ToxCard: Chronic Organophosphate Toxicity

Authors: Daniel Escobar, MD (Emergency Physician, Mercy Hospital Northwest Arkansas, Rogers, Arkansas), Ann-Jeannette Geib, MD (Emergency Medicine Attending; Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 34-year-old male presents to the Emergency Department with complaint of weakness to his arms and legs that has been worsening over the past 4 weeks. He has been having difficulty walking and is having trouble manipulating tools he uses for work with his hands. Along with this, he has had worsening leg cramps. He complains of eye irritation with redness with a burning sensation and tearing sometimes. When asked, he says he has had some cough and often feels nauseous. Lately, he has become forgetful and misplaces items and will forget the names of his coworkers.

On exam, he has dirt on his hands, clothes, and on his shoes, and he is wearing a uniform for a local farming company. There is a garlic-like odor filling the room. He is holding an emesis bag that he is constantly spitting into. Pupils are approximately 5mm, equal and reactive bilaterally. He has overt weakness to his lower extremities greater than his upper extremities. Muscle tone is normal. He has a glove and stocking pattern of numbness to his extremities. Motor and sensory findings are symmetrical. Patellar reflexes are 1+. He has no saddle anesthesia or back pain and denies any difficulty urinating or issues with defecation.

Vital signs: HR 54, RR 18, BP 118/74, SPO2 96%

Questions:

1. 1. What is the most likely causative agent that led to these findings?
      1. Paraquat
      2. Influenza vaccine
      3. Methanol
      4. Organophosphate
   2. Are his symptoms reversible?
      1. Yes
      2. No
      3. Maybe
   3. What therapy is best for this patient?
      1. Gastric lavage
      2. IVIG
      3. Fomepizole with Folate
      4. Atropine and Pralidoxime
      5. Avoid exposing environment

Background:

• The focus of this Tox Card are the chronic toxicity syndromes associated with organophosphate exposure. It is often the presentation of farm workers and others that come into contact with the agent, either through inhalation, ingestion, or dermal exposure, and exposure can be either intentional or unintentional. Exposures in small quantities over a long period of time leads to symptoms of chronic toxicity. Organophosphate poisoning in agriculturally centered communities has developed into a public health concern in developing countries, poisons millions and kills hundreds of thousands each year worldwide and is a reason why understanding organophosphate toxicity has become a critical addition to our knowledge of toxicology.^{1, 2, 4, 9}
• Organophosphates are one of many types of insecticide and are used worldwide to manage crops.
• Farmers treating sheep for parasites may be symptomatic after exposure, an illness called Dipper’s Flu.⁷ Farm workers come in contact with these toxic agents usually due to less safe methods of spraying, leading to cholinergic toxidromes.^{2, 4, 6, 7, 8, 9}
• Organophosphates exert their toxic effects by inhibiting acetylcholinesterase within the synaptic cleft, which leads to accumulation of acetylcholine, and subsequent overstimulation of postsynaptic nicotinic and muscarinic receptors. This leads to an enhanced, as well as a prolonged predominant cholinergic effect. Note that there is also sympathetic stimulation due to nicotinic preganglionic synapse stimulation, however a parasympathetic response predominates and produces the characteristic toxidrome.¹ Unlike carbamates, organophosphates irreversibly bind to acetylcholinesterase, permanently inhibiting its enzymatic activity through a process called Aging where covalent bonds are formed between the agent and acetylcholinesterase. Aging can take anywhere from minutes to days and is dependent on the specific organophosphate agent. Once aging occurs, it can take weeks for enough acetylcholinesterase to be synthesized to allow for clinical resolution of symptoms.

Clinical Presentation:

• Two clinical syndromes that occur with chronic organophosphate poisoning:¹
  1. Chronic toxicity
  2. Organophosphate induced delayed neuropathy
•  Two types of receptor effects
  1. Nicotinic (neuromuscular junction): Causes weakness (paralysis), seizures
     • Mnemonic is Days of the week (Mon-Sa) “MTWtHFS”: mydriasis, tachycardia, weakness, hypertension, fasciculations, seizure
  2. Muscarinic: Causes parasympathetic findings
     • Mnemonic is SLUDGE: Salivation, lacrimation, urination, defecation, GI pain/cramping, emesis
     • Another common mnemonic is DUMBELS: Diarrhea, urination, miosis/muscle weakness/muscle fasciculations, bronchorrhea/bradycardia/bronchospasm, emesis, lacrimation, salivation/sweating
     • The Killer Bs are the most immediately lethal findings: Bronchorrhea, bradycardia, bronchospasm

• Chronic Toxicity
  • Primarily seen with farm workers with constant exposures that build over time.^{1, 2}
  • Symmetric sensorimotor axonopathy: leg cramping to extremity weakness and paralysis.^{1, 2}
  • Sensory > Motor neurons with predilection for long axons.²
  • Ascending paralysis type manifestation can be confused for Guillian-Barré syndrome.¹
  • Long-term effects that include neuropsychological manifestations with delays in executive functioning, attention, psychomotor speed, verbal and memory functions, coordination, and more.^{5, 6}

• Organophosphate-Induced Delayed Neuropathy (OIDN)
  • 1 to 2 weeks after recovering from an acute poisoning (2-4 weeks post exposure).
  • Not related to cholinergic effects and often resolves completely with time, unlike the possible long-term complications seen with chronic toxicity.³
  • Similar to chronic toxicity syndrome
    • Ascending, distal extremity weakness with lower extremity cramping.³
    • CNS findings such as cognitive dysfunction, impaired memory, mood changes, autonomic dysfunction, and extrapyramidal signs.^{1, 5}

Diagnosis:

• Diagnosis is clinical and should be based on history, physical exam findings of cholinergic toxidrome, garlic-like or hydrocarbon odor on the patient, or if presenting with neuropathies as above.
• Two assays available used to help confirm diagnosis, however, do not guide treatment
  • Low levels of activity are consistent with organophosphate poisoning. These are send-out labs with turn-around times that make them unlikely to affect the ED course.³ However, may be helpful in diagnosing the chronic toxicity forms.
    1. Plasma butyrylcholinesterase (“pseudocholinesterase”) activity
       • Easier to assay and is more widely available
    2. Red cell acetylcholinesterase (“true cholinesterase”) activity
       • More accurate and specific

Management:

1. Decontamination and Appropriate Personal Protective Equipment (PPE)
   • Be sure to remove patient clothing and wash patient thoroughly with soap and water if this is a dermal exposure. This prevents ongoing exposure to the patient and ED staff. Make sure to dispose of clothing appropriately and wear PPE to prevent personal exposure. Organophosphates tend to adsorb onto leather goods such as shoes or belts, and these should be discarded with other hazardous waste, and not returned to the patient.¹
2. Avoid Further Exposure
   • The source of the problem is repeated chronic exposure.
   • Limit exposure with PPE if returning to the exposing environment.¹
   • Avoid cholinergic agents that will exacerbate symptoms.
3. Pharmacologic Therapy
   • Diazepam
     • Dose 5-10 mg IV bolus.
     • Used for treatment of acutely symptomatic anxiety, muscle fasciculations, and seizures.³
   • Antioxidants
     • Reactive oxygen radicals cause damage in acute, subchronic, and chronic exposure. Rat studies have shown beneficial effects with Vitamin E by reducing oxidative stress and may provide benefit.¹⁰
   • Novel Treatments Being Studied
     • Several ongoing animal studies ongoing including cytokine treatment, stem cell grafting, short-induction vectors, recombinant bacterial phosphotriesterases and hydrolases, other advanced neuroprotective drugs such as antiglutamatergic agents, GABA A receptor modulators, and more.¹⁰

Case Conclusion:

The patient was asked about his occupational duties, and it was discovered he performs daily insecticide spraying with malathion, an organophosphate. He was immediately decontaminated and observed for 4 hours. He was educated on wearing appropriate PPE or avoid his work environment altogether to reduce further low dose, high frequency organophosphate exposure. Follow up was set up with outpatient Primary Care and Toxicology for chronic organophosphate exposure and supportive therapy.

Answers to Questions:

1. D, Organophosphate; 2. C, Maybe; 3. E, Avoid exposing environment

Clinical Pearls:

1. Chronic toxicity is most often seen in agricultural settings due to recurrent accidental low dose exposures typically from lack of PPE and Education.
2. Exposure can occur via ingestion, dermal absorption, or inhalation from spraying.
3. There are two clinical syndromes with chronic toxicity, Chronic Toxicity and Organophosphate-Induced Delayed Neuropathy (OIDN), that lead to peripheral neuropathies and neurocognitive manifestations that may be irreversible.
4. Diagnosis is made clinically. Do not delay therapy in lieu of pending lab results.
5. Treatment mainstay is avoidance of further exposure. Otherwise, provide supportive care.
6. Possible incorporation and development of new therapies incoming.

References:

1. Tintinalli, J. E. (2019). Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9th Edition. McGraw-Hill Education. Section 15: Toxicology: 1301-1303.
2. Boostani R, Mellat A, Afshari R, et al: Delayed polyneuropathy in farm sprayers due to
3. chronic low dose pesticide exposure. Iran Red Crescent Med J 16: e5072, 2014. [PMID:
4. 25031861]
5. Cook Matt, Frey Aaron. Pesticides and Cholinergics. In: Mattu A and Swadron S, ed. CorePendium. Burbank, CA: CorePendium, LLC. https://www.emrap.org/corependium/chapter/recdvP3Xjhrp9vbC8/Pesticides-and-Cholinergics. Updated September 14, 2020. Accessed December 14, 2020.
6. Malla G, Basnet B, Vohra R, Lohani SP, Yadav A, Dhungana V. Parenteral organophosphorus poisoning in a rural emergency department: a case report. BMC Res Notes. 2013;6:524. Published 2013 Dec 9. doi:10.1186/1756-0500-6-524
7. Ross SM, McManus IC, Harrison V, Mason O: Neurobehavioral problems following
8. low-level exposure to organophosphate pesticides: a systematic and meta-analytic
9. Crit Rev Toxicol 43: 21, 2013. [PMID: 23163581]
10. Muñoz-Quezada MT, Lucero BA, Iglesias VP, et al. Chronic exposure to organophosphate (OP) pesticides and neuropsychological functioning in farm workers: a review. Int J Occup Environ Health. 2016;22(1):68-79. doi:10.1080/10773525.2015.1123848
11. Povey AC, Rees HG, Thompson JP, Watkins G, Stocks SJ, Karalliedde L. Acute ill-health in sheep farmers following use of pesticides. Occup Med (Lond). 2012;62(7):541-548. doi:10.1093/occmed/kqs099
12. Ecobichon DJ. Pesticide use in developing countries. Toxicology. 2001;160(1-3):27-33. doi:10.1016/s0300-483x(00)00452-2
13. Eddleston M, Chowdhury FR. Pharmacological treatment of organophosphorus insecticide poisoning: the old and the (possible) new. Br J Clin Pharmacol. 2016;81(3):462-470. doi:10.1111/bcp.12784
14. Balali-Mood M, Saber H. Recent advances in the treatment of organophosphorous poisonings. Iran J Med Sci. 2012;37(2):74-91.