Drugs & toxins associated seizures in emergency departments
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Xenobiotics induced convulsions are constituting 15 percentage of ED seizures. EP should know in and outs of the DTS. This presentation explores various aspects of DTS in the ED
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Drugs & toxins associated seizures in emergency departments
- 1. “Drugs & Toxins” Associated seizures in emergency department Dr . Venugopalan P P DA,DNB,MNAMS,MEM-GW Director & Lead consultant Emergency Medicine Aster DM healthcare
- 2. Why ? • Seizures are the outward manifestation of abnormal electrical activity in the brain. • Direct intoxication from known poisons or psychotropic drugs, withdrawal from medications or alcohol, or idiosyncratic reactions to pharmaceuticals cause seizure
- 3. Why? • Toxin changes in brain chemistry • Promote aberrant electro-cerebral responses which causes seizures • Drug- and toxin-associated seizures (DTSs) differ in etiology but may demonstrate
- 4. DTS- How it is differ? • Postictal state - confused • Ongoing electrical, subclinical status epilepticus • Continuous display electrical activities in brain even after cessation of convulsion • Aura - unlikely • Features of partial seizure like lateralized gaze and head deviation are rare
- 5. Seizure - Basics and facts • Cortical neurons implicated in seizure activity • Most prominent neurotransmitters are Glutamate and γ-aminobutyric acid (GABA)
- 6. Seizure - Basics and facts • Glutamate mediates excitatory synapses through one of several postsynaptic receptors • Modulate calcium- or sodium-induced membrane depolarization
- 7. Seizure - Basics and facts • GABAergic synapses are inhibitory • Causes opening chloride ion channels • Hyperpolarize the postsynaptic membrane • Preventing the formation of action potentials
- 8. GABA • Inhibitory • Chloride ion • Hyperpolarization • Prevent action potentials Glutamate ● Excitatory ● Calcium-Sodium channels ● Depolarization
- 10. Seizure activity • Excessive excitatory stimulation • Failure of inhibition of aberrant electrical activity • Both “Without GABA inhibition, prolonged glutamate release results in calcium-related neurotoxicity and neuronal death” KH Noe, EM Manno: Mechanisms underlying status epilepticus. Drugs Today (Barc).41 (4):257-266 2005
- 11. Conditions which changes Glutamate & GABA receptor subtype function Neonatal Hypoxia Childhood hyperthermia Traumatic Brain injury Increases Seizure likelihood
- 12. Individual seizure susceptibility varies based on transient factors • Sleep deprivation • Electrolyte disturbances • Intercurrent infections
- 14. Neuronal substrate for seizure propagation • Preceding factors • Neurotoxins are capable of tipping the balance of excitation and inhibition • Inhibitors of GABAergic transmission are potent seizure generators • Molecules that contribute to glutamate excitation
- 16. Electrophysiology of Drug & Toxin-associated Seizures
- 17. EEG Rhythmic EEG activity is identified by its frequency and amplitude Frequency measures fall into several ranges: • δ-range is less than 1 to 3 Hz • θ-range is 4 to 7 Hz • α-range is 8 to 13 Hz • β-range is 14 to 28 Hz.
- 19. EEG • Gradient of increasing amplitude and decreasing frequency from anterior to posterior leads • Frontal channels have lower-amplitude, β-frequency activity • Occipital channels are with higher-amplitude, resting α-frequency rhythm that attenuates with eye opening
- 20. Drugs and Toxins • Alter the appearance of the EEG, even in the absence of seizures. • Effect of most neurotoxins is nonspecific, with posterior background or diffuse slowing and changes in amplitude
- 21. Specific changes • Benzodiazepines and Barbiturates increase β-frequency amplitude and distribution, often obscuring other waveforms • At higher doses, these medications may result in diffuse slowing
- 22. Specific changes • Barbiturates Alternating bursts of high-amplitude activity followed by background suppression
- 23. Specific changes • Cocaine and Amphetamines Increase β-activity at lower levels of intoxication, and diffuse slowing at higher blood concentrations • Phencyclidine Unreactive θ-slowing with periodic bursts of δ-activity
- 24. DTS EEG DTSs shows features of generalized seizures. During the seizure • Diffuse & Anterior-predominant • Synchronous • Symmetrical https://expertconsult.inkling.com/read/dobbs-clinical-neurotoxicology-1st/chapter-11/chapter11-reader-9#3e6af e25c4b6466b84ee1b0b373a3643 • Short-duration • Sharply contoured spikes • Slow waves :longer-duration complexed and repeating in rhythmic fashion at 2 to 5 Hz.
- 25. Five S Synchronous Symmetrical Slow waves Short duration Sharp spikes Memory tips
- 26. EEG in DTS Interictal Epileptiform activity (between seizures) in the absence of seizure activity (Spikes or Polyspikes) • Lithium and Phenothiazines • Withdrawal from Alcohol,Benzodiazepines,or Barbiturates https://expertconsult.inkling.com/read/dobbs-clinical-neurotoxicology-1st/chapter-11/chapter11-reader-9#0d3fb 99b3c2e4310a1ff1bd9f5a27e14
- 27. EEG
- 28. Normal ,Resting , Wakeful , Posterior dominance
- 29. Prominent anterior and diffuse beta activity
- 30. Diffuse delta waves , slow and sharp waves
- 32. DTS Mimics ! • Psychogenic nonepileptic seizures • Syncope • Hypoglycemia • Panic attacks • Acute movement disorders
- 33. DTS Mimics ! • • Parasomnias • Non epileptic myoclonus • Migraines • Transient global amnesia • Transient ischemic attacks
- 34. Mimics in children • Nonepileptic staring spells • Tics • Shuddering attacks Benign entities and Movement disorders • Breath-holding spells • Gastroesophageal reflux
- 35. Xenobiotics
- 37. Seizurogenic
- 44. Sympathomimetic by seizurogenicSympathomimetic Toxidrome • Tachycardia • Hypertension • Mydriasis ● Diaphoresis ● Psychomotor agitation
- 45. Sympathomimetics- also cause • Intracerebral hemorrhage • Ischemic cerebral vascular accident • Neuroimaging should be considered before attributing seizures to purely pharmacological effects
- 46. Cocaine • Local anesthetic affect-Potentiate seizures -Fast sodium channel blockade. • Wide QRS tachycardia in severe cocaine toxicity • May be treated with bolus sodium bicarbonate therapy
- 47. Withdrawal and seizure Withdrawal syndromes ● Seizures ● Autonomic instability ● Ethanol ● Sedatives (e.g.benzodiazepines and barbiturates) ● Baclofen
- 48. Withdrawal and seizure • Tremor and visual hallucinations followed by generalized seizures • Autonomic instability • Seizures are typically brief • Status epilepticus is uncommon.
- 49. Withdrawal-Seizures Baclofen withdrawal Intrathecal pump failure results in refractory symptoms and is difficult to treat • Delirium • Hallucinations • Autonomic instability • Hyperthermia • Seizures - severe
- 50. Theophylline - Acute overdose • Vomiting • Sympathomimetic signs Agitation, Tremor, Tachycardia Supraventricular dysrhythmias
- 51. Theophylline - Acute overdose Seizures are a common sequelae of toxicity • Less likely to be observed with serum levels below 60 mg/L • Common with levels above 90 mg/L • Occur at lower concentrations in chronic toxicity
- 52. TCA & Seizures • Early overdose : predominance of anticholinergic symptoms • Moderate TCA overdose CNS depression, Widened QRS tachycardia & Seizures
- 53. Electrocardiography and TCA Overdose • Stratify the severity of intoxication • Surrogate for the degree of fast sodium channel blockade • QRS width greater than 100 msec (or >3 mm R wave in aVR) are at higher risk for seizures
- 55. ECG & Wide QRS @ Seizure
- 56. Opioid & Seizures Opioid toxidrome ● CNS depression ● Respiratory depression ● Miosis. Several opioids effects on pupil size and exhibit other unique toxicities, including seizures
- 57. Meperidine • Narcotic analgesic • Drug interactions • Contributing factor in the infamous Libby Zion case • Normeperidine -metabolite cause seizures when levels accumulate http://drbarronlerner.com/2009/03/03/libby-zion-a-life-changing-case-for-doctors-in-training/
- 59. Propoxyphene overdose • CNS depression • Seizures • Cardiac conduction abnormalities
- 60. Tramadol & Seizures • Newer analgesic • Partial μ-agonist • Monoamine reuptake inhibitor • Recently categorized under Schedule IV controlled substance (CS).
- 61. Tramadol • One animal study suggested that high doses of tramadol produced seizures only in kindled rats. • Human experience suggests that seizures may occur in 8% to 54% of tramadol exposures • Occasionally result in significant morbidity H Potschka, E Friderichs, W Loscher: Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy.Br J Pharmacol. 131 (2):203-212 2000
- 62. NonTCA,Antipsychotics & Lithium Serotonin-specific reuptake inhibitors (SSRIs) appear to be relatively safer in overdose compared to TCAs and venlafaxine • Generalized seizures are less common • Tend to be brief and self-limited
- 63. Venlafaxine • Serotonin–norepinephrine reuptake inhibitor • Overdose causing seizures and cardiotoxicity D Blythe, LP Hackett: Cardiovascular and neurological toxicity of venlafaxine. Hum Exp Toxicol. 18 (5):309-313 1999
- 64. Citalopram • Seizures • Supraventricular tachycardia • Wide-complex tachycardia • Responsive to sodium bicarbonate
- 67. NonTCA,Antipsychotics & Lithium Bupropion • Seizures - typically brief and self-limited • Status epilepticus approximately 15% to 19%
- 68. Clozapine and Olanzapine • Atypical antipsychotics • Highest potential to cause seizures from therapeutic dosing or overdose R Lennestal, C Asplund, M Nilsson, HA Lakso, T Mjorndal, S Hagg: Serum levels of olanzapine in a non-fatal overdose. J Anal Toxicol. 31 (2):119-121 2007
- 69. NonTCA,Antipsychotics & Lithium Lithium • Acute • Chronic • Acute on chronic Symptoms ● Nausea ● Vomiting ● Tremor ● Mental status alteration
- 70. ● Lithium 2 mEq/L ● Digoxin 2 ng/ml ● Theophylline 20mcg/ml Memory Tips 2-2-20
- 71. Severe toxicity • Coma • Hyperreflexia • Conduction disturbances • Seizures.
- 72. • No antidote for lithium intoxication • Mainstay therapy is to enhance elimination through administration of crystalloids and hemodialysis RT Timmer, JM Sands: Lithium intoxication. J Am Soc Nephrol. 10 (3):666-674 1999
- 74. Anticonvulsant Paradox Overdose of several anticonvulsants can paradoxically precipitate seizures.
- 75. Epileptic patient Seizurogenic anti -epileptics in overdose • Phenytoin • Carbamazepine • Vigabatrin
- 76. Tiagabine overdose • CNS depression • Coma • Agitation • Dystonia • Seizures • Status epilepticus • Hallucinations
- 77. Newer antiepileptics Lamotrigine Causes Seizures ● Therapeutic use ● High-dose dosage ● Overdose
- 78. Newer antiepileptics Topiramate ❖ CNS depression ❖ Status epilepticus
- 79. Refractory Seizures & Status Epilepticus • Xenobiotics induced seizures are typically brief and self-limiting • Occasionally produce status epilepticus • Seizures refractory to traditional treatments
- 80. INH • Hydrazine • Structurally similar rocket fuel & toxins from Gyromitra esculenta mushrooms Refractory Seizures & Status Epilepticus
- 81. • Functional deficiency of pyridoxal 5-phosphate (activated vitamin B6 ) • Inhibition of pyridoxine phosphokinase INH and seizures
- 82. INH and seizures • Pyridoxal 5-phosphate is an essential cofactor for glutamic acid decarboxylase • GABA synthesis is suppressed - leads to Seizures
- 83. INH and seizures
- 85. The mainstay of treatment is administration of intravenous pyridoxine • 20 mg/kg : Neurotoxicity • 80 to 150 mg/kg : Seizures and Severe toxicity. Toxic Doses
- 86. ● Lithium 2 mEq/L ● Digoxin 2 ng/ml ● Theophylline 20 mcg/ml ● INH Neurotoxicity 20 mg/Kg 2-2 20-20 Memory Tips
- 87. Water hemlock (Cicuta maculata) • Mistaken for wild carrots, parsnips, or turnips • Symptoms develop soon after even a small ingestion
- 88. Water hemlock (Cicuta maculata) • Delirium • Severe Seizures- Refractory to standard treatments • Cardiac arrest • Treatment is supportive • No specific antidote
- 89. Tinnitus and hearing loss —convulsion Salicylate intoxication Acute Chronic. •
- 90. Salicylate intoxication Acute poisoning • Gastrointestinal symptoms • Hyperventilation • Tinnitus
- 91. Salicylate intoxication • Seizures are typically a late • Ominous finding in severe salicylate intoxication • Precede cardiac arrest
- 92. Chronic or Severe poisoning • Worsening metabolic acidosis • Tachycardia • Diaphoresis • Mental status changes • Agitation. • Seizures - refractory • Cardiac arrest
- 93. Lignocaine Toxic doses ● Plain 3 mg /kg ● With adrenaline 7mg/kg Bupivacaine 3 mg /Kg
- 94. LA- ● Na channel blockers ● Seizurogenic mechanism E X C I T A T O R Y P A T H I N H I B I T A T O R Y P A T H InhibitsOveractivity
- 95. Local Anesthetic Agents Seizurogenic Most Toxic - Cardiac
- 98. Approach- DTS Clinical evaluation and resuscitation Good history determining etiologies 1. Emergency medical service personnel 2. Bystanders
- 99. Good history determining etiologies 3. Family members 4. Primary care physicians 5. Databases containing the patient’s medication record
- 100. • Airway • Breathing • Circulation • Data , Differentials & Detoxification • Empirical Anti- convulsants, Enhanced Elimination procedures Approach- DTS
- 101. Approach- DTS • IV • Oxygen • Monitors • Bedside Glucose
- 102. Tests ● Electrocardiography ● Chest x-ray ● Blood chemistry Tox screening depending on history ● Lactate ● Liver function tests ● Arterial blood gas
- 104. ● Drug concentrations should be interpreted carefully since they are only a single data point in time Tox screening
- 105. Tox screening • Drug levels need to be correlated to the time of ingestion, toxicokinetic profile, and clinical symptoms
- 106. Tox screening • Need to be obtained serially to safely and adequately prognosticate the significance of the exposure (e.g., Salicylates and Lithium).
- 107. Tox screening
- 108. Tox screening
- 109. Tox screening
- 110. Detoxification Gastrointestinal decontamination ● Gastric lavage ● Oral-activated charcoal ● Whole-bowel irrigation
- 111. Detoxification Enhanced elimination procedures • Urinary alkalinization • Multidose activated charcoal • Hemodialysis
- 112. • Patients who are actively seizing, anticipated to have seizures, or have significant CNS depression are at risk for complications including pulmonary aspiration. Detoxification
- 113. Detoxification • Consultation with a clinical toxicologist can be helpful in determining whether a decontamination procedure is warranted based on individual patient characteristics
- 115. Carefull … Identification and treatment medical complications of seizures • Hyperthermia • Metabolic acidosis • Rhabdomyolysis
- 116. • DTSs are often self-limited and abate without requiring antiepileptics • Up to 15% of patients with drug-related seizures, particularly if related to overdose, may present with status epilepticus require aggressive Carefull …
- 117. DTS induced Status Epilepticus Status epilepticus • Neurological emergency • 17% to 23% mortality rate • 10% to 23% of survivors suffering from persistent neurological disabilities
- 118. DTS induced Status Epilepticus • Convulsive and nonconvulsive status epilepticus • Generalized and partial status epilepticus • Toxic–metabolic etiologies cause up to 19% of cases of status epilepticus.
- 119. DTS status- Treatment Benzodiazepine receptors : • Potentiate the effect of GABA on GABAA receptors • Increase neuronal inhibition by increasing chloride permeability Benzo-diazepines are the first line
- 120. DTS status- Treatment • Neuronal hyperpolarization • Inhibit adenosine • Enhancing adenosine activity at A1 receptors • Aborting seizures caused by adenosine antagonists such as theophylline
- 121. Intravenous lorazepam up to a total dose of 0.1 mg/kg is preferred among the benzodiazepines. Benzodiazepines
- 122. Benzodiazepines Benzodiazepines may not be effective in some exposures, resulting in GABA depletion, such as INH toxicity
- 123. Non DTS status First-line therapy drugs phenytoin or the prodrug fosphenytoin
- 124. Phenytoin • Aggravate certain types of generalized seizures • Absence seizures • Myoclonus in juvenile myoclonic epilepsy
- 125. Phenytoin and fosphenytoin may not be effective in treating absence or myolconic status epilepticus
- 126. Non DTS status -Second line Phenobarbital • Second-line when a status epilepticus is refractory to benzodiazepines and phenytoin or fosphenytoin • Phenobarbital is often recommended after benzodiazepines for DTSs
- 127. Non DTS status -Second line Prolonged seizures caused by drugs and toxins with direct or indirect GABA antagonism are expected to respond to treatment with phenobarbital
- 128. Non DTS Status-Third line Sodium valproate • Antiepileptic drug effective for all seizure types • Multiple mechanisms of action • Increased GABA transmission
- 129. Sodium valproate • Reduced release of excitatory amino acids such as glutamate • Blockage of voltage-gated sodium channels • Serotonin and dopamine modulation.
- 130. Sodium valproate Multiple mechanisms of action, decreased risk of cardiovascular side effects, and rapid intravenous dosing make it a reasonable choice as a third-line treatment for DTSs
- 131. Other drugs Levetiracetam is a newer antiepileptic medication with an oral and intravenous formulation that has been used for treatment of status epilepticus
- 132. Levetiracetam • No serious or life-threatening toxicities even with rapid intravenous infusion. • Renally eliminated • Does not induce hepatic enzymes • No significant interactions with other drugs.
- 133. Refractory status epilepticus Generalized convulsive or nonconvulsive status epilepticus that continues after first- and second-line therapy or seizures persisting after 30 to 60 minutes of continuous treatment
- 134. Refractory status epilepticus • Midaz plus propofol • Intubation ventilation • Ketamine
- 135. Refractory status epilepticus • Barbiturate coma may be induced with pentobarbital or thiopental for refractory status epilepticus • Pentobarbital is the preferred agent
- 136. Ketamine • Unique anesthetic agent useful in refractory status epilepticus. • Unique mechanism of action as an NMDA receptor antagonist.
- 137. Ketamine • Neuroprotective properties in a chemical model of seizures and in the setting of status epilepticus
- 140. Summarising ….. • Toxins induced convulsion is not rare • Understanding of xenobiotics is vital for EPs • Anticonvulsants producing convulsions • Seizures produces metabolic instability and metabolic instability produces seizures but Toxins produces both. • ABCDE approach with DTS specific modifications
- 141. Interesting … Previously thought - Very safe analgesic Now showed that a potent seizurogenic Previously thought - seizurogenic. Now useful to treat Status epilepticus Ketamine Tramadol
- 142. Thanks a lot … www.drvenu.blogspot.in drvenugopalpp@gmail.com