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Torino, Centro Congressi Lingotto 9-11 Novembre 2006

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  1. Torino, Centro Congressi Lingotto 9-11 Novembre 2006 • V CONGRESSO NAZIONALE SIMEUTHE SIMEU/ACEP • "Emergency Medicine Congress" • Gabriella Paglia, MD • Neurology Department • ASO S Giovanni Battista - Torino Gabriella Paglia SIMEU-Torino

  2. Diagnosis: seizures • Seizures in the Emergency Department • Isolated uncomplicated seizure • Flurry of seizures (SE risk) • Status epilepticus • Refractory status epilepticus Gabriella Paglia SIMEU-Torino

  3. Status epilepticus • ILAE Classification 2001 Definitionfor SE • a seizure which shows no clinical signs of arresting after a duration encompassing the great majority of seizures of that type in most patients [at least 5 minutes commonly, postictal state not included] • or • recurrent seizures without resumption of baseline central nervous system function interictally • Refractory SE • SE lasting more than 30’ despite infusion of first and second line drugs Gabriella Paglia SIMEU-Torino

  4. Status epilepticus: classification • Generalized SE: generalized tonic-clonic SE,clonic SE, absence SE, tonic SE, myoclonic SE • Focal SE: epilepsia partialis continua of Kojevnikov, aura continua, limbic SE (psychomotor status), hemiconvulsive status with hemiparesis, partial somatomotor SE • Convulsive SE (GCSE) • Nonconvulsive SE Gabriella Paglia SIMEU-Torino

  5. Status epilepticus • GCSE differential diagnosis not difficult • “the easier the diagnosis, the worse the prognosis” • P.Thomas 2002 • Repetitive syncopes with clonic jerks • Decerebration tonic seizures • Myoclonic Nonepileptic Status • in some post-anoxic or metabolic encephalopathies myoclonic jerks are not related to a paroxystic EEG activity (Assal F, 2000): in these cases infusion of AEDs may be not appropriate • Psychogenic Nonepileptic Seizures • Walker 1996: 6/26 patient admitted in Intensive Unit Care had only behavioral troubles and 4/6 had orotracheal intubation Gabriella Paglia SIMEU-Torino


  6. Status epilepticus • Psychogenic SE • more frequent in women <40 years old with a history of epileptic seizures in childhood or exposure to epilepsy in others • more frequent in mentally retarded patients • not metabolic acidosis in ABG, prolactin and cortisol levels not increased • aspecific psychiatric pattern at MMPI or • personality disorder, conversion disorder, Műnchausen syndrome • critical pattern: progressive onset, eyes closed, back arching, pelvic thrusting, rarely morsus or respitarory disturbances with cyanosis, rarely traumatic lesions or bladder incontinence, not autonomyc disorders • behavioral troubles may be increased by inappropriate AED use • Pakalnis A 1991; Jagoda A, 1995 Gabriella Paglia SIMEU-Torino

  7. Status epilepticus • Incidence • 9.9-15,8/100 000 in European studies (excluding SE after anoxic encephalopathy following cardiac arrest) • 18,3-41/100 000 in US studies • Mortality rate (death within 30 days) • 22% in Richmond study 21% in Rochester • 10-33% in EU studies • Logroscino G et al., 2005 • Outcome is often related to the underlying cause of brain injury, to the duration of the seizure and to patient’s age • Lowenstein DH, 1999 Gabriella Paglia SIMEU-Torino

  8. Status epilepticus • Etiology • cerebrovascular disease 25% 41% • low levels of antiepileptic drug 20% 20% • alcohol/other drugs 15% 7% • CNS infection 10% • Hypoxia 10% • Metabolic and electrolyte disorders 10% • Tumor 5% 5% • Trauma 5% 10% • Hyperthermia 2% • Hauser ey al, 1990; DeLorenzo et al, 1992; Vignatelli L et al, 2003 24% Gabriella Paglia SIMEU-Torino

  9. Status epilepticus=emergency • Life-threatening condition • Neurological complications • Neuronal loss (hippocampus especially) • cerebral metabolic demand increased • (but cerebral blood flow and oxygenation are normally preserved or even elevated) • abnormal electrical discharges • (studies with paralyzed and artificially ventilated animals) • (Huff SJ, 2005) Gabriella Paglia SIMEU-Torino

  10. Status epilepticus=emergency • Systemic complications • metabolic lactic acidosis, hypercapnia, hypoglicemia, hyperkaliemia, hyponatriemia, leukocytosis • autonomic hyperprexia, vomiting, incontinence, hypotension (failure of cerebral autoregulation) • renal (acute renal failure from rhabdomyolysis, myoglobinuria) • cardiac/respiratory hypoxia, arrhythmia, pneumonia (high output failure) • Lowenstein DH, Alldredge BK. 1998 Gabriella Paglia SIMEU-Torino

  11. Status epilepticus: treatment • ED Priorities • stop SE and prevent seizure or SE recurrence • earlier treatment is more effective than later treatment in halting SE and prevent evolution to subtle SE • begin to treat if seizure activity doesn’t terminate within 5’ • stabilize the patient’s medical condition • look for the etiology of the seizures • coordinate care with appropriate physician • make disposition to the appropriate service and medical unit Gabriella Paglia SIMEU-Torino

  12. Status epilepticus: treatment • First line drugs: benzodiazepines • Etiological treatment, when possible • Treatment of systemic complication • Second line drugs: PHT, VPA, PB • General Anaesthesia Gabriella Paglia SIMEU-Torino

  13. Status epilepticus: treatment • EU • Outin HD et al. Prise en charge des états de mal épileptique. Rev Neurol 2002; 158:1059-68 France • van Rijckevorsel K et al. Standards of care for adults with convulsive status epilepticus: Belgian consensus recommendations. Acta Neurol Belg 2005;105:111-8 Belgium • Kalviainen et al, Refractory generlized convulsive status epilepticus:a guide to treatment. CNS Drug 2005;19:759-68 Finland • USA • Treatment of convulsive status epilepticus. Epilepsy Foundation of America. JAMA 1993 • Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970-6 Gabriella Paglia SIMEU-Torino

  14. Status epilepticus: treatment • Ideal AED for SE • Intravenous administration (it allows therapeutic tissue levels to be attained more rapidly) • Linear pharmacokinetics • Rapid action • Long-lasting epileptic effect • Minimal cardiopulmonary and other systemic effect • Minimal depression of neurological functions • Steinhoff BJ et al, Acta Neurol Scand 2003 Gabriella Paglia SIMEU-Torino

  15. Status epilepticus: treatment • Pre-hospital care • Time 0-5: diagnosis • ABC O2 therapy • intravenous acces rapid glucose determination • ECG • Time 6-10:treatment • Thiamine 100 mg e.v. • Glucose infusion: 50 ml 50 % if hypoglycemia • First line drugs: • Lorazepam 4 mg iv or diazepam 10 mg iv Gabriella Paglia SIMEU-Torino

  16. Status epilepticus: treatment • Lorazepam Diazepam • onset of effect 3-5’ 1-3’ (high lipid solubility) • effect duration 6-12 h 15-20’ (time redistribution) • elimination half-life 12h 24 h • dose 4 mg (A) 10-20mg (A) • 0.1 mg/kg (C) 0.2-0.5 mg/kg (C) • route IV or IM IV or PR • readministration 10-15’ not indicated • side-effects hypotension, respiratory suppression • cautions myasthenia gravis, narrow angle glaucoma Gabriella Paglia SIMEU-Torino

  17. Status epilepticus: treatment • First line drug: benzodiazepines • Diazepam vs lorazepam • “in patients with SE, lorazepam is better than diazepam, phenytoin or placebo for cessation of seizures, and diazepam is better than placebo. Lorazepam is better than diazepam for preventing SE requiring a different drug or general anaesthesia” • Prasad K et al, EBM 2006: a Cochrane Database Syst Rev Gabriella Paglia SIMEU-Torino

  18. Status epilepticus: treatment • First line drug: benzodiazepines • Diazepam vs lorazepam • “as initial intravenous treatment for overt generalized convulsive SE, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbitale or diazepam plus pheytoin, it is easier to use” • Treiman DM et al, N Engl J Med 1998 • Lorazepam 64.9% • Phenobarbital 58.2% • Diazepam + phenytoin 55.8% • Phenytoin 43.6% Gabriella Paglia SIMEU-Torino

  19. Status epilepticus: treatment • Emergency Department care • Time 10-20 • Intravenous access, ideally in a large vein • Serum test: including Ca++, Mg++ • toxicologic testing (AED, theophylline, isoniazide, ethanol) • ABG (arterial blood gas: metabolic acidosis) • Second line drug • phenytoin, valproic acid, topiramate, levetiracetam • (phenobarbital) • ECG and Blood pressure monitoring • CT scan to determine etiology Gabriella Paglia SIMEU-Torino

  20. Status epilepticus: treatment • Phenytoin Fosphenytoin • effect onset 15-30’ idem IV, longer IM • effect duration 12-24h idem • dose 18-20 mg/kg 15-20 mgPE/kg • administration rate 50 mg/min 100 mgPE/min • dose max 30 mg/kg • route IV IV or IM • advantages: lack of CNS and respiratory depression • controindication: SA block,AV block II-III,Adam Stoke S, BS • side-effects: hypotension, arrhythmias, cardiac arrest (QRS widening), skin reaction (purple glove syndrome) Gabriella Paglia SIMEU-Torino

  21. Status epilepticus: treatment • Valproic acid • Dose 25-30 mg/kg infusion rate 3-5 mg/Kg/min • Onset of effect: 15-20 min • Side effect: gastrointestinal distress, lethargy, tremors • Advantages: no respiratory or cardiac disturbances • “easy-to-use, safe and efficient formulation…in all seizure emergency situation…further controlled comparison studies have to be performed in the future” • Useful in patients with absence or myoclonic SE, or in patients already receiving VPA as oral chronic therapy, in children • (Yu KT, 2003; Peters CN, 2005; Misra UK, 2006) Gabriella Paglia SIMEU-Torino

  22. Status epilepticus: treatment • Emergency Department Care • Time 20-30 • phenobarbital • 20mg/kg, maximum infusion rate 100 mg/min IV • Onset of effect: 15-20’ Half-life: 3-5 days • Ventilation and intubation may be necessary • Hypotension may need treatment. • Diluted in propylene glycol. • France: doses in succession (5-10 mg/kg every 30’) to avoid general anaesthesia. • Italy: used only in GA Gabriella Paglia SIMEU-Torino

  23. Status epilepticus: treatment • Time 30+ : refractory status epilepticus • needs more aggressive treatment • Intensive Care Unit ventilation and haemodynamic support • EEG monitoring • GA given in doses that abolish all clinical and EEG epileptic activity, often till the burst-suppression pattern. • Once seizures have been controlled for 12-24 h continuous IV therapy should be gradually tapered off • During the withdrawal of GA, phenytoin or valproate should be given to ensure an adequate baseline of AED medication to prevent recurrenceKalviainen et al, 2005 Gabriella Paglia SIMEU-Torino

  24. Status epilepticus: treatment • Intensive Care Unit • propofol (Diprivan) • Phenolic compound • Growing anecdotal reports of use in RSE. • Dose: 1 mg/kg in 5’, then 5-10 mg/kg/h • Onset of effect 1’ duration 10’ • To stop if no resolution after 45’. • If resolution slow tapering off after 12-24h • May have paradoxal proconvulsant effect Gabriella Paglia SIMEU-Torino

  25. Status epilepticus: treatment • Intensive Care Unit • midazolam (Hypnovel) • 0.2 mg/kg in 1’ infusion rate 1-10 μg/Kg/min • onset of effect: 1’ effect duration 15-60’ • Respiratory depression, in EU used in general anaestesia. • To stop if no resolution after 60’ • If resolution continue 12h, than attempt to stop Gabriella Paglia SIMEU-Torino

  26. Status epilepticus: treatment • Intensive Care Unit • thiopental (Penthotal) • used in RSE since 1967 • Dose: 3-5 mg/kg in 3’, then 1-3 mg/kg/h • onset of effect: 1’, effect duration 20’ • Respiratory depression and hypotension • Deep anaesthesia, guided by EEG, seems related to a better outcome and fewer recurrence • Advantages: neuroprotective effect and lowering intracranial pressure Krishnamurthy KB et al, 1999 Gabriella Paglia SIMEU-Torino

  27. Status epilepticus: treatment • Intensive Care Unit • pentobarbital (Nembutal) • ketamine • lidocaine (may have paradoxal proconvulsant effect) Gabriella Paglia SIMEU-Torino

  28. Status epilepticus • Role of EEG • diagnosis in NCSE • diagnosis in myoclonic nonepileptic seizure • diagnosis of seizures or SE recurrence after a first episode • (24h monitoring) • necessary if a patient doesn’t regain consciousness • after 30’despite resolution of clinical SE • to differentiate between subtle SE, sedation, post-ictal confusion • Thomas P 2002, Treiman 1998 Gabriella Paglia SIMEU-Torino

  29. Status epilepticus: treatment • Subtle Status Epilepticus • electrical seizure activity that endures when the associated movements are fragmentary or even absent. • Commonly, this pattern can be the evolution of a GCSE • Significantly lower response rates to all treatment • EEG monitoring 24 h Gabriella Paglia SIMEU-Torino

  30. Gabriella Paglia SIMEU-Torino

  31. Gabriella Paglia SIMEU-Torino

  32. References • Lowenstein DH, Alldredge BK Status epilepticus. N Engl J Med 1998;338:970-6 • DeLorenzo RJ, Hauser WA, Towne AR et al. A propsective, population based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology1996;46:1029-35 • Logroscino G et al. Epilepsia 2005;46 Suppl 11:46-8 • Lowenstein DH. Epilepsia 1999;40 Suppl 1:S3-8; discussione S21-2 • van Rijckevorsel K et al. Acta Neurol Belg 2005;105:111-8 • Fernandez-Torre JL et al. Clin EEG Neurosci 2006;37:215-8 • Walker MC et al. Q J Med 1996;89:913-20 • Walker MC et al, Anaesthesia 1995;50:130-5 ++ • Pakanis A et al. Neuropsychiatric aspects of psychogenic status epilepticus. Neurology 1991;41:1104-1106 • Kalviainen et al, Refractory generlized convulsive status epilepticus:a guide to treatment. CNS Drug 2005;19:759-68 • Steinhoff BJ, Hirsch E, Mutani R, Nakken KO, Acta Neurol Scand 2003;107:87-95 Gabriella Paglia SIMEU-Torino

  33. References • Thomas P. Encycl Med Chir, Neurologie 2002, 17-045-A-40 • Treiman DM et al. A comparison of four tretmente for GCSE. Veterans Affair SE Cooperative Study Group. N Engl J Med 1998;339:792-8 • Assal F et al. L’état de mal résistant aux antiépileptiques. Neurol Clin 2000;30:139-145 • Outin HD et al. Rev Neurol 2002; 158:1059-68 • Jagoda A et al. Psychogenic status epilepticus. J Emerg Med 1995;13:31-5 • Vignatelli L, Tonon C, D’Alessandro R. Epilepsia 2003;44:964-8 • Treatment of convulsive status epilepticus. Recommendation of the Epilepsy foundation of America’s Working Group on SE. JAMA 1993, 270:854-9 • Krishnamurthy KB et al. Depth of EEG suppression and outcom ein barbiturate anesthetic treatment for refractory status epilepticus. Epilepsia 1999;40:759-62 • Misra UK et al. Sodium valproate vs phenytoin in SE: a pilot study. Neurology 2006;67(2):340-2 • Peters CN, Pohlamann-Eden B. Intravenousvalproate…. Seizure 2005;14:164-9 Gabriella Paglia SIMEU-Torino

  34. “The end” • Grazie • Thanks Gabriella Paglia SIMEU-Torino