DR. PRIYA KUBENDIRANPROF. DR. MAGESH KUMARM 1 UNIT

The Case… 18 Yrs old female was admitted on 23rd

April Alleged h/o consumption of organo

phosphorus pesticide (chlorpyrifos) Qty unknown; h/o vomiting present

O/E Pt Conscious, oriented, afebrile, excesive salivation Pupils miotic, 0.5mm PR: 70/min BP: 100/70mm Hg RR: 15/min Spo2: 90%

CVS: S1S2 heard

RS: NVBS heard, B/L crepitations

P/A soft

CNS: NFND

INVESTIGATIONS

Sr cholinesterase: 190 IU/L

CBC:

Hb: 10g%

TC: 8000/cu mm

DC: P60/L38/E2

ESR: 4/10

RFT:

Sugar: 90mg%

Urea: 20mg%

Creatinine: 0.5mg%

CXR: WNLECG: NSR

Treatment Given: Supportive Atropine Pralidoxime

DAY 4 Patient was shifted to ward

DAY 5 H/O altered sensorium since

morning H/O breathlessness H/O increased Salivation

O/E : Pt conscious, drowsy, afebrile Puplils miotic 0.5mm

CVS:S1S2 heard RS:NVBS heard,B/L Crackles heard P/A:soft CNS: Pupils miotic Plantar B/L flexor

Diagnosis - INTERMEDIATE SYNDROME

Was shifted back to IMCU

Serum cholinesterase levels: 28/04:221 IU/L 29/04:310IU/L 30/04:331 IU/L 01/05:500 IU/L

DAY 10 Pt transferred to ward DAY 12 Pt experienced difficulty in walking H/O dragging of feet while walking Had difficulty in holding slippers H/O difficulty in standing from

squatting posture No H/O upper limb involvement No H/O muscle twitching NO H/O cramps

NO H/O cranial nerve involvement NO H/O unsteadiness in dark,swaying,

involuntary movements H/O tingling sensation in the legs NO H/O alteration in bladder/bowel

habits NO H/O fever ,head injury

O/E : Pt conscious ,oriented, Hr functions normal Cranial nerves clinically normal EOM full range, pupils B/L 4mm

ERLA

Tone UL N N LL Power UL 5 5 LL hip 3 3 knee 3 3 ankle 3 3 Reflexes UL + + knee - - ankle - - plantar no response

Gait - couldn’t be tested No sensory deficit no cerebellar signs

Provisional diagnosis - ? Toxin induced

demyelination

NEURO LOGIST’S OPINION: ?post toxic demyelination Suggested inj methyl prednisolone NCS of all 4 limbs, EEG, MRI brain

INVESTIGATIONS : EEG : normal MRI BRAIN: normal LP : acellular, sugar - 50 mg/dl protein - 76 mg/dl NCS : s/o demyelination

TREATMENT & COURSE Inj methylprednisolone 1g iv od - 5

days Inj B complex im od

Her power gradually improved to grade 4

She was advised : T.Prednisolone 60 mg od -

tapering dose T. Ranitidine 150 mg bd BCT bd

FINAL DIAGNOSIS

ORGANOPHOSPHORUS POSONING / INTERMEDIATE SYNDROME / OPC INDUCED DELAYED NEUROPATHY

(OPIDN)

OPC POISONING

Very CommonCommon Poisoning In Tamilnadu 3 Million Cases, 20,000 Deaths /YR World

Wide. 1930, Schrader, German, Studied Mech of

Toxicity Weapon of Chemical Warfare.

Mechanism of OP’s

ANSPreganglionic Parasympathetic SympatheticSomatic

Nerves

Ach Ach Ach Ach Ach

Ganglion

Epi Skeletal Muscle

Ach Ach Norepi

Via

Bld

Effector

Organs

+ Pupil

-Heartrate

+Exocrine Glands

+GIT Smooth Muscle

+Lung Smooth Muscle

+Sweatgld

-Bloodvessel

[Some] - Pupil

+Heart Rate

-Gastrointestinal SM

-Lung SM

+Blood Vessels [Most]Often The Parasympathetic Features Predominates

Post Ganglionic

+ Death

Clinical Syndrome

Acute Cholinergic: Central Peripheral Muscarinic Peripheral Nicotinic

Intermediate Syndrome OPIDN: Delayed peripheral

neuropathy Neurocognitive dysfunction

Respiratory failureRespiratory failure}}

Muscarinic Effects (Wadia Type 1 syndrome

D iarrhoea U rination M iosis B radycardia, Bronchorrhoea, Bronchospasm E mesis L acrimation S alivation

NICOTINIC FEATURES: CENTRAL : LESS WITH CARBAMATES

(i) Muscle Fasciculations

[Striated]

(i) Paralysis

(ii) Muscle Weakness

(iii) Hypertension

(iv) Tachycardia

(v) Mydriasis [Rare]

(i) Unconsciousness

(ii) Confusion, Fatigue

(iii) Toxic Psychosis, Seizures

(iv) Resp. Depression

(v) Ataxia, Dysarthria

(vi) Extra Pyramidal Features.

DELAYED COMPLICATIONS

Occurs 24-96hrs,

Weakness of Ocular, Bulbar, Proximal Limb Muscles, And

Respiratory Failure.

Common With Dimethoate, Parathion, Malathion & Methly

Parathion

ChE Activity 20% or Less During Onset

Causative Factor – Inadequate Oxime Therapy / Premature

DIS.

Recovery in 4 – 18 Days. Electrophysiological study shows significant

decremental response at low frequency stimulation

INTERMEDIATE SYNDROME : [FIRST DESCRIBED IN 1987] [WADIA TY-II]

OPIDN (Organophosphorus induced delayed neurotoxicity)

The underlying pathology in OPIDN involves bilaterally symmetrical degeneration of

sensory and motor axons in distal regions of peripheral nerves and spinal cord tracts.

The distal part of longest, largest diameter fibers tend to be preferentially affected.

Lesions are characterized by the degeneration of axons with subsequent secondary degeneration of myelin

Pathogenesis

Due to inhibition of a protein called Neuropathy target esterase (NTE) by phosphorylation

NTE is an integral membrane protein present in all neurons and in some non-neural-cell types of vertebrates.

Recent data indicate that NTE is involved in a cell-signalling pathway controlling interactions between neurons and accessory glial cells in the developing nervous system

Organophosphates + NTE

initiate unknown events

toxin covalently attached to active-site of NTE

Toxic gain of function of NTE

(delay of 1±3 weeks), neuropathy with degeneration of long

axons

Neurological dysfunction of OPIDN

1. Latent period: Days to weeks

2. Progressive phase: Symmetric cramping,numbness and tingling in feet and legs, bilateral dragging of toes (foot-drop), flaccid paralysis.

3. Stationary Phase

4. Improvement Phase: Results from regeneration of PNS; CNS damage becomes unmasked as spasticity and exaggerated knee jerk.

5. Prognosis: Depends on severity of initial symptoms

Factors involved in the Development of OPIDN1. Chemical Structure2. Animal Species: Humans are most sensitive 3. Individual differences4. Dose or Concentration at Neurotoxicity Site: a. Exposure dose

b. Frequency of exposure c. Duration of exposure

d. Route of Exposuree. Other chemical exposure f. Stress

Chlorpyrifos-induced delayed polyneuropathy

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (>70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5–6 days

Eugenio Capodicasa et al, Archives of Toxicology Volume 65, Number 2,

CASE REPORT -Toxin induced neuropathy presenting as acute inflammatory demyelinating polyneuropathy

Calicut Medical Journal 2010 (Manthappa M et al)

An adult male patient presented to us with with

bilateral symmetric polyneuropathy resemblingacute inflammatory demyelinating neuropathy(AIDP). On further questioning, patient gavehistory of exposure to organophosphateinsecticides. Sural nerve biopsy revealedfeatures consistent with toxin inducedneuropathy.

CASE REPORT - Guillain-Barre Syndrome Due to Organophosphate Compound PoisonD Rajasekaran et al, JAPI October 2009

Clinical features and investigations of our patient strongly indicated that GBS that he had manifested as a sequelae of OPC poisoning which is possibly toxin induced delayed demyelination

Methylprednisolone treatment of an organophosphorus-induced delayed neuropathy

A high-dose regimen of methylprednisolone started 30 to 40 min after DFP exposure and lasting for 20 days prevented the development of OPIDN.

Thomas Baker and Anna StanecToxicology and Applied PharmacologyVolume 79, Issue 2, 30 June 1985,

Effects of Prednisolone and complex of vitamin B1,B2,B6 & B12 on organophosphorus compound induced delayed neurotoxicityFengyuan Piao et al, J Occup Health 2004

It was observed that delayed neuropathy induced by OPs could not be resisted completely by the treatment with prednisolone or vitamin b complex, but clinical signs of OPIDN and pathological changes in hens that received these 2 protective agents after OPs were less severe than those in hens that received only OPs

Chronic organophosphate inducedneuro psychiatric disorder (COPIND)

Is a neurodegenerative disorder that results from large toxic or small subclinical doses of OPCs.

Clinical signs, which continue for weeks to years, consist of neurological abnormalities

drowsiness, confusion, lethargy, anxiety, emotional lability, depression, fatigue ,irritability, memory

disturbances

Neuronal cell death is seen in various brain areas including cerebral cortex, hippocampal formation and cerebellum.

Cell death results from early necrosis or delayed apoptosis.