“Drugs & Toxins”

Associated seizures in
emergency department

Dr . Venugopalan P P

DA,DNB,MNAMS,MEM-GW

Director & Lead consultant

Emergency Medicine

Aster DM healthcare
 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
 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
 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
 Seizure - Basics and facts
• Cortical neurons implicated in seizure activity

• Most prominent neurotransmitters are

Glutamate and γ-aminobutyric acid

(GABA)
 Seizure - Basics and facts
• Glutamate mediates excitatory synapses through

one of several postsynaptic receptors

• Modulate calcium- or sodium-induced

membrane depolarization
 Seizure - Basics and facts
• GABAergic synapses are inhibitory

• Causes opening chloride ion channels

• Hyperpolarize the postsynaptic membrane

• Preventing the formation of action potentials

 GABA

• Inhibitory
Glutamate
● Excitatory • Chloride ion
● Calcium-Sodium
channels • Hyperpolarization
● Depolarization
• Prevent action

potentials
GlutamatE-Excitatory
GABA-Anti excitatory

Memory tips
 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
 Increases
Seizure Traumatic Childhood Neonatal
likelihood Brain injury hyperthermia Hypoxia

Conditions which changes Glutamate &

GABA receptor subtype function
Individual seizure susceptibility varies based

on transient factors

• Sleep deprivation

• Electrolyte disturbances

• Intercurrent infections
SEMIOLOGY OF DTS
ASSOCIATED
SEIZURES
 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

Electrophysiology of Drug & Toxin-associated
Seizures
 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.
 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

 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
 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
 Specific changes
• Barbiturates

Alternating bursts of high-amplitude activity

followed by background suppression

 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

 DTS EEG
DTSs shows features of generalized
• Short-duration
seizures.
• Sharply contoured spikes
During the seizure
• Slow waves :longer-duration
• Diffuse & Anterior-predominant
complexed and repeating in
• Synchronous
rhythmic fashion at 2 to 5 Hz.
• Symmetrical
https://expertconsult.inkling.com/read/dobbs-clinical-neurotoxicology-1st/chapter-11/chapter11-reader-9#3e6af
e25c4b6466b84ee1b0b373a3643
 Synchronous

Short duration

Five S
Symmetrical

Sharp spikes

Memory tips Slow waves

 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
EEG
Normal ,Resting , Wakeful , Posterior dominance
Prominent anterior and diffuse beta
activity
Diffuse delta
waves , slow
and sharp
waves
Generalized
Convulsion
 DTS Mimics !
• Psychogenic nonepileptic

seizures • Panic attacks

• Syncope • Acute movement disorders

• Hypoglycemia
 DTS Mimics !
• Parasomnias

• Non epileptic
• myoclonus
• Transient global amnesia
• Migraines
• Transient ischemic attacks
 Mimics in children
Benign entities and
Movement disorders
• Nonepileptic staring spells
• Breath-holding spells
• Tics
• Gastroesophageal reflux
• Shuddering attacks
Xenobiotics
Seizurogenic
 Memory
tips

OTIS
CAMPBELL
 Sympathomimetic by
Sympathomimetic
seizurogenic

Toxidrome

● Diaphoresis
• Tachycardia

● Psychomotor agitation
• Hypertension

• Mydriasis
Sympathomimetics- also
cause
• Intracerebral hemorrhage
• Ischemic cerebral vascular
accident
• Neuroimaging should be
considered before attributing
seizures to purely
pharmacological effects
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
 Withdrawal and seizure

Withdrawal syndromes ● Ethanol

● Sedatives (e.g.benzodiazepines and

● Seizures
barbiturates)
● Autonomic
● Baclofen

instability
 Withdrawal and seizure
• Tremor and visual hallucinations

followed by generalized seizures

• Autonomic instability

• Seizures are typically brief

• Status epilepticus is uncommon.

 Withdrawal-Seizures
Baclofen withdrawal
• Delirium

• Hallucinations

• Autonomic instability

• Hyperthermia

• Seizures - severe

Intrathecal pump failure results in refractory symptoms and is difficult to treat

 Theophylline - Acute
overdose
• Vomiting

• Sympathomimetic signs

Agitation, Tremor, Tachycardia

Supraventricular dysrhythmias
 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

 TCA & Seizures
• Early overdose : predominance of

anticholinergic symptoms

• Moderate TCA overdose

CNS depression, Widened QRS

tachycardia & Seizures

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
TCA & ECG@Seizures
ECG & Wide
QRS @
Seizure
 Opioid & Seizures
Opioid toxidrome
Several opioids effects on pupil size and
● CNS depression
exhibit other unique toxicities, including
● Respiratory
seizures

depression

● Miosis.
 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/
Propoxyphene overdose

• CNS depression

• Seizures

• Cardiac conduction abnormalities

 Tramadol & Seizures
• Newer analgesic

• Partial μ-agonist

• Monoamine reuptake inhibitor

• Recently categorized under Schedule IV

controlled substance (CS).

 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
 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

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
Citalopram

• Seizures

• Supraventricular tachycardia

• Wide-complex tachycardia

• Responsive to sodium bicarbonate

 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

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
 NonTCA,Antipsychotics & Lithium
Lithium
● Nausea
• Acute
● Vomiting
• Chronic
● Tremor
• Acute on chronic
● Mental status alteration
Symptoms
Memory
Tips
2-2-20

● Lithium 2 mEq/L
● Digoxin 2 ng/ml
● Theophylline
20mcg/ml
Severe toxicity

• Coma

• Hyperreflexia

• Conduction disturbances

• Seizures.
• 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

Seizurogenic anti -epileptics
 Anticonvulsant Paradox
Overdose of several anticonvulsants can

paradoxically precipitate seizures.

 Epileptic patient
Seizurogenic anti -epileptics in

overdose

• Phenytoin

• Carbamazepine

• Vigabatrin
 Tiagabine overdose

• CNS depression • Dystonia

• Coma • Seizures

• Agitation • Status epilepticus

• Hallucinations
 Newer antiepileptics
Lamotrigine

Causes Seizures

● Therapeutic use

● High-dose dosage

● Overdose
 Newer antiepileptics

Topiramate
❖ CNS depression
❖ Status epilepticus
Refractory Seizures & Status Epilepticus

• Xenobiotics induced seizures are typically brief

and self-limiting

• Occasionally produce status epilepticus

• Seizures refractory to traditional treatments

 Refractory Seizures & Status Epilepticus

INH

• Hydrazine

• Structurally similar rocket fuel &

toxins from Gyromitra

esculenta mushrooms
 INH and seizures
• Functional deficiency of pyridoxal

5-phosphate (activated vitamin B6)

• Inhibition of pyridoxine phosphokinase

 INH and seizures
• Pyridoxal 5-phosphate is an essential cofactor

for glutamic acid decarboxylase

• GABA synthesis is suppressed - leads to

Seizures
INH and seizures
 Coma
INH overdose

Refractory Triad Severe Lactic

Seizures Acidosis
The mainstay of treatment is
administration of intravenous pyridoxine

• 20 mg/kg : Neurotoxicity

Toxic • 80 to 150 mg/kg : Seizures and

Doses Severe toxicity.

 Memory Tips
● Lithium 2 mEq/L
● Digoxin 2 ng/ml
● Theophylline 20
2-2 mcg/ml
● INH Neurotoxicity
20-20 20 mg/Kg
 Water hemlock (Cicuta maculata)

• Mistaken for wild carrots, parsnips, or

turnips

• Symptoms develop soon after even a small

ingestion
 Water hemlock (Cicuta maculata)

• Delirium
• Treatment is supportive
• Severe Seizures- Refractory to
• No specific antidote
standard treatments

• Cardiac arrest
 Tinnitus and hearing loss
—convulsion
Salicylate intoxication

Acute

Chronic.

•
 Salicylate intoxication

Acute poisoning

• Gastrointestinal symptoms

• Hyperventilation

• Tinnitus
 Salicylate intoxication
• Seizures are typically a late

• Ominous finding in severe salicylate

intoxication

• Precede cardiac arrest

Chronic or Severe poisoning

• Worsening metabolic • Mental status changes

acidosis • Agitation.

• Tachycardia • Seizures - refractory

• Diaphoresis • Cardiac arrest

Lignocaine
Toxic doses
● Plain 3 mg /kg
● With
adrenaline
7mg/kg

Bupivacaine 3 mg /Kg
 I
LA-
N
E
X
H
I
● Na channel
C
I
B
I blockers
T T
A
T
A
T
● Seizurogenic
O O
R
Y
R
Y
mechanism
Overactivity P P
Inhibits
A A
T T
H H
 Local Anesthetic
Agents

Most Toxic -
Seizurogenic Cardiac
 Memory
Tips

Antidote

Intravenous intralipid
Intralipid dosage
schedule
 Approach- DTS
Clinical evaluation and resuscitation
Good history determining etiologies

1. Emergency medical service personnel

2. Bystanders
 Good history determining etiologies

3. Family members

4. Primary care physicians

5. Databases containing the patient’s

medication record
 Approach- DTS
• Airway
• Breathing
• Circulation
• Data , Differentials &
Detoxification
• Empirical Anti- convulsants,
Enhanced Elimination procedures
 Approach- DTS
• IV
• Oxygen
• Monitors
• Bedside Glucose
 Tests
● Electrocardiography ● Lactate

● Chest x-ray ● Liver function tests

● Blood chemistry ● Arterial blood gas

Tox screening depending on history

 Tox screening

● Drug concentrations should be

interpreted carefully since they

are only a single data point in time

 Tox screening
• Drug levels need to be correlated

to the time of ingestion,

toxicokinetic profile, and clinical

symptoms
 Tox screening
• Need to be obtained serially to safely

and adequately prognosticate the

significance of the exposure

(e.g., Salicylates and Lithium).

Tox screening
Tox screening
Tox screening
Detoxification
Gastrointestinal decontamination

● Gastric lavage

● Oral-activated charcoal

● Whole-bowel irrigation
 Detoxification
Enhanced elimination procedures

• Urinary alkalinization

• Multidose activated charcoal

• Hemodialysis
 Detoxification
• Patients who are actively seizing,

anticipated to have seizures, or have

significant CNS depression are at risk

for complications including pulmonary

aspiration.
 Detoxification
• Consultation with a clinical toxicologist can

be helpful in determining whether a

decontamination procedure is warranted

based on individual patient characteristics

 Carefull …
Identification and treatment medical

complications of seizures

• Hyperthermia

• Metabolic acidosis

• Rhabdomyolysis
 Carefull …
• 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

 DTS induced Status
Epilepticus
Status epilepticus

• Neurological emergency

• 17% to 23% mortality rate

• 10% to 23% of survivors suffering from persistent

neurological disabilities
 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.

 DTS status- Treatment
Benzo-diazepines are the first line
Benzodiazepine receptors :

• Potentiate the effect of GABA on

GABA receptors
A

• Increase neuronal inhibition by increasing

chloride permeability
 DTS status- Treatment
• Neuronal hyperpolarization

• Inhibit adenosine

• Enhancing adenosine activity at A1 receptors

• Aborting seizures caused by adenosine

antagonists such as theophylline

 Benzodiazepines

Intravenous lorazepam up to a

total dose of 0.1 mg/kg is preferred

among the benzodiazepines.

 Benzodiazepines

Benzodiazepines may not be effective

in some exposures, resulting in GABA

depletion, such as INH toxicity

 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

 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

 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
 Non DTS Status-Third
line
Sodium valproate

• Antiepileptic drug effective for all seizure types

• Multiple mechanisms of action

• Increased GABA transmission

 Sodium valproate

• Reduced release of excitatory amino acids such as

glutamate

• Blockage of voltage-gated sodium channels

• Serotonin and dopamine modulation.

 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
 Other drugs

Levetiracetam is a newer antiepileptic

medication with an oral and intravenous

formulation that has been used for

treatment of status epilepticus

 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.

 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

 Refractory status epilepticus
• Midaz plus
propofol
• Intubation
ventilation
• Ketamine
 Refractory status
epilepticus
• Barbiturate coma may be induced with

pentobarbital or thiopental for refractory status

epilepticus

• Pentobarbital is the preferred agent

 Ketamine
• Unique anesthetic agent useful in

refractory status epilepticus.

• Unique mechanism of action as an

NMDA receptor antagonist.

 Ketamine
• Neuroprotective properties in a

chemical model of seizures and in the

setting of status epilepticus

 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
 Interesting …
Previously
Previously thought -
thought - Very safe
seizurogenic. analgesic
Now useful Now showed
to treat that a
Status potent
epilepticus seizurogenic

Ketamine Tramadol
 www.drvenu.blogspot.in
drvenugopalpp@gmail.com

Thanks a lot …