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A Lady With Confusion

A Lady With Confusion. Dr Sinn Ting Ting, Maria AC, Department of Medicine Tseung Kwan O Hospital. F/ 34, F.6 teacher Good past health Presented with fever and flu-like symptoms for 1 week on 17/11/07 On and off memory loss for 1 week No headache, no nausea/vomiting

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A Lady With Confusion

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  1. A Lady With Confusion Dr Sinn Ting Ting, Maria AC, Department of Medicine Tseung Kwan O Hospital

  2. F/ 34, F.6 teacher • Good past health • Presented with fever and flu-like symptoms for 1 week on 17/11/07 • On and off memory loss for 1 week • No headache, no nausea/vomiting • No recent travel/ vaccination

  3. P/E: Temp 37.5 C • GCS 15,neck soft, no focal neurological sign • Chest, CV, abdomen: unremarkable • CXR: clear • WBC: 2.8(N : 56%, L:30%, M:1%, atypical lymphocytes:13%)

  4. Progress • Shortly after admission: developed L sided and then generalized tonic- clonic convulsion, aborted by valium. • Urgent CT brain : NAD • LP: • clear CSF, opening pressure: 15 cm H2O • CSF: WBC 6 /mm3; RBC 3/ mm3, • CSF protein 0.32g/L, CSF glucose 3.3 mmol/L( serum 8.4) • CSF:-ve culture for bacteria/AFB/fungus, viral titre for HSV,VZV <1:4, PCR for HSV – ve • Blood culture -ve

  5. Patient was initially given Pen G, cefotaxime, acyclovir, • Dilantin iv was given. • On and off agitation, memory deficit.

  6. EEG 19/11/07: • 2 episodes of subclinical seizure captured of which there is some subtle bilateral UL motor automatism in the second. The origin is from L temporal region (or both). • Impression: In the context of clinical presentation (fever,headache, viral prodrome), herpes simplex encephalitis complicated with temporal lobe epilepsy is strongly suspected. Suggest book MRI brain .

  7. MRI 21/11/07: • Bilateral asymmetrical brain edema is noted at the medial temporal lobes, more extensive on left side with abnormal contrast enhancement. The overall features are consistent with encephalitis which could account for the present seizure.

  8. EEG 24/11/07: • there is an episode of secondarily generalized seizure originated from L hemisphere. The semiology: the patient had initially head intermittent turn to R and R hand automatism(pronate and supinate) and lasted for 2-3 mins, then going to GTC ( the paroxymal of spike/ fast activity lasts for 1.5 mins)preceded by forceful head version to R . • Active interictal discharges from R centroparietal region.

  9. EEG 26/11/07: • compared with last EEG, the focus of interictal activity shifted to L occipital. One episode of secondarily generalized seizure captured originated from R hemisphere( last for 1.5 min). • Impression: multi-focal epilepsy(typical finding of post-encephalitic epilepsy)

  10. Literature Review :Part A

  11. 1. Is it a case of status epilepticus?

  12. What is SE ? • In 1962, the tenth European Conference on Epileptology and Clinical Neurophysiology defined SE as ‘a condition characterized by an epileptic seizure which is so frequently repeated or so prolonged as to create a fixed and lasting epileptic condition’. • The International Classification of Epileptic Seizures: an seizure lasting more than 30 mins or intermittent seizures from which the patient did not regain consciousness lasting for more than 30 mins.

  13. Treiman and colleagues defined overt convulsive SE as two or more generalized convulsions without full recovery of consciousness between seizures, or continuous convulsive activity for more than 10 mins. • Veterans Affairs Status Epilepticus Coorperative Study Group. NEJM 1998;339:792-8. • Lowenstein, Bleck, and Macdonald : a continuous, generalized seizure lasting greater than 5 mins( in an adult or child older than 5 years), or two or more seizures and the patient did not return to baseline consciousness.

  14. Nonconvulsive SE (NCSE) • NCSE constitutes 25-50% of all cases of status epilepticus. • Represents a prolonged state of seizure(s) without marked motor manifestations. • NCSE typically encompasses an ictal impairment of cognition, subtle facial or limb twitches, eye-open mutism, head or eye deviation, automatisms, and behavioral change.

  15. NCSE • No current universally accepted definitions of NCSE: • Cannot rely on clinical symptoms alone • Cannot rely simply on EEG criteria because there are no EEG patterns that are pathognomonic of NCSE, which can range from continuous ictal discharges to rhythmic and periodic patterns of undetermined significance. • Cannot based on duration alone either

  16. NCSE • It can be defined as a condition with a prolonged state of impaired consiousness or altered sensorium associated with continuous paroxysmal activity or electrographic discharges on the EEG. • A heterogeneous disorder with varied etiology and several subtypes.

  17. NCSE • Classification: • Age based: neonates, children, adults, elderly • According to etiology: acute brain injury, metabolic disorders, preexisting epilepsy with or without an epileptic encephalopathy. • Clinical classification based on International League Against Epilepsy : • Generalized NCSE: absence status, atypical absence, de novo late absence SE • Focal NCSE: simple partial, complex partial, subtle NCSE

  18. SE in coma

  19. 2. Advances in the pathophysiology of status epilepticus

  20. Pathophysiology of SE • 1. Excessive activation of excitatory amino acid receptors: • NMDA and AMPA glutamate receptors • 2. Reduction of GABA-mediated inhibition in the hippocampus • Prolonged seizures alter the GABAA receptor function( reduced potency and efficacy of GABA in activating chloride channels) • 3. Decrease in neuropeptides: • Neuropeptide Y • Gelanin

  21. Natural course of SE 3 distinct phases in clinical evolution: • 1. pseudo-status or impending SE • 2. convulsive status or established SE • 3. stuporous status or subtle SE • Clark and Prout. Status Epilepticus: a clinical and pathological study in epilepsy. Am J Insanity 1903;60:291-306.

  22. Basic Mechanisms Self-sustaining SE: • Human data shows that seizures lasting more than 30 min rarely stop spontaneously. • Animal study: after 30 min of intermittent stimulation of an excitatory glutaminergic pathway in the rat, stopping the stimulation no longer stops electrographic or behavioral seizures, which self-perpetuate for many hours and eventually become ‘subtle’

  23. Time-dependent pharmacoresistance: • Potency of benzodiazepines decrease 20 fold in 30 min of self-sustaining SE (SSSE). • Potency of phenytoin also decrease but at a slower rate. • NMDA blockers are not effective in the first 10-15 min of seizure, but are effective later in the course of SSSE.

  24. The initiation of SSSE can be easily blocked by many pharmacological agents which enhance inhibition or reduce excitation. • Once SSSE is established, it is effectively terminated by only a few agents, most of which inhibit glutaminergic neurotransmission.

  25. Biochemical cascades of SSSE • In seconds to mins, GABA receptors move from the synaptic membrane to the cytoplasm, where they are functionally inactive: reducing the no. of GABAA receptors for binding GABA or GABAergic drugs. • At the same time, ‘spare’subunits of AMPA(alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA(N-methyl-D-aspartic acid) receptors move from subsynaptic sites to the synaptic membrane, causing further hyperexcitability and explaining the preserved sensitivity to NMDA blockers late in the course of SE. • In mins to hours, increase the expression of proconvulsive neuropeptides and decrease the availability of inhibitory neuropeptides: this maintains enhanced excitability.

  26. 3. Use of anticonvulsants in status epilepticus: best current evidences

  27. Anticonvulsants • First- line : benzodiazepines (diazepam, lorazepam) • Second-line: phenytoin/ fosphenytoin, valproic acid, phenobarbital • RSE: iv anaesthetics : midazolam, propofol, barbiturates( thiopental, pentobarbital); inhalational anaesthetics(isoflurane, desflurane); nonanaesthetic: topiramate and levetiracetam.

  28. Diazepam • Mech: as with other benzodiazepines, it increase chloride conductance in CNS GABA-A receptors and thus decreasing neuronal excitability • 0.1-0.3 mg/kg iv • Onset : 10-20 s. • Duration : < 20 mins.

  29. Lorazepam • 0.02- 0.2 mg/kg iv • Peak effect: 2 mins • Duration of anti-seizure effect: 12-24 hours

  30. Phenytoin • Loading dose of 18-20 mg/kg • Infused at a rate of up to 50 mg/min • If necessary, an additional 10 mg/kg can be given. • The risk of hypotension and cardiac arrhythmias increase with higher infusion rates, partly due to propylene glycol used to solubilize phenytoin.

  31. Fosphenytoin • Phosphate ester pro-drug of phenytoin that is hydrolyzed into phenytoin by serum phosphatases within 8-15 mins. • Water soluble and can be infused at rate up to 150 mg/min • Despite this rapid administration, no clear evidence that fosphenytoin stops SE faster than phenytoin. • Cardiovascular side effects may be less frequent as there is no propylene glycol.

  32. A Comparison of four treatments for generalized convulsive SE A five-year randomized, double-blind, multicenter trial of four iv regimens in 518 patients with generalized convulsive SE( overt or subtle): • 1. diazepam(0.15 mg/kg) followed by phenytoin(18 mg/kg), • 2. lorazepam(0.1 mg/kg) • 3. phenobarbital (15 mg/kg) • 4. phenytoin(18 mg/kg) • Treiman et al. Veterans Affairs Status Epilepticus Cooperative Study. NEJM 1998;339:792-8

  33. Lorazepam vs diazepam in SE • RCT, 78 patients • Time of onset was almost the same. • Seizures were controlled in 89 % of the episodes treated with lorazepam and in 76 % treated with diazepam. • Leppik IE. JAMA 1983;249:1452-4.

  34. Valproic acid • Mech: broad-spectrum, modulate sodium and calcium channels, as well as inhibitory GABA transmission. • iv valporic acid has been advocated as a first-line agent for absence SE and a second-line agent for generalized or partial SE.

  35. Valproic acid • Currently there are 20 published studies(7 prospective and 13 retrospective)including 533 adults or children. These studies suggest that iv valproate is as effective as phenytoin/frosphenytoin in resolving SE in patients who have previously failed conventional first-line therapies such as benzodiazepines. • The most commonly reported effective doses were between 15 and 45 mg/kg in bolus(6mg/kg/hr) followed by 5 mg/kg/hr infusion. • The incidence of adverse events(mainly hypotension, dizziness, and thrombocytopenia) was low(< 10%) and independent of infusion rate. Lower risk of respiratory suppression.

  36. Phenobarbital • Mech: depresses neuronal excitability by enhancing the GABA receptor-coupled response • Loading doses of 15-20 mg/kg infused at a rate of 30-50 mg/min. An additional 10 mg/kg can be given if needed. • Adverse effects: hypotension via vasodilation and cardiac depression, hypoventilation, risk of prolonged sedation (half-life of 87-100 hours).

  37. Refractory status epileptics • Exact definition is unclear. • Different studies defining RSE with varying durations ( no time criteria, 30 mins, 1 hour, or 2 hours) and a lack of response to different numbers( two or three) and types of medications.

  38. Midazolam • Mech: positive allosteric modulation of GABA-A receptors( fast, chloride channels) which suppresses neuronal excitability. • Bolus of 0.2 mg/kg, followed by a continuous infusion of 0.05 -0.5 mg/kg/hr.

  39. Propofol • Alkyl-phenol GA • Mech: modulate GABA-A receptors. • Initial low-dose bolus of 1-2 mg/kg, followed by an infusion of 1-2 mg/kg/hr that is titrated as needed. Infusion rates up to 10-12 mg/kg/hr may be required. • Hypotension requiring vasopressor administration occurs in 50-70% of patients.

  40. Propofol Propofol infusion syndrome: • Characterized by refractory metabolic acidosis, cardiac failure, rhadomyolysis ,renal failure and sometimes death. • Occurs most often with prolonged(>48 hours) infusion at doses higher than 5 mg/kg/hr, severe head injury, lean mass, and concurrent use of catecholamines or steroids.

  41. Pentobarbital • Mech: depresses neuronal excitability by enhancing GABA receptor–coupled responses • First metabolite of thiopental • Compared with phenobarbital, pentobarbital has faster brain penetration (allowing faster control of seizures) a shorter half-life( allowing faster waking from coma) • Loading dose of 10 mg/kg infused at up to 100 mg/min, continuous infusion ranging from 1-4 mg/kg/hour.

  42. Pentobarbital • Associated with respiratory depression, myocardial depression, hypotension.

  43. A meta-analysis of 28 articles that included 193 adults with RSE compared pentobarbital, midazolem, and propofol. • Pentobarbital was associated with a sig. lower incidence of short-term treatment failure, breakthrough seizures, and the need to change to a different medication, but was also associated with a sig higher f of hypotension. • However, patients treated with pentobarbital tended to be treated to the point of burst suppression, whereas those treated with midazolam or propofol tended to be treated to seizure suppression. • Claasen, Hirsch. Epildepsia 2002; 43:146-53.

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