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3/19/2016

Shaken, not stirred: Toxin-induced Seizures

Barbara Koppel, M.D. New York Medical College

The American College of Medical Toxicology March 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.

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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.

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

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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

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COMMON MECHANISMS OF TOXIN-INDUCED SEIZURES’

1. Antagonism of GABA-mediated inhibition 2. Enhancement of excitatory, especially glutamatergic, transmission 3. Blockade of sodium channels 4. Adenosine antagonism 5. Glycine antagonism 6. 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, , benzo,barb) causes sustained hyperpolarization and anticonvulsant effect, stopping or blocking this can induce seizure

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Non GABA Mechanisms • Excitation can be affected in other transmitter systems too: Methylxanthines and caffeine act on adenosine receptors act on and serotonin 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

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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)

Dose/ Overdose relates to risk of and timing of seizure – Buproprion caused 14.9% of drug-induced seizures, occurred in 30% of buproprion overdose – Maproptiline 10% risk, 30% – TCAs 10%, 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

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 excitotoxicity Relative dose (small ingestee susceptible to smaller amount, more poisons in children)

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TOXINS AND DRUGS REPORTED TO INDUCE SEIZURES AND STATUS EPILEPTICUS - 1’- 1 and other Local Anesthetics - - cocaine - benztropine - lidocaine - - procaine - General Anesthetics Antidepressants - - buproprion - - - - - - ami-/ Antibiotics - cephalosporins - chlorpheniramine - - 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 INDUCE SEIZURES AND STATUS EPILEPTICUS - 2 Antineoplastics’ Drugs of abuse - bleomycin - - carmustine - cocaine - chlorambucil - lysergic acid diethylamide - cisplatin - phencylidine (PCP) - methotrexte Hypoglycemics - vinblastine - insulin Antivirals - sulfonylureas - acyclovir Immunosuppressives - - azathioprine Cardiovascular agents - cyclosporin - digoxin Insecticides - lidocaine - benzene hexachloride - disopyramide - - - organophosphates hydroxyzine - rotenone - mexiletine -

TOXINS AND DRUGS REPORTED TO INDUCE SEIZURES AND STATUS EPILEPTICUS - 3 Metal chelators’ - deferoxamine - alfentanil - EDTA - fentanyl penicillamine - meperidine Muscle Relaxants - - - pentazocine - albuterol - propoxyphene Neuroleptics Contrast media - thiothixene - iopamidol - - meglumine - lithium - metrizamide NSAIDS Rodenticides - ibuprofen - fluoroacetate - naproxen - strychnine - piroxicam - thallium - phenylbutazone Vaccines - salicylates - measles, pertussis

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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,=27,venl afaxine=23,=15,diphenhydramine=14,am itriptyline=14,CBZ=11,=10, • =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%, = 5/9%

• Thundiyil JG J Med Tox 2007;3(1):15

Psychotropics

Psychotropics Antidepressants, eg 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 delayed Maprotiline (not in overdose), Citalopram Nelson 2007;Clin Tox 45:315 Neuroleptics eg , , Aripripazole

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Most seizures come from overdose, especially psychotropics (suicide)

• Prescription medication toxicity epidemiology reflects prevalence of usage of those medications (eg tricyclicic overdoses less frequent since less prescribed, starting to see 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 , causes seizures in overdose • Nelson 2007;Clin Tox 45:315

Buproprion • 3rd commonest cause seizures (after benzo withdrawal and cocaine), • Depression, 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 , 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

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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 abuse Illicitly used for euphoria, disinhibition, “energy” boosts caused seizures in 7%of cases, rest had hallucinations, , tremor, tachycardia LeRoux G 2015 Drug Alc Depend 154:46-53 Caffeine in enemas, pills with high dose Synthetic 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 –ɤ hydroxyl butyrate (GHB) – Snead OC NEJM 2005 352:2721-2732

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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, , , , baclofen, GABA-ergic AED cause adaptation at GABA receptor, with increased number of receptors so after chronic use, with high amount, if stopped, overexcitation leads 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)

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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), , 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

+ Na channels GABAA receptors • Phenytoin 1938 • 1912 • Carbamazepine 1974 • Primidone 1954 • Lamotrigine 1994 • 1968 • Fosphenytoin 1996 • 1975 • Lacosamide 2008 • 2011 ++ Ca channels GABA transporter • Ethosuximide 1960 • Tiagabine 1997 • Gabapentin 1993 (α2-δ subunit voltage-gated) GABA transaminase Mixed • Vigabatrin 2009 • Valproate 1978 (largely unknown) Potassium channel • Felbamate 1993 • Retigabine 2011 • Lamotrigine 1994 (Na, Ca, AMPA) Synaptic vesicular protein (SV2A) • Topiramate 1996 • Levetiracetam 1999 (Na, Ca, Glu, GABA) • AMPA • Zonisamide 2000 (Na, Ca, DA, GABA) • Perampanel 2014

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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

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Which Benzodiazepine

• Guideline 2015 suggests q 20 minutes go to next line therapy. 1. IV , diazepam (IV or rectal), IM , then AEDs • Animal model using proprion-induced convulsions, clonazepam >GBP> High dose diazepam, others failed • Tutka P. Epilepsy Res 2005;64:13

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