Status epilepticus is defined usually as a condition in which epileptic activity persists for 30

Transcription

1 ii22 * J Neurol Neurosurg Psyhiatry 2001;70 (suppl II):ii22 ii27 THE MANAGEMENT OF STATUS EPILEPTICUS TONIC-CLONIC Correspondene to: Professor Simon Shorvon, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK s.shorvon@ion.ul.a.uk Simon Shorvon Status epileptius is defined usually as a ondition in whih epilepti ativity persists for 30 minutes or more. The seizures an take the form of prolonged seizures or repetitive attaks without reovery in between. There are various types of status epileptius and a lassifiation sheme is shown in table 1. STATUS EPILEPTICUS The annual inidene of toni-loni status is estimated to be ases per persons. It ours most ommonly in hildren, the mentally handiapped, and in those with strutural erebral pathology espeially in the frontal lobes. Most episodes of status develop without a prior history of epilepsy, and these are almost always aused by aute erebral disturbanes; ommon auses are erebral infetion, trauma, erebrovasular disease, erebral tumour, aute toxi or metaboli disturbanes, or hildhood febrile illness. In patients with pre-existing epilepsy, status an be preipitated by drug withdrawal, interurrent illness or metaboli disturbane, or the progression of the underlying disease, and is more ommon in symptomati than in idiopathi epilepsy. About 5% of all adult patients attending an epilepsy lini will have at least one episode of status in the ourse of their epilepsy; in hildren the proportion is between 10 25%. The physiologial hanges in status an be divided into two phases, the transition from phase 1 to 2 ourring after about minutes of ontinuous seizures (table 2, fig 1). In phase 1, ompensatory mehanisms prevent erebral damage. In phase 2, however, these mehanisms break down, and there is an inreasing risk of erebral damage as the status progresses. The erebral damage in status is aused by systemi and metaboli disturbane (for example, hypoxia, hypoglyaemia, raised intraranial pressure) and also by the diret exitotoxi evet of seizure disharges (whih result in alium influx into neurons and a asade of events resulting in nerosis and apoptosis). The main purpose of treatment is to prevent erebral damage. As this is, at least in part, aused by the diret evet of seizure ativity, it is imperative to ontrol overt and eletrographi seizure disharges. The risk of erebral damage inreases progressively after 1 2 hours of ontinuous status. If seizures are not ontrolled within this period, the patient should be onsidered to be in refratory status and general anaesthesia should be instituted. Table 1 Classifiation of status epileptius. Reprodued from Shorvon SD. A handbook of epilepsy treatment, with permission of the publisher, Blakwell Siene Status epileptius onfined to early hildhood Neonatal status epileptius Status epileptius in speifi neonatal epilepsy syndromes Infantile spasms Status epileptius onfined to later hildhood Febrile status epileptius Status in hildhood partial epilepsy syndromes Status epileptius in myoloni-astati epilepsy Eletrial status epileptius during slow wave sleep Landau-Kleffner syndrome Status epileptius ourring in hildhood and adult life Toni-loni status epileptius Absene status epileptius Epilepsia partialis ontinua Status epileptius in oma Speifi forms of status epileptius in mental retardation Syndromes of myoloni status epileptius Simple partial status epileptius Complex partial status epileptius Status epileptius onfined to adult life De novo absene status and late onset J Neurol Neurosurg Psyhiatry: first published as /jnnp.70.suppl_2.ii22 on 1 June Downloaded from on 19 August 2018 by guest. Proteted by opyright.

2 Table 2 Physiologial hanges in status epileptius. Reprodued from Shorvon SD. A handbook of epilepsy treatment, with permission of the publisher, Blakwell Siene Phase 1: ompensation During this phase, erebral metabolism is greatly inreased beause of seizure ativity, but physiologial mehanisms are suffiient to meet the metaboli demands, and erebral tissue is proteted from hypoxia or metaboli damage. The major physiologial hanges are related to the greatly inreased erebral blood flow and metabolism, massive autonomi ativity, and ardiovasular hanges Cerebral hanges Systemi and metaboli hanges Autonomi and ardiovasular hanges Inreased blood flow Hyperglyaemia Hypertension (initial) Inreased metabolism Lati aidosis Inreased ardia output Energy requirements mathed by supply of oxygen and gluose (inreased gluose and oxygen utilisation) Inreased latate onentration Inreased entral venous pressure Massive ateholamine release Tahyardia Inreased gluose onentration Cardia dysrhythmia Salivation Hyperpyrexia Vomiting Inontinene Phase 2: deompensation During this phase, the greatly inreased erebral metaboli demands annot be fully met, resulting in hypoxia and altered erebral and systemi metaboli patterns. Autonomi hanges persist and ardiorespiratory funtions may progressively fail to maintain homeostasis Cerebral hanges Systemi and metaboli hanges Autonomi and ardiovasular hanges Failure of erebral autoregulation; thus erebral blood flow beomes dependent on systemi blood pressure Hypoxia Hypoglyaemia Falling latate onentrations Falling energy state Rise in intraranial pressure and erebral oedema General measures in the treatment of toni-loni status epileptius Cardiorespiratory funtion In all patients presenting in status, the protetion of ardiorespiratory funtion takes first priority. Hypoxia is usually muh worse than appreiated, and oxygen should always be administered. Emergeny investigations Emergeny investigations should inlude assessment of the following: blood gases, gluose, renal and hepati funtion, alium, magnesium, full blood ount, lotting sreen, and antionvulsant onentrations. Serum should be saved for toxiology or virology or other future analyses. An eletroardiogram (ECG) should be performed. Initial emergeny treatment Initial treatment should inlude: emergeny intravenous antiepilepti drug treatment (see below) maintenane antiepilepti drugs orally or via a nasogastri tube intravenous thiamine and gluose if there is the possibility of aloholism gluose if hypoglyaemia is present the orretion of metaboli abnormalities if present the ontrol of hyperthermia pressor therapy for hypotension if present the orretion of respiratory or ardia failure. If the status is aused by drug withdrawal, the withdrawn drug should be immediately replaed, by parenteral administration if possible. Treatment may also be needed for ardia dysrhythmia, lati aidosis (if severe), rhabdomyolysis, or erebral oedema (in late status). Neurology in Pratie Hypoglyaemia Systemi hypoxia Hyponatraemia Falling blood pressure Hypokalaemia/ hyperkalaemia Falling ardia output Metaboli and respiratory Respiratory and ardia impairment aidosis (pulmonary oedema, pulmonary Hepati and renal dysfuntion embolism, respiratory ollapse, Consumptive oagulopathy, ardia failure, dysrhythmia) DIC, multiorgan failure Hyperpyrexia Rhabdomyolysis, myoglobulinuria Leuoytosis The physiologial hanges listed above do not neessarily our in all ases. The type and extent of the hanges depited depend on aetiology, linial irumstanes, and the methods of treatment employed. DIC, disseminated intravasular oagulopathy. Establish aetiology The outome of status to a great extent depends on the aetiology, and the urgent treatment of ausal fators is vital. Computed tomographi sanning and erebrospinal fluid examination are often neessary. The hoie of investigations depends on the linial irumstanes. Other ompliations Table 3 lists some of the ompliations enountered in status and these often need emergeny treatment in their own right. Failure to do so an perpetuate the status and worsen outome. Intensive are and seizure/eeg monitoring If seizures are ontinuing in spite of the measures taken above, the patient must be transferred to an intensive are setting, where intensive monitoring is desirable, inluding: intra-arterial blood pressure, apnography, oximetry, and entral venous and arterial pressure monitoring. Motor ativity in status diminishes over time, and may ease in spite of ongoing epilepti eletrographi ativity, espeially in omatose or ventilated patients. Suh eletrographi ativity is potentially damaging to the ortial neurones and anaestheti treatment is targeted to suppress it by the attainment of the anaestheti level of burst suppression. Both ongoing epilepti ativity, and also burst suppression, require neurophysiologial monitoring and this an be provided by either a full EEG or a erebral funtion monitor (CFM). The CFM has to be alibrated for eah individual patient, but then has the advantage over EEG of simpliity of use. Burst suppression provides an arbitrary physiologial target for the titration of barbiturate or anaestheti treatment, with drug dosing ommonly set at a level whih aims to produe burst suppression with inter-burst intervals of between 2 30 seonds. *ii23 J Neurol Neurosurg Psyhiatry: first published as /jnnp.70.suppl_2.ii22 on 1 June Downloaded from on 19 August 2018 by guest. Proteted by opyright.

3 ii24 * Neurology in Pratie Motor EEG Systemi Brain damage Brain metabolism Generalised onvulsions Reurrent seizures Isolated Lengthen Phase I BP Latate Gluose Brain parenhyma oxygenation Gluose utilisation CBF Brain utilisation Brain gluose Brain energy state Brain latate Oxygen utilisation Transition Seizures Phase II BP normal Gluose ph Latate Myolonus Eletromehanial dissolution PEDs Respiratory ompromise Hypothermia Convulsive Non-onvulsive (Min) (Min) (h) Time Figure 1 Temporal hanges whih our as toni-loni status epileptius progresses. Motor ativity lessens, the eletroenephalogram (EEG) evolves and profound physiologial hanges our, both systematially and erebrally. In the first 30 minutes or so, physiologial hanges are largely ompensatory, but as the seizures ontinue these ompensatory mehanisms break down. The biphasi evolution is emphasised periodi epilepti disharge (PED). 1, loss of reativity of brain oxygen tension; 2, mismath between the sustained inrease in oxygen and gluose utilisation and a fall in erebral blood flow; 3, a depletion of erebral gluose and glyogen onentrations; 4, a deline in erebral energy state. Reprodued from Shorvon SD. A handbook of epilepsy treatment, with permission of the publisher, Blakwell Siene. Table 3 Medial ompliations in status epileptius. Reprodued from Shorvon SD. A handbook of epilepsy treatment, with permission of the publisher, Blakwell Siene Cerebral Hypoxi/metaboli erebral damage Seizure indued erebral damage Cerebral oedema and raised interranial pressure Cerebral venous thrombosis Cerebral haemorrhage and infartion Cardiorespiratory and autonomi Hypotension Hypertension Cardia failure, tahy- and bradydysrhythmia, ardia arrest, ardiogeni shok Respiratory failure Disturbanes of respiratory rate and rhythm, apnoea Pulmonary oedema, hypertension, embolism, pneumonia, aspiration Hyperpyrexia Sweating, hyperseretion, traheobronhial obstrution Peripheral ishaemia Metaboli and systemi Dehydration Eletrolyte disturbane (espeially hyponatraemia, hyperkalaemia, hypoglyaemia) Aute renal failure (espeially aute tubular nerosis) Aute hepati failure Aute panreatitis Other Disseminated intravasular oagulopathy/multi-organ failure Rhabdomyolysis Fratures Infetions (espeially pulmonary, skin, urinary) Thrombophlebitis, dermal injury Premonitoring stage Diazepam 10mg iv (given over 2-5 min) or retally, repeated one 15 minutes later if status ontinues to threaten Or lorazepam 4mg iv bolus If seizures ontinue or status develops Stage of early status Lorazepam 4mg iv bolus (if not given earlier) If status ontinues after 30 min Stage of established status Phenobarbital iv infusion of 10mg/kg at a rate of 100mg/min (i.e, about 700mg in an average adult over 7 min) or Phenytoin iv infusion of 15mg/kg at a rate of 50mg/min (i.e, about 1000mg in an average adult over 20 min) or Fosphenytoin iv infusion of 15mg PE/kg at a rate of 100mg PE/min (i.e, about 1000mg PE in an average adult over 10 min) If status ontinues after min Stage of refratory status General anaesthesia with either: Propofol 2mg/kg iv bolus, repeated if neessary, and then followed by a ontinuous infusion of 5-10mg/kg/h initially, reduing to a 1-3mg/kg/h. When seizures have been ontrolled for 12h, the drug dosages should be slowly tapered over 12h or Thiopental: mg iv bolus given over 20s, with further 50mg boluses every 2-3 min until seizures are ontrolled, followed by a ontinuous iv infusion to maintain a burst supression pattern on the EEG (usually 3-5mg/kg/h). Thiopental should be slowly withdrawn 12h after the last seizure Figure 2 Emergeny drug treatment of toni-loni status in adults (PE = phenytoin equivalents). Reprodued from Shorvon SD. A handbook of epilepsy treatment, with permission of the publisher, Blakwell Siene. Drug treatment of toni-loni status epileptius It is onvenient to divide the treatment of status into stages. This is in reognition of the fat that the risk of erebral damage aused by seizure ativity is slight in the first hour or two of status, and inreases with duration of ongoing eletrographi ativity after this. Initially relatively simple treatment is given, but within two hours, if the epilepti ativity is not under ontrol, general anaesthesia is reommended. Many drugs an be given, and the author s reommended regimen is shown in fig 2 and table 4. There is little evidene that this regimen is greatly superior to other rational shemes. What is essential, however, is to have a protool for the treatment of status, and this simple measure has itself been shown to redue the morbidity and mortality of status. Premonitory stage of status epileptius In patients with established epilepsy, there is often a prodromal period before status develops in whih there is a gradual (over hours) inrease in the frequeny of epilepti seizures. Parenteral drug treatment during this stage will usually terminate the seizures and prevent true status developing. The onventional treatment is with either intravenous or retal diazepam. Intravenous diazepam is given at a rate not exeeding 2 5 mg/min, using the Diazemuls formulation. Retal administration is either as the intravenous preparation infused from a syringe via a plasti atheter, or as the ready made proprietary retal tube preparation Stesolid whih is onvenient and easy. Diazepam J Neurol Neurosurg Psyhiatry: first published as /jnnp.70.suppl_2.ii22 on 1 June Downloaded from on 19 August 2018 by guest. Proteted by opyright.

4 Table 4 Drug dosages for onvulsive status epileptius. Reprodued from Shorvon SD. A handbook of epilepsy treatment, with permission of the publisher, Blakwell Siene Drug Route Adult dose Paediatri dose Clomethiazole iv infusion of 0.8% solution suppositories should not be used, as absorption is too slow. The adult bolus intravenous or retal dose is mg, and in hildren the equivalent bolus dose is mg/kg. More reent work has shown that midazolam or lorazepam an serve are alternatives and have some advantages over diazepam, although the long experiene enjoyed by diazepam is not shared by these other drugs. Lorazepam an be given by an intravenous bolus of 4 mg in adults or 0.1 mg/kg in hildren; it is longer lasting than diazepam and the rate of injetion is not ritial. Midazolam has the advantage that it an be given by intramusular injetion or bual instillation. A published randomised trial has shown that bual midazolam has equal eyay and as rapid an ation as retal diazepam and is more onvenient, potentially faster to administer, and less stigmatising. The dose used is 10 mg drawn up into a syringe and instilled into the mouth between the heeks and gums. Early status epileptius This is defined as the first 30 minutes of status. It is usual to initiate treatment with a fast ating benzodiazepine, and intravenous lorazepam is the drug of hoie. Alternatives inlude other intravenous benzodiazepines or intravenous lignoaine, the latter possibly being preferable in patients with respiratory disease. In most episodes of status, initial treatment will be highly evetive. Even if seizures ease, ml ( mg) at 5 15 ml/min, then ml/min 0.1 ml/kg/min inreasing every 2 4 h as required Clonazepam iv bolus 1 mg at < 2 mg/min* µg at < 2 mg/min iv infusion Maintenane dose 10 mg/24 h Diazepam iv bolus mg at < 5 mg/min* mg/kg at < 2 5 mg/min retal administration mg* mg/kg iv infusion 3 mg/kg/day µg/kg/day Fosphenytoin iv bolus 15 mg PE/kg at a rate of < mg PE/min Maintenane dose: 4 5 mg/kg/day iv or im Isoflurane inhalation End tidal onentrations of 0.8 2% to maintain burst suppression Lidoaine iv bolus mg/kg at < 50 mg/min* iv infusion Maintenane dose: 3 4 mg/kg/h Lorazepam iv bolus 4 mg* 0.1 mg/kg Midazolam im or retally 5 10 mg* mg/kg* iv bolus mg/kg at < 4 mg/min* iv infusion mg/kg/h bual 10 mg 10 mg Paraldehyde retally or im 5 10 ml (approximately 1 g/ml) in equal volume of water* Pentobarbital iv infusion 5 20 mg/kg at a rate of < 25 mg/min, then mg/kg/h inreasing to 1 3 mg/kg/h ml/kg* Phenobarbital iv bolus 10 mg/kg at a rate of < 100 mg/min mg/kg at a rate of < 100 mg/min Maintenane: 1 4 mg/kg/day 3 4 mg/kg/day Phenytoin iv bolus/infusion mg/kg at a rate of < 50 mg/kg 20 mg/kg at a rate of < 25 mg/min Propofol iv infusion 2 mg/kg, then 5 10 mg/kg/h initially, reduing to 1 3 mg/kg/h to maintain burst suppression Thiopental iv infusion mg bolus given over 20 s, then further 50 mg boluses every 2 3 mins until seizures are ontrolled. Then infusion to maintain burst suppression (3 5 mg/kg/h) *May be repeated. PE, phenytoin equivalents, iv, intravenous; im, intramusular. Neurology in Pratie hour inpatient observation should follow. In persons without a previous history of epilepsy, hroni antiepilepti drug treatment should be introdued, and in those already on maintenane antiepilepti treatment this should be reviewed. Established status epileptius There are three alternative first line treatment options, but eah has drawbaks and status at this stage arries an appreiable morbidity. These are subanaestheti doses of phenobarbitone, phenytoin or fosphenytoin. All three are given by intravenous loading, and followed by repeated oral (phenytoin or phenobarbitone) or intravenous supplementation. Subanaestheti infusions of benzodiazepine drugs were one fashionable in the stage of established status. The infusions arry the risk of respiratory depression and hypotension. There is also a risk of sudden ollapse aused by aumulation of the drug. For all these reasons, infusions at this stage should not be given. Chormethiazole infusion has been frequently used in the treatment of status, but arries similar risks. Intravenous valproate has been proposed as a suitable treatment, but again experiene is limited. Lorazepam and lignoaine are essentially short term treatment, and so should not be employed at this stage. *ii25 J Neurol Neurosurg Psyhiatry: first published as /jnnp.70.suppl_2.ii22 on 1 June Downloaded from on 19 August 2018 by guest. Proteted by opyright.

5 ii26 * Neurology in Pratie Refratory status epileptius In most patients, if seizures ontinue for minutes in spite of the treatment outlined above, full anaesthesia is required. In some emergeny situations (for example, postoperative status, severe or ompliated onvulsive status, patients already in the intensive therapy unit (ITU)), anaesthesia an and should be introdued earlier. The prognosis in status requiring anaesthesia is muh poorer, and there is a high risk of mortality and morbidity. The priniples of treatment are similar for all anaesthetis, and a wide range of barbiturate and non-barbiturate anaestheti agents ould be used. Barbiturate anaesthetis are good antiepilepti drugs but have poor pharmaokinetis. Thiopental, for example, has saturable kinetis, has a strong tendeny to aumulate (thus reovery times are very long), an ause profound hypotension, and is subjet to aute tolerane. The non-barbiturates, suh as propofol, have muh more suitable pharmaokineti properties, but have little if any intrinsi antiepilepti properties their ation is simply to redue the EEG to a burst suppression pattern. Whih of these two approahes is most suessful in status has not been established. Benzodiazepine infusions an be given at anaestheti doses, in an ITU setting. Drug indued hypotension is a ommon side evet and the risks of drug aumulation ompliate their use. Midazolam is probably the benzodiazepine of hoie beause of its short half life and large volume of distribution, and enouraging early reports of its use in status have been published. All the anaestheti drugs are given in doses suyient to indue deep unonsiousness; therefore assisted respiration, intensive ardiovasular monitoring, and the full panoply of intensive are are essential. The depth of anaesthesia should be that whih abolishes all linial and EEG epilepti ativity (often requiring sedation to the point of burst suppression on the EEG), and erebral eletrial ativity must by neessity be visualised, either with a formal EEG or a erebral funtion monitor. Failure to respond to emergeny treatment In the great majority of ases, the above measures will ontrol the seizures and the status will resolve. If drug treatment fails, there are often ompliating fators. Common reasons for treatment failure are: (1) Inadequate drug treatment InsuYient emergeny antiepilepti drug treatment. A partiular problem is the administration of intravenous drugs at too low a dosage (for example, with phenobarbitone or phenytoin). Failure to initiate or ontinue maintenane antiepilepti drug therapy in parallel with the aute emergeny treatment. This will result in rerudesene of seizures one the evets of the emergeny drug treatment has worn ov. (2) Additional medial fators Medial ompliations an exaerbate seizures (table 3). Failure to treat (or identify) the underlying ause an result in intratable status. This is partiularly the ase in aute progressive erebral disorders and erebral infetions. (3) Misdiagnosis A ommon problem is to fail to diagnose pseudostatus whih, in speialist pratie, is more ommon than true epilepti status. Summary Most episodes of status develop de novo, without a prior history of epilepsy. In suh ases the status is almost always due to aute erebral pathology In patients with pre-existing epilepsy, status an be preipitated by drug withdrawal, interurrent illness or metaboli disturbane, or the progression of the underlying disease A main purpose of treatment is to prevent the erebral damage whih an result from status. As this is, at least in part, aused by the diret effet of seizure ativity, it is imperative to ontrol overt and eletrographi disharges The risk of erebral damage inreases progressively after 1 2 hours of ontinuous status. If seizures are not ontrolled within this period, the patient should be onsidered to be in refratory status and general anaesthesia should be instituted General measures in the treatment of status inlude: attention to ardiorespiratory funtion, emergeny investigation, initiation of maintenane antiepilepti drug treatment, use of intravenous gluose and thiamine, orretion of metaboli abnormalities, attention to hypotension, ardia dysrhythmia, hyperthermia, lati aidosis, rhabdomyolysis, metaboli disturbane, erebral oedema, EEG monitoring It is essential to have a protool for the treatment of status. This simple measure has itself been shown to redue the morbidity and mortality of status A typial protool for emergeny drug use is: Early status lorazepam Established status phenytoin, phenobarbitone or fosphenytoin Refratory status anaesthesia with either thiopentone or propofol EEG monitoring is essential in the anaesthetised patient to assess both response to treatment and also the depth of anaesthesia Treatment of non-onvulsive status epileptius Treatment of non-onvulsive status epileptius an take various forms (table 1). Typial absene status (petit mal status) an usually be stopped by intravenous benzodiazepine: diazepam mg/kg, lonazepam 1 mg ( mg in hildren) or lorazepam 0.07 mg/kg (0.1 mg/kg in hildren), repeated if required. If this is inevetive, intravenous hlormethiazole, phenytoin or valproate may be needed. In hildhood absene epilepsy, maintenane treatment with valproate or ethosuximide is required one the status is ontrolled. De novo absene status of late onset is a ondition whih presents in later life, usually without a history of reent epilepsy. It is ommonly aused by drug withdrawal (espeially psyhotropi drugs or benzodiazepines), and an be safely treated by intravenous diazepam, lorazepam or hlormethiazole. Long term maintenane treatment is not usually required. Complex partial status is usually best treated by benzodiazepine therapy. There is ontroversy about the need for intravenous treatment in omplex partial therapy, and in most reurrent or prolonged ases, oral therapy is probably optimum. Atypial absene status is best treated with oral benzodiazepine or other onventional antiepileptis. Both atypial absene and omplex partial status may be resistant to treatment, but most episodes are self terminating, albeit sometimes after hours of ontinuous seizure ativity. J Neurol Neurosurg Psyhiatry: first published as /jnnp.70.suppl_2.ii22 on 1 June Downloaded from on 19 August 2018 by guest. Proteted by opyright.

6 Key referenes 1 Brown JK, Hussain I. Status epileptius: 1. Pathogenesis. Dev Med Child Neurol 1991;33: A review of the pathogenesis of status, with an emphasis on hildhood status. 2 Meldrum BS. Exitotoxiity and epilepti brain damage. Epilepsy Res 1991;10: A review of the mehanisms of brain damage in status. 3 Shorvon SD. Status epileptius: its linial features and treatment in hildren and adults. Cambridge: Cambridge University Press A omprehensive review of all aspets of status epileptius. Want to know more? Data supplements Neurology in Pratie 4 Shorvon SD. Emergeny treatment of aute seizures, serial seizures, seizure luster and status epileptius. In: Shorvon SD. Handbook of epilepsy treatment. Oxford: Blakwell Siene, 2000: The urrent artile is largely derived from this hapter in this book whih is a review of all aspets of epilepsy treatment. 5 Treiman DM, Meyers PD, Walton NY, et al. A omparison of four treatments for generalized onvulsive status epileptius. Veterans Affairs status epileptius ooperative study group. N Engl J Med 1998;339: This is a report of one of the few randomised ontrolled studies in the field of status epileptius. However, the definition of status for inlusion into the study is wide, and not neessarily ommensurate with routine neurologial pratie outside the USA. Limited spae in printed journals means that interesting data and other material are often edited out of artiles; however, limitless yberspae means that we an inlude this information online. Look out for additional tables, referenes, illustrations. *ii27 J Neurol Neurosurg Psyhiatry: first published as /jnnp.70.suppl_2.ii22 on 1 June Downloaded from on 19 August 2018 by guest. Proteted by opyright.