Refractory Status Elipticus

Transcription

1 Refractory Status Elipticus

2 In the 13 th round Laufey Yr Sigurdardottir MD Nemours Children s Hospital Department of Neurology

3 NCH ED on Nov 29 th 2015 at 11:02 am First triage: fam here on vacation. pt has GERD and medication is not working. pt is gagging and spitting out everything she eats and drinks. 16 month old girl vacationing from PR Patient is a 16 month old healthy girl Few month history of episodes of gagging and drooling. No history of vomiting. Dx acid reflux. Zantac/Prepulsid of no help. Last few days episodes happening much more frequently Events start with staring, gagging, becoming cyanotic, rapid eye blinking and stiffening of lower > upper extremities. Episodes self resolve.

4 Exam Isabella is a normocephalic, healthy appearing nondysmorphic, toddler who is interactive with her mother. No organomegaly, no abnormal skin markings. NEUROLOGIC EXAMINATION: Mental Status: She will interact with parents by smiling to them, giving and taking what is handed to her and exhibits good eye contact. No repetitive behavior is seen. Cranial nerves are intact. PERL. Visual fields are full. EOM are conjugate. Facial expression is symmetric and gag/swallowing present Motor exam reveals normal muscle tone, symmetric spontaneous movements. Reflexes are present. Plantar response is flexor. Balance and coordination: No myoclonus, no ataxia, no obvious dysmetria

5 Initial course-lorazepam (Cl-)

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7 Followed by- Keppra 50 mg/kg iv load at 13:20 inhibits presynaptic Ca(V) channels; resultant reduction in neuronal excitability My optimism at the time No further seizures have been noted at this time which is at 4 pm 20 seizures captured before 6 pm Phenobarbital given at 6:30 pm- total 30 mg/kg iv prior to next morning. Lorazepam iv given After medication doses- 1-3 hour periods of seizure freedom were seen Over next 17 days seizure free only during general anesthesia or medication induced burst suppression Extensive medication trials were unsuccessful

8 By day 9

9 Medication chart and seizure count

10 Differential diagnosis Focal epilepsy-status epilepticus Structural brain abnormality Infectious etiology Autoimmune etiology Metabolic disorder Genetic condition Mild Developmental delay From any of the above disorders

11 Work-up Routine labs CBC, CMP, Ca, Mg, PO4- all normal CPK mildly elevated 270 Infectious work up Respiratory panel- negative CSF cultures and PCR negative Metabolic labs AA, Total carnitine, Acylcarnitine profile, lactic acid, biotinidase, urine OA- all normal CSF- wbc 2, rbc 0, gluc 58 protein 29 CSF Neurotransmitters- discussed but re-tap not performed Neuroimaging MRI 11/30 and 12/10 (w/mrs) normal Genetic testing Discussed but not sent off

12 What work-up do you do? 2006

13 Excluded refractory or febrile status epilepticus Laboratory studies- abnl in 6% Blood/CSF cultures-abnl 12.5% AED levels-low in 32% of patients on AEDs Toxicology-positive in 3.6% Metabolic testing- abnl in 4.2% Genetic testing- not commented on (article from 2006) Berkowic et al 2015 EEG- abnl in 43% Neuroimaging- abnl in 7.3%

14 Berkowic et al 2015 Why genetic diagnosis is so important Reduces need for invasive work-up Identifies the why is this happening? Gives the parents a group to identify with Can help targeting therapy

15 Genetic therapy targeting SCN1A- avoid Na+ channel drugs (PHT,CBZ, OXC, LMT) SCN2A/8A-not as clear Na+ drugs might even be helpful KCNQ2-LOF K+ch gene-rtg and CBZ, PHT helpful SLC2A1-Glut1- Ketogenic diet helpful ALDH7A/PNPO- Pyridoxine/P5P helpful KCNT-Quinidine helpful GRIN2A- Memantine possibly helpful PEPDC5- Rapamycin analogues helpful? GABA A rec subunits-jme, FSP, CAE- targeted GABA enhancing drugs-allosteric modulation

16 When do acute repetitive seizures become status 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 In retrospect I feel that our patient s ARS became status epilepticus earlier than I did in real time.

17 ILAE New classification of Status epilepticus 2015

18 Therapy course in our case Benzodiazepine: iv lorazepam Prehospital Treatment of Status Epilepticus (PHTSE) 2001 lorazepam (2 mg), diazepam (5 mg), or placebo lorazepam (59.1%), diazepam(42.6%) over placebo (21.1%) The subsequent Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) study IM midazolam (10 mg) vs IV lorazepam (4 mg) solidified these results 73.4% midazolam and 63.4% lorazepam had stopped seizing on arrival at ED

19 Benzodiazepines Rampart 2012

20 Benzodiazepine and Keppra- SAMUKeppra Navarro et al 2016: Prehospital Treatment With iv Levetiracetam Plus iv Clonazepam or Placebo Plus iv Clonazepam in Status Epilepticus Is simultaneous use of clonazepam and Keppra preferable to clonazepam alone for SE (outside of hospital). Results: No benefit of the combination therapy CLN alone 84% seizure control <15 minutes CLN + LEV 74% seizure control <15 minutes Established Status Epilepticus Treatment Trial (ESETT) Comparing VPA/PHT/LEV in pt >age 2 yrs in benzo refractory SE No results yet

21 Should we have chosen Keppra? Is it safe: Egunsola et al 2016 Risk of rash is less than with placebo (RR 0.5) AEs more likely with polytherapy (60%)/monotherapy (20%) Most serious were behavioral (RR 1.9), anxiety (RR 4.8) Is it effective: Weijenberg et al 2015: Review of monotherapy of Keppra in children: Evidence not yet available to confirm that Keppra is effective as monotherapy but the studies reviewed did suggest efficacy comparable to other agents Iwasaki et al 2014: LEV efficacy in children for focal seizures CPSz 60% compared to SPSz 80% <6 yrs: <60% while >6 yrs: >75%

22 Should we have chosen Keppra? Khongkhatithum et al 2015: IV Keppra in Thai children Keppra efficacious in 59% overall Levetiracetam Cryptogenic : ARS 60% vs SE 83% In symptomatic patients the efficacy was <20% for SE No effect at Na+ or T-type Ca++ channels Does not work thru the benzodiazepine receptor No effect on GABA transaminase or GAD inhibits presynaptic Ca(V) channels (N-type); resultant reductions in neuronal excitability

23 Berkowitz et al 2014

24 Next choices Phenobarbital: (Cl-) Better than PHT if patient were to have Dravet syndrome Levels to mid 30 s IV PHB controlled status in 81% in recent article (Moramoto 2013) Phenytoin: (Na+) No help at levels of Topiramate: (modification of Na(+)-and/or Ca(2+)-dependent action potentials, enhancement of GABA-mediated Cl- fluxes into neurons) No help (dose to 10 mg/kg/day) Clonazepam (Cl-) and Oxcarbazepine (Na+) Chosen in the few days where po meds were felt to be an option.

25 Propofol (GABA agonist, NMDA antagonist, Na+, Cannabinoid) Administered for anesthesia for MRI on two occasions and then for sedation prior to transfer to Miami Seemed to control seizures even without burst suppression Not appropriate for long term use Propofol infusion syndrome (PRIS) 21 patients who developed this syndrome reported arrhythmia in all cases (100%), rhabdomyolysis (42%), lactic acidosis (62%), renal failure (38%), lipemia (33%), and elevated hepatic enzymes (28%). 13 patients died (66%). Pathogenesis: direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism Risk factors: Young age, critical illness and administration >48hrs

26 Pentobarbital (Cl-) Burst suppression coma as treatment for refractory status epilepticus is well known. Agents: midazolam, propofol, pentobarbital, thiopental, ketamine A meta-analysis comparing midazolam, propofol, and pentobarbital infusions for RSE (Claassen et al 2002) treatment with pentobarbital : lower frequency of short-term treatment failure, breakthrough seizures, and changes to a different continuous infusion Starts with bolus 5-15 mg/kg iv and then maintained with (can go higher) mg/kg/hour Onset of action minutes and T1/2 is hours

27 Comparison of Intravenous Anesthetic Agents for the Treatment of Refractory Status Epilepticus (Reznik 2016)

28 Clobazam (Cl-) Sivakumar S et al 2015 Efficacious in the termination of refractory SE Mean dose of 1.0 mg/kg/day Successful termination of RSE was seen in 76.5% Duration of SE at the introduction of clobazam 4 days Internalization of synaptic GABA A receptors during prolonged SE, results in BZD pharmacoresistance Hence, this demonstration of efficacy for a drug with a primarily GABA-mediated mechanism of action and after prolonged SE is a significant finding.

29 Lacosamide (enhances the slow inactivation of voltage-gated sodium channels) 19 studies looking at efficacy of iv lacosamide overall success of aborting status of 56%. Grosso R et al 2014 Lacosamide in refractory status epilepticus iv load 8-10 mg/kg Effective aborting SE in 45 % (<12hr)

30 12/14/2016

31 What were our chances? Lewena 2006: When benzodiazepines fail? Sz control was achieved in 30% with the combination of first and second line therapy. Anaesthesia was required in 70% (85% if sz >30 minutes) Falco-Walter J et al 2016 ongoing seizure activity causing internalization, and therefore loss, of GABA A receptors from the synaptic membrane Sz activity causes an increase in the number of excitatory receptors (NMDA and AMPA) in the synaptic membrane Meds that increase GABA become less effective, while those that work on NMDA and AMPA receptors are unaffected

32 What to do in the 13 th round? Define the problem Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the onset of anaesthetic therapy, including those cases that recur on the reduction or withdrawal of anaesthesia YEP we were there! Define what to do next and who can do it Neurologic ICU needed Ongoing medication trials Possible surgical options In light of initial focal interictal activity Additional neuroimaging modalities Initiation of ketogenic diet

33 12/16/2016 Patient airlifted, intubated, sedated to Nicklaus Children s Hospital to the Neurologic ICU service of Ann Hyslop Little did I know of what was in store for her and her family. My last words were: I ll see you after the New Year- don t worry

34 Thank you

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