Status Epilepticus
Ramshekar Menon*, Ashalatha Radhakrishnan**, Kurupath Radhakrishnan***
Abstract
Status epilepticus (SE) is a neurological emergency resulting from prolonged clinical or electroencephalographic
seizure activity. Refractory SE refers to the persistence of seizure activity despite the initiation of first- and second-
line anticonvulsant therapy. Sinister outcomes are often attributed to the etiology of SE. Despite randomized
multicentre trials of established and promising therapeutic options, the management and prognostication in SE are
fraught with challenges. Neither the duration of SE nor time-delay to initiation of therapy should discourage the
aggressive approach to the management of SE. Neurointensive care of patients with SE consists of an algorithmic
approach tailored to the etiology and systemic complications that arise as a consequence. This approach is also
driven by the persistence of electrographic seizure activity, which is best followed with continuous EEG monitoring.
The extent of patient support has to be augmentative to the degree of encephalopathy/coma and impairment of
vital functions. Potential interactions of anticonvulsant drugs with other co-medications need to be considered
during the course of treatment. This review discusses the existing literature on the epidemiological aspects, clinical
approach, treatment and prognostication of SE.
Introduction Convulsive SE
S tatus epilepticus (SE) in simple terms is used to describe
a series of uninterrupted seizures which result in an
impairment of normal brain function, which if not treated as a
Convulsive SE generally refers to the generalized tonic-
clonic SE which is the most dangerous type of SE. Generalized
convulsive SE classically has been defined as recurrent
medical emergency results in high morbidity and mortality.1-3 SE generalized convulsions without full and complete recovery
is one of the most common medical emergencies, with an overall of consciousness between seizures or as a single prolonged
annual incidence of 10-41 per 100,000.1-6 The incidence of SE has convulsion without the characteristic evolution of a single
shown a decreasing trend in both developing and developed discrete seizure.11 The definition of duration of convulsive SE
countries over the years. Age-specific incidence rates of SE show has been a subject of controversy over the years. Most authors
a U-shaped curve with a bimodal distribution peaking in very have suggested a seizure activity lasting 30 minutes for defining
young and the elderly.7 SE. However, for practical purposes, a duration of 5 minutes as
proposed by Lowenstein et al.11 may be better adopted for adults
Definition and Classification and children aged above 5 years.
The International League against Epilepsy (ILAE) has defined
SE as a seizure that persists for a sufficient length of time, or Non-convulsive SE
repeated frequently enough that recovery between attacks does Non-convulsive SE is a state of electromechanical dissociation
not occur.8 However, the definitions and classifications are still where the epileptiform discharges evident on the EEG are not
evolving and an ILAE task force is currently developing a new accompanied by clinical manifestations other than obtundation,
draft on a definition and classification of SE.9 For the purpose hardly discernible motor manifestations or coma. 12 Non-
of this review, we classify SE based on the presence or absence convulsive SE has long been subdivided into 2 categories:
of motor manifestation into convulsive and non-convulsive absence status and complex partial status. Patients with non-
(Figure 1).10 A third category is often recognized comprising the convulsive SE need to be managed as convulsive SE, using EEG
boundary syndromes including epileptic encephalopathies and as a guide rather than clinical observations as the determinant
acute forms of coma with status-like electroencephalography of response to treatment.
(EEG) patterns.
Phases of SE
The physiological changes in SE evolve in
two phases: the first is the compensated stage
during which cerebral damage is prevented by
the physiologic mechanisms which compensate
the increased metabolic demands because of
seizures. After 30 to 60 minutes of continuous
seizures, the patient moves into the second or the
decompensated stage when these compensatory
mechanisms are overwhelmed and there is potential
for neuronal injury with persistence of seizures.13
Fig. 1 : Classification of status epilepticus The cerebral damage is caused by systemic and
metabolic disturbances (hypoxia, hypoglycemia, acidosis and
Assistant Professor, **Associate Professor, ***Senior Professor,
*
raised intracranial pressure) and also by the direct excitotoxic
Department of Neurology, R Madhavan Nayar Center for effect of seizure discharges, which result in calcium inux
Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical
into neurons and a cascade of events resulting in necrosis and
Sciences and Technology, Trivandrum 695 011.
SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL. 61 59
General Emergency Measures one randomized trial and was found to be equally effective in
adults.43 Therefore, in the absence of clear rational evidence so
The maintenance of airway, breathing and circulation is the far, an experienced physician can choose pragmatically from
priority in patients presenting with SE. The reversible factors one among them as the clinical situation warrants. They have to
which should be kept in mind that include hypoglycemia, be continued in the oral form once the seizures are controlled.
hyponatremia, hypocalcemia, hypomagnesemia, acidosis,
hyperthermia and hypoxia. If alcoholism is suspected, patient
should be given a bolus dose of 100 mg thiamine followed by
Refractory SE
dextrose infusion. Hypoxia may not be clinically manifest and There is no single well-accepted definition for refractory SE.
oxygen supplementation is recommended in all patients in SE. For practical purposes, when adequate doses of two intravenous
Emergency investigations should include the following: blood anticonvulsants fail to terminate seizures, the status is said to be
gases, glucose, renal and hepatic functions, calcium, magnesium, refractory. At this stage general anesthetic medications are used
full blood count, clotting screen, and AED concentrations. Serum for the control of seizures after intubating the patient.33 With the
should be stored for toxicology or virology or other future use of these agents, majority of SE will get controlled, and hence
analyses. An electrocardiogram should be performed. the failure of therapy is usually attributable to dose-limiting side
effects or due to an inadequate target dose. Withdrawal seizures
Antiepileptic Drug Therapy in SE while tapering the drugs are reported in 0.3% to 9% cases.33
All treatment protocols in SE are based on a staged approach The various drugs used in refractory SE are midazolam,
(33,34). The AEDs used in SE can be broadly divided into first thiopental sodium/pentobarbital and propofol.33,44 Of these,
and second line drugs. The detailed protocol of therapy and the there is a trend towards more preference for midazolam in
dosages are provided in Figure 3 and Table 1. that the control of seizures, lesser rate of withdrawal seizures
and fewer side effects are exhibited by this drug as compared
First-line drugs to the other two.44 Propofol is associated with potentially fatal
Randomized controlled trials comparing the efficacy of first- propofol infusion syndrome produced by depression of cellular
line medications in SE are scarce and hence the protocols for and mitochondrial functions and is commonly seen in children
management are heterogeneous. In early SE, the drug of choice and patients co-medicated with catecholamines and steroids.
is intravenous benzodiazepines.33 Administration of intravenous Thiopentone anesthesia was more commonly associated with
benzodiazepines, lorazepam or diazepam has shown similar death, which may be a reflection of the severity of the status.
benefits in studies although the safety profile may be slightly The end point of anesthetic treatment in SE is to achieve burst-
in favor of the former. Intravenous midazolam is also being suppression pattern in the EEG.
increasingly used, but has not been studied in any double-blind
randomized trial.35 Pertinent to the first-line management would Super-refractory SE
be the issue of respiratory or hemodynamic compromise that
Super-refractory SE is a relatively newer terminology used to
may be incurred during bolus dosing with benzodiazepines
define SE that continues for 24 hours or more after the initiation
or phenytoin, especially in children and the elderly. Recent
of anesthesia, including those cases in which the SE recurs on
studies including an open labelled randomized study from
the reduction or withdrawal of anesthesia.45 Ketamine infusion
India have emphasized equivalence of efficacy and safety of
was studied in a small group of patients with super-refractory SE
levetiracetam in comparison to first line AED like lorazepam.36,37
and 82% achieved satisfactory control. Inhalational anesthetics,
Though cost of therapy is an issue, availability as an intravenous
isoflurane and desflurane were also found to be useful for initial
preparation, favourable pharmacokinetic profile and longer
control in small case series.45
duration of action of levetiracetam could make it an acceptable
alternative as a first line agent during a cluster of seizures or SE Intravenous magnesium has excellent efficacy in the treatment
in a hemodynamically unstable patient. of seizures due to eclampsia and in congenital or acquired
hypomagnesemia. Serum magnesium level should be done in all
Second-line drugs
patients with refractory SE. Pyridoxine is effective in SE related
Once the SE is established, intravenous AEDs need to be to pyridoxine deficiency. Immunosuppressive regimens like
administered. The agents available are phenytoin, valproate steroids, intravenous immunoglobulin, and plasma exchange
and levetiracetam.33 Intravenous fosphenytoin or phenytoin is may are effective as many of the refractory seizures have occult
generally preferred world-over as first choice if the seizures are immunologic causes. Ketogenic diet has effect in SE related
not controlled with benzodiazepines. Fosphenytoin is preferred to epileptic encephalopathies. Hypothermia of 32 to 35C,
over phenytoin due to the favorable side effect profile especially preferably delivered by endovascular cooling is an effective
lack of thrombophlebitis. In a comparative trial of phenytoin, measure and affords neuroprotection as well, but one should
valproate and levetiracetam, phenytoin was not statistically be aware of the various systemic complications.45
different in efficacy from the other two and levetiracetam was
Neurosurgery has been used in many centers for refractory
found to be less efficient than valproate to control SE.38
SE and is mainly targeted against the etiology of the seizures.
The other parenteral AEDs available recently is lacosamide, Resection of cortical dysplasia is the most frequently performed
but data on its effectiveness and its comparative efficacy surgery. Magnetic and electrical stimulation therapies like
with other drugs are not available presently.39,40 There are no transcranial magnetic stimulation, vagus nerve stimulation,
head to head comparative prospective trials between them. deep brain stimulation and electroconvulsive therapy are
A few randomized studies from India with either one or two experimental forms of treatment used in SE.45
of them displayed almost similar efficacy especially between
phenytoin and valproic acid,41,42 although there are no studies Outcome
comparing levetiracetam or lacosamide with these agents from
India. Topiramate orally was compared with phenytoin in Mortality from SE in various studies is up to 20%.1,5,33 Major
determinant of the outcome in SE is the underlying etiology and
62 SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL. 61
is not related to the type of medications used or duration of SE.31,44 status epilepticus of different causes: A systematic review. Arch
In one study which specifically looked into the duration elapsed Neurol 2010;67:931-40.
before instituting correct treatment in SE, a duration of less than 7. Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC.
10 hours was associated with a better overall outcome, but this Incidence, cause, and short-term outcome of convulsive status
was not significant once etiology, presentation in a comatose state epilepticus in childhood: prospective population-based study.
and type of SE were accounted for.46 In a study on convulsive SE Lancet 2006;368:2229.
from India by Murthy et al.,31 the overall mortality was 10.5%, 8. Commission on Classification and Terminology of the International
with lack of response to first-line treatment being a predictor League Against Epilepsy. Proposal for revised clinical and
electroencephalographic classification of epileptic seizures. Epilepsia
of mortality (p < 0.001). Also, longer duration of seizures was
1981;22:489501.
associated with increased morbidity (p=0.001).31 These facts
reflect on the importance of emergent treatment of SE by medical/ 9. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van
Emde Boas W, Engel J, French J, Glauser TA, Mathern GW,
para-medical staff at the primary health care contact point.
MosheSL,Nordli D, Plouin P, Scheffer IE. Revised terminology and
Study of SE in 84 patients from our Institute over a period of concepts for organization of seizures and epilepsies: report of the
10 years showed the distribution of types of SE as convulsive SE ILAE Commission on Classification and Terminology, 20052009.
in 90.7%, non-convulsive SE in 6.5%, and myocloinc SE in 2.8%. Epilepsia 2010;51:67685.
Majority (60%) events were remote symptomatic. Mean delay 10. Trinka E, Hfler J, Zerbs A. Causes of status epilepticus. Epilepsia
between onset of SE and initiation of treatment was 12.8 hours 2012;53:12738.
and only in 11% events, appropriate treatment was started within 11. Lowenstein DH, Bleck T, Macdonald RL. Its time to revise the
1 hour of onset of SE. In 79% of events, SE could be aborted definition of status epilepticus. Epilepsia 1999;40:120-2.
with use of first- and second-line drugs. Case fatality rate was 12. Husain AM, Horn GJ, Jacobson MP. Non-convulsive status
11%, 22% developed neurological sequelae and 67% returned epilepticus: usefulness of clinical features in selecting patients for
to baseline. Acute symptomatic SE, older age, sensorium at the urgent EEG. J Neurol Neurosurg Psychiatry 2003;74:189-91.
time of admission and delayed hospitalization were predictors 13. Shorvon S. The management of status epilepticus. J Neurol Neurosurg
of poor outcome. Psychiatry 2001;70(suppl II):227.
14. Mazarati AM, Wasterlain CG, Sankar R, Shin D. Self-sustaining
Conclusions status epilepticus after brief electrical stimulation of the perforant
path. Brain Res 1998;801:2513.
For the general physician, recognition of SE in both its
convulsive and non-convulsive or subtle forms is of paramount 15. Chen J, Wasterlain C. Status epilepticus: pathophysiology and
management in adults. Lancet Neurol 2006;5:24656.
importance. Prompt initiation of first- and second-line therapy is
critical for management of this devastating condition and early 16. Theodore WH, Porter RJ, Albert P, Kelley K, Bromfield E, Devinsky
O, Sato S: The secondarily generalized tonic-clonic seizure: a
referral is important when ventilatory care and intravenous
videotape analysis. Neurology 1994;44:1403-7.
anesthesia are anticipated. The role of emergent EEG cannot be
overemphasized not only in the recognition of non-convulsive SE 17. Delorenzo RJ, Garnett LK, Towne AR, DeLorenzo RJ, Garnett LK,
Towne AR, Waterhouse EJ, Boggs JG, Morton L, Choudhry MA,
but also when continuous intravenous therapy is to be initiated
Barnes T, Ko D. Comparison of status epilepticus with prolonged
with midazolam or barbiturates. Diagnosis and management seizure episodes lasting from 10 to 29 minutes. Epilepsia 1999;40:164
of the precipitating event are likely to determine the outcome 9.
of SE related to acute symptomatic etiologies. Primary health 18. WasterlainCG, Mazarati AM, Naylor D, Niquet J, Liu H,
care centers should be equipped with basic facilities for the Suchomelova L, Baldwin R, Katsumori H, Shirasaka Y, Shin D,
initial management of SE. With more and more governmental Sankar R. Short-term plasticity of hippocampal neuropeptides
and nongovernmental ambulance service facilities becoming and neuronal circuitry in experimental status epilepticus. Epilepsia
available in major cities and towns, pre-hospital treatment of 2002;43(suppl 5):209.
SE needs emphasis. These measures, hopefully, will improve 19. Treiman DM, Walton NY, Kendrick C. A progressive sequence of
the outcome of SE in terms of both the morbidity and mortality electroencephalographic changes during generalized convulsive
during the coming years. status epilepticus. Epilepsy Res 1990;5:4960.
20. Mazarati AM, Wasterlain CG. N-methyl-D-asparate receptor
References antagonists abolish the maintenance phase of self-sustaining status
1. DeLorenzo RJ, Hauser WA, Towne AR. A prospective, population- epilepticus in rat. Neurosci Lett 1999;265:18790.
based epidemiologic study of status epilepticus in Richmond, 21. Kapur J, Macdonald RL. Rapid seizure-induced reduction of
Virginia. Neurology 1996;46:102935. benzodiazepine and Zn2+ sensitivity of hippocampal dentate
2. Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. granule cell GABAA receptors. J Neurosci 1997;17:753240.
Incidence of status epilepticus in Rochester, Minnesota, 19651984. 22. Naylor DE, Liu H, Wasterlain CG. Trafcking of GABA(A) receptors,
Neurology 1998;50:73541. loss of inhibition, and a mechanism for pharmacoresistance in status
3. Coeytaux A, Jallon P, Galobardes B, Morabia A. Incidence ofstatus epilepticus. J Neurosci 2005;25:772433.
epilepticus in French-speaking Switzerland: EPISTAR. Neurology 23. Hamil NE, Cock HR, Walker MC. Acute down-regulation of
2000;55:6937. adenosine A(1) receptor activity in status epilepticus. Epilepsia
4. Knake S, Rosenow F, Vescovi M, Oertel WH, Mueller HH, WirbatzA, 2012;53:177-88.
Katsarou N, Hamer HM, Status Epilepticus Study Group Hessen 24. Aminoff MJ, Simon RP. Status epilepticus: causes, clinical features
(SESGH). Incidence of status epilepticus in adults in Germany: a and consequences in 98 patients. Am J Med 1980;69:65966.
prospective, population-based study. Epilepsia 2001;40:75962. 25. Lowenstein DH, Alldredge BH. Status epilepticus at an urban
5. Vignatelli L, Tonon C, DAlessandro R. Bologna Group for theStudy publichospital in the 1980s. Neurology 1993;143:4838.
of Status Epilepticus. Incidence and short-term prognosis of status 26. DeLorenzo RJ, Pellock JM, Towne AR, Bogges JG. Epidemiologyof
epilepticus in adults in Bologna, Italy. Epilepsia 2003;44:9648. status epilepticus. J ClinNeurophysiol1995;12:31625.
6. Neligan A, Shorvon S. Frequency and prognosis of convulsive
SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL. 61 63
27. Fountain NB. Status epilepticus: risk factors and complications. 37. Mctague A, Kneen R, Kumar R, Spinty S, Appleton R. Intravenous
Epilepsia 2000;41(Suppl.2):S23S30. levetiracetam in acute repetitive seizures and status epilepticus in
28. Vignatelli L, Tonon C, DAlessandro R. Bologna Group for the Study children: Experience from a childrens hospital. Seizure 2012;21:529-
of Status Epilepticus. Incidence and short-term prognosis of status 534.
epilepticus in adults in Bologna, Italy. Epilepsia 2003;44:9648. 38. AlvarzV,Januel J-M, Burnand B, Rossetti AO. Second line status
29. Mhodj I, Nadiaye M, Sene F, Sow PS, Sow HD, Diagana M, Diaye IP, epilepticus treatment: comparison of phenytoin, valproate and
Diop AG. Treatment of status epilepticus in a developing country. levetiracetam. Epilepsia 2011;52;1292-6.
Neurophysiol Clin 2000;30:1659. 39. Hfler J, Unterberger I, Dobesberger J, Kuchukhidze G, Walser G,
30. Garzon E, Fernandes RM, Sakamoto AC. Analysis of clinical Trinka E. Intravenous lacosamide in status epilepticus and seizure
characteristicand risk factors for mortality in human status clusters. Epilepsia 2011;52:14852.
epilepticus. Seizure 2003;12:23745. 40. Trinka E. What is the evidence to use new intravenous AEDs in
31. Murthy JMK, Jayalaxmi S, Kanikannan M. Convulsive status status epilepticus? Epilepsia 2011;52(Suppl. 8):358.
epilepticus: clinical prole in a developing country. Epilepsia 41. Misra UK, Kalitha J, Rajesh P. Sodium valproate versus phenytoin
2007;48:221723. in status epilepticus: a pilot study. Neurology 2006;67:340-2.
32. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, 42. Agarwal P, Kumar N,Chandra R,Gupta G, Antony A,Garg N.
PaleschY, Barsan W. Intramuscular versus intravenous therapy for Randomised study of intravenous valproate and phenytoin in status
prehospital status epilepticus. N Engl J Med 2012;366:591600. epilepticus. Seizure 2007;16;527-32.
33. Shorvon S, Baulac M, Cross H, Trinka E, Walker M. The drug 43. Synowiec AS, Yandora KA, Yenugadhati V. The efficacy of
treatment of status epilepticus in Europe: censensus document from topiramatein adult refractory status epilepticus: experience of a
a workshop at the first London Colloquium on Status Epilepticus. tertiary care center. Epilepsy Res 2012;98:232-7.
Epilepsia 2008;49:127785. 44. Shorvon S, Trinka E. Status epilepticus making progress. Epilepsia
34. Cock HR, ESETT Group. Established status epilepticus treatment 2011;52(Suppl.8):1-2.
trial (ESETT). Epilepsia 2011;52(Suppl. 8):502. 45. Shorvon S, Ferlisi M. The treatment of super-refractory status
35. Claassen J. Treatment of refractory status epilepticus with epilepticus: a critical review of available therapies and a clinical
pentobarbital, propofol, or midazolam: a systematic review. treatment protocol. Brain 2011;134:280218.
Epilepsia 2002;43:146153. 46. Drislane F, Blum A, Lopez M, Gautam S, Schomer D. Duration of
36. Misra UK, Kalita J, Maurya PK. Levetiracetam versus lorazepam in refractory status epilepticus and outcome: Loss of prognostic utility
status epilepticus: a randomized, open labeled pilot study. J Neurol after several hours. Epilepsia 2009;50:1566-71.
2012;259:645-8.