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  IN THIS Article
 ::  Abstract
 :: Introduction
 :: Epidemiology
 :: History
 :: Definition
 :: Classification of SE
 :: Pathophysiology
 ::  Physiological an...
 :: Management of SE
 ::  Stage-wise Treat...
 :: Prognosis
 :: Acknowledgment
 ::  References
 ::  Article Figures
 ::  Article Tables

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REVIEW ARTICLE
Year : 2011  |  Volume : 57  |  Issue : 3  |  Page : 242-252

Status epilepticus: Why, what, and how


Department of Neurology, Sanjay Gandhi PGIMS, Lucknow, Uttar Pradesh, India

Date of Submission24-Nov-2009
Date of Decision19-Dec-2009
Date of Acceptance07-Dec-2010
Date of Web Publication22-Sep-2011

Correspondence Address:
U K Misra
Department of Neurology, Sanjay Gandhi PGIMS, Lucknow, Uttar Pradesh
India
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DOI: 10.4103/0022-3859.81807

PMID: 21941070

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 :: Abstract 

Status epilepticus (SE) is an important neurological emergency with high mortality and morbidity. The first official definition of SE was the product of 10 th Marseilles colloquium held in 1962 which was accepted by International League Against Epilepsy in 1964. There are as many types of SE as of seizures. SE is supposed to result from failure of normal mechanisms that terminate an isolated seizure. In half of the cases, there is no history of epilepsy and SE is precipitated by some intercurrent infection. In children, it is often infection, whereas in adults, the major causes are stroke, hypoxia, metabolic derangements, and alcohol intoxication or drug withdrawal. The treatment of SE aims at termination of SE, prevention of seizure recurrence, management of precipitating causes, and the management of complications. The extent of investigations done should be based on the clinical picture and cost benefit analysis. The first line antiepileptic drugs (AED) for SE include benzodiazepines, phenytoin, phosphenytoin, and sodium valproate. Mortality of SE ranges between 7 and 39% and depends on underlying cause and response to AEDs.


Keywords: Electroencephalography, status epilepticus, etiology, treatment


How to cite this article:
Nair P P, Kalita J, Misra U K. Status epilepticus: Why, what, and how. J Postgrad Med 2011;57:242-52

How to cite this URL:
Nair P P, Kalita J, Misra U K. Status epilepticus: Why, what, and how. J Postgrad Med [serial online] 2011 [cited 2014 Jul 30];57:242-52. Available from: http://www.jpgmonline.com/text.asp?2011/57/3/242/81807



 :: Introduction Top


Status epilepticus (SE) is an important neurological emergency with high mortality and morbidity. The incidence of SE varies depending on the population studied. [1],[2],[3],[4],[5] In India, the incidence of SE is likely to be high due to high prevalence of epilepsy, central nervous system (CNS) infections, and treatment gap. Considering the 18.3 per 100 000 population incidence of SE in USA and extrapolating it to India, it is estimated that the incidence of convulsive SE is likely to exceed 183 000, resulting in heavy burden on the society. This review focuses on the management of SE with theoretic and clinical considerations involved in choosing antiepileptic drugs (AED).


 :: Epidemiology Top


The annual incidence of SE in US is 18.3 to 41 per 100 000 population and in Europe, 10.3 to 17.1 per 100 000 population and that of nonconvulsive SE is 2 to 8 per 100 000. [1],[2],[3],[4],[5],[6] SE incidence is probably higher in poorer populations. [2] In half of the cases, there is no history of epilepsy and SE is precipitated by some intercurrent infection. In children, the etiology of SE is usually infection and in adults, the major causes are stroke, hypoxia, metabolic derangements, and alcohol intoxication or drug withdrawal. [7] In patients with epilepsy, SE is often precipitated by drug withdrawal due to noncompliance with antiepileptic drugs. SE of focal onset accounts for the majority of cases of SE. An epidemiological study on SE reported that 69% of episodes in adults and 64% of episodes in children were of focal onset; these resulted in secondary generalization in 43% in the adults and 36% in children. The incidence of SE was bimodally distributed, occurring most frequently in the first year of life and after 60 years of age. Males are affected more frequently than the females, which is partly attributed to lower seizure threshold in males compared with females. [1],[2] Patients above 60 years of age are at the highest risk of developing SE, with an incidence of 86 per 1 000 000 population per year. [1],[2] A hospital-based study from India, however, revealed peak incidence during fourth and fifth decades. In about 53.8% of patients, SE was due to either CNS or systemic infections. [8] However, etiology may vary depending on the population studied. Studies from intensive care units (ICUs) have demonstrated that SE is a major cause of coma. [9],[10] Fourteen percent of patients with convulsive SE remained in altered sensorium after control of convulsions; on Electroencephalography (EEG), they were found to have nonconvulsive SE, thus highlighting the importance of either regaining the consciousness or absence of epileptiform discharges on EEG. [9]


 :: History Top


Epilepsy is known since antiquity. The term epilepsy is derived from Greek word Epilambenein meaning "to seize" or "to attack." In Ayurvedic literature, epilepsy is mentioned as Apasmara (apa - negation or loss, smara - recollection or consciousness) and it is mentioned in Chinese literature as early as 770 to 221 BC. At around 400 BC, epilepsy was described as "sacred disease"; its first description is in the writings of Babylon during 300 to 600 BC. [11] The term SE first appeared in English literature in the translation of the lecture of Desire Bournville who gave the detailed clinical description. [12] The term has evolved from the phrase "etat de mal" which was a slang used by epileptic patients in Paris.


 :: Definition Top


The first definition of SE probably comes from Clark and Prout: "maximal development of epilepsy in which seizures are so frequent that coma and exhaustion are continuous between the seizures." [13] In his text book of neurology, Kinner Wilson described SE as the severest form of epilepsy. [14] The first official definition of SE was the product of 10 th Marseilles colloquium held in 1962 which was accepted by ILAE (International League Against Epilepsy) in 1964. [15] SE is a seizure that persists for a significant length of time or is repeated frequently enough to produce a fixed and enduring epileptic condition. This definition was retained in the revised classification published in 1971 and was slightly modified a decade later as "a seizure that persists for sufficient length of time or repeated frequently enough that recovery between attacks does not occur." [16] The official definition did not specify the duration of seizures. Over the years, various investigators have tried to define the duration of 30 minutes. The basis for this lies in the animal studies during 1970s and 1980s, which revealed significant brain damage after 30 minutes of seizure, despite control of blood pressure (BP), respiration, and temperature. [17],[18],[19],[20]

The mechanism of neuronal injury in human beings is complex and includes factors other than the duration of SE such as systemic derangements due to persistence of seizures. [21] Moreover, the duration and therapeutic response of SE may depend upon the underlying etiology. [22] It has been observed that spontaneous cessation of generalized convulsive seizures is unlikely after 5 minutes [23] ; hence, for defining SE, duration as short as 5 minutes has been suggested. [24] The duration of typical isolated seizure is easy to define. In a study on thousands of patients with generalized tonic clonic seizures, it was found that tonic phase lasted for 1 to 20 seconds; clonic phase, 30 seconds; and postictal tonic contraction, up to 4 minutes. [25] Using Video EEG analysis of 47 patients, the mean duration of tonic clonic phase of seizure was 62 seconds (range, 16-108 seconds). [23] In a patient with continuous seizures, it is unreasonable and impractical to wait for 30 minutes before treatment is initiated. In the prehospital treatment of SE, the duration of SE was defined as seizures persisting for more than 5 minutes. [24] In Veterans Affairs cooperative trial on treatment of generalized convulsive SE, the duration of 10 minute was used to define SE. [26]

Operational definition for generalized SE in adults and older children (>5 years) refers to >5 minutes of continuous seizure or 2 or more discrete seizures between which there is incomplete recovery of consciousness. Mechanistic definition of SE refers to a condition in which there is failure of normal factors that serve to terminate a typical generalized tonic clonic seizure. [21] Some studies have compared seizures of 10 to 29 minutes duration with seizures lasting >30 minutes and found that half of the seizures of 10 to 29 minutes stop spontaneously even without AED. [27]


 :: Classification of SE Top


Classification of SE is necessary for the appropriate management. There are several schemes for classifying SE. Seizure type by the ILAE [28] and its dichotomy of focal and generalized onset are also used to categorize SE on the basis of the assumption that there is a status epilepticus equivalent for every seizure type. Using both clinical and EEG criteria, SE is subdivided into generalized convulsive status (tonic-clonic, tonic, clonic, and myoclonic), generalized nonconvulsive (absence) status, elementary partial status (with several subtypes), and complex partial status. SE can also be categorized according to patients' age into SE confined to early childhood, later childhood, childhood and adult life, and confined to adult life [Table 1]. [29] Epilepsy Research Foundation Workshop defines nonconvulsive SE as a term used to denote a range of conditions in which electrographic seizure activity is prolonged and results in nonconvulsive clinical symptoms. [30] A convenient formulation of non convulsive status epilepticus (NCSE) is the alteration of consciousness or behavior from baseline state for at least 30 minutes without convulsive movements, and the presence of one or more of the following epileptiform patterns:
Table 1: Classification of status epilepticus based on age


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  1. Repetitive focal or generalized epileptiform activity (spikes, sharp waves, spike-and-wave, sharp-and-slow wave complexes) or rhythmic theta or delta activity at more than two per second.
  2. The above EEG patterns at less than one per second, but with improvement or resolution of epileptic activity and improvement in the clinical state following intravenous (IV) injection of a rapidly acting AED, such as a benzodiazepine.
  3. A temporal evolution of epileptiform or rhythmic activity at more than 1 Hz with change in location or frequency over time.


A simple classification of NCSE may be into (1) complex partial SE (CPSE) and (2) generalized nonconvulsive SE. [31]

However, NCSE is best subdivided by age, and further subdivided into the forms of NCSE seen in the epileptic encephalopathies, acute brain injury, and those with a history of epilepsy without encephalopathy and some boundary syndromes. [30]


 :: Pathophysiology Top


SE is thought to result from failure of mechanisms that normally terminate an isolated seizure. This failure can arise from abnormal persistence of excessive excitation or ineffective recruitment of inhibition. Experimental studies suggest that there is an induction of reverberating seizure activity between hippocampus and parahippocampal structures and seizure progresses through a sequence of distinct electrophysiological changes. [32] The proposed mechanisms of SE are as follows:

  1. Constant activation of hippocampus.
  2. Loss of GABA-mediated inhibitory synaptic transmission in hippocampus.
  3. Glutaminergic excitatory synaptic transmission, important for sustaining SE.


Excitatory amino acids are thought to be involved in the pathogenesis of SE, which is supported by the fact that prolonged SE occurs following ingestion of mussels containing domoic acid, an analogue of glutamate. [33] In experimental SE, seizures rapidly become self-sustaining and continue long after the withdrawal of the epileptogenic stimulus whether chemical or electrical. [34],[35],[36],[37],[38],[39] Vicedomini and Nadler in their self-sustaining model of SE showed that a series of ten after-discharges were sufficient to trigger self-sustaining SE and once self-sustaining SE is established, it is easily stopped only by drugs which directly or indirectly inhibit glutamatergic neurotransmission. [40],[41] Barbiturates and other GABAergic drugs never become totally ineffective but lose potency and may require high doses resulting in cardiovascular depression. [42]

It is suggested that in the first few seconds, there is protein phosphorylation, opening and closure of the ionic channels, release of neurotransmitters and modulators, and receptor desensitization. In seconds to minutes, receptor trafficking results in the movement of the existing receptors from the synaptic membrane into the endosomes, or their mobilization from storage sites to the synaptic membrane. This process drastically changes excitability by altering the number of inhibitory and excitatory receptors available in the synaptic cleft. [43] In minutes to hours time range, there are plastic changes in neuropeptide modulators which are often maladaptive, leading to a state of raised excitability. This is supported by immunocytochemical and confocal microscopy studies which have revealed a decrease in the number of GABA-A subunits present on the synaptic membrane and an increase inside the cell. [43] Endocytosis of the GABA-A receptors might partly explain the failure of GABA-A inhibition and the progressive pharmacoresistance to benzodiazepines (BDZ) as self-sustaining SE proceeds. [43],[44],[45],[46] Other mechanisms like accumulation of intracellular chloride or higher bicarbonate might also play a part in loss of GABA-mediated inhibition. [47],[48] Interestingly, extrasynaptic GABA-A receptors do not endocytose, raising the possibility that stimulation of those extrasynaptic receptors might be useful in the treatment of SE. At the same time, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl D-aspartate (NMDA) receptor subunits move to the synaptic membrane where they form additional excitatory receptors [Figure 1]. This change further increases excitability during uncontrolled seizures. [49] Neuronal damage in SE result from sustained NMDA-mediated neuronal stimulation which leads to apoptosis. [50] When these neuronal cells are depolarized, the Mg 2+ ions blocking the channel diffuses outward, allowing sodium ions and Ca 2+ to flood the cell, resulting in a cascade of Ca +2 -mediated cytotoxic events, leading to neuronal injury, cell lysis, and cell death. The cell destruction triggered in this manner may be reversible if SE is terminated within the first hour. It has been shown that heat-shock protein (72 kDa, HSP-72) is induced in some neurons in SE and that it may have a neuroprotective role. [51]
Figure 1: Schematic diagram shows change in postsynaptic receptors after continued status epilepticus. The GABAergic receptors are endocytosed and its number is decreased by clathrin, and the clathrin-coated vesicles are destroyed by the endosomes; however, the glutamate receptors are upregulated. C = clathrin-coated vesicle

Click here to view


In experimental studies following generalized tonic clonic SE, brain damage has been demonstrated; hyperthermia was demonstrated to result in hippocampal damage. [52] In animal studies, despite optimal control of BP, temperature, partial pressure of oxygen, and partial pressure of carbon di oxide, SE resulted in neuronal damage in substantia nigra pars reticularis after 30 minutes and in third and fourth layer of neocortex as well as in CA1 and CA4 pyramidal neurons of hippocampi after 45 to 120 minutes. [18]


 :: Physiological and Systemic Changes Top


In the early stage of SE, there is massive release of catecholamines [53] which result in tachycardia, arrhythmias, high systemic, pulmonary, and left atrial pressure, and occasionally pulmonary edema. [19],[54],[55],[56],[57] Blood glucose is elevated. [19] Respiratory failure and lactic acidosis result in metabolic acidosis. Hyperpyrexia with increased white cell counts in SE may be mistaken for infection. [58] Low-grade cerebrospinal fluid (CSF) pleocytosis may follow SE. [51],[59] BP declines 15 to 30 minutes after SE and may be markedly low after 2 hours of continuous seizure activity. Besides, there may be hypoglycemia. [19] Renal failure may occur because of rhabdomyolysis and myoglobinuria. [60] In the initial phase of SE, cerebral blood flow increases to meet the elevated demands, thereby increasing the intracranial pressure. [61] Later, cerebral edema ensues; in focal seizures, focal brain edema may be present. In general, the physiological changes in SE can be divided into two phases. In phase 1, compensatory mechanisms prevent cerebral damage. In phase 2, these mechanisms fail and there is an increasing risk of cerebral damage as the status progresses. The transition from phase 1 to phase 2 occurs after about 30 to 60 minutes of continuous seizures. These physiological changes do not necessarily occur in all the patients. The type and extent of the changes depend on etiology, clinical circumstances, and the methods of treatment used. [62]


 :: Management of SE Top


The first step in managing SE is to ascertain that the patient has seizures. A single generalized seizure with complete recovery may not require treatment. Once diagnosis of SE is made, the treatment should be started immediately. Though the duration of seizure for diagnosis of SE is controversial, any patient who arrives in emergency and is convulsing would require aggressive treatment. The treatment of SE should proceed with the following 4 aims:

  • Termination of SE
  • Prevention of seizure recurrence
  • Management of precipitating causes
  • Management of complications


Maintaining the patient's airway and oxygenation is most important step in the management of SE. Intubation is not required if airway is patent. BP and pulse should be checked. In patients with history of seizures, one should check if patient has missed the medication recently. A screening neurological examination is necessary to check for focal intracranial lesion.

One should promptly obtain IV access and send the blood for blood sugar, serum electrolyte, and AED levels (if the patient was on treatment with AED), intoxicants screen (if no cause is found), and blood counts wherever indicated. Isotonic saline infusion should be started; however, if hypoglycemia is suspected, 100 mg thiamine followed by 50 ml 25% glucose solution is infused. Thiamine is used to avert Wernicke's encephalopathy in a susceptible patient. Blood gases should be determined to ensure adequate oxygenation.

Acidosis, hypoxia, and hyperpyrexia are commonly associated and generally resolve with control of SE. Pharmacological treatment of SE is initiated according to the accepted guidelines. Imaging (computed tomography [CT] scan) is recommended after stabilization of patient. If imaging is normal, CSF examination is performed to rule out CNS infection.

Utility of different tests in SE

A number of tests such as lumbar puncture, metabolic and toxin screening, genetic studies, and imaging studies are recommended in the management of SE. These tests should not be blindly recommended but should be obtained depending on the clinical need.

EEG: In a patient with convulsive SE, where the diagnosis is clinically apparent, performing EEG may be difficult and may not be required. However, it may be useful in a patient with SE who remains comatose, despite control of convulsions (coma in such patients may be due to drug overdose or ongoing seizures) and to rule out nonconvulsive SE.

The following four patterns of EEG changes have been reported in SE: discrete, merging, continuous, and periodic lateralizing epileptiform discharges. In human beings, however, the sequential transition of EEG is not always found. In a study on 70 patients with SE, EEG revealed discrete pattern in 4, merging in 5, continuous in 5, periodic in 6, multiple patterns in 2, and slowing in 29 patients. Clinical seizure recurred within 24 hours in 38 patients, 15 of them had epileptiform discharges at 1 hour EEG. [63] Early EEG after 1 hour of control of convulsive SE predicted seizure recurrence. EEG can help to confirm that the episode of SE has ended, especially when there are doubts about ongoing subtle seizures. EEG monitoring of patients up to 24 hour after clinical signs of SE had ended, revealed that nearly half of their patients continued to demonstrate electrographic seizures that often had no clinical correlation. EEG monitoring of SE patients after clinical control of SE is thus regarded important for optimal management. [9] The patients with SE who fail to recover rapidly and completely should be monitored by EEG for at least 24 hour to ensure that the recurrent and/or subtle SE are not missed. Monitoring is also advised if there are periodic discharges on EEG in SE patients who are in altered sensorium, though they do not have obvious seizures. Periodic discharges in such a situation predict SE recurrence. In comatose patients without clinical signs of seizure activity, up to 8% met criteria for nonconvulsive SE. [64] The duration and delay in diagnosis of nonconvulsive SE was strongly linked to mortality in another ICU-based study. [65] American Academy of Neurology has made specific recommendation regarding various investigations in SE, including EEG in children. [66] An EEG may be considered in a child presenting with new onset SE as it may determine whether there are focal or generalized abnormalities that may influence diagnostic and treatment decisions (Level C, class III evidence) [67],[68],[69],[70],[71],[72] (Levels and classes of evidence explained in [Table 2] and [Table 3]). [73] Although NCSE occurs in children who present with SE, there are insufficient data to support or refute recommendations regarding whether an EEG should be obtained to establish this diagnosis (Level U). An EEG may be considered in a child presenting with SE if the diagnosis of pseudo SE is suspected (Level C, class III evidence). [74]
Table 2: Classes of studies


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Table 3: Recommendation levels A-C or U


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Neuroimaging

During SE, neuroimaging may be used to exclude other neurologic conditions. Therefore, it is important to identify the neuroimaging features that are associated with SE. In a study on three patients, the magnetic resonance imaging (MRI) and CT findings during partial SE mimicked those of acute ischemic stroke. Diffusion weighted imaging (DWI) and T2-weighted MRI showed cortical hyperintensity with a corresponding low apparent diffusion coefficient, and CT showed an area of decreased attenuation with effacement of sulci and loss of gray-white differentiation. However, the lesions did not respect vascular territories; there was increased signal of the ipsilateral middle cerebral artery on MRA, and leptomeningeal enhancement appeared on postcontrast MRI. On follow-up imaging, the abnormalities had resolved. [75] Several case studies have demonstrated reduced Apparent Diffusion Co efficients (ADCs) in patients with focal SE. [75],[76],[77] Combined use of DWI and perfusion imaging in a series of 10 patients presenting with CPSE showed regional hyperintensity on DWI, and a reduction of the ADC in (i) hippocampal and pulvinar region of the thalamus in six, (ii) pulvinar and cortical regions in 2, (iii) only the hippocampal region in 1, and (iv) hippocampal, pulvinar, and cortex in 1. In all the patients, a close spatial correlation of focal hyperperfusion with areas of ADC/DWI changes was present. Follow-up MRI examinations showed partial or complete resolution of diffusion and perfusion abnormalities, depending on the length of the follow-up interval. [78] DWI and T2-weighted changes were seen throughout the cerebral cortex, hippocampus, amygdale, and medial thalamus in rat brains after 4 hours of SE. [79] According to the guidelines, neuroimaging may be considered for the evaluation of the child with SE if there are clinical indications or if the etiology is unknown (Level C, class III evidence). [67],[68],[70],[71],[72] If neuroimaging is done, it should only be done after the child is appropriately stabilized and the seizure activity controlled. There is insufficient evidence to support or refute recommending routine neuroimaging in SE (Level U).

Recommendations for other investigations

There are insufficient data to support or refute whether blood cultures should be done on a routine basis in children in whom there is no clinical suspicion of infection (Level U).

There are insufficient data to support or refute whether LP should be done on a routine basis in children in whom there is no clinical suspicion of a CNS infection (Level U).

AED levels should be considered when a child with epilepsy on AED prophylaxis develops SE (Level B, class II and III evidence). [68],[69],[80],[81],[82],[83],[84]

Toxicology testing may be considered in children with SE when no apparent etiology is immediately identified. It should be noted that a specific serum toxicology level is required, rather than simply urine toxicology screening (class III). [67],[68],[85],[86],[87],[88],[89],[90],[91]

Studies for inborn errors of metabolism may be considered when the initial evaluation reveals no etiology, especially if there is a preceding history suggestive of a metabolic disorder (Level C, class III evidence). [67],[69],[82],[83],[86],[87],[90],[92]

There are insufficient data to support or refute whether genetic testing (chromosomal or molecular studies) should be done routinely in children with SE (Level U).

For routine practice, one can follow some simple measures; CSF examination is indicated if CNS infection is suspected. AED levels should be tested if the patient was on AED and there is a likelihood of drug default. EEG is useful in the first seizure and for the diagnosis of nonconvulsive SE. Genetic and metabolic studies are recommended if there is family history of inborn errors of metabolism or clinical suggestion of a hereditary metabolic or genetic disease. Toxicology tests are recommended if no other cause of SE could be found out.

Pharmacologic therapy of SE

The goal of pharmacologic therapy is rapid termination of clinical and electrical seizures. The drugs for controlling SE should be administered parenterally. Midazolam and paraldehyde can be given intramuscularly; diazepam, midazolam, and paraldehyde by the rectal route; but all others must be given by IV injection [Table 4].
Table 4: Antiepileptic drugs used in status epilepticus


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In a survey among neurologists in USA, the first choice for the treatment of generalized convulsive SE was lorazepam (76%) followed by fosphenytoin or phenytoin (PHT) (95%) if the first line therapy fails. When both failed, 43% physician would choose phenobarbital, 19% would use either infusion phenobarbitone, midazolam, or propofol, and 16% would choose IV sodium valproate (SVA). [93] In VA co-operative study, the success rate of different drugs was 64.9% for lorazepam, 58.2% for phenobarbitone, 55.8% for PHT/diazepam, and 43.6% for PHT alone. In this study, lorazepam demonstrated statistically significant advantage over PHT (P = 0.02). There was no significant difference among other agents. AEDs had been categorized into first line, 2 nd line, and 3 rd line. Aggregate response to 2 nd line was 7% and 3rd line was 2.3%. [26] Earlier, 85% success rate with lorazepam has been reported in convulsive SE. [94]

Benzodiazepines

The benzodiazepines (BDZ) are among the most effective AEDs in the treatment of SE. The commonly used BDZ are diazepam, lorazepam, and midazolam. This class of drugs enhances GABA and barbiturate receptor complex.

Diazepam

Diazepam is one of the drugs of choice for first line management of SE, as evidenced by randomized controlled trials (RCTs). [24],[95],[96] It enters CNS rapidly because of high lipid solubility but after 15 to 20 minutes is redistributed in the body, thus reducing its clinical efficacy. [24],[97] Sufficient cerebral levels are reached within one minute of a standard IV injection and rectal administration produces peak levels at about 20 minutes. Despite this fast distribution half life, the elimination half life is about 24 hours; the sedative effect, therefore, could accumulate with repeated administration. Diazepam in dose of 5 to 10 mg/min controls seizures in 75% patients. [26],[94],[96] Adverse effects include respiratory suppression, hypotension, and sedation. Diazepam can be administered by intramuscular, IV, and per rectal routes. Bolus IV doses of diazepam should be given in an undiluted form at a rate not exceeding 2 to 5 mg/min. The adult bolus IV or rectal dose in SE is 10 to 20 mg; additional 10 mg doses can be given at 15 minute intervals, to a maximum of 40 mg. In children, the equivalent bolus dose is 0.2 to 0.3 mg/kg.

Lorazepam

Lorazepam has emerged as preferred BDZ for management of SE based on RCT. [95] Lorazepam is less lipid soluble than diazepam with distribution half life of 2 to 3 hours compared with 15 minutes for diazepam. Hence, it has a longer duration of action. Lorazepam binds more tightly to GABA receptors compared with diazepam, resulting in longer duration of action. The usual dose of lorazepam is 4 to 8 mg and the anticonvulsant effect lasts 6 to 12 hours. This can be repeated once after 20 minutes if no effect has been observed. Its main disadvantage is the rapid development of tolerance, repeated doses being much less effective, and the drug has no place as long-term therapy. It has a broad spectrum of activity and terminates seizures in 75 to 80% cases. [94] Sudden hypotension or respiratory collapse is less likely because of its relative lipid-insolubility and the lack of accumulation after single bolus injections.

Midazolam

Midazolam is commonly used as first choice BDZ for treating SE in Europe. [98],[99],[100],[101],[102] It can be given by intramuscular injection, as well as by the rectal or IV routes. Midazolam has short-lived action and there is tendency to relapse following a single bolus injection. It is cleared from the body faster than diazepam with less tendency to accumulate. Midazolam is usually given intramuscularly or rectally in premonitory status, in a dose of 5 to 10 mg (in children, 0.15-0.3 mg/kg), which can be repeated once after 15 minutes. 5 to 10 mg IV bolus injection can also be given (repeated to a maximum of 0.3 mg/kg in adults). There is limited experience of an IV infusion.

Which of the BDZ to choose: Comparison of IV diazepam (10 mg) and lorazepam (4 mg) as first line treatment of SE in a randomized double blind trial on 78 patients did not show any difference in efficacy or latency of action, but the number of patients was too small to define true significance. Seizures were terminated 58% in diazepam and 78% in lorazepam group at latency of 2 and 3 minutes, respectively. [94]

Phenytoin

Phenytoin (PHT) is one of the most effective drugs in treating SE. PHT causes relatively little respiratory or cerebral depression, although hypotension is more common. The initial infusion of PHT takes 20 to 30 minutes in an adult, and the onset of action is slow. The usual PHT solutions have a pH of 12, and if added to large volumes of fluid at lower than physiological pH (5% glucose), precipitation may occur in the bag or tubing; normal saline is safer. The rate of infusion of PHT solution should not exceed 50 mg/min, and it is prudent to reduce this to 20 to 30 mg/min in the elderly. The adult dose is 15 to 18 mg/kg and main advantage of PHT is lack of sedative side effect; however, a number of potential serious side effects may occur. Cardiac arrhythmia and hypotension have been reported in individuals above 40 year of age. It is likely that these side effects are due to rapid administration and propylene glycol which is used as its diluent. In addition, local irritation and dizziness may accompany IV administration.

Fosphenytoin

Fosphenytoin was approved by Food and Drug Administration (FDA) in 1996 for the treatment of SE. It is a water-soluble prodrug of PHT which is completely converted into PHT in 8 to 15 minutes following IV administration; hence, the side effects related to propylene glycol are avoided. [103] Fosphenytoin is 100% bioavailable and is rapidly and completely converted to PHT in adults after IV and intramuscular administration. [104],[105] Conversion is mediated by both alkaline and acid phosphatases present ubiquitously on cell surfaces of vascularized tissue [106] and the rate of conversion is independent of age, race, and gender. In patients with impaired renal and hepatic function, the conversion is actually rapid as a result of self displacement from plasma proteins and increased clearance to PHT; therefore, 10 to 20% dose reduction may be considered in these patients and also in patients with hypoalbuminemia. Fosphenytoin, like PHT, is used for treating acute partial and generalized tonic clinic seizures. It is metabolized by liver and its half life is 14 hours. Therapeutic plasma PHT concentration is achieved faster with fosphenytoin than PHT. This may be related to several factors such as faster rate of infusion, rapid conversion, and displacement of PHT by fosphenytoin from the plasma protein binding site. 1.5 mg fosphenytoin is equivalent to 1 mg of PHT. The dose concentration and infusion rates are expressed as PHT equivalent (PE). The initial dose of fosphenytoin is 15 to 20 mg PE/kg and can be infused 150 mg PE/min (3 times faster than IV PHT). Fosphenytoin can be given intramuscularly, but therapeutic concentration is not achieved till 30 minutes. [107]

Phenobarbital

Phenobarbital is used in SE when BDZ and PHT have failed to control seizures. Initial loading dose is 15 to 20 mg/kg. Since high dose of phenobarbital is sedating, airway protection is important to prevent aspiration. IV phenobarbital is also associated with hypotension. It may take about 30 minutes for the therapeutic dose to be infused. It is diluted in polyethylene glycol which results in complications such as renal failure, myocardial depression, and seizures. These limitations restrict the use of phenobarbital in patients who have not responded to other drugs.

Sodium valproate

FDA approved sodium valproate (SVA) for the use in SE in 1997. Parenteral SVA is used primarily for rapid loading and when oral therapy is not possible. It has a broad spectrum and may also be useful in absence and myoclonic SE. In a study on 60 SE patients, majority of whom had convulsive SE, seizures were aborted by SVA in 66% and by PHT in 42%. SVA as a second choice was effective in 79% and PHT in 25% patients, suggesting the higher efficacy of SVA compared with PHT. [108] Patients not responding to 2 first line AEDs may be given parenteral SVA, especially in the setting where intubation and artificial ventilation are not feasible. It is given as a bolus of 30 mg/kg and can be infused at a rate of 3 to 6 mg/kg/min. [109]

Paraldehyde

Paraldehyde [110],[111],[112] is a drug still widely used in the treatment of SE, especially as an alternative to diazepam in early stage of SE, where IV administration is difficult or conventional AEDs are contraindicated or proved ineffective. The drug is given rectally or intramuscularly and absorption by both routes is fast and complete. The onset of action is rapid and paraldehyde is effective for many hours. Seizures tend to recur after initial control. Toxicity is unusual provided, the correct dose of paraldehyde is not exceeded, it is freshly reconstituted and is not decomposed. Inappropriately diluted or decomposed paraldehyde is highly toxic by any route of administration. The intramuscular injection must be deep into the muscle (usually gluteal), well away from the sciatic nerve. IV infusion is now rarely recommended. Paraldehyde also reacts with rubber and plastic, but a plastic syringe is acceptable if given rapidly after drawing the solution. It can be given at a dose of 10 to 20 ml of 50% solution rectally or intramuscularly (children, 0.07-0.35 ml/kg), which can be once repeated after 15 to 30 minutes. For rectal or intramuscular administration, it is diluted in equal measure with normal saline or arachis oil. For IV administration, it should be given as a 5% infusion in 5% dextrose, freshly made up every three hours.

Thiopentone

Thiopentone [113],[114],[115],[116] is a barbiturate anesthetic. It should be given in ICU settings as patients require intubation and artificial ventilation. The most troublesome side effect is persisting hypotension and many patients require pressor therapy. Thiopentone has a strong tendency to accumulate and may also cause acute hypersensitivity. It should be administered cautiously in the elderly, and in those with cardiac, hepatic, or renal diseases. Formal clinical trials of its safety and effectiveness in either adults or children are few. Thiopentone can react with polyvinyl infusion bags or infusion sets. The continuous infusion should be made up in normal saline. The aqueous solution is unstable if exposed to air. Thiopentone is infused as 100 to 250 mg bolus over 20 seconds, with further 50 mg boluses every 2 to 3 minutes until seizures are controlled, with intubation and artificial ventilation. The IV infusion is then continued at the minimum dose required to control seizure activity (burst suppression on the EEG), usually between 3 and 5 mg/kg/h. After 24 hours, the dose should be controlled by blood level monitoring. Thiopentone should be continued for no less than 12 hours after seizure activity has ceased, and then slowly discontinued.

Propofol

Propofol [117],[118],[119] is a nonbarbiturate anesthetic agent. Although it is widely used in the management of refractory SE, published experience is limited. Propofol is highly lipid soluble and has a high volume of distribution resulting in rapid action. Its effects are maintained only whilst the infusion is continued. Propofol administration causes profound respiratory and cerebral depression, requiring assisted ventilation. Long-term administration causes marked lipaemia and may result in acidosis. It may cause involuntary movements which should not be mistaken for seizures. Its safety in young children has not been established. It can be given as 2 mg/kg bolus dose which can be repeated if seizures continue, succeeded by an infusion of 5 to 10 mg/kg/h guided by EEG. The dose should be gradually reduced, and the infusion tapered 12 hours after seizure remission. In the elderly, the dose should be lowered.

Levetiracetam

Levetiracetam (LEV) is the (S) enantiomer of piracetam. It was initially approved by FDA as an add-on therapy for the treatment of patients with partial onset seizures in 1999. The mechanism of action differs from other AEDs and appears to be related to its binding to the synaptic vesicle protein 2A. It was introduced for the treatment of SE in 2006 and there are insufficient data on the safety and efficacy of this drug in SE. However, there are several case reports and retrospective analysis supporting its use in SE. [120],[121],[122] One ICU-based prospective study has shown that LEV is useful in refractory SE. [123] European Federation of Neurological Societies proposes the usefulness of LEV for the treatment of refractory complex partial SE. [124]

Lacosamide

This drug does not seem to act by any of the mechanisms of currently available AEDs, but the exact molecular mechanisms of action of lacosamide have not yet been clarified. In addition to exerting anticonvulsant activity, it has shown to have the potential to retard kindling-induced epileptogenesis. [125] One case report has shown that IV lacosamide is effective in the treatment of nonconvulsive SE. [126] Another case report showed efficacy of oral lacosamide in refractory convulsive SE. [127] However, further large randomized studies are required to prove the efficacy and safety of this drug for the treatment of SE.


 :: Stage-wise Treatment of SE Top


The drug treatment of tonic clonic SE can be divided into different stages like premonitory stage, stage of early SE (0-30 minutes), stage of established SE (30-90 minutes), and stage of refractory SE (after 60/90 minutes).

Premonitory stage

In patients with established epilepsy, usually, a prodromal phase (the premonitory stage) presages status, during which seizures become increasingly frequent or severe. The early treatment gives better result and prevents the evolution of seizures to SE. In this stage, diazepam, midazolam, or paraldehyde is highly effective. These drugs may be administered at home under careful supervision. Midazolam has the advantage that it can be given by intramuscular injection or buccal instillation. A randomized trial has shown that buccal midazolam has equal efficacy and is as rapid as rectal diazepam. [128] It is more convenient, potentially faster to administer, and less stigmatizing. The dose used is 10 mg drawn up into a syringe and instilled into the mouth between the cheeks and gums.

Stage of early SE (0-30 minutes)

Once SE has developed, treatment should be carried out in hospital, under close supervision. Fast-acting BDZ such as IV lorazepam or diazepam are the drugs of choice. Rectal or intramuscular paraldehyde is a useful alternative to BDZ in early status, where facilities for IV injection or for resuscitation are not freely available. Majority of patients respond to these treatments. Patients with SE should be observed for 24 hours in the hospital following remission.

Stage of established SE (30-90 minutes)

The stage of established SE can be operationally defined as SE which has continued for 30 minutes despite treatment in early-stage. By this time, the physiological decompensation begins. Intensive care facilities are desirable. The first-line treatment options at this stage are PHT, fosphenytoin, or phenobarbitone, loading intravenously followed by repeated oral or IV supplementation. IV valproate or LEV may be considered particularly when intensive care facilities and ventilatory support are not available.

Stage of refractory SE (after 60/90 minutes)

If seizures continue for 60 to 90 minutes after the initiation of therapy, the stage of refractory status is reached and full anesthesia is required in ICU care. Prognosis of these patients is poor with high mortality and morbidity. A number of anesthetic agents have been administered, although few have been subjected to formal evaluation and all have drawbacks. The most commonly used anesthetics are as follows: the IV barbiturate thiopentone or propofol with full range of intensive care facilities, including EEG monitoring.


 :: Prognosis Top


The short-term mortality of SE has been reported as 7.6 to 39%. [1],[2],[3],[4],[5] Such a wide range is probably due to the differences in the study design, cause of SE, and healthcare facility. Underlying etiology is a powerful predictor of mortality, but not the seizure semiology. The predictors of mortality from SE included duration of seizures, age of onset, and etiology. [2],[129] The patients with cerebral anoxia, stroke, and CNS infection have high mortality. [8],[130] Patients with SE due to alcohol withdrawal and AED default or low therapeutic dose have relatively low mortality rate. In Richmond study, mortality was higher in adults (26%) compared with children (3%). [2] In a hospital-based study, mortality was 15.6% among 96 patients with a first SE episode. For the first SE episode, death was associated with potentially fatal etiology, age ≥65 years, and stupor or coma at presentation, but not with gender, history of epilepsy, SE type, or if treated late (≥1 hour). [131] A recent study on NCSE found extent of impairment of consciousness as the predictor of mortality. [132] In a retrospective review of patients of neuro ICU during 1993 to 2002, 43% patients were refractory to first line drugs and encephalitis was the most important cause of refractory SE. However, low levels of AED were associated with nonrefractory SE. Hyponatremia in the first 24 hours was significantly associated with refractory SE. [133] In nonfatal cases, SE is associated with significant morbidity. Studies have shown cognitive decline, as documented by neuropsychological testing after prolonged secondarily generalized partial SE. [134] SE is a neurological emergency and early treatment results in lesser mortality and better recovery.


 :: Acknowledgment Top


We thank Mr. Rakesh Kumar Nigam for secretarial help.

 
 :: References Top

1.Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Incidence of status epilepticus in Rochester, Minnesota, 1965-1984. Neurology 1998;50:735-45  Back to cited text no. 1
    
2.DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A prospective ,population based epidemiologic study of status epilepticus in Richmond,Virginia. Neurology 1996;46:1029-35  Back to cited text no. 2
    
3.Coeytaux A, Jallon P, Galobardes B, Morabia A. Incidence of status epilepticus in French speaking Switzerland. Neurology 2000;55:693-7  Back to cited text no. 3
    
4.Knake S, Rosenow F, Vescovi M, Oertel WH, Mueller HH, Wirbatz A, et al. Status Epilepticus Study Group Hessen (SESGH). Incidence of status epilepticus in adults in Germany: A prospective, population-based study. Epilepsia 2001;42:714-8.  Back to cited text no. 4
    
5.Vignatelli L, Tonon C, D'Alessandro R; Bologna Group for the Study of Status Epilepticus. Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy. Epilepsia 2003;44:964-8.  Back to cited text no. 5
    
6.Meierkord H, Holtkamp M. Non-convulsive status epilepticus in adults: clinical forms and treatment. Lancet Neurol 2007;6:329-39.  Back to cited text no. 6
    
7.Walker MC. The epidemiology and management of status epilepticus. Curr Opin Neurol 1998;11:149-54.  Back to cited text no. 7
    
8.Kalita J, Nair PP, Misra UK. A clinical, radiological and outcome study of status epilepticus from India. J Neurol 2010;257:224-9.  Back to cited text no. 8
    
9.DeLorenzo RJ, Waterhouse EJ, Towne AR, Boggs JG, Ko D, DeLorenzo GA, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998;39:833-40.   Back to cited text no. 9
    
10.Narayanan JT, Murthy JM. Nonconvulsive status epilepticus in a neurological intensive care unit: profile in a developing country. Epilepsia 2007;48:900-6.   Back to cited text no. 10
    
11.Wilson JV, Reynolds EH. Texts and documents.Translation and analysis of a cuneiform text forming part of Babylon treatise on epilepsy. Med Hist 1990;34:185-98.   Back to cited text no. 11
    
12.Bourneville DM.Recherches cliniques et therapeutiques sur l'epilepsie et l' hysterie Paris: Dilahaye,1876.  Back to cited text no. 12
    
13.Clark L, Prout T. Status epilepticus A clinical and pathological study in epilepsy .Am J Insanity 1903;60:291-306.  Back to cited text no. 13
    
14.Wilson S. Neurology. Baltimore Williams and Wilkins ,1940  Back to cited text no. 14
    
15.Commision on international classification of epileptic seizures. A proposed international classification of epileptic seizures. Epilepsia 1964;5:297-306.  Back to cited text no. 15
    
16.Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501.  Back to cited text no. 16
    
17.Sarice Bassin ,Teresa L Smith , Thomas P Bleck clinical review: Status Epilepticus critical care 2002;6:137-42.  Back to cited text no. 17
    
18.Nevander G, Ingvar M, Auer R, Siesjo BK . Status epilepticus in well oxygenated rats causes neuronal necrosis. Ann Neurol 1985;18:281-90.  Back to cited text no. 18
    
19.Meldrum BS, Horton RW. Physiology of status epilepticus in primates. Arch Neurol 1973;28:1-9.  Back to cited text no. 19
    
20.Lothman E. Biochemical basis and pathophysiology of status epilepticus. Neurology 1990;40:13-23.  Back to cited text no. 20
    
21.Lowenstein DH, Bleck T, Macdonald RL. It's time to revise the definition of status epilepticus. Epilepsia 1999;40:120-22  Back to cited text no. 21
    
22.Bleck T. Convulsive disorders. Status epilepticus. Clin Neuropharmacol 1991;14:191-198.   Back to cited text no. 22
    
23.Theodore WH, Porter RJ, Albert P, Kelley K, Bromfield E, Devinsky O, et al. The secondarily generalized tonic clonic seizure: A video tape analysis. Neurology 1994;44:1403-7.  Back to cited text no. 23
    
24.Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-7.  Back to cited text no. 24
    
25.Gastaut H, Broughton R. Epileptic seizures: Clinical and Electrographic features, diagnosis and treatment Springfield. IL:Charles C.Thomas1972:25-90.  Back to cited text no. 25
    
26.Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al. A comparison of four treatments for genetalized convulsive status epilepticus. N Engl J Med 1998;339:792-8.  Back to cited text no. 26
    
27.DeLorenzo RJ, Garnett LK, Towne AR, Waterhouse EJ, Boggs JG, Morton L, et al. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes. Epilepsia 1999;40:164-9.   Back to cited text no. 27
    
28.Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:676-85.  Back to cited text no. 28
    
29.Shorvon S. Status epilepticus:It's clinical features and treatment in children and adults.Cambridge,UK:Cambridge University Press 1994.  Back to cited text no. 29
    
30.Walker M, Cross H, Smith S, Young C, Aicardi J, Appleton R, et al. Nonconvulsive status epilepticus: Epilepsy Research Foundation workshop reports. Epileptic Disord 2005;7:253-96.  Back to cited text no. 30
    
31.Peter W. Kaplan The EEG of status epilepticus. J Clin Neurophysiol 2006;23:221-9.  Back to cited text no. 31
    
32.Lothman EW, Bertram EH 3rd, Stringer JL. Functional anatomy of hippocampal seizures. Prog Neurobiol 1991;37:1-82.   Back to cited text no. 32
    
33.Perl TM, Bédard L, Kosatsky T, Hockin JC, Todd EC, Remis RS. An outbreak of encephalopathy caused by eating mussels contaminated with domoic acid. N Engl J Med 1990;322:1775-80  Back to cited text no. 33
    
34.Buterbaugh GG, Michelson HB, Keyser DO. Status epilepticus facilitated by pilocarpine in amygdala-kindled rats. Exp Neurol 1986;94:91-102.  Back to cited text no. 34
    
35.Morrisett RA, Jope RS, Snead OC, III. Status epilepticus is produced by administration of cholinergic agonists to lithium-treated rats: Comparison with kainic acid. Exp Neurol 1987;98:594-605.   Back to cited text no. 35
    
36.Suchomelova L, Baldwin RA, Kubova H, Thompson KW, Sankar R, Wasterlain CG. Treatment of experimental status epilepticus in immature rats: Dissociation between anticonvulsant and antiepileptogenic effects. Pediatr Res 2006;59:237-43.  Back to cited text no. 36
    
37.Mazarati AM, Wasterlain CG, Sankar R, Shin D. Self-sustaining status epilepticus after brief electrical stimulation of the perforant path. Brain Res 1998;801:251-3.  Back to cited text no. 37
    
38.Lothman EW, Bertram EH, Bekenstein JW, Perlin JB. Selfsustaining limbic status epilepticus induced by 'continuous'hippocampal stimulation: Electrographic and behavioral characteristics. Epilepsy Res 1989;3:107-19.  Back to cited text no. 38
    
39.Lothman EW, Bertram EH, Kapur J, Stringer JL. Recurrent spontaneous hippocampal seizures in the rat as a chronic sequel to limbic status epilepticus. Epilepsy Res 1990;6:110-8.  Back to cited text no. 39
    
40.Vicedomini JP, Nadler JV. A model of status epilepticus based on electrical stimulation of hippocampal afferent pathways. Exp Neurol 1987;96:681-91.  Back to cited text no. 40
    
41.Mazarati AM, Wasterlain CG. N-methyl-D-asparate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat. Neurosci Lett 1999;265:187-90.  Back to cited text no. 41
    
42.Krishnamurthy KB, Drislane FW. Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus. Epilepsia 1996;37:863-7.  Back to cited text no. 42
    
43.Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 2005;25:7724-33.  Back to cited text no. 43
    
44.Naylor DE, Wasterlain CG. GABA synapses and the rapid loss of inhibition to dentate gyrus granule cells after brief perforant-path stimulation. Epilepsia 2005;46:142-7.   Back to cited text no. 44
    
45.Mazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Time dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res 1998;814:179-85.  Back to cited text no. 45
    
46.Kapur J, Macdonald RL. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J Neurosci 1997;17:7532-40.  Back to cited text no. 46
    
47.Kaila K, Voipio J. Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate conductance. Nature 1987;330:163-5.   Back to cited text no. 47
    
48.Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995;269:977-81.  Back to cited text no. 48
    
49.Wasterlain CG, Liu H, Mazarati A, Balwin RA. NMDA receptor trafficking during the transition from single seizures to status epilepticus. Ann Neurol 2002;52:16.   Back to cited text no. 49
    
50.Bleck TP. Refractory status epilepticus in 2001.Arch Neurol 2002;59:188-9.   Back to cited text no. 50
    
51.Wasterlain CG, Fujikawa DG, Penix L, Sankar R. Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 1993;34:S37-53.   Back to cited text no. 51
    
52.Meldrum BS, Brierly JB. Prolonged epileptic seizure in primates. Ischemic cell change and its relation to ictal physiological events. Arch Neurol 1973;28:10-7.   Back to cited text no. 52
    
53.Benowitz NL, Simon RP, Copeland JR. Status epilepticus: Divergence of sympathetic activity and cardiovascular response. Ann Neurol 1986;19:197-9.  Back to cited text no. 53
    
54.Gravenstein JS, Anton AH, Wiener SM, Tetlow AG. Catecholamine and cardiovascular response to electroconvulsive therapy in man. Br J Anaesth 1965;37:833-9.  Back to cited text no. 54
    
55.Kiessling M, Hossman KA, Kleihues P. Pulmonary edema during bicuculline-induced seizures in rats. Exp Neurol 1981;74:430-8.   Back to cited text no. 55
    
56.Simon RP, Bayne LL, Tranbaugh RF, Lewis FR. Elevated pulmonary lymph flow and protein content during status epilepticus in sheep. J Appl Physiol 1982;52:91-5.   Back to cited text no. 56
    
57.Oxbury JM, Whitty CW. Causes and consequences of status epilepticus in adults. A study of 86 cases. Brain 1971;94:733-44.   Back to cited text no. 57
    
58.Aminoff MJ, Simon RP. Status epilegticus. Causes, clinical features and consequences in 98 patients. Am J Med 1980;69:657-66.   Back to cited text no. 58
    
59.Schmidley JW, Simon RP. Postictal pleocytosis. Ann Neurol 1981;9:81-4.  Back to cited text no. 59
    
60.Grossman RA, Hamilton RW, Morse BM, Penn AS, Goldberg M. Nontraumatic rhabdomyolysis and acute renal failure. N Engl J Med 1974;291:807-11.   Back to cited text no. 60
    
61.Howse DC, Caronna JJ, Duffy TE, Plum F. Cerebral energy metabolism, pH and blood flow during seizures in the cat. Am J Physiol 1974;227:1444-5.   Back to cited text no. 61
    
62.Shorvon S. The management of status epilepticus. J Neurol Neurosurg Psychiatry 2001;70 2:II22-7.  Back to cited text no. 62
    
63.Kalita J, Misra UK, Patel R. Initial EEG in status epilepticus is helpful in predicting seizure recurrence. Electromyogr Clin Neurophysiol 2006;46:139-44.  Back to cited text no. 63
    
64.Towne AR, Waterhouse EJ, Boggs JG, Garnett LK, Brown AJ, Smith JR Jr, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;54:340-5.  Back to cited text no. 64
    
65.Lowenstein DH, Aminoff MJ. Clinical and EEG features of status epilepticus in comatose patients. Neurology 1992;42:100-4.  Back to cited text no. 65
    
66.Riviello JJ Jr, Ashwal S, Hirtz D, Glauser T, Ballaban-Gil K, Kelley K, et al. American Academy of Neurology Subcommittee; Practice Committee of the Child Neurology Society. Practice parameter: Diagnostic assessment of the child with status epilepticus (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2006;67:1542-50.  Back to cited text no. 66
    
67.Lacroix J, Deal C, Gauthier M, Rousseau E, Farrell CA. Admissions to a pediatric intensive care unit for status epilepticus: A 10-year experience. Crit Care Med 1994;22:827-32.   Back to cited text no. 67
    
68.Dunn DW. Status epilepticus in children: Etiology, clinical features, and outcome. J Child Neurol 1988;3:167-73.   Back to cited text no. 68
    
69.Karasalihoglu S, Oner N, Celtik C, Celik Y, Biner B, Utku U. Risk factors of status epilepticus in children. Pediatr Int 2003;45:429-34.   Back to cited text no. 69
    
70.Gulati S, Kalra V, Sridhar MR. Status epilepticus in Indian children in a tertiary care center. Indian J Pediatr 2005;72:105-8.   Back to cited text no. 70
    
71.Shinnar S, Kang H, Berg AT, Goldensohn ES, Hauser WA, Moshe SL. EEG abnormalities in children with a first unprovoked seizure. Epilepsia 1994;35:471-6.   Back to cited text no. 71
    
72.Shinnar S, Berg AT, Moshe SL, O'Dell C, Alemany M, Newstein D, et al. The risk of seizure recurrence following a first unprovoked afebrile seizure in childhood: An extended follow-up. Pediatrics 1996;98:216-25.  Back to cited text no. 72
    
73.Bernard S. Chang, Daniel H. Lowenstein Practice parameter: Antiepileptic drug prophylaxis in severe traumatic brain injury: Report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 2003;60;10-6  Back to cited text no. 73
    
74.Pakalnis A, Paolicchi J, Gilles E. Psychogenic status epilepticus in children: Psychiatric and other risk factors. Neurology 2000;54:969-70.   Back to cited text no. 74
    
75.Lansberg MG, O'Brien MW, Norbash AM, Moseley ME, Morrell M, Albers GW. MRI abnormalities associated with partial status epilepticus. Neurology 1999;52:1021-7.  Back to cited text no. 75
    
76.Kim JA, Chung JI, Yoon PH, Kim DI, Chung TS, Kim EJ, et al. Transient MR signal changes in patients with generalized tonic clonic seizure or status epilepticus: Periictal diffusion-weighted imaging. AJNR Am J Neuroradiol 2001;22:1149-60.   Back to cited text no. 76
    
77.Diehl B, Najm I, Ruggieri P, Foldvary N, Mohamed A, Tkach J, et al. Periictal diffusion-weighted imaging in a case of lesional epilepsy. Epilepsia 1999; 40:1667-71.  Back to cited text no. 77
    
78.Szabo K, Poepel A, Pohlmann-Eden B, Hirsch J, Back T, Sedlaczek O, et al. Diffusion-weighted and perfusion MRI demonstrates parenchymal changes in complex partial status epilepticus. Brain 2005;128:1369-76   Back to cited text no. 78
    
79.Fabene PF, Marzola P, Sbarbati A, Bentivoglio M. Magnetic resonance imaging of changes elicited by status epilepticus in the rat brain:diffusion-weighted and T2-weighted images, regional blood volume maps, and direct correlation with tissue and cell damage. Neuroimage 2003;18:375-89.  Back to cited text no. 79
    
80.Phillips SA, Shanahan RJ. Etiology and mortality of status epilepticus in children: A recent update. Arch Neurol 1989;46:74-6.   Back to cited text no. 80
    
81.Garzon E, Fernandes RM, Sakamoto AC. Analysis of clinical characteristics and risk factors for mortality in human status epilepticus. Seizure 2003;12:337-345.   Back to cited text no. 81
    
82.Kwong KL, Lee SL, Yung A, Wong VC. Status epilepticus in 37 Chinese children: Aetiology and outcome. J Paediatr Child Health 1995;31:395-8.   Back to cited text no. 82
    
83.Ibrahim SH, Yezdan MA, Nizami SQ. Status epilepticus in children: A five-year experience at Aga Khan University Hospital. J Pak Med Assoc 2003;53:597-9.   Back to cited text no. 83
    
84.Maytal J, Novak G, Ascher C, Bienkowski R. Status epilepticus in children with epilepsy: the role of antiepileptic drug levels in prevention. Pediatrics 1996;98:1119-21.   Back to cited text no. 84
    
85.Aicardi J, Chevrie JJ. Convulsive status epilepticus in infants and children: A study of 239 cases. Epilepsia 1970;11:187-97.   Back to cited text no. 85
    
86.Tabarki B, Yacoub M, Selmi H, Oubich F, Barasaoui S, Essoussi AS. Infantile status epilepticus in Tunisia: Clinical, etiological and prognostic aspects. Seizure 2001;10:365-9.   Back to cited text no. 86
    
87.Scholtes FB, Renier WO, Meinardi H. Status epilepticus in children. Seizure 1996;5:177-84.   Back to cited text no. 87
    
88.Mah JK, Mah MW. Pediatric status epilepticus: A perspective from Saudi Arabia. Pediatr Neurol 1999;20:364-9.   Back to cited text no. 88
    
89.Yager JY, Cheang M, Seshia SS. Status epilepticus in childhood. Can J Neurol Sci 1988;15:402-4.   Back to cited text no. 89
    
90.Kwong KL, Chang K, Lam SY. Features predicting adverse outcomes of status epilepticus in childhood. Hong Kong Med J 2004;10:156-9.   Back to cited text no. 90
    
91.Maegaki Y, Kurozawa Y, Hanaki K, Ohno K. Risk factors for fatality and neurological sequelae after status epilepticus in children. Neuropediatrics 2005;36:186-92.   Back to cited text no. 91
    
92.Eriksson KJ, Koivikko MJ. Status epilepticus in children: Aetiology, treatment and outcome. Dev Med Child Neurol 1997;39:652-8.  Back to cited text no. 92
    
93.Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: A survey of neurologists. J Neurol Sci. 2003;211:37-41.   Back to cited text no. 93
    
94.Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452-4.   Back to cited text no. 94
    
95.Lowenstein DH. Status epilepticus. West J Med 1998;168:263.  Back to cited text no. 95
    
96.Shaner DM, McCurdy SA, Herring MO, Gabor AJ. Treatment of status epilepticus: A prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 1988;38:202-7.  Back to cited text no. 96
    
97.Ramsay RE, Hammond EJ, Perchalski RJ, Wilder BJ. Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol 1979;36:535-9.  Back to cited text no. 97
    
98.Parent JM, Lowenstein DH. Treatment of refractory generalized status epilepticus with continuous infusion of midazolam. Neurology 1994;44:1837-40.   Back to cited text no. 98
    
99.Dundee JW, Halliday NJ, Harper KW, Brogden RN. Midazolam: A review of its pharmacological properties and therapeutic uses. Drugs 1984;28:519-43.  Back to cited text no. 99
    
100.Galvin GM, Jelinek GA. Midazolam: An effective intravenous agent for seizure control. Arch Emerg Med 1987;4:169-72.  Back to cited text no. 100
    
101.Ghilain S, Van Rijckevorsel-Harmant K, de Barsy TH. Midazolam in the treatment of epileptic seizures. J Neurol Neurosurg Psychiatry 1988;51:732.   Back to cited text no. 101
    
102.Jawad S, Oxley J, Wilson J, Richens A. A pharmacodynamic evaluation of midazolam as an antiepileptic compound. J Neurol Neurosurg Psychiatry 1986;49:1050-4.  Back to cited text no. 102
    
103.Ramsay RE, DeToledo J. Intravenous administration of fosphenytoin: Options for the management ofseizures. Neurology. 1996;46:S17-19.   Back to cited text no. 103
    
104.Eldon MA, Loewen GR, Voigtman RE, Holmes GB, Hunt TL, Sedman AJ. Pharmacokinetics and tolerance of fosphenytoin and phenytoin administered intravenously to healthy subjects. Can J Neurol Sci 1993;20:S180.  Back to cited text no. 104
    
105.Boucher BA, Feler CA, Dean JC, Michie DD, Tipton BK, Smith KR Jr, et al. Pharmacotherapy. The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. Pharmacotherapy 1996;16:638-45  Back to cited text no. 105
    
106.Leppik IE, Boucher R, Wilder BJ, Murthy VS, Rask CA, Watridge C, et al. Phenytoin prodrug: Preclinical and clinical studies. Epilepsia 1989;30 Suppl 2:S22-6.  Back to cited text no. 106
    
107.Uthman BM, Wilder BJ, Ramsay RE. Intramuscular use of fosphenytoin: An overview. Neurology 1996;46:S24-8.   Back to cited text no. 107
    
108.Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: A pilot study. Neurology 2006;67:340-2.  Back to cited text no. 108
    
109.Wheless JW, Vazquez BR, Kanner AM, Ramsay RE, Morton L, Pellock JM. Rapid infusion with valproate sodium is well tolerated in patients with epilepsy. Neurology 2004;63:1507-8.   Back to cited text no. 109
    
110.Koren G, Butt W, Rajchgot P, Mayer J, Whyte H, Pape K, et al. Intravenous paraldehyde for seizure control in newborn infants. Neurology 1986;36:108-11.  Back to cited text no. 110
    
111.Browne TR. Paraldehyde, Chlormethiazole, and Lidocaine for treatment of status epilepticus. In:Delgado Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Status epilepticus: mechanisms of brain damage and treatment. Advances in neurology, vol 34.New York: Raven Press, 1983:509-517.  Back to cited text no. 111
    
112.Lockman LA. Paraldehyde. In: Levy RH, Dreifuss FE,Mattson RH, Meldrum BS, Penry JK, eds. Antiepileptic Drugs, 3rd ed. New York: Raven Press, 1989:881-886.  Back to cited text no. 112
    
113.Partinen M, Kovanen J, Nilsson E. Status epilepticus treated with barbiturate anaesthesia with continuous monitoring of cerebral function. Br Med J 1981;282:520-1.  Back to cited text no. 113
    
114.Young EB, Blume WT, Bolton CF, Warren KG. Anesthetic barbiturates in refractory status epilepticus. Can J Neurol Sci 1980;7:291-2.  Back to cited text no. 114
    
115.Orlowski JP, Erenberg G, Lueders H, Cruse RP. Hypothermia and barbiturate coma for refractory status epilepticus. Crit Care Med 1984;12:367-72.  Back to cited text no. 115
    
116.Lowenstein DH, Aminoff MJ, Simon RJ. Barbiturate anesthesia in the treatment of status epilepticus: clinical experience of 14 patients. Neurology 1988;38:395-400.  Back to cited text no. 116
    
117.MacKenzie SJ, Kapadia F, Grant IS. Propofol infusion for control of status epilepticus. Anaesthesia 1990;45:1043-5.  Back to cited text no. 117
    
118.Alia G, Natale E, Mattaliano A, Daniele O. On two cases of status epilepticus treated with propofol. Epilepsia 1991;32:77.  Back to cited text no. 118
    
119.Wood PR, Browne GP, Pugh S. Propofol infusion for the treatment of status epilepticus. Lancet 1988;1:480-1.   Back to cited text no. 119
    
120.Berning S, Boesebeck F, van Baalen A, Kellinghaus C. Intravenous levetiracetam as treatment for status epilepticus. J Neurol 2009;256:1634-42  Back to cited text no. 120
    
121.Möddel G, Bunten S, Dobis C, Kovac S, Dogan M, Fischera M, et al. Intravenous levetiracetam: A new treatment alternative for refractory status epilepticus. J Neurol Neurosurg Psychiatry 2009;80:689-92.  Back to cited text no. 121
    
122.Eue S, Grumbt M, Müller M, Schulze A. Two years of experience in the treatment of status epilepticus with intravenous levetiracetam. Epilepsy Behav 2009;15:467-9.  Back to cited text no. 122
    
123.Tripathi M, Vibha D, Choudhary N, Prasad K, Srivastava MV, Bhatia R, et al. Management of refractory status epilepticus at a tertiary care centre in a developing country. Seizure 2010;19: 109-11.  Back to cited text no. 123
    
124.Meierkord H, Boon P, Engelsen B, Göcke K, Shorvon S, Tinuper P, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2010;17:348-55.  Back to cited text no. 124
    
125.Brandt C, Heile A, Potschka H, Stoehr T, Löscher W. Effects of the novel antiepileptic drug lacosamide on the development of amygdala kindling in rats. Epilepsia 2006;47:1803-9.  Back to cited text no. 125
    
126.Kellinghaus C, Berning S, Besselmann M. Intravenous lacosamide as successful treatment for nonconvulsive status epilepticus after failure of first-line therapy. Epilepsy Behav 2009;14:429-431  Back to cited text no. 126
    
127.Tilz C, Resch R, Hofer T, Eggers C. Successful treatment for refractory convulsive status epilepticus by non-parenteral lacosamide. Epilepsia 2010;51:316-7.  Back to cited text no. 127
    
128.Mpimbaza A, Ndeezi G, Staedke S, Rosenthal PJ, Byarugaba J. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: A randomized clinical trial. Pediatrics 2008;121:e58-64   Back to cited text no. 128
    
129.Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27-34.  Back to cited text no. 129
    
130.Misra UK, Kalita J, Nair PP. Status epilepticus in central nervous system infections: an experience from a developing country. Am J Med 2008;121:618-23.   Back to cited text no. 130
    
131.Rossetti AO, Hurwitz S, Logroscino G, Bromfield EB. Prognosis of status epilepticus: Role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosurg Psychiatry 2006;77:611-5.  Back to cited text no. 131
    
132.Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology 2003;61:1066-73.  Back to cited text no. 132
    
133.Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in aneurological intensive care unit. J Neurol Neurosurg Psychiatry 2005;76:534-9.   Back to cited text no. 133
    
134.Krumholz A, Sung GY, Fisher RS, Barry E, Bergey GK, Grattan LM. Complex partial status epilepticus accompanied by serious morbidity and mortality. Neurology 1995;45:1499-50.  Back to cited text no. 134
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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