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`sJC':
`For reprint orders, please contactreprrntsegture-drugs.com
`
`Review
`
`
`
`Pharmacologic management of
`convulsive status epilepticus
`in childhood
`
`Kai ErikssonT and Reetta Kalvia'inen
`
`
`
`
`
`
`
`
`
`The incidence of convulsive status epilepticus in children is approximately
`20-50/100,000/year, and is an emergency requiring prompt medical intervention.
`Prolonged seizures lasting over 5 min are unlikely to stop spontaneously, and
`time-to-treatment influences treatment response. Prolonged seizures should thus be
`treated as early status epilepticus. Mortality and morbidity increase significantly with the
`length of ongoing seizure activity, especially after 60 min. Benzodiazepines remain the
`first-line drug therapy due to their rapid onset of action. Recent studies imply that buccal
`midazolam is more effective and easier to administer than rectal diazepam.
`Phenytoin/fosphenytoin and phenobarbital administered intravenously remain the
`second-line treatments of choice, whilst barbiturates and midazolam as intravenous
`
`anesthetics are used for third-line treatment. Electroencephalogram monitoring is
`essential to evaluate the electrophysiologic treatment response and depth of
`anesthesia, especially in refractory status epilepticus. In the future, more individualized
`protocols and pathways are needed in order to optimize treatment responses.
`Randomized clinical trials are needed to evaluate new treatment protocols, which
`should not only stop the seizures more effectively but also be safer and include some
`neuroprotective elements to halt the cascade of neuronal injury and minimize the risk for
`neurologic morbidity caused by the convulsive status epilepticus.
`
`Erpert Rev. Neurotherapeuticr 5(6), 777—783 (2005)
`
`The hallmarks of status epilepticus (SE) are con-
`tinuous or rapidly repeating epileptic seizures
`and the time point at which a seizure becomes
`unlikely to end spontaneously is the main char-
`acteristic for SE. SE occurs in children of all ages
`and is a neurologic emergency requiring active,
`prompt and monitored pharmacologic and sup-
`portive medical intervention. Any seizure type
`can present as SE and therefore the current
`International League against Epilepsy proposal
`for classification of SE follows the classification
`
`of epileptic seizures (1|. A simplified classification
`for convulsive, nonconvulsive and neonatal SE
`has been used when treatment recommenda-
`tions have been outlined [2], since these three
`
`forms of SE have very different clinical presenta—
`tions. etiologies, pathophysiologies and medical
`outcomes. This review focuses on convulsive
`(0513, which is
`the most
`common and
`potentially harmful form of the disorder.
`
`Background
`The overall incidence of CSE is estimated to
`
`in
`20—50/100,000/year
`approximately
`be
`children under the age of 15 years [3.4]. The
`incidence is highest in infants and young chil—
`dren under the age of 4 years and 4-8 out of
`1000 children are expected to experience an
`episode of CSE before the age of 15 years [5].
`CSE as the first seizure in developing epilepsy
`occurs in approximately 30% of patients and
`approximately 15—40% of all SE episodes
`occur in patients with diagnosed epilepsy [6.7].
`In others, CSE represents an isolated episode
`related to either acute symptomatic or febrile
`etiology. Etiology of the CSE episode is also
`highly age-bound, being acute symptomatic in
`infants,
`febrile in young children and in
`school-aged children and adolescents remote
`symptomatic
`and
`idiopathic/cryptogenic
`etiologies predominate [8].
`
`10.1586/14737175.5.6.777
`
`© 2005 Future Drugs Ltd
`
`ISSN 14734175
`
`777
`
`
`
`AQUESTIVE EXHIBIT 1109 Page 0001
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`
`
`

`

`Eriksson & Kalviainen
`
`The duration and factors that contribute to the duration of a
`
`single convulsive seizure are not well known. Isolated epileptic
`seizures in adults usually last for 1—2 min [9]. In children, sei-
`zures that last longer than 5 min are unlikely to stop spontane-
`ously and it has been suggested that once a seizure has lasted for
`a 7 min it is very likely to became self-sustaining, which means
`that the longer the seizure lasts the less likely it is to stop spon-
`taneously [10]. Increased seizure duration is commonly regarded
`as an important factor for increased morbidity and mortality.
`The time from seizure onset to initial treatment is presumed to
`be critical in attaining seizure control, and the administration
`
`of effective treatment is essential in preventing cerebral injury
`and neurologic sequelae [11].
`Mortality and morbidity due to CSE in children has
`declined since the 19705, and current studies show mortality
`rates of between 0 and 3% [7,12—14] and permanent neurologic
`sequelae between 10 and 20% [12.13.15]. Outcome after SE is
`influenced by the interaction between several factors, includ-
`ing age, etiology and total duration of the seizures, and the
`concomitant physiologic disturbances [16]. The risk of brain
`
`damage and mortality increases with the length of ongoing
`seizure
`activity,
`especially after
`the SE has
`lasted for
`60 min [17,18] and the risk progressively increases after 1—2 h
`of continuous status [19]. Acute mortality and morbidity
`related to SE is usually due to systemic and metabolic distur-
`bances, and also to the direct excitotoxic effect of the seizure
`
`discharges. Lower mortality and morbidity figures may be
`partly due to current treatment practices since more aggressive
`algorithms for prolonged convulsive seizures are currently
`recommended for children and adults [20-23].
`
`Management of convulsive status epilepticus in children
`Time to treatment
`
`The goal of CSE treatment is to terminate both the clinical
`and electrical seizure activity as rapidly as possible. In adults,
`response of initial treatment of SE has been shown to decline
`
`from 80% in patients whose treatment began within 30 min
`from the onset of seizures, to less than 40% in patients with
`treatment initiated 2 h or later from seizure onset
`[24]. In
`children, 40—80% of patients receive their first treatment
`within 30 min of seizure onset [4.11], and the risk of poor
`treatment response also appears to increase as the seizure
`endures; over 30 min treatment delay of convulsive seizures
`in children has been shown to be independently and
`significantly associated with delayed treatment response in a
`population-based study [4].
`On the other hand,
`in children with epilepsy, prolonged
`seizures can be stressful events for parents and they may be too
`frightened to clearly assess the situation and determine the
`proper course of action, or
`they may call
`for emergency
`assistance unnecessarily since, given the currently available
`treatment options for seizure emergencies, not every seizure or
`cluster warrants a visit to the emergency department. There-
`fore, patient and family education is crucial for the practical
`management of epilepsy and families of people with epilepsy
`
`should have an individualized emergency plan in place, includ—
`ing how long to wait before initiating treatment and when to
`call for medical assistance [11].
`
`Early convulsive status epilepticus: first-line treatment
`Early SE can be defined as an epileptic seizure abnormally pro-
`longed for over 5 min; there is operational need for emergency
`drug treatment to abort the seizure activity. Benzodiazepines
`(BDZS) are preferred as initial drug therapy for CSE since they
`have a rapid onset of action. The effect of BDZS is mediated via
`
`their interaction with the BDZ binding site on the y-amino-
`butyric acid (GABA)A-receptor, resulting in enhanced CABA-
`mediated inhibition. Rectal diazepam (DZP) has been the
`golden standard for out-of—hospital pharmacologic manage-
`ment of CSE and it has been reported to be effective in acute
`repetitive and prolonged seizures [25]. Generally,
`the recom-
`mended dose is 10 mg for children over 15 kg, and 0.5 mg/kg
`for children under 15 kg, repeated once if necessary. The use of
`other rectally administered BDZs (e.g., lorazepam [LZPD has
`been studied, without significantly better response rates com—
`pared with DZP [26]. The risk of treatment-related side effects
`(respiratory depression) has been shown to increase with more
`than two doses of BDZs and treatment guidelines are suggested
`to be modified so that prehospital treatment is also taken into
`account when further treatment is evaluated [27].
`An alternative route of administration of BDZs as a rescue
`
`medication is with an intravenous preparation or buccal liquid
`(where available) of midazolam (MDL) used buccally, but this
`treatment is currently unlicensed for this indication. However.
`randomized or controlled studies comparing buccal MDL with
`rectal DZP [28.29], and a case report of effectiveness and conven-
`ience of use [30], have shown buccal/nasal MDL to be a poten-
`tial alternative. In the first randomized, controlled trial, buccal
`MDL was more likely than rectal DZP to stop acute
`tonic—clonic seizures within 10 min (65 vs. 41%, p < 0.001) in
`children at the hospital emergency room and the use of MDL
`was not associated with an increased incidence of respiratory
`depression. Buccal MDL was also found to be easier and more
`acceptable to administer, a view shared by nursing staff and
`parents. However,
`if this treatment
`is used, an individual
`preplanned protocol and careful
`instructions (i.e., dose and
`method of application)
`for parents and caregivers must be
`provided for each patient.
`The most commonly used first-line intravenous BDZs are
`LZP and DZP. Randomized, controlled studies show that these
`two drugs have similar onsets of action and adverse effects (res-
`piratory depression and impaired consciousness), and they are
`both clinically efficient in 2—3 min [26]. Since LZP has a longer
`duration of action (12—24 h) than DZP (15—30 min), current
`treatment algorithms usually recommend LZP as initial intra-
`venous treatrnent. The recommended dose for intravenous LZP
`
`is 0.05—0.l mg/kg up to 4 mg and the dose can be repeated
`after 5 min if the seizures continue. The recommended dose for
`
`intravenous DZP is 0.2-0.4 mg/kg up to 10 mg and this dose
`can also be repeated once. The efficacy of first-line treatment
`
`
`
`778
`
`Ewart Rev. Neurodmapeutlc: 5(6) , (Z005)
`
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`

`

`Treatment of status epilepticus in childhood
`
`(BDZs, either rectally or intravenously) for prolonged convul-
`sive seizures (over 5 min) in children was 58% in a retrospective
`population-based study [7].
`
`Established convulsive status epilepticus:
`second-line treatment
`
`Established CSE is defined as a condition in which epileptic
`seizure persists for 30 min or more, but second—line therapies
`should be considered earlier. as soon as it becomes evident that
`CSE persists after the administration of BDZs. A third (33%)
`of children with prolonged seizures need second-line pharma-
`cologic treatment [7]. Intravenous phenobarbital (PB) has been
`shown to be effective as second—line drug treatment for CSE in
`children [31], the anticonvulsant effect being mediated through
`enhanced GABA-inhibition via binding with the barbiturate
`site of the GABAA-receptor. The intravenous loading dose in
`children is
`15—20 mg/kg and the maintenance doses of
`2.5 mg/kg at 24 h and 48 h has been considered to be sufficient
`in maintaining serum concentrations within the therapeutic
`range for 72 h [32]. The monitoring and support of vital
`functions is essential due to the depressant effects of PB on
`respiration, level of consciousness and blood pressure.
`Phenytoin (PHT) has been shown to be effective in terminat-
`ing SE in adults, but its utility as an initial therapy is limited by
`the slow rate of the drug administration and the attendant
`delay in attaining the anticonvulsant effect. The major mecha-
`nism of action of PHT is blockage of voltage-gated sodium
`channels. Intravenous fosphenytoin (fosPHT) as a PHT pro-
`drug is an alternative (although more costly) and is currently
`preferred over PHT due to its water solubility and normal pH,
`allowing more rapid administration and less infusion-related
`side effects [22]. The fosPHT dose required to obtain thera-
`peutic serum levels in adults for 24 h is 18 mg PHT equivalent
`(PE)/kg given as a loading dose at a maximum rate of 150 mg
`PE/min [33]. In children, the loading dose of 15 mg PE/kg may
`be effective and safer, but controlled trials are lacking. Cardiac
`complications and allergic reactions can occur with fosPHT
`due to its conversion into PHT but the risk for hypotension
`may be lower.
`In children in which PHT/fosPI-IT or PB cannot be used due
`
`to allergic reactions. other medical conditions (e.g., progressive
`myoclonus epilepsy) or the type of CSE (e.g., myoclonic SE), the
`use of valproate (VPA) is favored, and this drug has been used
`intravenously [34], although there is no official approval for its use
`in SE. The loading dose is 15—40 mg/kg with an infusion rate of
`3 mg/kg/min or 200 mg/min. In the presence of enzyme-induc-
`ing drugs (e.g., carbamazepine, PHT and PB) the VPA doses
`need to be up to 40 mg/kg as a loading dose [35]. The intravenous
`maintenance dose for VPA in children is 7.5 mg/kg administered
`four-times daily [36]. There is no marked depression of conscious-
`ness and respiration, but hypotension has been described in pedi-
`atric patients [37]. There are no controlled clinical trials compar-
`ing the safety and efficacy of VPA with other medical treatments
`for SE and the place of VPA in the management of SE in general
`is currently unknown.
`
`Refractory convulsive status epilepticus:
`third-line treatment
`
`SE that does not respond to first-line BDZS or second—line anti-
`epileptic drugs (e.g., PHT/fosPI-IT or PB), and lasts over
`60—120 min is usually considered refractory CSE and requires
`an even more aggressive treatment. In a retrospective popula-
`tion-based study in children, 9% of the CSE episodes could be
`regarded as refractory SE [7]. The optimal treatment for refrac-
`tory CSE has not been defined [38]. The pharmacologic treat-
`ment of refractory CSE is general anesthesia with continuous
`intravenous anesthetics administered in doses, which abolish all
`
`clinical and electrographic epileptic activity often requiring
`sedation to the point of burst suppression in the electro-
`encephalogram (EEG). Burst suppression pattern on the EEG
`provides a physiologic target for the titration of the intravenous
`treatment. If burst suppression is the target, the drug dosing is
`commonly set at a level with interburst intervals between 2 and
`30 s [21].
`
`Barbiturate anesthetics (pentobarbital in the USA and thio-
`pental in Europe and Australia) have been the most used and
`highly effective general anesthetics for refractory SE both for chil-
`dren and adults, and they probably remain the only way to stop
`seizure activity with certainty in severe refractory cases. However,
`myocardial depression, hypotension, delayed postinfusion respi-
`ratory recovery and ileus necessitating total parenteral nutrition
`as well as increased susceptibility to Gram—positive infections are
`the limitations [21]. Pentobarbital is used as a 10—15 mg/kg bolus
`followed by continuous infusion of 0.5—1 mg/kg/h and thiopen-
`tal as 3-5 mg/kg initial bolus with 1-2 mg/kg additional boluses
`within 3—5 min up to clinical response with a maximum of
`10 mg/kg and then continuous
`infusion at
`the rate of
`3—5 mg/kg/h [16.39].
`In individual cases, higher continuous
`infusion rates may be needed ($7.5 mg/kg/h) [40].
`MDL as an imidazobenzodiazepine drug has been used intra-
`venously in the treatment of SE with a loading dose of
`0.2 mg/kg, repeated until clinical response up to a maximum of
`2 mg/kg
`and continued with infusion at
`the
`rate
`of
`005—2 mg/kg/h [21]. The most common disadvantage of MDL
`treatment is breakthrough seizures, which may be managed with
`an additional bolus and increase in the intravenous rate by
`20% [22]. Other problems include tachyphylaxis and a prolonged
`half-life. The clinical response can usually be observed between
`10 min and l h, and if seizures continue, more effective
`(suppressive) treatment options should be considered [23].
`Intravenous propofol, which has been used for the treatment
`of refractory CSE, acts at a location other than the BDZ bind-
`ing site and modifies the chloride channel in a way that is dif-
`ferent from 31325 and barbiturates [22]. However, in critically ill
`patients, propofol
`infusion syndrome (e.g., rhabdomyolysis.
`acidosis and cardiac arrhythmias) associated with doses over
`5 mg/kg/h for prolonged sedation has been described [41]. The
`risk for propofol infusion syndrome appears to be far greater in
`children than adults [42] and the use of propofol for sedation
`has been contraindicated in many countries (e.g., USA, Canada
`and the EU) in children under the age of 15 years.
`
`
`
`www.future-drugs.com
`
`779
`
`
`
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`
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`

`

`Eriksson & Kalviainen
`
`Regardless of drug selected, the patient should be managed in
`an intensive care unit setting since artificial ventilation, hemo-
`dynamic support and invasive monitoring is often necessary.
`Additionally, EEG monitoring is essential during the treatment
`of refractory CSE. Without EEG monitoring. the response of
`antiepileptic drug (AED) treatment is difficult to verify since
`subclinical. electrographic seizure activity may persist after the
`control of clinical symptoms. Once seizures have been control-
`led for at least 12 h, intravenous therapy should be gradually
`tapered off if the drug is MDL. Gradual tapering is probably
`not necessary with pentobarbital or thiopental. However, intra-
`venous anesthetics should be reintroduced if CSE recurs during
`or shortly after tapering off of the treatment.
`
`Prevention of recurrence
`
`In order to prevent the recurrence of CSE, intravenous PHT,
`fosPHT or VPA administration should be continued to
`ensure an adequate baseline for AED medication before with-
`drawal of the continuous intravenous anesthetics. In addition
`to PHT/fosPHT/VPA, levetiracetam (LEV) may also become
`available for clinical use as an intravenous formulation [43].
`AEDs that are only available in an enteral form can be given
`via a nasogastric tube or by percutaneous endoscopic gastros-
`tomy and, although enteral AEDs may not always be suffi-
`ciently absorbed and can reach unpredictable serum levels in
`critically ill patients. these medications are important for pre-
`venting breakthrough and withdrawal seizures, particularly
`directly
`prior
`to
`the
`tapering
`off
`of
`intravenous
`anesthetics [23]. Children with epilepsy should have their ear-
`lier medications continued, but doses should be optimized. If
`additional medication is needed, the best AEDs to be started
`quickly in this setting are gabapentin for focal seizures and
`LEV and topiramate for all seizure types [44]. All these drugs
`can be safely initiated with high dosages without an increased
`risk of idiosyncratic reactions.
`
`Conclusions
`
`CSE is a neurologic emergency that requires prompt recogni-
`tion and aggressive pharmacologic management. The goal of
`the treatment is to terminate the clinical and electrical sei-
`
`zure activity as soon as possible. BDZs are initial drug ther-
`apy since they are potent and have a rapid onset of action.
`The evident risk for the refractoriness of seizures lasting over
`30 min should underline the need for rapidly proceeding
`into the next stages of the treatment protocol; PHT/fosPI-IT
`and PB are established second-line intravenous drugs. The
`patients refractory for first- and second-line treatments need
`even more aggressive intervention, which often requires seda-
`tion to the point of burst-suppression in the EEG, and the
`patients have to be managed in an intensive care unit setting.
`EEG monitoring is essential to evaluate the electrophysio-
`logic treatment response and the depth of anesthesia, espe-
`cially in refractory CSE. It is essential for each emergency
`and intensive care unit to have a general algorithm for the
`treatment of CSE.
`
`Expert commentary
`In early CSE, the different BDZs probably have equal efficacy,
`but the route of administration (e.g., rectal vs. buccal) may be
`crucial for compliance of the parents and caregivers and facili-
`tate early intervention. According to present knowledge,
`the
`availability of nonrectal application routes favors the use of
`MDL (buccally) — although it is currently unlicensed for this
`indication and should be used only following training accord-
`ing to individualized instructions drawn by the specialist. The
`intravenous use of LZP has pharmacologic advantages over
`DZP (e.g., longer duration of action) and it may be regarded as
`first-line intravenous treatment for CSE, even by paramedics in
`the out-of-hospital setting, but the safety of intravenous BDZs
`in this setting needs further study.
`In established CSE it would be rational to choose consecutive
`AEDs with different modes of action. Since both BDZs and PB
`act via GABAergic binding sites and have an additive respira-
`tory depressant effect when combined, the intravenous drugs
`with other modes of action, such as PHT/fosPHT (which
`block the sodium channels) may be safer and more effective in
`seizures unresponsive to BDZs, although controlled studies
`supporting this are lacking. As the administration of more than
`two doses of BDZs also increases the risk for adverse effects,
`such as respiratory depression, it is important to move forward
`in the treatment protocol to second— or third-line treatment
`
`options in the hospital, if adequate doses of BDZs have already
`been given in the prehospital setting.
`the
`limit
`In refractory CSE, adverse effects of propofol
`options for anesthetics in children. Barbiturates probably
`remain the only agent to ensure the abortion of both clinical
`and electrographic seizure activity with minimal risk of break-
`through seizures (problem with MDL) and immediate relapse
`after drug withdrawal or severe adverse reactions (problems
`with propofol). Barbiturates may also have beneficial effects on
`the secondary physiologic disturbances associated with CSE,
`such as the risk of increased intracranial pressure. and they are
`reported to also exhibit protective properties related to cerebral
`blood flow and oxygen consumption.
`
`Five-year view
`
`Time-to-treatment is crucial in the management of CSE. In
`optimal cases the treatment
`is administered as soon as
`it
`
`becomes evident that the seizure is not going to end spontane-
`ously. is repeated. or otherwise atypical, for a given child. In the
`future,
`ideally, the treatment steps will be undertaken earlier
`using adequate doses of effective drugs applied through accessi-
`ble routes of administration, with rapid procession to the next
`step if earlier steps are ineffective (TABLE 1). On the other hand,
`treatment should be administered according to the length of
`the seizure estimated in each case individually, which means
`that rapidly proceeding from first-line medication straight to
`third-line treatment may be necessary in newly admitted
`patients if the duration of the CSE without cessation has, out
`of hospital, already exceeded 60 min or the clinical situation
`otherwise indicates the need for this.
`
`
`780
`
`Ewart Rev. Mumfhelapeutlc: 5(6). (2005)
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`

`Treatment of status epilepticus in childhood
`
`
`
`Table 1. Current schematic treatment phases of early, established and refractory convulsive status epilepticus and how
`
`they might be optimized in the future with drug options available at the moment.
`
`
`
`ME
`
`Drugs currently used
`
`Out of hospital/nonmedical Out of hospital/medical
`persons (e.g., parents)
`personnel (e.g., paramedics)
`Rectal DZP
`
`None or rectal DZP only
`
`In hospital/emergency room
`or department
`
`In hospital/intensive
`care unit
`
`Intravenous BDZ and/or
`intravenous PHT/fosPHT, PB, VPA
`
`General anesthesia
`
`Intravenous PHT/fosPHT, PB, VPA General anesthesia
`
`Refractory SE
`Established SE
`arly SE
`
`First-Iine
`Second line
`Third line
`
`
`Step 1
`Step 2
`Step 3
`Step 4
`Time
`>5 min
`>5 min
`>30 min
`>60 min
`
`Drug administration
`
`
`
`
`Drugs used in optimal
`situation in future
`
`
`Buccal MDL
`
`Intravenous LZP
`
`BDZ: Benzodiazepam: DZP: Diazepam; LZP: Lorazepam: MDL: Midazolam; PB: Phenobarbitone; PHT; Phenytoin; SE: Status epilepticus; VPA: Valproate.
`
`
`
`the individualization of the treatment will
`In the future,
`become important. This means adjusting general algorithms into
`individualized treatment protocols and pathways that will take
`into account, for example, the individual responses to different
`drugs, especially for those with repetitive CSE episodes. In pedi-
`atric epilepsy, a predecided individual emergency plan should
`also be in place in order to minimize the emotional stress of fam-
`
`ilies and children associated with seizure emergencies. This plan
`should include, for example, how long to wait before initiating
`treatment and when to call for medical assistance [11].
`
`In the future, randomized clinical trials will hopefully determine
`the best treatment for CSE in children. These trials should include
`the randomizations between the different anesthetics, such as bar-
`biturates and MDL, but also take into account the goal of treat-
`ment; cessation of seizures versus suppression of EEG activity.
`There is also a need for new treatment options for CSE. These
`new drugs should stop the seizures more effectively and be safer
`than those currently used. They should also include some neuro-
`protective elements to halt the cascade of neuronal injury and
`minimize the risk for neurologic morbidity caused by the CSE.
`
`Key issues
`
`a -
`
`Convulsive status epilepticus is a medical emergency requiring prompt medical intervention.
`
`- Convulsive seizure lasting over 5 min should be regarded as early status epilepticus and treated as such.
`
`° Time to treatment influences treatment response.
`
`- Mortality and morbidity increase with the length of ongoing seizure activity. especially after 60 min.
`- Electroencephalogram monitoring is essential in order to evaluate the electrophysiologic treatment response and the depth
`of anesthesia.
`
`- Benzodiazepines (e.g., buccal midazolam and intravenous lorazepam) as first-line, phenytoin/fosphenytoin and phenobarbital
`intravenously as second-line, and intravenous anesthetics (barbiturates, midazolam) as third-line drugs form the core for general
`treatment algorithms.
`
`-
`
`In the future. individualized treatment protocols and pathways are needed in order to optimize individual responses to drugs and
`minimize the emotional stress of families and children associated with acute seizure episodes.
`- Randomized clinical trials are needed to determine the best treatment in children.
`
`' New treatment options that would stop the seizures more effectively, be safer and include some neuroprotective elements are
`needed for convulsive status epilepticus.
`
`
`
`References
`
`Papers of special note have been highlighted as:
`- of interest
`
`0' of considerable interest
`5 1
`Engel J. A proposed diagnostic scheme for
`people with epileptic seizures and with
`
`D 2
`
`epilepsy: report of the ILAE Task Force on
`Classification and Terminology. Epilepria
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