Refractory status epilepticus

Status epilepticus is a life threatening neurological emergency. In persons with status epilepticus, if administration of a benzodiazepine and at least one antiepileptic drug has failed then management protocols for refractory status epilepticus should be put into effect. The article summarises the causes, effects, pathophysiology and treatment protocols for refractory status epilepticus.The concept of super refractory status and newer etiologies and therapeutic options are also discussed. Neurology Asia 2013; 18 (Supplement 1) : 67 – 71 Address for correspondence: Dr Manjari Tripathi, Additional Professor in Neurology, Room No 705, Department of Neurology, All India Institute of Medical Sciences (AIIMS), Ansari nagar, 29 Aurobindo Marg, New Delhi, 110029, India. E mail: [email protected] INTRODUCTION Status epilepticus (SE) is the second most common neurological emergency after acute stroke having an incidence of 10-40 per 100,000. Irrespective of the timeframe, SE that persists despite adequate administration of benzodiazepines and at least one antiepileptic drug (AED) is labelled refractory status epilepticus (RSE). The reported incidence of RSE is estimated at 31–43% of all SE episodes, however one prospective study reports lower incidence at 24.6%. Commonest cause of RSE are encephalitis, massive stroke, rapidly progressive brain tumours. The shortterm fatality rates for RSE is between 16%-39%. Mortality in RSE occurs after the cessation of seizures and is mostly related to the underlying clinical problem highlighting the fact that underlying cause of SE is the most important predictor of clinical outcome. Functional outcome after RSE is very poor and the chances of returning to baseline clinical status is approximately 21% as compared to 63% for non refractory SE. PATHOPHYSIOLOGY OF REFRACTORY STATUS EPILEPTICUS RSE patients have many systemic complications which includes arrhythmias, pulmonary edema, metabolic acidosis, and rhabdomyolysis. Rat models have shown that SE responds to benzodiazepine (GABAa agonists) or phenytoin (sodium channel blocker) when administered early. As time passes by RSE becomes more resistant to these drugs, because of internalization of GABAa receptors (inhibitory) in the neuronal cytoplasm, and the overexpression of NMDA receptors (excitatory). However the clinical evidence for the refractoriness cannot be fully accounted by loss of inhibition or overexpression. TREATMENT OF REFRACTORY STATUS EPILEPTICUS There are 3 distinct steps in controlling SE; benzodiazepines for early seizure control, conventional AED for early resistance and anaesthetics for RSE. Benzodiazepines have the best available evidence. (Figure 1). The validated clinical SE severity score (STESS) can help to decide treatment strategy. With four variables (age, seizure semiology, extent of consciousness impairment, and history of previous seizures as a surrogate for cause), STESS is readily applicable in clinical settings, relies on straightforward clinical criteria, and has a robust negative predictive value for mortality (ie, patients with a low score are very unlikely to have a fatal outcome. As SE becomes refractory to therapy, coma induction with an anaesthetic, mostly a barbiturate, propofol or midazolam, is usually required (Table 1). The optimal agent for refractory SE should exert a GABAa agonistic and NMDA antagonistic action, be fast acting, with a short elimination half-life, and have a favourable risk profi le. Midazolam is a benzodiazepine with a short half-life after a single bolus but on repeated administrations, it increases to 6-50 hrs. Constant monitoring and dose changes need to be made because of the concern of tachyphylaxis and adverse effects.18 Propofol has a very short half-life allowing for rapid titration and withdrawl. It primarily acts by modulating GABAa receptors however it also acts on sodium and calcium channels Neurology Asia 2013; 18 (Supplement 1) 68 and probably on NMDA receptors. Since it is administered as an oil emulsion, it carries a risk of propofol infusion syndrome (PIS), which consists of cardiocirculatory collapse with hypertrigleridemia, rhabdomyolysis and lactic acidosis.19,20 (Table 2) This has mainly been reported in young children as it results mainly Established RSE GCSE: IV Midazolam 0.2mg/kg then 0.2-0.6mg/kg/hr or IV propofol 2mg/kg then 2-10mg/kg/hr Focal-complex or absence: valproate, levitracetam, lacosamide. topiramate IV Pentobarbital 5mg/kg then 1-5mg/kg/hr or IV thiopental 1mg/kg then 1-5mg/kg/hr Other drugs: lidocaine, verapamil, magnesium Other Anaesthetics: isofl urane, desfl urance and ketamine Other approaches: surgery, VNS, ECT, ketogenic diet Figure 1. Algorithm for refractory status epilepticus (RSE) treatment. Increased refractoriness is indicated by background shading intensity; third line drugs are on the right column. RSE, refractory status epilepticus; GCSE, generalized convulsive status epilepticus; VNS, vagus nerve stimulation; ECT, electroconvulsive therapy from the impairment of mitochondrial activity and use of free fatty acids. Retrospective series estimated the incidence of PIS in RSE as 7% (fatal) and 38% (non-fatal).21 Barbiturates are the oldest compounds used in RSE. They have a tendency to accumulate in the adipose tissues accounting for the increased halfTable 1: Pharmcacological characteristics of anesthetics used in refractory status epilepticus22 Barbiturates Propofol Midazolam Used since Before 1960 End of 1980 Early1990 Mechanism of action: GABAa agonistic +++ +++ +++ NMDA antagonistic + + Ca channel modulation + + Na channel modulation + Elimination half-life (hrs) THP:14-36; PTB:15-22 1-2 6-50 Accumulation +++ + ++