Toxins induced seizures: Understanding mechanisms and management approaches
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Drug- and toxin-associated seizures (DTSs) differ from other seizures in their etiology but can demonstrate similar clinical features. DTSs are commonly caused by toxins that alter brain chemistry and disrupt the balance of excitation and inhibition. Specific toxins like cocaine, theophylline, and opioids can induce seizures through various mechanisms of action. Treatment of DTSs involves clinical evaluation, supportive care, enhanced toxin elimination, and empirical anti-seizure medications. DTS-induced status epilepticus requires aggressive treatment typically starting with benzodiazepines, followed by phenytoin, phenobarbital, or valproate if seizures persist. Careful monitoring and management of medical complications is also important
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Toxins induced seizures: Understanding mechanisms and management approaches
- 1. Toxins induced seizures: Shaken not stirred Venugopalan P P DA,DNB,MNAMS,MEM-GW Director ,Emergency Medicine Aster DM healthcare Toxicon; national conference on toxicology 11,12,13th August 2017 ,Kodaikanal
- 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 that promote aberrant electro- cerebral responses which causes seizures. Drug- and toxin-associated seizures (DTSs) differ in etiology but may demonstrate distinct clinical features, which allow identification and treatment.
- 4. DTS- How it is differ? • Postictal state - confused • Ongoing electrical, subclinical status epileptics • Continuous display electrical activities in brain even after cessation of convulsion • Aura - unlikely • Features of partial seizure like laterlaized 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) Glutamate mediates excitatory synapses through one of several postsynaptic receptors, which modulate calcium- or sodium-induced membrane depolarization. GABAergic synapses are inhibitory and causes opening chloride ion channels, which hyperpolarize the postsynaptic membrane, preventing the formation of action potentials.
- 6. GABA- Inhibitory Chloride ion Hyperpolarizatio n Prevent action potentials Glutamate Excitatory Calcium-Sodium channels Depolarization.
- 8. 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
- 9. Conditions changes Glutamate &GABA receptor subtype function Individual seizure susceptibility varies based on transient factors Sleep deprivation Electrolyte disturbances Intercurrent infections Neonatal hypoxia Childhood hyperthermia Traumatic brain injuryIncreases Seizure likelihood
- 10. SEMIOLOGY OF DTS ASSOCIATED SEIZURES
- 11. 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
- 13. Electrophysiology of Drug- and Toxin-associated Seizures
- 14. 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.
- 15. 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
- 16. 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
- 17. 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 Barbiturates, alternating bursts of high-amplitude activity followed by background suppression Cocaine and Amphetamines also increase β-activity at lower levels of intoxication, and diffuse slowing at higher blood concentrations Phencyclidine induces a pattern of unreactive θ-slowing with periodic bursts of δ-activity
- 18. DTS EEG DTSs shows features of generalized seizures. During the seizure Diffuse & Anterior-predominant Synchronous Symmetrical Short-duration Sharply contoured spikes Slow waves :longer-duration ,are complexed and repeating in rhythmic fashion at 2 to 5 Hz.42
- 19. EEG in DTS Epileptiform activity interictally (between seizures) in the absence of seizure activity, including spikes or polyspikes Lithium and Phenothiazines Withdrawal from Alcohol,43 Benzodiazepines,44 or Barbiturates.
- 24. Mimics- DTS Psychogenic nonepileptic seizures Syncope Hypoglycemia Panic attacks Acute movement disorders Parasomnias Nonepileptic myoclonus Migraines Transient global amnesia Transient ischemic attacks
- 25. Mimics in children Benign entities and movement disorders Nonepileptic staring spells Tics Shuddering attacks Breath-holding spells Gastroesophageal reflux
- 32. Sympathomimetic by seizurogenic Cocaine Local anesthetic affect-Potentiate seizures -Fast sodium channel blockade. Wide QRS tachycardia can be seen in severe cocaine toxicity May be treated with bolus sodium bicarbonate therapy. Sympathomimetic toxidrome includes tachycardia, hypertension, mydriasis, diaphoresis, and psychomotor agitation Sympathomimetics- also cause Intracerebral hemorrhage Ischemic cerebral vascular accident Neuroimaging should be considered before attributing seizures to purely pharmacological effects
- 33. Withdrawal and seizure Withdrawal syndromes - Seizures and autonomic instability are typically seen with withdrawal from Ethanol, Sedatives (e.g., benzodiazepines and barbiturates) & Baclofen Tremor and visual hallucinations followed by generalized seizures and autonomic instability. Seizures are typically brief Status epilepticus is uncommon.
- 34. Withdrawal-Seizures Baclofen withdrawal Delirium Hallucinations Autonomic instability Hyperthermia Seizures, which can be severe Intrathecal pump failure results in refractory symptoms and is difficult to treat .
- 35. Theophylline - Acute overdose Vomiting Sympathomimetic signs, including agitation, tremor, tachycardia, and supraventricular dysrhythmias 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.
- 36. TCA & Seizures Early overdose may have a predominance of anticholinergic symptoms Moderate TCA overdose- CNS depression, widened QRS tachycardia & Seizures Electrocardiography 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
- 38. Opioid & Seizures Opioid toxidrome - CNS depression, respiratory depression, and miosis. Several opioids - effects on pupil size and exhibit other unique toxicities, including seizures Propoxyphene overdose - CNS depression Seizures Cardiac conduction abnormalitiesMeperidine Narcotic analgesic Drug interactions Contributing factor in the infamous Libby Zion case Normeperidine -metabolite cause seizures when levels accumulate.
- 39. Tramadol & Seizures Newer analgesic Partial µ-agonist Monoamine reuptake inhibitor One animal study suggested that high doses of tramadol produced seizures only in kindled rats.104 Human experience suggests that seizures may occur in 8% to 54% of tramadol exposures Occasionally result in significant morbidity
- 40. NonTCA,Antipsychotics & Lithium Serotonin-specific re-uptake 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 Citalopram Seizures Supraventricular tachycardia Wide-complex tachycardia Responsive to sodium bicarbonate Venlafaxine Serotonin–norepinephrine reuptake inhibitor Overdose causing seizures and cardiotoxicity.114
- 43. NonTCA,Antipsychotics & Lithium Bupropion Seizures - typically brief and self-limited Status epilepticus approximately 15% to 19% Clozapine and Olanzapine Atypical antipsychotics Highest potential to cause seizures from therapeutic dosing or overdose.125
- 44. NonTCA,Antipsychotics & Lithium Lithium Acute, chronic, or acute on chronic Symptoms may include Nausea, Vomiting, Tremor, and Mental status alteration Severe toxicity Coma Hyperreflexia Conduction disturbances Seizures. No antidote for lithium intoxication Mainstay therapy is to enhance elimination through administration of crystalloids and hemodialysis.126
- 45. Epileptic patient Overdose of several anticonvulsants can paradoxically precipitate seizures. Seizurogenic anti epileptics in overdose Phenytoin Carbamazepine Vigabatrin
- 46. Newer anti-epileptics Lamotrigine Seizures from therapeutic use, high-dose usage, and overdose Topiramate CNS depression Status epilepticus Tiagabine overdose CNS depression Coma Agitation Dystonia Seizures Status epilepticus Hallucinations
- 47. Refractory Seizures & Status Epilepticus Xenobiotics induced seizures are typically brief and self-limiting Occasionally produce status epilepticus Seizures refractory to traditional treatments
- 48. INH Hydrazine Structurally similar rocket fuel and toxins from Gyromitra esculenta mushrooms Functional deficiency of pyridoxal 5- phosphate (activated vitamin B6) Inhibition of pyridoxine phosphokinase. Pyridoxal 5-phosphate is an essential cofactor for glutamic acid decarboxylase GABA synthesis is suppressed - leads to seizures. Refractory Seizures & Status Epilepticus
- 49. INH overdose Doses 20 mg/kg can cause neurotoxicity 80 to 150 mg/kg -seizures and severe toxicity. The mainstay of treatment is administration of intravenous pyridoxine Triad of INH overdose Coma Severe Lactic AcidosisRefractory Seizures
- 50. Water hemlock Water hemlock (Cicuta maculata) Mistaken for wild carrots, parsnips, or turnips Symptoms develop soon after even a small ingestion Delirium Salivation Severe Seizures- Refractory to standard treatments Cardiac arrest Treatment is supportive No specific antidote exists.
- 51. Tinittus and hearing loss —convulsion Salicylate intoxication Acute or chronic. Acute poisoning Gastrointestinal symptoms Hyperventilation Tinnitus Chronic or Severe poisoning Worsening metabolic acidosis Tachycardia Diaphoresis Mental status changes Agitation. Seizures - refractory Cardiac arrest Seizures are typically a late and ominous finding in severe salicylate intoxication and may precede cardiac arrest
- 52. Lignocaine Curcum oral paresthesia Tinnitus Facial Twitching Convulsion Respiratory arrest Cardiac arrest Toxic doses Plain 3mg /kg With adrenaline 7mg/kg
- 53. Approach- DTS Clinical evaluation and resuscitation Good history determining etiologies Emergency medical service personnel Bystanders Family members Primary care physicians Databases containing the patient’s medication record
- 54. Airway Breathing Circulation Data , Differentials & Detoxification Empirical Anti convulsants, Enhanced Elimination procedures IV Oxygen Monitors Bedside Glucose Approach- DTS
- 55. Tests Electrocardiography Chest x-ray Blood chemistry Lactate Liver function tests Arterial blood gas Tox screening depending on history
- 57. Drug concentrations should be interpreted carefully since they are only a single data point in time Drug levels need to be correlated to the time of ingestion, toxicokinetic profile, and clinical symptoms Need to be obtained serially to safely and adequately prognosticate the significance of the exposure (e.g., salicylates and lithium). Tox screening
- 61. Detoxification Gastrointestinal decontamination Gastric lavage Oral-activated charcoal Whole-bowel irrigation Enhanced elimination procedures Urinary alkalinization Multidose activated charcoal Hemodialysis
- 62. Patients who are actively seizing, anticipated to have seizures, or have significant CNS depression are at risk for complications including pulmonary aspiration. Consultation with a clinical toxicologist can be helpful in determining whether a decontamination procedure is warranted based on individual patient characteristics. Detoxification
- 64. Carefull … Identification and treatment medical complications of seizures Hyperthermia Metabolic acidosis Rhabdomyolysis Cardiac dysrhythmias Head, spinal, and orthopedic trauma Metabolic and medical complications can be the result of seizures underlying toxic profile of the exposure, or both.
- 65. 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 antiepileptic therapy Carefull …
- 66. DTS induced Status Status epilepticus Neurological emergency 17% to 23% mortality rate 10% to 23% of survivors suffering from persistent neurological disabilities. Convulsive and nonconvulsive status epilepticus Generalized and partial status epilepticus Toxic–metabolic etiologies cause up to 19% of cases of status epilepticus.
- 67. DTS status- Treatment Benzodiazepine receptors : Potentiate the effect of GABA on GABAA receptors Increase neuronal inhibition by increasing chloride permeability Neuronal hyperpolarization Inhibit adenosine Enhancing adenosine’s activity at A1 receptors Aborting seizures caused by adenosine antagonists such as theophylline Benzo diazepines are the first line
- 68. Intravenous lorazepam up to a total dose of 0.1 mg/kg is preferred among the benzodiazepines. Benzodiazepines may not be effective in some exposures, resulting in GABA depletion, such as INH toxicity Benzodiazepines
- 69. Non DTS status First-line therapy drugs - phenytoin or the prodrug fosphenytoin Phenytoin Aggravate certain types of generalized seizures Absence seizures Myoclonus in juvenile myoclonic epilepsy Phenytoin and fosphenytoin may not be effective in treating absence or myolconic status epilepticus
- 70. Non DTS -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 Prolonged seizures caused by drugs and toxins with direct or indirect GABA antagonism are expected to respond to treatment with phenobarbital
- 71. Third line Sodium valproate Antiepileptic drug effective for all seizure types Multiple mechanisms of action Increased GABA transmission Reduced release of excitatory amino acids such as glutamate Blockage of voltage-gated sodium channels Serotonin and dopamine modulation. 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
- 72. Other drugs Levetiracetam is a newer antiepileptic medication with an oral and intravenous formulation that has been used for treatment of status epilepticus No serious or life-threatening toxicities even with rapid intravenous infusion. Renally eliminated Does not induce hepatic enzymes Nosignificant interactions with other drugs.
- 73. Refractory status epileptics 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
- 74. Refractory status epilepticus Midaz plus propofol Intubation ventilation Ketamine Barbiturate coma may be induced with pentobarbital or thiopental for refractory status epilepticus Pentobarbital is the preferred agent
- 75. Ketamine Unique anesthetic agent useful in refractory status epilepticus. Unique mechanism of action as an NMDA receptor antagonist. Neuroprotective properties in a chemical model of seizures and in the setting of status epilepticus
- 78. 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
- 79. Interesting … Previously thought - seizurogenic … Now useful to treat Status epileptics Previously thought - Very safe analgesic Now showed that a potent seizurogenic
- 80. Thanks a lot … www.drvenu.blogspot.in drvenugopalpp@gmail.com