Tonic status epilepticus …

K P Vinayan MD DM

Epilepsy & Seizures

Updated 12.19.2023
Released 01.25.2013
Expires For CME 12.19.2026

Tonic status epilepticus

Author: K P Vinayan MD DM

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Editor: Solomon L Moshé MD

Tonic status epilepticus

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Introduction

Overview

Tonic status epilepticus is a serious, sometimes fatal disorder, which is seen mostly in children with neurocognitive impairment and severe epilepsy, such as Lennox-Gastaut syndrome. Tonic status epilepticus usually comprises repetitive tonic seizures, which might last for days to weeks or rarely even months. Characteristically, as the status progresses, motor symptoms tend to lessen whereas autonomic disturbances, including respiratory depression, become more prominent. Only electrographic evidence of tonic seizures might remain in the later stages. Video-EEG monitoring is usually needed for the recognition of autonomic status epilepticus, particularly when motor manifestations are minimal. There were a few earlier reports of tonic status epilepticus associated with benzodiazepines and valproate intake. Newer antiepileptic drugs, such as lacosamide, have been reported as effective. Although there are some reports on the efficacy of ketogenic diet in super refractory status epilepticus (SRSE) and febrile infection-related epilepsy syndrome (FIRES), the data specifically on tonic status epilepticus are lacking. Unfortunately, most of the systematic studies of tonic status epilepticus are dated 40 years ago, and more recent literature is very minimal. Available information on clinical manifestations, investigative procedures, pathophysiology, and optimal management of patients with tonic status epilepticus is reviewed in this article. Multicentric prospective registries are needed to provide further insight into the current status of this rare syndrome.

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 necessary in later stages to identify ictal electrographic activity associated with very minimal clinical features.
	• Tonic status epilepticus occurs mostly in children with neurocognitive impairment and mainly in those with Lennox-Gastaut syndrome.
	• There are some rare case reports of acute symptomatic tonic status epilepticus in adults and the elderly.
	• Tonic status epilepticus may occur occasionally in association with the intake of benzodiazepines and valproate.
	• Newer antiepileptic drugs, such as lacosamide, appear promising in this condition.

Historical note and terminology

Tonic status epilepticus has been nearly exclusively studied systematically by Henri Gastaut and his Marseille School of epileptology (26; 24; 54; 45). 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 (24).

The ILAE proposal of 1989 described status epilepticus in Lennox-Gastaut syndrome as “a frequent event, which might manifest as stuporous states with myoclonias, tonic, and atonic seizures” (11). The ILAE Task Force on classification classified tonic status epilepticus with other generalized types of status epilepticus (15) 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” (16).

The most recent ILAE proposal and the ILAE position papers on seizures and classification have not dealt specifically with status epilepticus (05; 19; 47). However, the report of the ILAE Task Force on the Classification of Status Epilepticus 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 (56). 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” (56). This definition is conceptual, with two 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 for 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, 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 may be incorporated into the definition, without changing the underlying concepts. This division into two time points has clear clinical implications: time point 1 determines the time at which treatment should be considered or started, whereas time point 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 report provides no specific 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, which might occur in Ohtahara, West, and Lennox-Gastaut syndromes (56).

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” (44).

In the report of the 12, generalized onset tonic seizures 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 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.

When there is a consistent focality of spikes or maximal amplitude of ictal rhythm, a focal onset should be considered.

Differential diagnosis.

• Epileptic spasms: The motor contraction is often shorter in duration (less than 2 seconds); epileptic spasms often occur in a cluster.
• Focal seizure: Supplementary sensorimotor cortex of frontal lobe
• Syncope
• Nonepileptic seizures

Related syndromes.

• Lennox-Gastaut syndrome
• Epilepsy with myoclonic-atonic seizures

Adapted from (12).

Clinical manifestations

Presentation and course

Descriptions of tonic status epilepticus usually refer to children with neurocognitive impairment and severe epilepsy associated with widespread cerebral dysfunction, such as the Lennox-Gastaut syndrome or other epileptic encephalopathies (26; 24; 54; 45; 03; 48; 30). Rarely, tonic status epilepticus may occur in patients with long-standing pharmacoresistent idiopathic generalized epilepsy (34). There are some rare case reports of tonic status epilepticus in adult patients and the elderly (38; 18). Tonic status epilepticus was also noted to be induced by drugs, mainly intravenous injection of benzodiazepines in Lennox-Gastaut syndrome (43; 54).

Tonic status epilepticus in Lennox-Gastaut syndrome and other epileptic encephalopathies. Tonic status epilepticus in children with 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).

Tonic status epilepticus as illustrated in the classical studies of Gastaut and associates

Tonic status epilepticus as illustrated in the classical studies of Gastaut and associates. Two tonic seizures during tonic status epilepticus. The one on the top of the figure was associated with a fully developed global tonic se...

All types of tonic seizures (axial, axiorhizomelic, global) may happen in an episode. These seizures might have a longer duration (around 70 seconds) compared to isolated tonic seizures. Their repetition rate is very high and may reach up to 100 per hour. However, as the status progresses, motor symptoms tend to lessen whereas autonomic disturbances become more prominent. There may be only electrographic evidence of tonic seizures in the end stages.

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 (24).

Tonic seizures may be symmetrical and asymmetrical. 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 one side. Similarly, asymmetrical contraction of the appendicular muscles may lead to the elevation of one arm before the other. At times, the asymmetry is such that the seizure seems unilateral (hemitonic seizure) (26).

Clinical manifestations may be minimal from onset in a small number of patients with tonic status epilepticus. They may also appear as electrographic tonic seizures without any motor features (45).

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 (51).

In some cases, 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 seizures. 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 (24).

Duration of tonic status epilepticus is usually very long, with an average of 9 days. It may sometimes continue for several weeks (26; 24; 45) or months (53).

Tonic status epilepticus in patients with long-standing pharmacoresistant idiopathic generalized epilepsy. Tonic status epilepticus is probably extremely rare in idiopathic generalized epilepsy. Three such patients have been reported (34). All of them developed tonic status epilepticus in their late teens or early adulthood. There was a 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 one such episode, attacks characterized by elevation and flexion of both arms, flexion of the neck and trunk, upward eye deviation, and unresponsiveness lasting up to 4 seconds occurred every 5 minutes. Ictal EEGs showed generalized polyspike activity.

The second patient probably had perioral myoclonias with absences. Tonic seizures consisted of brief tonic asymmetric posturing of both arms along with upward eye deviation, contraction of perioral muscles, and 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 electroclinically documented in one patient (06).

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. 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 two types of frequent, discontinuous, repetitive, and polymorphic generalized discharges: (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 (02).

Status epilepticus manifested with absence and tonic seizures in an adult patient

Samples from video-EEG of status epilepticus manifested with absence and tonic seizures in a 48-year-old woman with unclassified idiopathic generalized epilepsy from the age of 11 years. She realized from previous experiences with...

Tonic status epilepticus induced by intravenous injection of benzodiazepines and other antiepileptic drugs in children with complex epilepsies. Tonic status epilepticus induced by intravenous injection of benzodiazepines for the treatment of nonconvulsive status epilepticus was reported many years ago (36; 25; 43; 54). Children had complex epilepsies (mainly Lennox-Gastaut syndrome) with frequent multiple seizure types. Benzodiazepines (nitrazepam, clonazepam, or diazepam) were used for the cessation of nonconvulsive status epilepticus, mainly atypical absence status epilepticus although most of these children also had other concurrent types of seizures. The main adverse effect was the transformation of the clinical situation to tonic status epilepticus and the EEG to rapid polyspikes of tonic seizures.

Tassinari and colleagues reported tonic status epilepticus precipitated by intravenous diazepam or nitrazepam in five patients with Lennox-Gastaut syndrome (54). All of the patients except one were in a state of confusion at the time of the injection and showed numerous or continuous discharges of slow spike-waves. All the patients had received other injections of benzodiazepines with little effect, and all of them except one had episodes of tonic status in the past.

Another child with intractable tonic, myoclonic, and atonic seizures was also reported (43). She also had lengthy episodes of confusion and unresponsiveness associated with atypical spike-and-wave discharges separated by brief periods with low voltage theta-waves in the EEG. 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 these discharges. Each of these electrographic rhythms was accompanied by a severe tonic seizure without intervening return of consciousness. The seizures were characterized by retraction of the lips, wide opening of the mouth, and up-rolling of eyes. Head and neck arched back with spinal hyperextension. The limbs became somewhat hypertonic; there was clenching of the left fist and semipurposeful movement of the right arm. The child had a long, piercing cry, became apneic, and had incontinence. 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 conscious although still confused. After 1 hour she became more alert.

Two cases of tonic status epilepticus attributed to valproate were also reported in the literature (10; 28). The first case was a 14-year-old boy with frequent generalized tonic-clonic seizures from the age of 6 years, EEG abnormalities of brief generalized discharges at 3 Hz spike-wave, and mild learning difficulties. On two occasions when valproate was added to prophylactic treatment with phenobarbitone, he developed frequent, 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 long axorhizomelic 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 (10). The second one was an 8-year-old boy with Doose syndrome (epilepsy with myoclonic-atonic seizures), who developed a tonic status epilepticus immediately after the intravenous administration of valproate for an absence status epilepticus (28). No motor manifestations were noted.

Tonic status epilepticus in adults and elderly. There are only very limited reports of tonic status epilepticus in adults. In 2011, Ostrow and Kaplan reported the case of a 24-year-old woman who presented to the emergency department with prolonged tonic status epilepticus that evolved into stimulus-induced diffuse voltage attenuation (SIDVA) pattern in the setting of aseptic meningoencephalitis (38). There was no history of seizures. She never had further events after recovery. In 2019, Fernandez-Torre and colleagues described the case of an elderly woman on chronic treatment with psychotropic drugs who developed an episode of generalized tonic status epilepticus (18). Motor manifestations were subtle and difficult to recognize as seizures, and a detailed video-EEG picked up the tonic status epilepticus, which was initially refractory to conventional antiseizure drug therapy including levetiracetam and valproate but was finally controlled with lacosamide. In another report, refractory tonic status epilepticus in a 29-year-old woman with anti NMDAR encephalitis responded to antiepileptic drugs and immunomodulatory treatment (33).

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. Morbidity and mortality of tonic status epilepticus have not been systematically assessed after the classical studies of Gastaut and associates more than 40 years ago (26; 24; 45). Optimistically, the outcome may be better now with newer therapeutic options and advancements in the management of status epilepticus.

Biological basis

Etiology and pathogenesis

The exact etiopathogenesis of tonic status epilepticus is currently not clear. This rare seizure type is mainly reported in complex childhood epilepsies. Most of the earlier reports were in children with Lennox-Gastaut syndrome, where the semiological features have been described very vividly (26; 24; 54; 45). Most of these children had features of extensive cerebral damage or dysfunction. Tonic status epilepticus has also been reported in other epileptic encephalopathies like myoclonic-atonic epilepsy. There is a possibility that subcortical generators or synchronization has a considerable contribution to the generation and development of tonic status epilepticus. With the advancement in genetic techniques, there is now a greater possibility of the emergence of newer syndromes with a high propensity for tonic status epilepticus from the etiologically heterogeneous group that was previously included under the umbrella diagnosis of Lennox-Gastaut syndrome.

Emergence of tonic status epilepticus in temporal correlation with the administration of benzodiazepines and valproate is another peculiar entity (36; 25; 43; 54). All of these children had complex epilepsies commonly categorized as Lennox-Gastaut syndrome. The exact etiopathogenesis of this development is not clear. Most of these cases were reported prior to the development of advanced radiological and genetic diagnostic techniques. None of the third-generation antiepileptic drugs are implicated thus far.

Tonic status epilepticus has also been described very rarely in cases of idiopathic generalized epilepsy. Most of these cases had several atypical features for idiopathic generalized epilepsy. The semiological features of tonic status epilepticus in these cases were not identical to the children with Lennox-Gastaut syndrome (34).

Isolated cases of tonic status epilepticus have been reported in adults and the elderly. Most of them had acute symptomatic seizures in relation to recent cerebral insults (38; 33).

Pathophysiology

The exact neurobiology of tonic status epilepticus is not clearly elucidated. However, subcortical structures like the brainstem may be significantly involved as in tonic seizures (09; 59; 14; 22; 17; 46). Because the brainstem projects widely to the cortex, a central role for the brainstem also would better explain the occurrence of tonic status epilepticus even in patients of Lennox-Gastaut syndrome with focal pathologies. Secondary bilateral synchrony from cortical, mainly frontal foci has been implicated as a major neurobiological mechanism for the development of “generalized” epileptic seizures of epileptic encephalopathies like Lennox-Gastaut syndrome (27; 08; 35; 37; 39; 07).

Differential diagnosis

Confusing conditions

There is no major differential diagnosis of tonic status epilepticus when it happens in children with Lennox-Gastaut syndrome. The differentiation from other types of nonconvulsive or convulsive status epilepticus is of paramount importance. Proper identification of tonic status epilepticus needs considerable clinical skill when motor manifestations are mild or absent. Video-EEG is probably mandatory for confirmation in such a scenario. The diagnosis may be impossible on clinical grounds alone without EEG when tonic status epilepticus appears mainly with confusion (51; 23). EEG remains the major diagnostic tool to differentiate tonic status epilepticus with inconspicuous motor manifestations from atypical absence status epilepticus of Lennox-Gastaut syndrome or other complex epilepsies.

Focal tonic status epilepticus of purely neocortical origin may be exceptional. In focal neocortical tonic seizures like those of the supplementary motor area onset, tonic posturing is distinctly different from that seen in tonic status epilepticus. Focal tonic seizures usually occur in neurocognitively normal patients who do not have other types of seizures (myoclonic, atonic, absence) that are so common in patients with generalized onset tonic seizures.

Associated and underlying disorders

Tonic status epilepticus is usually associated with Lennox-Gastaut syndrome or other epileptic encephalopathies (26; 24; 54; 45; 03; 48; 30; 56). Rarely, tonic status epilepticus may also occur in patients with pharmacoresistent idiopathic generalized epilepsy (34) or be induced by drugs, mainly intravenous injection of benzodiazepines for the treatment of nonconvulsive status epilepticus in children with Lennox-Gastaut syndrome (43; 54). For details see the clinical manifestations section.

With the current advancement in genetic techniques and deep phenotyping, there is a strong possibility that specific monogenic developmental or epileptic encephalopathies might emerge from the electroclinically defined cohort of tonic status epilepticus.

There are also some rare case reports of tonic status epilepticus occurring in elderly women with altered mental status (23; 18), in a neonate with pyridoxal 5'-phosphate-dependent epilepsy (58), in a 24-year-old woman without a history of epilepsy in the setting of aseptic meningoencephalitis (38), and in a 29-year-old woman with anti-N-methyl-D-aspartate receptor encephalitis (33).

Electroclinical manifestations of tonic status epilepticus may also be seen in comatose or critically ill patients mainly, after severe brain anoxia.

Electroclinical tonic status epilepticus in a comatose patient after severe brain anoxia

Repetitive diffuse electrical discharges of very rapid spikes associated with bilateral tonic flexor spams of fingers and wrists. The patient died soon after this video-EEG. (Contributed by Dr. C P Panayiotopoulos)

These features, which are usually associated with a fatal outcome, are often subtle and require EEG monitoring for their diagnosis (20). Prognosis does not appear to improve with treatment.

Diagnostic workup

The general diagnostic workup of patients with tonic status epilepticus is similar to the workup for the epileptic syndrome in which these seizures occur (see, for example, Lennox-Gastaut syndrome).

The recognition of tonic status epilepticus is clinical, but this often requires confirmation with ictal 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. It might often remain as asymmetrical and predominant over the anterior regions and the vertex:

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

(2) This is usually followed by a less rapid rhythmic discharge at 10 Hz.

(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 to 5 minutes for hours or even days, the motor manifestations progressively attenuate from one seizure to another even becoming imperceptible (infraclinical 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 electroclinical dissociation may be noted with brief, repetitive bursts of hypersynchronous discharges without interruption for several minutes, clinically associated with a prolonged seizure (26).

In some patients, intermixed periods of diffuse, slow spike-wave discharges may also be noted, which might also be considered characteristic of atypical absence seizures.

Management

Tonic status epilepticus is a serious and life-threatening condition with significant autonomic disturbances and apnea. However, no clear evidence-based data exist on the optimal management of these seizures, and the current management options are entirely empirical. There are several guidelines and protocols for the optimal management of convulsive (generalized tonic-clonic) status epilepticus, but these may or may not apply for tonic status epilepticus (01; 40; 31; 49; 49). Abortive treatment with benzodiazepines, which are currently the first-line treatment of convulsive status epilepticus, might be a little risky in view of the few earlier reports of benzodiazepine-induced tonic status epilepticus. Intravenous sodium valproate and phenytoin are widely used options, although valproate may also induce tonic status epilepticus in some rare cases (see clinical manifestations).

Intravenous lacosamide has been reported as beneficial in three patients aged 12 to 17 years with refractory tonic status epilepticus (32). All patients had symptomatic generalized epilepsy with intellectual disability and electrographically proven tonic seizures with ictal low-voltage fast activity. All three patients were on multiple antiepileptic drugs, and two were undergoing vagus nerve stimulation. Bolus doses of lacosamide (2 to 2.5 mg/kg) were used after three or more standard antiepileptic drugs had been ineffective. Two patients responded to a single dose, and one required two doses for seizure termination. In one 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 two patients (32). Fernandez-Torre and colleagues reported a centenarian woman on chronic treatment with psychotropic drugs who developed an episode of generalized tonic status epilepticus (18). Motor manifestations were subtle and difficult to recognize as seizures, and a detailed video-EEG contributed to accurate and prompt diagnosis. This status epilepticus was initially refractory to conventional antiseizure drug therapy including levetiracetam and valproate but was finally controlled with lacosamide.

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. 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 years. Within days of recurrence, 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 the sedating antiepileptic drugs; there were no apparent adverse effects. Intermittent seizures and self-limiting clusters subsequently recurred, which was controlled with rufinamide at 4.4 g/day, the ketogenic diet, and a combination of valproate and, later, carbamazepine (55).

Stiripentol might also be effective in tonic status epilepticus resistant to benzodiazepines (29).

The ketogenic diet may have significant beneficial effects in epileptic encephalopathies alone or combined with corticosteroids (61).

The ketogenic diet is currently an established treatment for pharmacoresistant complex epilepsies of childhood, including Lennox-Gastaut syndrome (61; 52). In addition, there are some reports of the beneficial effect of ketogenic diet therapy for new-onset refractory status epilepticus, especially febrile infection-related epilepsy syndrome (41; 42). However, data specific to tonic status epilepticus are yet to emerge.

In conclusion, there is an urgent need for multicenter prospective registries for better characterization of semiological features and the etiopathogenesis of tonic status epilepticus based on the current advancement in genetic diagnoses, which might help in developing evidence-based guidelines for out-of-hospital and in-hospital management of tonic status epilepticus. The therapeutic efficacy and safety of midazolam, which is now becoming the first-line treatment of nonconvulsive and convulsive status epilepticus, should be specifically assessed. Further studies are also needed to offer precision medicine based on genetic analysis in refractory tonic status epilepticus (62).

Neurosurgical interventions are sometimes needed in drug-resistant cases of focal convulsive status epilepticus (21; 63). However, there are no data to support such an intervention in generalized tonic status epilepticus.

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 polymorphic, pharmacoresistant seizures. Antiepileptic drugs may reduce the frequency of seizures. However, it is doubtful whether they can affect the long-term outcome. It is better to avoid drugs that might cause drowsiness or worsening of seizures, cognition, and behavior. Lennox-Gastaut syndrome and other complex epileptic disorders with tonic seizures require a multidisciplinary approach to management that is demanding for the family and the treating healthcare professionals (13; 57; 60).

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 (40; 60). Caution should be exercised with antiepileptic drugs causing drowsiness and an increase in the frequency of seizures.

Cannabidiol has provided high evidence of efficacy against intractable seizures of Lennox-Gastaut syndrome and other epileptic encephalopathies (60; 04). However, there are no definite data specifically on tonic status epilepticus.

Anti-N-methyl-D-aspartate receptor encephalitis with tonic status epilepticus requires appropriate immunotherapy (33).

Outcomes

Tonic status epilepticus is associated with significant morbidity and mortality, which requires intensive medical care and administration of multiple antiepileptic drugs.

Media

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

K P Vinayan MD DM

Dr. Vinayan of the Amrita Institute of Medical Sciences has no relevant financial relationships to disclose.
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Editor

Solomon L Moshé MD

Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.
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Former Authors

C P Panayiotopoulos MD PhD
Jerome Engel Jr MD PhD
C P Panayiotopoulos MD PhD

Patient Profile

Age range of presentation: 12 to 65+ years
Sex preponderance: Female=male
Heredity: None
Population groups selectively affected: None
Occupation groups selectively affected: None

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Tonic status epilepticus

Associated Disorders

Lennox-Gastaut syndrome
Developmental or epileptic encephalopathies

Differential Diagnosis

atypical absence status epilepticus
focal tonic status epilepticus of purely neocortical origin
generalized tonic clonic status epilepticus

Also Relevant

Absence status epilepticus
Asymmetric tonic seizures
Generalized onset tonic seizures
Generalized tonic-clonic status epilepticus
Lennox-Gastaut syndrome
- Myoclonic status epilepticus
- Subtle status epilepticus

Tonic status epilepticus

Introduction

Overview

Key points

Historical note and terminology

Differential diagnosis.

Related syndromes.

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Pathophysiology

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated and underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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