Neurological complications of OP poisoning

1. Neurological complications of
OP poisoning

2. • Organophosphates are frequently used pesticides can result in serious morbidity and
mortality with over 50,000 organophosphorus compounds have been synthesized since
the first one by Clermont in 1857.
• Clinical symptoms range from the classic cholinergic syndrome to flaccid paralysis and
intractable seizures, with mortality ranging from 10 to 22%
• Common in male and in younger population.
• OP are classified as diethyl (e.g. parathion, chlorpyrifos, dichlofenthion, phorate)
and
dimethyl (e.g. dimethoate, dichlorvos, malathion) pesticides

3. Mechanism of toxicity in acute organophosphorus
poisoning
• Maximum toxic effect is through inhalation followed by gastrointestinal and
dermal absorption.
• Inhibition of cholinesterases, which includes acetylcholinesterase and
butyrylcholinesterase.
• Differ by their location, substrate specificity and function. Inhibition of particularly
acetylcholinesterase is primary mechanism of toxicity.
• Central role of acetylcholinesterase is to terminate signaling at cholinergic
synapses by breakdown of neurotransmitter acetylcholine into choline and acetic
acid.

4. • Acetylcholinesterase assay (or erythrocyte cholinesterase assay) is gold standard
for laboratory assessment of OP poisoning.
• Acetylcholinesterase activity seems to be significantly more inhibited in various
types of OP poisoning than plasma cholinesterase activity.

8. • Three different types of paralysis are recognized based largely on time of
occurrence and their differing pathophysiology:
• Type I paralysis or acute paralysis
• Type II paralysis or Intermediate syndrome
• Type III paralysis or Organophosphate- induced delayed polyneuropathy

9. • Type I paralysis or acute paralysis is seen during the initial cholinergic phase.
• This is when large numbers of both muscarinic and nicotinic receptors are
occupied by acetylcholine, leading to persistent depolarization at the
neuromuscular junction.
• Clinical features include muscle fasciculation, cramps, twitching and weakness.
• At this stage patient may require ventilatory support due to weakness of
respiratory muscles leading to respiratory depression and arrest.

11. Acute cholinergic crisis

12. Atropine
• Mainstay of treatment, and should be started as soon as the airway is secured.
• Starting dose of atropine is a 2mg IV bolus. Subsequent doses of 2-5mg every 5-15
minutes should be administered until atropinization is achieved.
• Signs of adequate atropinization include increased heart rate (>100 beats/min.),
moderately dilated pupils, a reduction in bowel sounds, a dry mouth and decrease in
bronchial secretions.
• Continuous atropine infusions are used in some centers in doses of 0.02-0.08mg/kg/hr.
• Dose of atropine required is maximal on day 1 and tends to decrease over the next few
days. Atropine does not reverse the skeletal muscle effects.

13. Cholinesterase reactivator
• Oximes are nucleophilic agents that re-activate phosphorylated
acetylcholinesterase by binding to organophosphorus molecule.
• Use of oximes in acute OP poisoning has been a controversial subject for last two
decades as there have been very few randomized controlled trials that have
addressed role of pralidoxime (PAM).
• direct reaction converting organophosphate to harmless compound, transient
reaction protecting enzyme from further inhibition.
• Reactivation of the inhibited alkyl phosphorylated enzyme to free the active unit
(if given early enough)

14. • reactivating action of pralidoxime is most marked at nicotinic skeletal
neuromuscular junction. It does not reverse muscarinic manifestations of
organophosphorus poisoning.
• Pralidoxime should be started as early as possible to prevent permanent
binding of OP to acetylcholinesterase.
• Once this has occurred, receptor regeneration is required to allow recovery.

15. • Recommended dose of pralidoxime in OP poisoning is 1 gram, by intravenous
injection, every 6-12 hour in adults (maximum dose 12g/24 hours) and 25-
50mg/kg in children.
• Pralidoxime continued until adequate spontaneous ventilation is achieved by
the patient.
• The effective plasma concentration is 4mg/litre and the patient should show signs
of improvement 10-40 minutes after its administration.
• Side effects of pralidoxime include drowsiness, visual disturbances, nausea,
tachycardia and muscle weakness.

16. Type II paralysis or Intermediate syndrome
• This was first described in 1974 by Wadia sir as type II paralysis and
subsequently termed "The Intermediate Syndrome" by Senanayake.
• This syndrome develops 24-96 hours after poisoning.
• Following recovery from the acute cholinergic crisis, and before expected onset
of delayed neuropathy, some patients develop a state of muscle paralysis.
• The cardinal feature of the syndrome is muscle weakness affecting proximal
limb muscles and neck flexors. There is a relative sparing of the distal muscle
group.

17. • One of the earliest manifestations in these patients is the inability to lift their head
from the pillow (due to a marked weakness in neck flexion).
• This is a useful test to establish whether or not a patient is likely to develop
respiratory muscle weakness.
• Of the cranial nerves, those supplying extra-ocular muscles are mostly
involved, with a lesser effect on VII and X.
• This syndrome persists for about 4-18 days and most patients will survive unless
infection or cardiac arrhythmias complicate course.

18. Intermediate syndrome
• Disorder of NMJ. Its exact underlying mechanisms are not known.
• Senanayake and Karalliedde in their first report of IMS suggested that syndrome might
be caused by pathologic change in postsynaptic end-plate region of striated muscles.
Proposed mechanism of IMS are:
• Downregulation or desensitization of postsyneptic Ach Receptors.
• Prolonged Ach esterase inhibition.
• Failure of post syneptic Ach release.
• Oxidative stress related myopathy and Muscle necrosis.

19. Treatment
• Mainly supportive and there are no specific antidotes available for this devastating
syndrome.
• With supportive therapy, recovery from IMS occurs 5-18 days after onset of weakness.
• Regression of toxic signs among patients who survived IMS followed a distinct pattern.
• Muscle power first resumed in cranial nerve-innervated muscles, followed by respiratory
muscles, proximal muscles, and neck flexors.

20. Type III paralysis or organophosphate- induced
delayed
polyneuropathy (OPIDP)
• Sensory-motor distal axonopathy that usually occurs after ingestion of large
doses of OP compound.
• Neuropathy presents as weakness and ataxia following a latent period of 2-4
weeks.
• Usually present with symptoms of cramping muscle pain followed by numbness and
paraesthesia in distal upper and lower limb.

21. Organophosphate induced delayed polyneuropathy
• Can cause foot drop, wrist drop, muscle wasting and deformity such as claw hands.
• Physical examination: symmetrical flaccid weakness of distal muscle with variable
sensory loss and tendon reflex are lost or reduced; absent ankle reflex being a constant
feature and in high dose of intake- pyramidal tract involvement

24. • Pathophysiology of OPIDN Neuropathy inducing OP compounds cause inhibition of
carboxylesterase i.e. NTE (neuropathy target esterase).
• Degeneration of distal regions of large, long myelinated axons as primary lesion, which
progresses to Wallerian-like degeneration of affected fiber regions. Inhibition of NTE is
necessary antecedent to OPIDN but precise relationship has not been defined till now.
• Physiological function of NTE is not known.
• Dichlorovos and nerve agent are not associated with OPIDN.

25. Treatment
• Recovery from OPIDN is incomplete and may be limited to the hands and feet, although
substantial functional recovery after 1-2 years may occur in younger patient.
• Currently no drug is approved for treatment of OPIDN.
• Following drugs are under trial:
• Phenylmethylsulfonyl fluoride (PMSF)- serine protease inhibitor.
• Corticosteroid

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