Status Epilepticus: An Overview

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REVIEWARTICLE

Status Epilepticus: An Overview Venkata Ramesh Yasam1,*, V.Senthil2,*, Satya Lavanya Jakki1 and N. Jawahar2 1,2

Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Udhagamandalam, Tamil Nadu - 643001, India

ARTICLEHISTORY Received: December 11, 2016 Revised: December 17, 2016 Accepted: December 30, 2016 DOI: 10.2174/13892002186661701060917 05

Abstract: Status epilepticus (SE) is an emergency situation, where immediate and effective treatment is required in least possible time as it is associated with neuronal damage, systemic complications, substantial morbidity and mortality depending on status type, duration, age and etiology. In the past few years, morbidity and mortality rate were improved, probably may be due to aggressive use of anti-epileptic drugs in emergency situations. Present literature gives an overview of the conditions leading to SE and its management guidelines in hospital and out of hospital setting emphasizing on the available drug therapies.

Keywords: Anti-epileptic drugs, Delivery systems, Management protocols, Drug therapy, Status epilepticus, Drug interactions. 1. INTRODUCTION The term ‘epilepsy’ was derived from the Greek word epilambanein, meaning, ‘to be overwhelmed by surprise’ or ‘to be seized’. Epilepsy is a serious neurological condition affecting 1-2% of the world population, characterised by recurrent, unprovoked seizures, sensory disturbances, abnormal behavior and loss of consciousness or all of these. Seizures can be divided into three major groups: focal, generalised and unknown (Fig. 1). Among all form of seizures, status epilepticus (SE) is a medical emergency that require immediate therapy. Status epilepticus is a neurologic emergency wherein an individual suffers from continuous or repetitive seizures in the brain, each lasting five minutes or more without regaining consciousness between seizures. The latest recommendation about the classification of SE was proposed based on various axes like semiology, etiology, electroencephalography (EEG) correlates and age. SE is a life threatening emergency with a high risk of serious neurological sequelae. SE should be seen as a complication of many disorders and caused mainly due to cerebral insult, either acute, acute on chronic or part of a chronic neurological condition. Main concern in SE is to stop seizures initially, as it affects the brain locally and systematically depending on the seizures severity and period of time. While maintaining and assessing the vital signs, rigorous effort must be made to identify and treat the underlying cause until it is managed [1, 2].

organisation (WHO) statistics, around 50 million people have epilepsy worldwide, and approximately 80% of epilepsy occurs in developing countries [5].

2. EPIDEMIOLOGY Calmeil (1824) first used the term état de mal, which at present is called Generalized Tonic-Clonic SE (GTCSE); which is characterized by repeated convulsive generalized seizures, without gaining consciousness or by confusion for few hours or days [3, 4]. The incidence of SE has a bimodal distribution, with the highest frequency in infants and children during their first 3 years of life and after the age of 60 years. Among adults, the highest risk of developing SE was observed in patients older than 60 years, with a frequency of 86 per 100,000 persons per year. As per world health *Address correspondence to these authors at the Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Udhagamandalam, Tamil Nadu, India; Tel: +91 8508325369; Fax: +91-423-2442937; E-mails: [email protected], [email protected] 1 these authors contributed equally to this work

4.1. Out-of-Hospital Treatment Treatment for SE should be started as soon as possible because there is a compelling need for effective treatment that can be initiated in the out-of-hospital phase by caregivers or paramedics. Use of pre-hospital treatment is now more widespread and many studies have demonstrated its effectiveness in treatment of SE with benzodiazepines. In a double-blind prospective study of more than 200 patients, out-of-hospital treatment for SE was compared on the use of I.V. lorazepam, diazepam and placebo [3]. Termination of SE was observed on admission to the hospital in 59.9% of those treated with lorazepam, 42.6% of those treated with diazepam and 21.1% of those treated with placebo. Risk and complications like respiratory depression, cardiac arrhythmia and hypotension were less frequent after being treated with lorazepam (10.6%) and diazepam (10.3%) as compared with placebo (22.5%). Furthermore after benzodiazepine treatment, short-term case fatality rates were lowered

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3. VARIOUS CONDITIONS LEADING TO SE Table 1 Summarizes the various factors triggering SE. In paediatrics, failure to stop SE leads to systemic cardiovascular dysfunction such as bradycardia, cardiac arrhythmia, tachycardia etc. SE has short term mortality rates ranging from 15% - 20% and increases with age. Therefore, initial and aggressive intervention provides the better chance for successful treatment of SE [6-9]. 4. MANAGEMENT OF SE AND GUIDELINES The main goal in the management and treatment of SE (Convulsive and nonconvulsive) is to maintain vital functions by terminating the seizures and identifying the underlying cause in the least possible time and treat it (Table 2). Treatment should be done in a structured approach developed by most experienced clinicians and team. During this time, both therapeutic and diagnostic interventions need to be carried out by explaining the condition clearly to the caregivers. In most of the countries, they have their own treatment recommendations and protocols for SE treatment based on a comprehensive literature review and subsequent expert consensus or they follow the international treatment guidelines [10-13].

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Fig. (1). Classification of epilepsy seizure types.

Table 1.

Potential underlying etiology triggering SE.

Autoimmune encephalitis CNS infections Drug issues

Genetic diseases: Head trauma Metabolic disturbances Mitochondrial disorders: Psychiatric Pre-existing epilepsy Remote CNS pathology

Anti-N-methyl-D-aspartic acid receptor antibodies, anti-voltage-gated potassium channel complex antibodies, paraneoplastic syndromes Encephalitis (Nonspecific encephalitis, Japanese encephalitis, Herpes simplex encephalitis, Malaria), Meningitis (tubercular, fungal, pyogenic), abscess, granuloma (Neurocysticercosis, tubercular), cerebral toxoplasmosis •

Non-compliance with AEDs

•

Withdrawal from opioid, benzodiazepine, barbiturate, alcohol and AEDs

•

Drug toxicity

Chromosomal aberrations, inborn errors of metabolism, malformations of cortical development, neurocutaneous syndromes Concussion, with or without epidural or subdural hematoma, intracranial hypertension, intracranial tumours (primary and secondary, benign or malignant) Electrolyte abnormalities, hypercarbia, hypoglycemia, hypoxia Lactic acidosis and stroke-like episodes (MELAS), alpers disease, occipital lobe epilepsy/MSCAE, neuropathy, ataxia and retinitis pigmentosa (NARP), mitochondrial encephalopathy, leigh syndrome, myoclonic encephalopathy with ragged red fibres (MERRF) Psychogenic spells, fuge states Breakthrough seizures Stroke, abscess, cortical dysplasia, traumatic brain injury

Stroke

Ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral sinus thrombosis

Toxic

Drug overdose, poisoning

Organ failure Special considerations in children

Others

Respiratory failure, thyroid and adrenal disorders Liver failure, renal and cardiac failure •

CNS infections, especially bacterial meningitis, inborn errors of metabolism, and ingestion are frequent causes of SE

•

Acute symptomatic SE is more frequent in younger children with SE

•

Prolonged febrile seizures are the most frequent cause of SE in children

Vasculitis, sepsis, chronic ethanol abuse in setting of ethanol intoxication or withdrawal, hypertensive encephalopathy, posterior reversible encephalopathy syndrome, hypoxia, cardiac arrest and cerebrovascular diseases

Status Epilepticus: An Overview

Table 2.

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The etiology, diagnostic work-up and prognosis for patients with SE. Convulsive SE

Nonconculsive SE

Definition

Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures

Non-Convulsive Status Epilepticus (NCSE) is persistent (e.g. >30 minute) change in behaviour and or mental processes from baseline associated with continuous epileptiform EEG changes but without major motor signs.

Treatment paradigms

As shown in Figure 3

Degree of aggressiveness

Fatal and prompt treatment is required.

Implications

Basic tests to be done in all patients

•

Usual oral AED therapy maintenance or reinstatement.

•

Under EEG control, intravenous benzodiazepines are used particularly if the diagnosis is not established.

•

Referral for EEG monitoring and/or specialist advice.

Less common and treatment is less urgent when compared with convulsive SE.

1.

Continuous monitoring of EEG and vital signs.

2.

Finger-stick glucose

3.

Laboratory tests: AED levels, magnesium, calcium (total and ionized), complete blood count, blood glucose and basic metabolic panel.

4.

Computed tomography (CT) scan.

Additional tests to be considered based on clinical presentation

Prognosis

1.

Brain magnetic resonance imaging (MRI)

2.

Lumbar puncture (LP)

3.

Toxic drug screening including toxins those frequently causing seizures (i.e., theophylline, isoniazid, cocaine, cyclosporine, alcohol, organophosphates, tricyclic antidepressants and sympathomimetics).

4.

Other laboratory tests: Inborn metabolism errors, serial troponins, AED levels, coagulation studies, liver functionality tests, arterial blood gas, and toxicology screening in blood and urine.

Mortality:

Mortality:

• At hospital discharge, 30 and 90 days: 10–20, 19–27 and 19 %.

At hospital discharge and 30days: 20–50 and 65 %

• The mortality of children in retrospective and prospective study was 3-11 and 3%.

Factors associated with poor outcome after NCSE:

Morbidity • Severe cognitive and neurological: 11–16 % • Functional status deterioration: 23–26 % • At 90 days after SE, Marked functional impairment: 39% (glasgow outcome scale score 2–4) Good recovery: 43 % (glasgow outcome scale score 5) Factors associated with poor outcome after GCSE: • Older age, duration of seizures, de novo development of SE in hospitalized patients, underlying etiology, presence of medical complications, onset focal neurological signs and impairment of consciousness. Mortality rate: • Development of de novo in hospitalized patients: 61% • In patients with adequate therapy: 8 % • In patients with insufficient therapy: 45 % • Delay in treatment and treatment gaps, medical complications, insufficient doses, lack of proper ventilation, EEG monitoring and wrong route of administration. • Adherence to standard protocols will help in better seizure control.

• Longer seizure duration, underlying etiology and impairment of mental status. • Mortality was 36% in patients diagnosed and treated for seizures within 30min compared with patients diagnosed and treated after 24h was 75%. • Patients treated and resolved from NCSE within 10h vs. mortality in patients with seizures continued longer than 20h were 10 and 85%. • 27% mortality was seen in NCSE after hospital discharge vs. 3 % comparing patients (with vs. without) known acute medical

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up to 7.7% in lorazepam and 4.5% in diazepam as compared with placebo (15.7%). Rectal dosage forms like diazepam are also considered as the most popular out-of- hospital treatment for many years [14, 15]. However, in the convulsive patient, rectal route of administration is difficult and embarrassing in public places. As an alternate, buccal midazolam was preferred over rectal dosage forms but the oral accessibility during seizures is challenging. A highly qualified, trained medical person is required for the use of I.V. route, where access is not practically possible in an emergency situation when the patient is not in a hospital. In such cases, nasal route of delivery was another promising and prominent first-line treatment option for the out-of hospital treatment of SE. Application of the nasal spray is convenient compared with the usual buccal, rectal and I.V. routes. Pharmacokinetics of nasal midazolam and I.V. route were compared and demonstrated in a study with healthy volunteers proving nasal routes high bioavailability and rapid uptake. It is also easy for parents, carers and paramedics to use and provide better seizure control than rectal diazepam [16]. 4.2. On Arrival of Hospital 4.2.1. In all Patients The initial treatment for a patient presenting to hospital in SE should be (Fig. 2): • Assessed for their airway and administer O2. •

Check blood pressure, circulation, respiratory rate and monitor heart rate along O2 saturation and vital signs are needed to be observed.

4.2.2. In Some Patients If SE persists, then some additional tests should be done. • •

•

Full blood count, blood culture, coagulation studies, bacter ial and viral PCR tests, Capillary blood gas, urea, true blood glucose, urine culture, electrolytes, calcium, toxic drug screen, anticonvulsant levels, hematologic chemistries were investigated. Establish I.V. line with normal saline. Once patient is stable, neuroimaging may be helpful.

4.3.2. Additional Investigation and History Examination • Obtain history by concentrating on episode antecedents, previous episodes, treatment, an accurate chronology of this seizure and information from carers, parents and paramedics is often useful. • Sometimes additional tests and screening studies for urine toxicology, ammonia, organic and urine amino acids may be helpful for better treatment. Based on the above results, alternative doses will be suggested if necessary along with standard doses. 5. ANTICONVULSANT DRUG THERAPY IN THE EMERGENCY ROOM Therapy involves exploring the potential routes (Table 3) for effective AEDs administration (Table 4 and Fig. 2) depending on the patient condition and status. Therapy was divided into various stages depending on the time of SE onset (i.e., early, established and refractory status). Seizures lasting longer than 30 minutes despite treatment with a benzodiazepine and intravenous (I.V.) AEDs are considered as established SE whereas SE in its most severe form with continuous or repetitive seizures lasting longer than 2h without responding to first- and second-line AED therapy are categorised under refractory SE (RSE).

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5.1. Benzodiazepines Benzodiazepines like diazepam, midazolam and lorazepam are the most commonly used and preferred initial choice of therapy for the treatment of SE, mainly because of their rapid onset of action and high efficacy in cessation of seizures; all benzodiazepines rapidly enter Cerebrospinal fluid (CSF), with peak concentrations usually attained within 15 min of dosage. The primary mechanism of action of benzodiazepines is receptor mediated enhancement of GABAergic transmission and along they also control continuous neuronal firing in a manner similar to phenytoin and carbamazepine. Several studies have compared the effectiveness of benzodiazepines like diazepam, lorazepam in the treatment of SE [17, 18]. Comparison studies revealed that the less lipophilic nature of lorazepam and its smaller volume of distribution lead to its serum and CSF levels increase much more slowly than that of diazepam. But it remains longer period of time in brain than in the serum, leading to its longer intracerebral half-life [12h] with increased brain: serum ratios over time as compared with diazepam (1520min) and, therefore, a potentially longer anti-convulsive effect. In accordance with recent data and cochrane review, it is clear that this property which lorazepam superior and first line drug in the acute treatment of SE. Signs of breathing disturbances, hypotension, and consciousness should be checked. In refractory SE, barbiturates are preferred over benzodiazepines due to alteration in the functional properties of hippocampal dentate granule cell GABA(A) receptors leading to loss of animals sensitivity to diazepam during SE [1722]. 5.2. Phenytoin Phenytoin rapidly controls and shows prolonged effect in controlling seizures. Traditionally, phenytoin treatment follows after benzodiazepine treatment. Phenytoin has many advantages, even though many more alternatives are available. Phenytoin is used when benzodiazepines fail to control seizures and sometimes also used along with benzodiazepines for prolonged effect to control seizure. It is advantageous in that it is not sedative and it can be easily switched to oral delivery if SE is terminated. Its inadequate dose is the major problem using it in emergency. In general, 20mg/kg is required, occasional an additional dose up to 5-10mg/kg is necessary to control seizures, but the maximum tolerated rate of administration is 50 mg/min; at this rate in 28-30% causes hypotension and in 2% causes arrhythmias (ectopic beats or bradycardia) in the patients above age of 50 years with pre-existing cardiac disease. So for administering 1000mg least possible time required is 20min, but practically it is administered more slowly. This slow rate of administration and severe cardiovascular side-effects are the occasional reasons for its failure. On injecting phenytoin solution paravenously, it leads to severe tissue damage, phlebitis (purple glove syndrome) in 1.5% of patients due to its high alkaline pH 12. Phenytoin is hepatically metabolised and its drug interactions with concomitant medication needs to be considered [23-25]. 5.3. Fosphenytoin Fosphenytoin has been recommended and preferred over conventional phenytoin for SE mainly for three reasons; (1) administration is faster than phenytoin, (2) it has a pH of 8.5 compared to phenytoin pH 12, and (3) ethanol or propylene glycol is not present in vehicle, thereby reducing the potential for cutaneous or cardiovascular side-effects. Fosphenytoin infusion rate can be tolerated up to three times faster than those for phenytoin and within 10min, therapeutic concentrations are established [25]. Fosphenytoin initial dose is 15-20mg phenytoin equivalents per kilogram. Fosphenytoin is administered at a rate of 100-150 mg/min compared with 50 mg/minute for phenytoin. I.V. administration is preferred over intramuscular administration during SE, because absorption is unreliable and can take as long as 30 minutes with lower local toxicity. Clinically significant side-effects like cardio-vascular or hypotension,



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Fig. (2). Algorithm for the management and treatment of status epilepticus.

Table 3.

Potential routes of administration for antiepileptic drugs.

Table (3) contd…. Route/Site of Administration

Route/Site of Administration

Delivery Mechanism

Oral

Swallowing Buccal mucosa

Intranasal

Inhalation

Transdermal

Transdermal

Brain

Carrier vehicles

Sublingual Parenteral

Cerebrospinal

Implant

Delivery Mechanism

Polymer wafers

Subcutaneous

encapsulated cells

Intramuscular

Infusion pumps

Intravenous

micro/nanoparticles

Intrathecal

Local activation of prodrugs

Convection

Liposomes

Intraventricular

Vaginal

Gelling suppositories

Intracranial

Rectal

Gel Liquid

Extracranial


Table 4.

Yasam et al.

Delivery routes for effective AEDs administration.

Formulation Oral formulations

Rectal administration

Anti-Epileptic Drug

Formulation Type

Felbamate

Suspension, tablet

[49]

Lorazepam

Suspension, tablet

[16]

Pregabalin

Solution, capsules

[50]

Topiramate

Tablet, capsule, sprinkle capsule

[40]

Zonisamide

Capsules

[51]

Clonazepam

Suspension, tablet, disintegrating tablet

[52]

Lacosamide

Solution, tablet

[53]

Oxcarbazepine

Suspension, tablet

[54]

Rufinamide

Suspension, tablet

[55]

Vigabatrin

Powder for solution or suspension, tablets

[56]

Ethosuximide

Syrup, capsule

[57]

Lamotrigine

Tablet, chewable tablet, disintegrating tablet, ER tablet

[47]

Phenobarbital

Suspension, tablet, chewable, capsule, elixir, ER tablet, ER capsule, SR tablet

[58]

Tiagabine

Tablet

[59]

Valproate

Syrup, tablet, sprinkle capsules, DR tablet, ER tablet

[27]

Carbamazepine

Suspension, syrup, tablet, chewable tablet, SR tablet, ER tablet, ER capsule

[60]

Gabapentin

Solution, tablet, capsule

[61]

Levetiracetam

Solution, tablet, ER tablet

[34]

Primidone

Suspension, tablet, chewable tablet

[62, 63]

Midazolam

Syrup, solution

[17]

Phenytoin

Suspension, tablet, chewable tablet, capsule

[21]

Clobazam

Tablet

[64]

Stiripentol

Capsule

[65]

Diazepam

Suspension, tablet

[18, 19]

Phenobarbital

[66]

Valproate

[29]

Lamotrigine

[45]

Carbamazepine

[67]

Levetiracetam

[35]

Topiramate

[41]

Diazepam

[20]

Buccal and sublingual formulations

Midazolam

[68]

Lorazepam

[16]

parenteral formulations

Midazolam

IV, IM

[69]

Diazepam

IV, IM

[18, 70]

Levetiracetam

IV, IM

[71]

Fosphenytoin

IV, IM

[25]

Phenobarbital

IV

[58, 72]

Lorazepam

IV, IM

[16, 73]

Intranasal administration

Midazolam

[74]

Diazepam

[75]

Lorazepam

[76]



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Table (4) contd….

Formulation

Anti-Epileptic Drug

Formulation Type Novel delivery systems of AEDs.

Nanoemulsions

Lamotrigine

Intranasal

[46]

Clonazepam

Intranasal

[77]

Diazepam

Transdermal

[78]

Intranasal

[79]

MRZ 2/576 or probenecid

Parenteral

[80]

Diazepam

Oral

[81]

Clozapine

Parenteral

[82]

Nanocrystals

Lorazepam

Intranasal

[83]

Transdermal patch

Tiagabine

Transdermal

[84]

Osmotic pumps

Carbamazepine (Tegretol XR)

Oral

[85]

Magneto-nanoparticles

Ethosuximide

Parenteral

[86]

AMT

Parenteral

[87]

Carbamazepine

Oral

[88]

Diazepam

Oral

[89]

Solid lipid nanoparticles

Polymeric nano- or micro-particles

Liposomes

Thyrotropin

Intranasal

[46]

Ethosuximide

Parenteral

[90]

Phenytoin

Oral

[23]

GABA

Parenteral

[91]

Superoxide dismutase

Parenteral

[92]

Valproic acid

Parenteral

[30]

Amiloride

Parenteral

[93]

soft-tissue damage and phlebitis are less common. Most notable and potential advantage of substituting fosphenytoin for phenytoin is “purple glove syndrome” prevention, characterised by discoloration, distal limb oedema and pain [26]. In conclusion, we prefer fosphenytoin over phenytoin, especially when peripheral I.V. administration is planned/unavoidable. 5.4. Valproic Acid and Sodium Valproate Valproic acid I.V. infusion is used to treat SE. Valproate when compared with phenytoin by randomised study results shown no conclusive statistical difference (one sided t-tests were used) [27]. Even though it lacks class I evidence, I.V. valproate was used to treat SE as a third line drug in countries like Norway, Germany and it was used as first and second line drug for absence status, focal seizure without loss of awareness and focal seizure with alteration of awareness based on more than 300 published and documented cases of SE. On this basis and experience only it was seemed to be well effective and tolerated. It is eliminated hepatically. Switching to oral at any time is the possible advantage of treating with I.V. valproate. It has disadvantages like rare occurrences of pancreatitis, pharmacological interactions, especially with phenobarbital, possible induction of valproate encephalopathy and it is difficult to differentiate from on-going SE. Furthermore, valproate should not be used in patients with severe liver and mitochondrial diseases. In a prospective, open-label, multicentre, dose-escalation study of I.V. sodium valproate administered to patients with SE, 6 mg/kg/min infusion rate were maintained and doses of up to 30

mg/kg were well tolerated, without any clinically significant negative effects on pulse rate and blood pressure but caused only reversible mild-to-moderate adverse events, even among unstable SE patients with hypotension [28-32]. 5.5. Phenobarbitone In the first two years of life in neonatal and early infantile SE, phenobarbitone is used as a first line AED in treatment. The dosage prominently varies and depends on the age and weight of the patient respectively. On failure of benzodiazepine and phenytoin, phenobarbitone given at 20mg/kg dose, was found to have response latency and shorter cumulative convulsion when compared with combination of benzodiazepine and phenytoin in a small, nonblinded, randomised trial. It has some severe side effects like depression of respiratory drive, level of conciousness, which are accentuated on subsequent benzodiazepine administration. The major concern is its deleterious behavioral and cognitive side effects, so it should be evaded in school going children [33]. 6. NEW GENERATION ANTI-EPILEPTIC DRUGS 6.1. Levetiracetam It is used as on add-on drug in treating partial refractory and some generalized epilepsies like, progressive myoclonic epilepsies or refractory absence. It is not recommended as a first line drug in newly diagnosed epilepsies, though recent data support its role in the adolescent’s genetic generalized epilepsies, Juvenile myoclonic epilepsy (JME). The effective dose is 20-60mg/kg/day. The starting


dose is 20mg/kg in two doses by increasing dose levels for every 12 weeks till 60 mg/kg/day. It is the most effective and promising treatment option in hepatic failure patients, as it is not hepatically metabolised and has no known drug-drug interactions with minimal respiratory and cardiovascular side effects or sedation. Levetiracetam (LEV) is not approved for the treatment of SE; even though data so far suggest that it may be an effective and welltolerated treatment for SE hence further prospective, controlled, randomized evaluation in a larger number of patients is warranted. Common adverse effects like aggression, rarely a contradictory increase in seizure frequency may occur and this should be monitored carefully [34-36]. For the first time a prospective study was conducted in 30patients (14 males and 16 females whose ages ranged between 17 and 90 years) over a period of one year, to determine the efficacy of LEV (I.V.) in the treatment of SE. The patients were given LEV (I.V.) with dosages ranging between 10004000 mg/day. By the end of the study SE was terminated in 76.6% (23 patients) indicating LEV (I.V.) was safe, well tolerated and effective with no major adverse effects in treating SE [37]. In a retrospective study conducted in 67 patients, to treat SE, LEV (I.V.) was studied as a second line of therapy in patients un-responsive to diazepam (I.V.). In 86.9% (58 patients) of the cases, SE stopped within 3h. Results showed the usefulness of LEV (I.V.) in SE with high rates of seizure freedom, with good tolerance and low rate of adverse events making it an attractive alternative as second line therapy [38]. In another retrospective study conducted in 50 patients (19 male and 31 female) less than 18 years of age, were given LEV (I.V.) with an infusion rates ranging from 2 to 66 mg/kg/min for either acute repetitive seizures or for SE. From the results it was evident that cessation of seizure was obtained in 59.6% with no adverse drug reactions or untoward effects during the therapy proving its safety and efficacy for treatment of acute repetitive seizures and SE in both children and adolescents [39]. 6.2. Topiramate Topiramate is used as a second line add-on treatment in refractory partial and generalized epilepsies. It also used in certain syndromes like Lennox Gastaut and Dravet’s. Its use as first line monotherapy is associated with significant adverse effect profile in newly diagnosed epilepsy. It should be started in b.i.d (twice in a day) doses of 0.5-1 mg/kg, increasing dose weekly up to 510mg/kg, reaching highest dose of 10-30 mg/kg. Rapid escalation (every 3 days) of dose is considered in exceptional situation like SE, infantile spasms. Topiramate suspension administered via nasogastric tube at a dosage ranging from 300 to 1,600 mg/d in aborting refractory SE. However, high doses have higher incidence of adverse events and such effects include lethargy, weight loss, metabolic acidosis, eye symptoms like watering and eye pain (glaucoma/myopia), redness, blurring, oligohydrosis should be clinically monitored. Weight loss and decreased appetite are expected and should be informed in prior to parents or carers. By avoiding calcium supplements and maintaining hydration minimises risk of renal stones. Finally by converting to topimarate monotherapy, minimises the cognitive adverse effects [40-42]. In this study, factors associated with the use of topiramate in refractory SE were retrospectively reviewed over a 12-year period. Among 445 SE episodes treated for SE, 71 refractory SE episodes in 65 patients that fulfilled the criteria were included into this study. In 17/71 (23.9%) episodes, patients received topiramate for the treatment of refractory SE with a median starting dose of 100 mg/day to maximum dose of 225 mg/day. In all the episodes treated with topiramate, seizure control was achieved. But this study itself does not yield evidence for particular efficacy of topiramate in refractory SE. Therefore, need for confirmation by studies with larger numbers of refractory SE episodes is indispensable [43]. A prospective single center open-label non-randomized clinical trial was conducted in 20 patients (6 female and 14 male) 18 years

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of age and older with SE over a period of 12 months. Topiramate (400 mg stat and then 200 mg Bid) was administered through nasogastric tube, to patients, where failure of at least two standard AEDs was observed and the standard third or fourth line therapies were not available. Results conclude that topiramate was successful in terminating SE in 25% (5) patients; possibly successful in 55% (11) patients; and not successful in 20% (4) patients, without any clinically significant adverse effects. This treatment was proved to be potentially efficacious and well tolerated, especially in resource limited settings [44]. 6.3. Lamotrigine As per national health and care excellence (NICE) guidelines (CG137), lamotrigine is used as monotherapy in newly diagnosed focal, absence, myoclonic and tonic-clonic seizures, occasionally in JME. Lamotrigine paradoxically worsens the myoclonic jerks and add-on in absence, focal motor, tonic and tonic-clonic refractory generalized epilepsies and syndromes like Lennox Gastaut syndrome. When administered alone, initial dose should be 0.5 mg/kg, when given along with carbamazepine, phenobarbitone, or phenytoin, lamotrigine dose should be 0.6 mg/kg, and when administered along with valproate, lamotrigine dose should be 0.2 mg/kg. Every 2 weeks the dose should be doubled to maximum of 15mg/kg (alone) and with valproate 5mg/kg/day and higher when used with enzyme inducers. Lamotrigine has to be titrated slowly to prevent Stevens Johnson syndrome and rashes [45-47]. 7. AEDs MECHANISM OF DRUG INTERACTIONS The vast majority of clinically important and most widely used AEDs interactions result from induction or inhibition of drug metabolizing enzymes, affects their activity. 7.1. Enzyme Induction Phenobarbital, Phenytoin and Fosphenytoin are enzyme inducing AEDs. They stimulate the activity of a variety of glucuronyl transferases (GT), epoxide hydrolase, CYP enzymes (cytochrome P450) including CYP (1A2, 2C9, 2C19 and 3A4) and reduce the serum concentration of concurrently administered AEDs notably tiagabine, lamotrigine, benzodiazepine, topiramate, valproic acid and sodium valproate. Phenytoin and fosphenytoin also involves in metabolism of carbamazepine and subjects it to heteroinduction. Very few newer AEDs like Lamotrigine have the ability as older AEDs to share their broad spectrum enzyme-inducing activity at dosages 200mg/day. Tissue-selective stimulation of CYP3A4 by topiramate helps in stimulating oral contraceptive steroids metabolism. Most of the newer AEDs are cleared fully or partly by inducible enzymes as shown in the Table 5 and becomes target for enzyme induced interactions [48]. 7.2. Enzyme Inhibition Most of the first generation drugs are drug metabolizing enzyme inducers. But valproic acid differs from them and acts as an inhibitor rather than an inducer, including those involved in the conversion of carbamazepine-10,11- epoxide to the epoxide hydrolase (corresponding diol), the Lamotrigine glucuronidation and the oxidation of phenobarbital. Potent metabolic inhibition and elevation in the serum levels of valproic acid, sodium valproate, phenytoin and phenobarbital was caused by felbamate, an AED rarely used because of serious hepatic and haematological toxicity. In patients taking valproate and sodium valproate, therapeutic and toxic effects will be seen at lower than the required total serum phenytoin concentration to produce equivalent effects in patients not taking valproate. Other clinically important interactions and increase in serum concentrations mediated by enzyme inhibition and metabolism of an AED are inhibited by drugs used for other indications as shown in Table 5 [48].


Table 5.


9

AEDs main route of elimination and increase in their serum concentration by other drugs presumably by inhibiting their Metabolism.

AEDs

Major Route of Elimination

Major Enzyme System Involved

PHEN

Oxidation

CYP2C9 and CYP2C19

Interfering Drug

AEDs: Sulthiame, valproic acid, felbamate, oxcarbazepine AM :

Isoniazid, sulfaphenazole, chloramphenicol, miconazole, fluconazole

AD : Imipramine, viloxazine, sertraline, fluoxetine, trazodone, fluvoxamine ANDs: Tamoxifen, tegafur, doxifluridine, fluorouracil MISC: Sulfinpyrazone, chlorpheniramine, diltiazem, ticlopidine, amiodarone, tolbutamide, disulfiram, omeprazole, Allopurinol, cimetidine, tacrolimus, dextropropoxyphene, phenylbutazone, azapropazone PBT

CBZ

Oxidation

CYP2C9 and

+ N-glucosidation (75% of the dose) and renal excretion (25%)

CYP2C19

Oxidation

CYP3A4 (active 10,11epoxide metabolite cleared by epoxide

AEDs : Sulthiame, valproic acid, felbamate, phenytoin AM :

Chloramphenicol

MISC : Dextropropoxyphene

hydrolase)

AEDs : Valproic acid, valpromide, felbamate AM :

Isoniazid, troleandomycin, ketoconazole, clarithromycin, ritonavir, erythromycin, metronidazole, fluconazole

AD :

Trazodone, viloxazine, nefazodone, fluoxetine, fluvoxamine

MISC : Quetiapine, verapamil, danazol, diltiazem, dextropropoxyphene, cimetidine, ticlopidine, risperidone LTG

VA

Glucuronide conjugation

Oxidation (>50%) and glucuronide (30–40%)

Glucuronyl transferase type 1A4 Glucuronyl transferases Conjugation, mitochondrial oxidases and CYPs

AEDs : Valproic acid AD :

Sertraline

AEDs: Felbamate AM : Isoniazid AD : Sertraline MISC: Cimetidine

CBZ - Carbamazepine; PHEN - Phenytoin; VA - Valproic acid; LTG - Lamotrigine; PBT - Phenobarbitone; AEDs – Anti Epileptic Drugs; AD – Antidepressants; AM - Antimicrobials: ANDs -Antineoplastic drugs; MISC – Miscellaneous.

8. CURRENT ISSUES IN THE TREATMENT OF STATUS EPILEPTICUS a) Management of SE depends on treatment rapidity and it should be continued sequentially until electrographic and clinical seizures are halted. b) Critical care treatment and continuous monitoring should be started under expert physician committee with initial and first line of drug therapy treatments and continued until further therapy is consider successful or futile. c) For control of SE urgently, following AED therapy is recommended like I.V. phenytoin/fosphenytoin, levetiracetam, sodium valproate along with Lamotrigine (in some cases depending on the patient response). d) As treatment options, benzodiazepines like I.V. lorazepam or I.M. midazolam or rectal diazepam should be given as emergent initial therapy. e) SE therapy recommendations should consist of continuous infusion of AEDs along by dose titration until cessation of burst suppression or electrographic seizures. f) After 24-48h of electrographic control, continuous AED infusion can be withdrawn slowly by monitoring recurrent seizures by continuous EEG under maintenance doses. g) Alternative therapies are considered and reserved in patients not responding to regular SE AED therapy in cessation of sei-

zures and also considered when ICU team specialised in SE treatment fails to treat. 9. RECOVERY FROM SE AND TREATMENT STRATEGY After recovery from the SE episodes, the post-SE phase is mainly dependent on the underlying cause, medical problems and complications related to the episode such as pneumonia, aspiration. At this stage, the patient might be on multiple AED medications, which may be partly responsible for the morbidity. So the main aim at this stage is minimise and control the number of drugs and doses the patient has to take and optimise them to a lowest effective dose of an appropriate drug by eliminating the un-necessary medication to minimise the adverse effects. At this stage careful titration is involved measuring AED serum levels, as the effective AED doses are decreased and other interacting medication, antibiotics are withdrawn, the AED dose may become insufficient leading to breakthrough seizure in patients. 10. CONCLUSION As illustrated in this review, epilepsy is a well-known disorder dating back centuries affecting both patients economically and socially. Still in many countries outreach for proper facilities to treat epilepsy is far behind due to various reasons including its long term therapy, continues therapeutic observation and pharmacoresistance. From early 19th century, epilepsy has drawn attention in and making continuous progress in its research to develop better drugs and


drug therapies. Up to now only a handful of drugs are successful in treating the epileptic condition and fallen short of expectations, with up to one-third of the patients continuing to experience seizures or unacceptable side-effects related to medication. Many treatment strategies were developed and some of them still under research. On comparing with earlier treatments, present treatment therapies and strategies are much more advanced in identifying and treating seizures. Apart from it, early identification and treatment initiation is the major step in controlling the seizures in the least possible time, once the seizures has lasted 5-10min then it should be considered as SE and treatment should be started in according. In some cases, OSA may also causes seizures. Proper treatment guidelines are not established due to lack of proper studies and related evidences. Therefore, randomized placebo controlled studies at multiple centres are needed to recruit a sufficient number of patients and to further investigate the interaction of OSA and epilepsy. In arresting seizures in an out of hospital setting, pre-hospital treatment plays a key role; it helps in controlling seizure activity because longer the SE is untreated, it is more difficult to control and has the highest risk of further permanent neuronal impairment, brain damage, morbidity and mortality. The treatment can be given through multiple routes in acute and chronic seizures. Once in hospital setting, I.V. route of benzodiazepines are the drug of choice, later oral route of delivery can be started to achieve stable therapeutic concentration. Accessing I.V. route in pre-hospital treatment is practically impossible in an emergency situation. A highly trained, qualified medical person is required for this procedure. Oral route therapy is also a mainstay treatment in chronic seizure disorders. During treatment the behavioural issues such as opposing behavior or oral aversion; medical and surgical issues such as gastrointestinal ileus or severe pseudoobstruction and no oral intake before and after surgeries for many hours, such conditions inhibit oral dosing of medications for long periods of time and in some patient population require weeks to months or longer treatment when the oral route of delivery is not available. Thus, in SE and this patient population need an alternate route of administration than oral. In the pre-hospital treatment where parenteral route is not available, in such situations rectal, buccal and intranasal benzodiazepines are considered. They are efficacious and can control and shorten duration of SE and hospital stay, it can be given safely by parents, carers and paramedics. Buccal and rectal route of delivery is not possible in most of the cases and it also depends on the seizure severity. Drug administration and access to buccal and rectal routes is difficult during convulsion, rectal route access is also socially embarrassing and can be used only in children and in a few cases in adults. Therefore there is a need for alternate medication route in infants, children and adults. Thus, intranasal becomes an alternative fast-acting delivery route like intranasal midazolam. On reaching hospital emergency department, the appropriate drug doses should be given based on the protocols established. The initial results with the novel delivery systems and technologies are exciting. Commercially very few are available and successful in the market. Therefore, there is a significant need for considerable development and standardization of these delivery systems. The recommendations for future research in both academia and industry are that they must give much more insight and focus on challenges facing at present for treating patient epileptic condition and improving social life. Thus, our view is that the research from all sides in the field will give some positive results over the next 5 years with further development in all the areas of drug therapy with high-quality evidence. LIST OF ABBREVIATIONS SE = Status epilepticus

Yasam et al.

GTC WHO PCR AED RSE CSF GABA JME OSA CPAP CYP EEG

= = = = = = = = = = = =

Generalized Tonic-Clonic world health organisation Polymerase chain reaction Anti – epileptic drugs Refractory status epilepticus Cerebrospinal fluid Gamma – amino butyric acid Juvenile myoclonic epilepsy Obstructive sleep apnea Continuous positive airway pressure Cytochrome P Electroencephalography

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS I would like to dedicate this work in the memory of Dr. A.P.J. Abdul Kalam. REFERENCES [1]

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