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).

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.

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).

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).

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).

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 (40).

Prevention

Detection and avoidance of seizure facilitating factors are part of the appropriate management of all complex epilepsies. 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

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.

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:

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.

Special considerations

Pregnancy

Patients who experience tonic status epilepticus might usually have frequent epileptic seizures and might be on polypharmacy, with potential teratogenic effects.

Anesthesia

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