Barbara Koppel, M.D.New York Medical College

Shaken, not stirred: Toxin-induced Seizures

The American College of Medical ToxicologyMarch 19, 2016

Seizures

• Seizure defined as abnormal neuronal discharge that can cause excessive motor activity, usually tonic contraction followed by clonic jerks, lasts usually < 1 minute followed by depressed mental status or confusion for a few minutes (primary generalized)

Status Epilepticus • Convulsive SE is a prolonged or repeated

seizures without regaining consciousness > 30 minutes, but for practical purposes >5

• Nonconvulsive SE develops after prolonged convulsions or in patients with recurrent partial sz disorder with minimal motor signs, looks like delirium or “altered” mental state.

• Incidence high if continuous EEG used.

Epileptic spikes, generalized

Partial Seizure

• One area of brain is discharging, often temporal lobe so patient has subjective phenomena such as hallucination, or motor cortex with jerking of limbs or face opposite to brain focus

• Can evolve into secondary generalized convulsion

Motor activity but not sz

• Tetanus, myoclonus, tremor, neuroleptic malignant syndrome can all be misinterpreted as seizures but don’t have same deleterious effects on brain.

• (Serotonin syndrome, camphor, strychnine, theophylline/caffeine overdose, lithium)

Incidence of toxin-seizures not known

• Poison control series in several countries estimate .08 -6.1% of new onset seizures;

• If seizure is self-limited it is unlikely to be reported anywhere, so single center series helpful

• Often seizures mixed in with other complications, esp. cardiovascular

Toxin-induced seizures• Seizures are usually generalized• Status epilepticus in 4-10%• Thundiyil 2011;7:16

• Seizures may not be reported if not the most life-threatening issue

• Occur more often in patients with epilepsy• Dose effects are present, ie drugs can be safe

unless deliberately overdosed, or small person gets many pills or toxin is combined with another toxin or something that affects its metabolism

Transmitters

• Endogenous Excitatory Amino Acids, such as aspartate and glutamate, act on NMDA and AMPA receptors which open sodium and calcium channels.

• Inhibitory transmitters, eg. GABA and Glycine, open chloride channels tonically or in bursts depending on the location at the large receptor complexes.

• Toxins affect release, storage and reuptake of neurotransmitters. Chronic exposure can change membrane structures

COMMON MECHANISMS OFTOXIN-INDUCED SEIZURES’

1. Antagonism of GABA-mediated inhibition2. Enhancement of excitatory, especially glutamatergic,

transmission3. Blockade of sodium channels 4. Adenosine antagonism5. Glycine antagonism6. Blockage of GABA production through lack of pyridoxal 5

phosphatate

GABA key to toxin-seizures

• Cage convulsants ( picrotoxin, tetramine) block the GABA/Cl channel from inside.

• Hydrazines (INH, rocket fuel) decrease GABA production by interfering with pyridoxines or pypo4 coenzyme function

• GABA (provided by AED, alcohol, benzo,barb) causes sustained hyperpolarization and anticonvulsant effect, stopping or blocking this can induce seizure

Non GABA Mechanisms • Excitation can be affected in other

transmitter systems too: Methylxanthines and caffeine act on adenosine receptorsAntidepressants act on dopamine and serotoninCannabidiol acts on CBD receptors

Indirect toxin-caused seizures

• Metabolic, especially hyponatremia (“ecstasy”), hypomagnesemia (beer intoxication), post hypoxia (opiate overdose), post cardiac arrest (TCA overdose)

BASIC THALAMOCORTICAL CIRCUIT

Toxin-induced seizures• Seizures are usually generalized (but others

harder to detect, require continuous EEG)• Sutter R J Clin Neurophysiol 2016;33:25-31

• Status epilepticus in 4-10%• Thundiyil 2011;7:16

• Occur more often in patients with epilepsy, and lower degree of toxin exposure can trigger seizure if history of epilepsy (or possible kindling effect)

– Buproprion caused 14.9% of drug-induced seizures, occurred in 30% of buproprion overdose

– Maproptiline 10% risk, Amoxapine 30%– TCAs 10%, Citalopram 7%– With extended release form of buproprion

lower seizure risk but in OD delayed status epilepticus

• Nelson 2007;Clin Tox 45:315 , Cock HR Epilepsy &Behavior 2015;49:76

Dose/ Overdose relates to risk of and timing of seizure

Seizures affected by toxin“dose”

Reflect access to the toxin(OTC> (front of counter >behind), number

of pills dispensed at a time Coingestion with other things can affect metabolism or augment excitotoxicityRelative dose (small ingestee susceptible to smaller amount, more poisons in children)

TOXINS AND DRUGS REPORTED TO INDUCESEIZURES AND STATUS EPILEPTICUS - 1’- 1

Ethanol and other alcohols AnticholinergicsLocal Anesthetics - atropine

- cocaine - benztropine- lidocaine - diphenhydramine- procaine - scopolamine

General Anesthetics Antidepressants- enflurane - buproprion -

etomidate - clomipramine- ketamine - doxepin- methohexital - ami-/nortriptyline

Antibiotics Antihistamines- cephalosporins - chlorpheniramine- ciprofloxacin - diphenhydramine- isoniazid - hydroxyzine- imipenem/cilastatin

https://www.epilepsy.com/information/professionals/resource-library/tables/toxins-and-drugs-reported-induce-seizures (Epilepsy Foundation)

TOXINS AND DRUGS REPORTED TO INDUCESEIZURES AND STATUS EPILEPTICUS - 2

’Antineoplastics Drugs of abuse- bleomycin - amphetamines- carmustine - cocaine- chlorambucil - lysergic acid diethylamide- cisplatin - phencylidine (PCP)- methotrexte Hypoglycemics- vinblastine - insulin

Antivirals - sulfonylureas- acyclovir Immunosuppressives- amantadine - azathioprine

Cardiovascular agents - cyclosporin- digoxin Insecticides- lidocaine - benzene hexachloride- disopyramide - carbamates- metoprolol - organophosphates

hydroxyzine - rotenone- mexiletine- propranolol

TOXINS AND DRUGS REPORTED TO INDUCESEIZURES AND STATUS EPILEPTICUS - 3

’Metal chelators Opioids- deferoxamine - alfentanil- EDTA - fentanyl

penicillamine - meperidineMuscle Relaxants - morphine

- baclofen - pentazocine- albuterol - propoxyphene

Neuroleptics Contrast media- thiothixene - iopamidol- haloperidol - meglumine- lithium - metrizamide

NSAIDS Rodenticides- ibuprofen - fluoroacetate- naproxen - strychnine- piroxicam - thallium- phenylbutazone Vaccines- salicylates - measles, pertussis

Examples from case series• Swiss series single-agent overdose reports

1997-2010, 313/15,441 were seizures. • Absolute numbers reflect use in population• Medications listed include mefanamic acid

(NSAID)=51,citalopram=34,trimipramine=27,venlafaxine=23,tramadol=15,diphenhydramine=14,amitriptyline=14,CBZ=11,maprotiline=10,

• quetiapine=10• Reichert C Clin Tox 2014;52(4):629

California series

• 386 reports in 2003• Buproprion=23%, diphenhydramine =8.3,

TCAs=7.7%, tramadol =7.5%, amphetamines = 6.9%, isoniazid = 5.9%, venlafaxine = 5/9%

• Thundiyil JG J Med Tox 2007;3(1):15

Psychotropics

PsychotropicsAntidepressants, eg tricyclics seizures reported in 6^ of overdoses Thundiyil 2011;J Med Tox 7:16

Therapeutic doses of buproprion responsible for 15% of all drug-induced seizures at one poison center, can be delayedMaprotiline (not in overdose), Citalopram Nelson 2007;Clin Tox 45:315

Neuroleptics eg Clozapine, Risperidone, Aripripazole

Most seizures come from overdose, especially psychotropics (suicide)

• Prescription medication toxicity epidemiology reflects prevalence of usage of those medications (eg tricyclicic antidepressant overdoses less frequent since less prescribed, starting to see gabapentin causing seizures and PRES)

• TCAs have seizures in 6% of overdoses, arrhythmia and prolonged QT can cause syncope Thundiyil 2011;J Med Tox 7:16

• (Quarternary antidepressant maprotiline taken off the market for seizures)

• Buproprion caused 14.9% of drug-induced seizures, some in therapeutic doses.

• Citalopram, but not escitalopram, causes seizures in overdose• Nelson 2007;Clin Tox 45:315

Buproprion• 3rd commonest cause seizures (after benzo

withdrawal and cocaine), • Depression, nicotine dependence, bulimia• (Burst suppression EEG in comatose OD)• Mundi JP J Intensive Care Med 2012;27:384

MOA Buproprion

• Inhibit presynaptic reuptake transporters of dopamaine and norepinephrine, through negative feedback can reduce firing of those neurons in brainstem.

• Increase action of monoamine transporter-2 which pumps transmitters from cytosol to presynaptic vesicles

• Foley KF Expert Rev Neurother 2006;6(9):1249

Delayed Seizures

• Series of OD of buproprion-XL

• 117 patients, 31.6% seized, 1/3 after 8 hrs and 49% had more seizures after that

• Starr P Am J Emerg Med 2009;27(8):911

Stimulants• “Stimulants”

Used for ADHD, weight loss, wakefulness in “proper” dose no seizures

Sympathomimetics in recreational abuseIllicitly used for euphoria, disinhibition, “energy” boosts caused seizures in 7%of cases, rest had hallucinations, anxiety, tremor, tachycardia

LeRoux G 2015 Drug Alc Depend 154:46-53

Caffeine in enemas, pills with high doseSynthetic cannabinoids with paradoxical effects “spice, K2”

Illicit Substances

• Stimulate and block reuptake of NE, DA, 5HT.

• Can cause extreme sleep deprivation– Amphetamines(“Bath salts”,“Meth”) – High dose synthetic cannabis– ɤ hydroxyl butyrate (GHB) – Snead OC NEJM 2005 352:2721-2732

Cocaine

• Seizures with sniffed cocaine in pts with epilepsy, with IV or inhaled (crack) in anyone because amount in CNS much higher

• Koppel 1996 Epilepsia 37:875-878

Withdrawal seizures

• Inhibitory substances such as alcohol, benzodiazepine, barbiturate, hypnotic, baclofen, GABA-ergic AED

cause adaptation at GABA receptor, with increased number of receptors so after chronic use, with high amount, if stopped, overexcitationleads to seizure and sometimes other withdrawal symptoms such as tremor, tachycardia, anxiety, hallucinations/ DTs

Antibiotics

– Penicillin applied directly to brain of animals are one experimental model of epilepsy

– Imipenem reported a 3% incidence of seizures but often used without dose adjustment for body mass or Cr clearance or in critically ill patients with other reasons to seize. In our series reported in 2001, the rate of seizures was 3.9/1000 patient-days before and after imipenem treatment and 4/1000 during treatment (ie sz risk not increased by imipenem).

– Cephalosporin when used to irrigate unruptured aneurysm craniotomy sites ↑ seizure incidence in first postoperative day

– Quinolones, especially in elderly, cause nonconvulsive seizures– Isoniazid special mechanism (don’t produce GABA in overdose)

Figure 2 Types of antibiotic-associated encephalopathy

Shamik Bhattacharyya et al. Neurology 2016;86:963-971

© 2016 American Academy of Neurology

Antiepileptics (high doses) can cause seizures

• Occur mostly Na channel blockers such as phenytoin, carbamazepine (serum AED twice maximum level), tiagabine, topiramate and lamotrigine, usually in overdose, sometimes in therapeutic doses

• Rare with gabanergic meds GBP, VPA

• Barry JD Neurologic Clin 2011 29:539-563

MOLECULAR TARGETS OF ANTISEIZURE DRUGS

• Phenytoin 1938• Carbamazepine 1974• Lamotrigine 1994• Fosphenytoin 1996• Lacosamide 2008

Na+ channels• Phenobarbital 1912• Primidone 1954• Diazepam 1968• Clonazepam 1975• Clobazam 2011

GABAA receptors

• Ethosuximide 1960• Gabapentin 1993

(α2-δ subunit voltage-gated)

Ca++ channels

• Valproate 1978(largely unknown)

• Felbamate 1993• Lamotrigine 1994

(Na, Ca, AMPA)

• Topiramate 1996(Na, Ca, Glu, GABA)

• Zonisamide 2000(Na, Ca, DA, GABA)

Mixed

• Tiagabine 1997GABA transporter

• Vigabatrin 2009

GABA transaminase

• Levetiracetam 1999• AMPA receptor antagonist• Perampanel 2014

Potassium channel• Retigabine 2011

Synaptic vesicular protein (SV2A)

Approach to Patient

• Stabilize especially cardiovascular• Try to find the toxin using screening,

witnesses, empty bottles, I-Stop in NY• Observe if isolated seizure, prolonged if

long acting med used• SE as per guideline• Nonconvulsive SE need cEEG .

Treatment

• Isolated seizures observe only • SE use standard protocols• 1. Benzodiazepine (choice up to prescriber)• 2. Phenytoin/Phenobarbital• 3. ValproicAcid/Lacosamide/Leviteracetam• 4. General anesthesia• Glauser T Guideline in Neurology and Epilepsia, • Bachhuber A CNS Neurosci 2016;22(3):178

Which Benzodiazepine

• Guideline 2015 suggests q 20 minutes go to next line therapy. 1. IV lorazepam, diazepam (IV or rectal), IM midazolam, then AEDs

• Animal model using proprion-induced convulsions, clonazepam >GBP> High dose diazepam, others failed

• Tutka P. Epilepsy Res 2005;64:13