulsive (tonic-clonic) status epilepticus, both time points are based on animal experiments and clinical research. This evidence is incomplete; furthermore, there is considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of status epilepticus, but as knowledge and understanding increases, time points can be defined for specific forms of status epilepticus based on scientific evidence and incorporated into the definition, without changing the underlying concepts. This division into 2 time points has clear clinical implications: the time point of operational dimension 1 determines the time at which treatment should be considered or started, whereas the time point of operational dimension 2 determines how aggressively treatment should be implemented to prevent long-term consequences. The time domain may vary considerably between different forms of status epilepticus. This new report provides no description or time points (t1 or t2) of tonic status epilepticus, which is simply classified among other types of status epilepticus with prominent motor features that occurs in Ohtahara, West, and Lennox-Gastaut syndrome (Trinka et al 2015).

Shorvon considers tonic status epilepticus amongst “nonconvulsive status epilepticus occurring in both childhood and adult life with epileptic encephalopathy: (3a) Nonconvulsive status epileptic in the Lennox-Gastaut syndrome (i) Atypical absence status epilepticus (ii) Tonic-status epilepticus” (Shorvon 2007).

In the American Academy of Neurology practice parameter, tonic status epilepticus is cited amongst “convulsive status epilepticus that occurs with overt clinical signs, such as tonic, tonic-clonic, or clonic motor movements. Nonconvulsive status epilepticus occurs when either electrographic status epilepticus is associated with altered awareness without overt clinical signs, or altered awareness with subtle motor signs, such as minimal eyelid blinking” (Riviello et al 2006).

The 2014 ILAE “Epilepsy Diagnosis” manual has not dealt with status epilepticus (Commission on Classification and Terminology of the International League Against Epilepsy 2017); generalized onset tonic seizures are categorized as 1 of the 5 types of generalized seizure (convulsive, absence, tonic, atonic, myoclonic) and are described as follows:

A generalized tonic seizure involves bilaterally increased tone of the limbs typically lasting seconds to a minute. They often occur out of sleep and in runs of varying intensity of tonic stiffening. The individual is unaware during these events. At the beginning of tonic seizures with more intense stiffening, individuals may make an expiratory sound. More severe and prolonged tonic seizures may have a vibratory component, which may be confused with clonic jerking. Tonic seizures often occur in individuals with intellectual impairment. Caution. Although asymmetry can occur in a generalized tonic seizure, if consistent focal features are seen from seizure to seizure, then consider focal seizure involving the frontal lobe. Note. Tonic seizures are one type of seizure that can result in a “drop attack” (also known as astatic seizure); other causes of drop attacks include myoclonic (especially in younger children), atonic, and myoclonic-atonic seizures.

EEG Background/Interictal/Activation. Please refer to specific syndromes and etiologies in which this seizure type occurs.

EEG Ictal. Tonic seizures show diffuse or generalized accelerating low amplitude paroxysmal fast activity, which is often bilateral and predominates in the anterior and vertex regions. Caution. Consistent focality of spikes or maximal amplitude of ictal rhythm, then consider focal seizure. Differential diagnosis. • Epileptic spasms: The motor contraction is often shorter in duration (< 2 seconds); epileptic spasms often occur in a series. • Focal seizure: Supplementary sensorimotor cortex of frontal lobe • Syncope • Nonepileptic seizures

Related syndromes. • Lennox-Gastaut syndrome • Epilepsy with myoclonic-atonic seizures

Adapted from (Commission on Classification and Terminology of the International League Against Epilepsy 2017).

Clinical manifestations

Presentation and course

Descriptions of tonic status epilepticus usually refer to children with neurocognitive impairment and severe epilepsy, such as the Lennox-Gastaut syndrome or other epileptic encephalopathies, associated with widespread cerebral dysfunction (Gastaut et al 1963; Gastaut and Broughton 1972; Tassinari et al 1972; Roger et al 1974; Aicardi 1994; Shorvon 1994; Hartman 2010). Rarely, tonic status epilepticus may occur in patients with long-standing pharmacoresistent idiopathic generalized epilepsy (Kobayashi et al 2005). There are also reports of tonic status epilepticus induced by drugs, mainly intravenous injection of benzodiazepines for treatment of nonconvulsive status epilepticus in children with Lennox-Gastaut syndrome (Prior et al 1972; Tassinari et al 1972).

Tonic status epilepticus in Lennox-Gastaut syndrome or other epileptic encephalopathies. Tonic status epilepticus in children Lennox-Gastaut syndrome or other epileptic encephalopathies comprises frequent tonic seizures that are repetitive and discontinuous, often mixed with other types of seizures (atypical absence, atonic, myoclonic and generalized tonic-clonic).{embed="pagecomponents/media_embed" entry_id="8952"} All types of tonic seizures (axial, axio-rhizomelic, global) can happen in every episode, and their manifestations are initially similar to that of isolated tonic fits but with longer duration (around 70 seconds). Their repetition rate is very high and may reach 100 per hour. However, characteristically as the status progresses, motor symptoms tend to lessen whereas autonomic disturbances become more prominent. At final stages, there may be only electrographic evidence of tonic seizures. Progressive decrease of the muscular contraction may take place during status, the global tonic seizures changing into axorhizomelic, and subsequently, into axial types. The autonomic phenomena, on the other hand, continue and may even intensify. Eventually the motor component may become so minimal (eg, only repeated superior ocular deviation) that on clinical examination the attacks are believed to have ceased. Nevertheless, death may be imminent as a result of cumulative effects of the autonomic changes, particularly bronchial secretions and respiratory depression. Such an evolution obviously requires immediate clinical recognition with continuous EEG monitoring and prompt therapy (Gastaut and Broughton 1972).

Tonic seizures may be symmetrical and asymmetrical with alternating side emphasis from 1 to another seizure. For example, asymmetrical contraction of the neck muscles or of the ocular muscles may lead to a deviation of the head or of the eyes to 1 side. Similarly, asymmetrical contraction of the appendicular muscles may lead to the elevation of 1 arm before the other. At times, the asymmetry is such that the seizure seems unilateral (hemitonic seizure) (Gastaut et al 1963).

In 14% of incidences of tonic status epilepticus, clinical manifestations are slight from onset, and in 17% they appear as electrographic tonic seizures without any motor features (Roger et al 1974).

Cognition between attacks varies but in most cases is moderately to severely impaired or the patient is in coma. Occasionally, tonic status epilepticus may appear as a confusional state (Somerville and Bruni 1983). In other seizures the motor and autonomic components are not marked, so that loss of consciousness emerges as the predominant symptom. The attacks then appear as an atypical form of absence. It can only be distinguished clinically from a typical absence (classical petit mal absence) by the tonic, rather than rhythmic or phasic, nature of any residual motor or autonomic features (palpebral movements, fluctuations in pupillary diameter, etc.). In certain seizures any or all of the vegetative phenomena (mydriasis, perspiration, lacrimation, tachycardia, flushing, or other) may become so accentuated that the attack would have to be considered as an autonomic generalized epileptic seizure (Gastaut and Broughton 1972).

Duration of tonic status epilepticus is usually very long for an average of 9 days and may continue for weeks to 4 (Gastaut et al 1963; Gastaut and Broughton 1972; Roger et al 1974) or even 5 months (Tanganelli and Regesta 1991).

Tonic status epilepticus in patients with long-standing pharmacoresistent idiopathic generalized epilepsy. Tonic status epilepticus is probably extremely rare in idiopathic generalized epilepsy. Three such patients have been reported (Kobayashi et al 2005). These 3 patients had mainly clinical features of idiopathic generalized epilepsy, but had developed, in addition, focal discharges, diffuse EEG abnormalities, and some focal or diffuse neuropsychological dysfunction. Attacks of tonic status epilepticus happened in their late teens or early 20s though onset of other seizures was in childhood. There was clear predominance of arm involvement, which was different from the usual axial involvement of Lennox-Gastaut syndrome. Tonic seizures responded to treatment but were not completely controlled in any of the patients.

The first patient was a 24-year-old woman with onset of typical absence seizures at age 5 years and EEG 2.5 to 3Hz generalized spike-wave discharges. Nocturnal symmetrical tonic seizures, lasting 10 to 20 seconds, appeared during adolescence, mostly related to her menstrual cycle. After the age of 15, she was hospitalized on several occasions for clusters of such attacks amounting to tonic status epilepticus. In 1 such episode, attacks occurred every 5 minutes characterized by elevation and flexion of both arms, flexion of the neck and trunk, upward eye deviation, and unresponsiveness lasting up to 4 seconds. Ictal EEGs showed generalized polyspike activity.

The second patient probably had perioral myoclonia with absences. Tonic seizures consisted of brief tonic asymmetric posturing of both arms, more evident on the right side, upward eye deviation, and contraction of perioral muscles with some downward deviation of the labial commissures. These were associated with generalized polyspikes with fragmentation and irregular generalized spike-wave discharges.

The third patient had unspecified seizures from childhood. Tonic seizures consisted of tonic stiffening and slight flexion of the arms and neck associated with altered consciousness.

In a report of 12 cases of adult absence status epilepticus, bizarre hemitonic seizures were documented in 1 patient clinically and on EEG (Berkovic and Bladin 1983).

In another report, a 48-year-old woman with unclassified idiopathic generalized epilepsy from the age of 11 years realized from previous experiences with similar lengthy events that she was in status epilepticus when she felt “weird, like in a trance, missing pieces of conversation,” and she went to the hospital (Agathonikou et al 1998). Despite written instruction, no diazepam was administered. She was alert, attentive, cooperative, and well behaved, but she seemed depressed. Movement and speech were normal. Video-EEG showed frequent, discontinuous, repetitive, and polymorphic generalized discharges of 2 types: (a) irregular 2 to 4 Hz spike/multiple spike and slow wave and (b) fast poly-spikes activity. She was able to count with no errors, but there was interruption or delay in counting during the generalized discharges. Motor ictal symptoms occurred only during the paroxysmal rapid spikes and consisted of tonic eyes and mouth opening with backward head deviation. Video-EEG was recorded 7 hours from onset of symptoms, which ended with a generalized tonic-clonic seizure 1 hour later (Agathonikou et al 1998).{embed="pagecomponents/media_embed" entry_id="8953"}

Tonic status epilepticus induced by intravenous injection of benzodiazepines for the treatment of nonconvulsive status epilepticus in children with severe epilepsies. There are 8 reported cases in which tonic status epilepticus was induced by intravenous injection of benzodiazepines for the treatment of nonconvulsive status epilepticus (Martin 1970; Gastaut et al 1971; Prior et al 1972; Tassinari et al 1972). Children had severe epilepsies (mainly Lennox-Gastaut syndrome) and frequent multiple seizure types. Benzodiazepines (nitrazepam, clonazepam, and diazepam) were used for the cessation of nonconvulsive status epilepticus and mainly atypical absence status epilepticus although most of these children also had other concurrent types of seizures. The main adverse effect was on the transformation of the clinical situation to tonic status epilepticus and the EEG to rapid polyspikes of tonic seizures.

The most complete report of such a situation is by Tassinari and colleagues of tonic status epilepticus precipitated by intravenous diazepam or nitrazepam in 5 patients with Lennox-Gastaut syndrome (Tassinari et al 1972). This was followed immediately by numerous tonic seizures, both subclinical and clinical, amounting to true tonic status. All the patients, with 1 exception, were at the time of the injection in a state of confusion and showed numerous or continuous discharges of slow spike-waves. All the patients had received other injections of benzodiazepine with little effect, and all except 1 had already had episodes of tonic status.

The case of Prior and associates was also a child with intractable tonic, myoclonic, and atonic seizures (Prior et al 1972). She also had lengthy episodes of confusion and unresponsiveness associated with EEG atypical spike-and-wave discharges separated by brief periods with low voltage theta-waves. Diazepam was given intravenously in an attempt to improve the clinical state and to see if the spike-and-wave activity could be completely abolished and whether a focal discharge would remain. After 3 mg, there was an abrupt change in both the EEG and the clinical state. Spike- and-wave complexes were replaced by high-voltage spike discharges at 10 to 14 Hz, lasting about 40 seconds and recurring every 1 to 2 minutes. Postictal delta-activity followed the spikes. Each discharge was accompanied by a severe tonic seizure without intervening return of consciousness. The fits were characterized by retraction of the lips, the mouth opening widely, and eyes rolling upwards; head and neck arched back and some spinal hyperextension occurred. The limbs became somewhat hypertonic; there was clenching of the left fist and semi-purposeful movement of the right arm. The child emitted a long piercing cry and became apneic; she was incontinent. A total of 8 mg diazepam was given, but this did not result in control of the tonic status; nor was there at any time EEG or clinical evidence of sleep. During the next 20 minutes, the discharges gradually returned to atypical spike-wave complexes; the attacks lessened, and the child became more accessible although still confused. After 1 hour she was more alert.

Of interest also are 2 cases of tonic status epilepticus attributed to valproate (Capocchi et al 1998; Grande-Martin et al 2016). The first case was a 14-year-old boy with frequent generalized tonic clonic seizures from the age 6 years, EEG abnormalities of brief generalized discharges at 3 Hz spike-wave, and mild learning difficulties. On 2 occasions when valproate was added to prophylactic treatment with phenobarbitone, he developed frequent, short and long axorhizomelic tonic seizures constituting tonic status epilepticus. The short axorhizomelic seizures, lasting only 2 to 5 seconds, were more frequent and mainly involved the face, neck, and upper limb muscles. The less frequent long axorhizomelic seizures, lasting 15 to 20 seconds, began in the neck and face muscles and rapidly involved the upper and lower limbs. On EEG, brief tonic seizures were characterized by the sudden appearance of a generalized, very rapid, high amplitude activity at about 20 Hz. The axorhizomelic long seizures appeared initially with a sudden flattening of all electrical activity corresponding to the involvement of the axial muscles, followed by rapid activity, increasing in amplitude on all the derivations, corresponding to tonic involvement of the limb muscles. There was no evidence of hyperammonemia or hepatic damage (Capocchi et al 1998). The second was a case of an 8-year-old boy with Doose syndrome (epilepsy with myoclonic-atonic seizures) (Grande-Martin et al 2016).

Prognosis and complications

Tonic status is a serious and sometimes fatal condition of patients suffering from serious and often intractable epileptic disorders such as Lennox-Gastaut syndrome (Roger et al 1974). Morbidity and mortality of tonic status epilepticus have not been systematically assessed after the classical studies of Gastaut and associates more than 30 years ago (Gastaut et al 1963; Gastaut and Broughton 1972; Roger et al 1974). Optimistically, the outcome may be better now with newer therapeutic options and improved management of status epilepticus.

Biological basis

Localization

There are more questions than answers in regard to the localization and pathophysiology of tonic status epilepticus, such as, for example, why this predominantly happens in Lennox-Gastaut syndrome irrespective of etiology and why it lasts as long as days or months. However, the brainstem may be significantly involved as for tonic seizures (Burnham 1985; Veliskova et al 2004; Djukic et al 2006; Fusco et al 2008; Faingold and Evans 2010; Scantlebury 2010). Because the brainstem projects widely to the cortex, a central role for the brainstem would also explain how tonic status epilepticus occurs even in patients of Lennox-Gastaut syndrome with focal pathology. Secondary bilateral synchrony from cortical, mainly frontal, foci has been implicated in “generalized” epileptic seizures of epileptic encephalopathies (Gastaut and Zifkin 1988; Blume 1994; Kobayashi et al 1994; Palva et al 2005; Blume 2009). Secondary bilateral synchrony has been considered the main pathophysiological mechanism in a third of cases of typical Lennox-Gastaut syndrome (Ohtahara et al 1995).

Etiology and pathogenesis

Status epilepticus is a broad term comprising all types of epileptic seizures that fail to stop at their usual time course and that last for over 30 minutes (Panayiotopoulos 2010). The duration of an epileptic seizure is the result of a balance between pathophysiologically determined self-initiating, self-sustaining, and self-terminating mechanisms. Any seizure that fails to stop at its usual time course becomes unlikely to stop spontaneously and enters into status epilepticus because its self-sustaining processes are unopposed by self-terminating mechanisms. Status epilepticus may not terminate either because self-sustaining processes accelerate or become stronger over self-terminating processes or because the natural homeostatic seizure-suppressing mechanisms responsible for seizure termination are not activated or are weak. The pathophysiology of status epilepticus, its effect on the brain, and the risk to the patient differ significantly among different types of status epilepticus and, therefore, tonic status epilepticus.

Epidemiology"

The incidence and prevalence of tonic status epilepticus are not precisely known. Tonic status epilepticus is more common in Lennox-Gastaut syndrome, which has a high prevalence of about 5% to 10% of children with seizures (Panayiotopoulos 2010).

Prevention

Detection and prevention of seizure facilitating factors are part of the appropriate management of Lennox-Gastaut syndrome. Intercurrent febrile illnesses, vomiting, changes in treatment regimens, sedation, and psychological stress may facilitate seizures and status epilepticus. Children with Lennox-Gastaut syndrome are particularly vulnerable in an unstable and nonstimulating environment in which they experience irregular patterns of sleep, diet, and medication.

Differential diagnosis

Seizure phenomenology

There is no major differential diagnosis of tonic status epilepticus when this happens in children with Lennox-Gastaut syndrome. Then, the primary problem is their differentiation from other types of nonconvulsive or convulsive status epilepticus and their identification when motor manifestations are mild or absent. Video-EEG is probably mandatory for their confirmation. The diagnosis may be impossible on clinical grounds alone without EEG when tonic status epilepticus appears mainly with confusion (Somerville and Bruni 1983; Garmel et al 1992). It is also with EEG that tonic status epilepticus with inconspicuous motor manifestations can be differentiated from atypical absence status epilepticus of Lennox-Gastaut syndrome or other epilepsies.

Focal tonic status epilepticus of purely neocortical origin may be exceptional or not occur. Focal neocortical tonic seizures like those of the supplementary motor area of tonic posturing are distinctly different from those happening in tonic status epilepticus. Considering their clinical and EEG characteristics, focal tonic seizures should not be difficult to differentiate from generalized onset tonic seizures, bearing in mind that they usually occur in neurocognitively normal patients who do not have other types of seizure (myoclonic, atonic, absence) that are so common in patients with generalized onset tonic seizures. However, the problem may be when the latter are from focal epileptogenic foci with secondary bilateral synchrony.

Underlying disorders

Tonic status epilepticus is usually associated with Lennox-Gastaut syndrome or other epileptic encephalopathies (Gastaut et al 1963; Gastaut and Broughton 1972; Tassinari et al 1972; Roger et al 1974; Aicardi 1994; Shorvon 1994; Hartman 2010; Trinka et al 2015). Rarely, tonic status epilepticus may also occur in patients with pharmacoresistent idiopathic generalized epilepsy (Kobayashi et al 2005) or be induced by drugs, mainly intravenous injection of benzodiazepines for treatment of nonconvulsive status epilepticus in children with Lennox-Gastaut syndrome (Prior et al 1972; Tassinari et al 1972). For details see Clinical manifestations section.

There are also a few case reports of tonic status epilepticus occurring in an older woman with alter mental status (Garmel et al 1992), in a neonate with pyridoxal 5'-phosphate-dependent epilepsy (Veerapandiyan et al 2011), and in a 24-year-old woman without a history of epilepsy in the setting of aseptic meningoencephalitis (Ostrow and Kaplan 2011).

Electroclinical manifestations of tonic status epilepticus may also be seen in comatose or critically ill patients mainly, after severe brain anoxia.{embed="pagecomponents/media_embed" entry_id="8954"} These features are usually associated with a fatal outcome. Prognosis does not appear to improve with treatment.

Diagnostic workup

The general diagnostic workup of patients with tonic status epilepticus is relevant to the epileptic syndrome with which this occurs (see, for example, Lennox-Gastaut syndrome).

The recognition of tonic status epilepticus is clinical, but this often requires confirmation with ictal EEG (preferably video-EEG). This is particularly important in cases of tonic status epilepticus with minor motor manifestations when autonomic disturbances predominate or with symptoms of confusion.

The ictal EEG during tonic seizures shows bilateral synchrony, often asymmetrical and predominating in the anterior regions and the vertex:

(1) Very rapid (20 ± 5 Hz) discharges, initially of low amplitude, progressively increasing to 50 to 100 µV.

(2) A more ample and less rapid rhythmic discharge at 10 Hz, identical to that of the tonic phase of the generalized tonic-clonic seizures (epileptic recruiting rhythm), except that it may be of high amplitude from the onset.

(3) Flattening of all EEG activity alone or in combination with fast paroxysms is also common. During status epilepticus of tonic seizures with repetition every 2-5 min for hours or even days, the motor manifestations progressively attenuate from one seizure to another even becoming imperceptible (infra-clinical seizures), whereas the EEG manifestations remain unchanged. This indicates the importance of the EEG for the diagnosis and treatment of these cases of status epilepticus. In certain exceptional cases of tonic status epilepticus another type of electro-clinical dissociation occurs and merits mention. Brief hypersynchronous discharges succeed one another without interruption for several minutes. This corresponds clinically not with a large number of seizures but with one particularly prolonged seizure (Gastaut et al 1963).

In addition, there may be intermixed periods of diffuse slow spike-wave discharges characteristic of atypical absence seizures.

Management

Tonic status epilepticus is a serious and life-threatening condition with significant autonomic disturbances and apnea. Yet, out-of- or in-hospital management of tonic status epilepticus is entirely empirical. There are lifesaving guidelines and protocols for the treatment of convulsive (generalized tonic-clonic) status epilepticus, but these may or may not apply for tonic status epilepticus (Abend et al 2010; Panayiotopoulos 2010; Holtkamp 2011; Shorvon 2011; Shorvon and Ferlisi 2011). Physicians may be reluctant to recommend rescue benzodiazepines (which are the first-line treatment of convulsive status epilepticus) because of the few reports cited above of benzodiazepine-induced tonic status epilepticus. Intravenous sodium valproate and phenytoin is a widely used option, and there is an increasing number of reports on the beneficial effect of the intravenous administration of newer antiepileptic drugs (levetiracetam, lacosamide, topiramate, rufinamide) for in-hospital management of convulsive status epilepticus.

Intravenous lacosamide has been reported as beneficial in 3 patients aged 12 to 17 years with refractory tonic status epilepticus (Jain and Harvey 2012). All patients had symptomatic generalized epilepsy with intellectual disability and electrographically proven tonic seizures with ictal low-voltage fast activity. All 3 patients were on multiple antiepileptic drugs, and 2 were undergoing vagus nerve stimulation. Bolus doses of lacosamide (2 to 2.5 mg/kg) were used after 3 or more standard antiepileptic drugs had been ineffective. Two patients responded to a single dose, and 1 required 2 doses for seizure termination. In 1 patient who was on continuous video-EEG monitoring, clinical seizure cessation was immediate whereas the electrographic seizures took 30 minutes to resolve, without need for further lacosamide. Continued intravenous lacosamide resulted in non-life-threatening side effects in 2 patients, which may require switching to oral formulation in lower doses or restricting use to acute management only (Jain and Harvey 2012).

Rufinamide, which may be useful as adjunctive treatment in Lennox-Gastaut syndrome, has been reported as beneficial in a single case of tonic status epilepticus with electroclinical features reminiscent of Lennox-Gastaut syndrome (McMurray and Striano 2016; Ohtsuka et al 2016; Thompson and Cock 2016). A 24-year-old man with mild autism spectrum disorder and learning disability presented with a recurrence of tonic seizures, having been seizure- free and off medication since the age of 10. Within days of recurrence, with no identified precipitant, the seizures rapidly escalated until they were occurring every 1 to 2 minutes, greater than 95% of the time. Benzodiazepines, phenobarbitone, and levetiracetam had no impact. Valproate was partially successful at high doses, but led to a hyperammonemic encephalopathy. Burst suppression was eventually achieved only with a combination of ketamine, propofol, and barbiturate with hypothermia. Subsequent trials with high doses of lacosamide, phenobarbitone, further benzodiazepines, and topiramate were of no benefit, with seizure recurrence on multiple attempts at withdrawal over a 6 week period. As the electroclinical picture had features reminiscent of Lennox-Gastaut syndrome, rufinamide was rapidly titrated up to a total dose of 3 g/day over 5 days. The patient's seizures abated completely for several days despite withdrawal of all sedation, with no apparent adverse effects. Intermittent seizures and self-limiting clusters subsequently recurred, but had further improved with rufinamide at 4.4 g/day, the ketogenic diet, and a combination of valproate and later, carbamazepine (Thompson and Cock 2016).

Stiripentol may be effective in tonic status epilepticus resistant to benzodiazepines (Grosenbaugh and Mott 2013).

In conclusion, there is an urgent need of guidelines for out- and in-hospital management of tonic status epilepticus. The role of midazolam, which is becoming the first-line treatment of nonconvulsive and convulsive status epilepticus, should be assessed.

Neurosurgical interventions are sometimes needed in drug-resistant cases of convulsive status epilepticus (Winkler 2013).

Gene therapy manipulation of subcortical structures may be an approach that could be used to target generalized refractory status epilepticus of any type (Walker et al 2013).

General management of patients at risk for tonic status epilepticus. Avoidance of precipitating factors and optimal prophylactic medication is of paramount importance in the management of patients with tonic seizures who usually have multiform and pharmacoresistent seizures. Antiepileptic drugs may reduce them but do not control them, and it is doubtful if they affect the outcome. Rational polytherapy is often required though this is rarely successful. Avoiding drugs that may cause drowsiness or worsen seizures, cognition, and behavior is an important aspect of management.

Lennox-Gastaut syndrome and other epileptic severe disorders with tonic seizures require a multidisciplinary approach to management that is demanding and often frustrating for the family and the treating healthcare professionals and can only be supportive and palliative. A management strategy should include the following elements: • Treatment of epileptic seizures with appropriate medications and nonpharmacological methods • Treatment of behavioral and cognitive problems with appropriate educational programs • Physical therapy for the patient's physical disabilities • Family support.

Antiepileptic drugs effective in tonic seizures are: valproate, lamotrigine, phenytoin, clobazam, topiramate, and zonisamide. Combinations of these antiepileptic drugs are often needed (Panayiotopoulos 2010). Caution should be exercised with antiepileptic drugs causing drowsiness that precipitates seizures.

The ketogenic diet may have significant beneficial effects in epileptic encephalopathies alone or combined with corticosteroids (Ville et al 2015).

Neurosurgery is often considered as effective either as a curative or a palliative option in selected cases of epileptic encephalopathies (Fridley et al 2013).

Special considerations

Pregnancy

Patients subjected to tonic status epilepticus have frequent epileptic seizures and are usually on polypharmacy, which have adverse effects on pregnancy.

Anesthesia

Particular care and caution should be taken in patients that may need general anesthesia.

References cited

Abend NS, Gutierrez-Colina AM, Dlugos DJ. Medical treatment of pediatric status epilepticus. Semin Pediatr Neurol 2010;17:169-75. PMID 20727486

Agathonikou A, Panayiotopoulos CP, Giannakodimos S, Koutroumanidis M. Typical absence status in adults: diagnostic and syndromic considerations. Epilepsia 1998;39:1265-76. PMID 9860061

Aicardi J. Epilepsy in Children. 2nd Ed. New York: Raven Press, 1994.

Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51(4):676-85. PMID 20196795

Berkovic SF, Bladin PF. Absence status in adults. Clin Exp Neurol 1983;19:198-207. PMID 6439444

Blume WT. Clinical intracranial overview of seizure synchrony and spread. Can J Neurol Sci 2009;36(Suppl 2):S55-7. PMID 19760904

Blume WT. Lennox-Gastaut syndrome and secondary bilateral synchrony: a comparison. In: Wolf P, editor. Epileptic Seizures and Syndromes. London: John Libbey & Company Ltd, 1994:285-97.

Burnham WM. Core mechanisms in generalized convulsions. Fed Proc 1985;44:2442-5. PMID 3886432

Capocchi G, Balducci A, Cecconi M, et al. Valproate-induced epileptic tonic status. Seizure 1998;7:237-41. PMID 9700838

Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99. PMID 2502382

Commission on Classification and Terminology of the International League Against Epilepsy. Available at:EpilepsyDiagnosis.org. Accessed January 2017.

Djukic A, Lado FA, Shinnar S, Moshe SL. Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other. Epilepsy Res 2006;70:68-76. PMID 16829044

Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001;42:796-803. PMID 11422340

Engel J Jr. Report of the ILAE classification core group. Epilepsia 2006;47:1558-68. PMID 16981873

Faingold CL, Evans MS. Pathophysiology of generalized tonic-clonic seizures. In: Panayiotopoulos CP, editor. Atlas of Epilepsies. Springer, 2010:243-6.

Fridley J, Reddy G, Curry D, Agadi S. Surgical treatment of pediatric epileptic encephalopathies. Epilepsy Res Treat 2013;2013:720841. PMID 24288601

Fusco L, Specchio N, Yagi K, Seino M, Vigevano F. Generalized tonic seizures. In: Engel J Jr, Pedley TA, editors. Epilepsy: a Comprehensive Textbook. Second ed. Philadelphia: Wolters Kluwer/Lippincott William and Wilkins, 2008:611-8.

Garmel GM, Jacobs AK, Eilers MA. Tonic status epilepticus: an unusual presentation of unresponsiveness. Ann Emerg Med 1992;21:223-7. PMID 1739219

Gastaut H, Broughton R. Epileptic seizures: clinical and electrographic features, diagnosis and treatment. Springfield Illinois: Charles C Thomas, 1972.

Gastaut H, Courjon J, Poire R, Weber M. Treatment of status epilepticus with a new benzodiazepine more active than diazepam. Epilepsia 1971;12:197-214. PMID 5004981

Gastaut H, Roger J, Ouahchi S, Timsit M, Broughton R. An electro-clinical study of generalized epileptic seizures of tonic expression. Epilepsia 1963;4:15-44. PMID 13963212

Gastaut H, Zifkin BG. Secondary bilateral synchrony and Lennox-Gastaut syndrome. In: Niedermeyer E, Degen R, editors. The Lennox-Gastaut Syndrome. New York: Alan R Liss, 1988:221-42.

Grande-Martin A, Pardal-Fernandez JM, Carrascosa-Romero MC, De Cabo C. Tonic seizure status epilepticus triggered by valproate in a child with Doose syndrome. Neuropediatrics 2016;47(3):187-9. PMID 26979444

Grosenbaugh DK, Mott DD. Stiripentol in refractory status epilepticus. Epilepsia 2013;54 Suppl 6:103-5. PMID 24001087

Hartman AL. Generalized tonic status epilepticus. In: Panayiotopoulos CP, editor. Atlas of epilepsies. London: Springer, 2010:519-22.

Holtkamp M. Treatment strategies for refractory status epilepticus. Curr Opin Crit Care 2011;17:94-100. PMID 21178612

Jain V, Harvey AS. Treatment of refractory tonic status epilepticus with intravenous lacosamide. Epilepsia 2012;53:761- 2. PMID 22462573

Kobayashi E, Thomas P, Andermann F. Tonic status epilepticus in patients with idiopathic generalized epilepsy. Epileptic Disord 2005;7:327-31. PMID 16338675

Kobayashi K, Nishibayashi N, Ohtsuka Y, Oka E, Ohtahara S. Epilepsy with electrical status epilepticus during slow sleep and secondary bilateral synchrony. Epilepsia 1994;35:1097-103. PMID 7925158

Martin D. [Intravenous use of nitrazepam (Mogadan) in the treatment of epilepsy]. Neuropadiatrie 1970;2:27-37. PMID 5001124

McMurray R, Striano P. Treatment of adults with Lennox-Gastaut syndrome: further analysis of efficacy and safety/tolerability of rufinamide. Neurol Ther 2016;5(1):35-43. PMID 26861566

Ohtahara S, Ohtsuka Y, Kobayashi K. Lennox-Gastaut syndrome: a new vista. Psychiatry Clin Neurosci 1995;49:S179- 83. PMID 8612138

Ohtsuka Y, Yoshinaga H, Shirasaka Y, Takayama R, Takano H, Iyoda K. Long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome receiving adjunctive rufinamide therapy: an open-label study following a randomized clinical trial. Epilepsy Res 2016;121:1-7. PMID 26827266

Ostrow LW, Kaplan PW. Tonic status and electrodecremental paroxysms in an adult without epilepsy. Epileptic Disord 2011;13:99-101. PMID 21393096

Palva JM, Palva S, Kaila K. Phase synchrony among neuronal oscillations in the human cortex. J Neurosci 2005;25:3962- 72. PMID 15829648

Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment. Rev. 2nd ed. London: Springer, 2010.

Prior PF, Maclaine GN, Scott DF, Laurance BM. Tonic status epilepticus precipitated by intravenous diazepam in a child with petit mal status. Epilepsia 1972;13:467-72. PMID 4626573

Riviello JJ Jr, Ashwal S, Hirtz D, et al. Practice parameter: diagnostic assessment of the child with status epilepticus (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2006;67:1542-50. PMID 17101884

Roger J, Lob H, Tassinari AC. Status epilepticus. In: Magnus O, Lorentz de Haas AM, editors. Handbook of Clinical Neurology. Vol. 15. The Epilepsies. Amsterdam: North Holland, 1974:145-88.

Scantlebury MH. Pathophysiology of catastrophic epileptic syndromes. In: Panayiotopoulos CP, editor. Atlas of Epilepsies. Springer, 2010:251-62.

Shorvon SD. Status epilepticus: its clinical features and treatment in children and adults. Cambridge: Cambridge University Press, 1994.

Shorvon S. What is nonconvulsive status epilepticus, and what are its subtypes. Epilepsia 2007;48(Suppl 8):35-8. PMID 18329994

Shorvon S. The treatment of status epilepticus. Curr Opin Neurol 2011;24:165-70. PMID 21378567

Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802-18. PMID 21914716

Somerville ER, Bruni J. Tonic status epilepticus presenting as confusional state. Ann Neurol 1983;13(5):549-51. PMID 6408978

Tanganelli P, Regesta G. Refractory tonic generalized status epilepticus: report of a case of exceptionally prolonged duration. Eur Neurol 1991;31:413-8. PMID 1756769

Tassinari CA, Dravet C, Roger J, Cano JP, Gastaut H. Tonic status epilepticus precipitated by intravenous benzodiazepine in five patients with Lennox-Gastaut syndrome. Epilepsia 1972;13:421-35. PMID 4626571

Thompson AG, Cock HR. Successful treatment of super-refractory tonic status epilepticus with rufinamide: first clinical report. Seizure 2016;39:1-4 PMID 27161668

Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus - report of the ILAE Task Force on classification of status epilepticus. Epilepsia 2015;56(10):1515-23. PMID 26336950

Veerapandiyan A, Winchester SA, Gallentine WB, et al. Electroencephalographic and seizure manifestations of pyridoxal 5'-phosphate-dependent epilepsy. Epilepsy Behav 2011;20:494-501. PMID 21292558

Veliskova J, Claudio OI, Galanopoulou AS, et al. Seizures in the developing brain. Epilepsia 2004;45(Suppl 8):6-12. PMID 15610187

Ville D, Chiron C, Laschet J, Dulac O. The ketogenic diet can be used successfully in combination with corticosteroids for epileptic encephalopathies. Epilepsy Behav 2015;48:61-5. PMID 26057351

Walker MC, Schorge S, Kullmann DM, Wykes RC, Heeroma JH, Mantoan L. Gene therapy in status epilepticus. Epilepsia 2013;54 Suppl 6:43-5. PMID 24001071

Winkler PA. Surgical treatment of status epilepticus: a palliative approach. Epilepsia 2013;54 Suppl 6:68-71. PMID 24001078

**References especially recommended by the author or editor for general reading.

ICD and OMIM codes

ICD codes

ICD-10: Grand mal status epilepticus: G41.0 Tonic-clonic status epilepticus: G41.0 Other status epilepticus: G41.8 Status epilepticus, unspecified: G41.9

Profile

Age range of presentation

02-05 years 06-12 years

Sex preponderance

Female=male

Family history

None

Heredity

None

Population groups selectively affected

None

Occupation groups selectively affected

None

Differential diagnosis list atypical absence status epilepticus focal tonic status epilepticus of purely neocortical origin

Associated disorders

Lennox-Gastaut syndrome Other epileptic encephalopathies like Ohtahara and West syndrome