Tuesday, May 10, 2016

Advances in status epilepticus

Trinka E, Brigo F, Shorvon S. Recent advances in status epilepticus. Curr Opin
Neurol. 2016 Apr;29(2):189-98.


Purpose of review This review discusses advances in the understanding of the mechanisms of status epilepticus and its current treatment approaches. Many of these have been topics at the 5th London-Innsbruck Colloquium on status epilepticus 2015.

Recent findings A new definition and classification of status epilepticus was proposed, which is expected to improve treatment and stimulate research. A better understanding of the failure of seizure suppressing mechanisms and the initiation of self-sustaining seizures begins to translate into the clinical arena. Drugs, such as allopregnanolone, cannabinoids, sec-butylpropylacetamide and valnoctamide, may better target these seizure-perpetuating mechanisms. The concept of combinatorial treatments has further developed, but yet trials in humans are lacking. A new prognostic outcome-score and electroencephalography-criteria for nonconvulsive status epilepticus are ready for clinical use. Alternative routes, such as intranasal or buccal, have been explored in a number of trials suggesting that intramuscular midazolam is at least as effective as intravenous lorazepam and buccal or intranasal midazolam is at least as effective as rectal diazepam.

Summary Despite progress in basic science, translation into the clinical field remains difficult. There is hope, that the two large phase III studies in the established and refractory status that started recruitment in 2015 will better inform the clinicians in this emergency situation.


From the article:

In 2015, a Task Force of the ILAE defined status epilepticus as 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, which 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 seizure'. The timeframe for t1 was set at 5 min for generalized convulsive status epilepticus, and at 10 min for focal status epilepticus with impairment of consciousness (formerly designated as complex partial status epilepticus)...

Bhatnagar and Shorvon searched the genetic databases for genes associated with status epilepticus and identified mutations in 122 genes. The genetic mutations identified were found only in rare conditions and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. To date, no 'pure status epilepticus genes' have been identified...

On the basis of these criteria, an expert panel at the 4th London Innsbruck Colloquium on acute Seizures in Salzburg, Austria proposed the working diagnostic criteria for NCSE (Table 2). EEG patterns with spatiotemporal evolution or epileptiform discharges faster than 2.5 Hz should deserve treatment. Conversely, more 'static' patterns such as diffuse polymorphic δ activity, spindle coma, α coma, low output voltage or burst suppression do not reflect nonconvulsive ongoing seizure activity. Finally, some patterns such as generalized periodic discharges or lateralized periodic discharges with a frequency of less than 2.5 Hz or rhythmic discharges faster than 0.5 Hz have uncertain clinical and diagnostic significance. In these cases, at least one of the additional criteria is required for a diagnosis of nonconvulsive status epilepticus: subtle clinical ictal phenomena, typical spatiotemporal evolution or response to antiepileptic drug treatment.

Generalized periodic discharges (GPD) are commonly encountered in metabolic encephalopathy and following cerebral hypoxia. Their clinical significance is unclear, and it is debatable whether in these conditions treatment with antiepileptic drugs is of any benefit...

The therapeutic principle 'time is brain' applies not only for stroke but also for status epilepticus, as the prognosis of status epilepticus worsens with increasing duration of seizure activity. Indeed, prompt recognition and earliest treatment of status epilepticus are associated with lower morbidity and mortality, fewer drugs required in hospitals and reduction in seizure duration. A timely administration of rescue medication in a prehospital setting may, therefore, prove useful to prevent progression to status epilepticus (in the case of isolated brief seizures or recurrent unprovoked seizures) and to limit the duration of ongoing seizure in the case of early status epilepticus. Intravenous administration requires gaining access to an intravenous route, which may prove difficult in some situations (e.g. patients with convulsive seizures or infants) resulting in a treatment delay...

A comprehensive systematic review assessed all studies reporting data on propofol used in refractory status epilepticus. Twenty-four studies with 143 cases of status epilepticus were included. Propofol administration led to complete status epilepticus termination in 68%, withdrawal seizures in 6%, breakthrough seizures in 1%, discontinuation because of side-effects in 6% and death during treatment in 8%.

One RCT comparing propofol with thiopental sodium in the treatment of refractory status epilepticus found no difference with regard to control of status epilepticus, mortality and return to baseline clinical conditions at 3 months. However, this study was terminated before completing because of difficulties in patient enrolment and was therefore underpowered...

This review shows that despite the enormous advances in the understanding of basic mechanisms, the translation into the clinical arena is still difficult. Clinical trials in this field are costly and logistically demanding. Newer drugs targeting various other mechanisms, such as allopregnanolone, cannabinoids or valproate derivatives, show promising results in preclinical animal models and first human trials. There is one phase III trial in superrefractory status epilepticus (NCT02477618) currently recruiting patients. Another remarkable phase III trial (NCT01960075) comparing the efficacy of levetiracetam, valproate and (fos)phenytoin in established status epilepticus (Established Status Epilepticus Trial) also started recruitment in 2015. This trial uses an innovative adaptive design and its results are expected to inform clinical practice in the future. The new definition and classification, EEG consensus criteria for nonconvulsive status epilepticus and a new outcome score will further help to better delineate patient cohorts and improve risk stratification in future clinical trials.


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