93

Clinicul Neurology and Newosurgq~. 94 (1992) 93-103 0 1992 Elsevier Science Publishers B.V. All rights reserved 0303-X467/92/$05.00

CLINEU

00191

Review article _

Neurological

aspects of organophosphate

Jan L. De Bleeckef”, Jacques “Neurolog_v Department,

L. De Reucka and Jan L. Willemsb

Ghent Universit_v Hospital, and bHe_vnlans Institute @Pharmacology, (Received (Revised,

18 September,

received

(Accepted

Key words:

Organophosphorus

compound;

poisoning

1991)

10 January,

7 February,

Neuromuscular

Ghent State University, Ghent, Belgium

1992)

1992)

transmission;

Intermediate

syndrome;

Polyneuropathy;

Myopathy Summary Besides their well-known

anticholinesterase

action

resulting

in a typical

acute cholinergic

(OP) agents are capable of producing several subacute or chronic neurological at the neuromuscular junction results in muscle fiber necrosis. The significance intoxication is unknown. Organophosphate-induced some OP compounds all capable of remarkably

crisis, organophosphorus

syndromes. The acute over-stimulation of this OP-induced myopathy in human

delayed neuropathy (OPIDN) arises l-3 weeks after exposure to inhibiting a distinct esterase called neuropathy target esterase (NTE)

during a critical time period. An experimental hen model has been designed to screen new OP compounds as to their delayed neurotoxic effects. The recently described intermediate syndrome emerges 14 days after an apparently welltreated cholinergic crisis. Its main clinical features are sudden respiratory paralysis, cranial motor nerve palsies, and proximal limb muscle and neck flexor weakness. Whether or not this is a separate entity in OP agent toxicology remains to be seen. Further type of underlying

studies are required neuromuscular

to further

dysfunction

determine

its clinical

and paraclinical

nia gravis, e.g. diisopropyl [2], tetraethyl pyrophosphate (OP) compounds all share the same (Fig. 1). Since their first synthesis in

1854 [l], thousands of OP agents have been developed, especially during and after World War II. Most of them are able to phosphorylate

carboxylic

esterases

and the actual

involved.

Introduction Organophosphate structural formula

characteristics

(such as

phosphorofluoridate (DFP) (TEPP) [3], and octomethyl

pyrophosphotetramide (OMPA) [4]. Some OP esters are still used to treat glaucoma (Ecothiopate). In addition to these beneficial agricultural, veterinary, and medical uses, some highly potent OP anticholinesterase compounds, including tabun, sarin, soman, and VX have

acetylcholinesterase, AChE) after losing their so-called “leaving group”. They are mainly used as insecticides

been used as “nerve gases” in chemical warfare. Other OP agents have no “leaving group”, are there-

(e.g. parathion, E.605), and in veterinary medicine. Some have also been used in the medical treatment of myasthe-

fore unable to inhibit carboxylic esterases, and have mainly been used as plasticizers, stabilizers in lubricating and hydraulic oils, flame retardants, and gasoline additives. The widespread availability of anticholinesterase OP agents entailed a high incidence of accidental or intentional poisonings, reaching epidemic proportions in

Corrrspondencr

Department, USA.

ro: Jan De Bleecker,

Neuromuscular

Research

M.D., Mayo Clinic, Neurology Lab.,

Rochester.

MN 55905.

94

ioorsi

developing countries [5]. The WHO has estimated that about 1 million cases of unintentional acute pesticide poisoning

occur

parathion

[6]. In

method

each year, India,

for suicide

poisoning

poisoning

of farmers’

cause of childhood scientists

is the

[7,8]. In western than

in agriculture

children

death

as esterase

inhibition

stimulation

at muscarinic

peripheral

and the central

countries

/\

is rare, but OP

remains

in acute cholinergic

nervous

to light another

structural

over-

synapses

system

formula pounds.

of organophosphate

com-

and neuro-

in OP compounds

and nicotinic

Fig. 1. General

an avoidable

[9]. Neurologists

results

X

R2

coun-

of the

[lo]. In addi-

tion to these acute phenomena, several subacute and chronic manifestations of OP agent intoxication have earned the attention of neurologists. The description of neuropathy delayed an organophosphate-induced brought

P

leading

in developing

have always been interested

(OPIDN)

\/

involving

are the main source of OP poison-

far less frequently

tries. Accidental

commonly

OP ingestion

attempts

too, suicide attempts ing, albeit

most

neurological

compli-

cation of some of these compounds. The elucidation of its biochemical and pathological mechansims supplied neuroscientists with an interesting model. Neurotoxicologists and occupational neurologists try to detect early involvement by neuropsychological and neurophysiological screening of low-dose exposed workers [ 1 l-141. The recent description of an apparently new romuscular syndrome, the so-called intermediate

neusyn-

paralysis

of the diaphragm

cles, is most cardiorespiratory

depression

highly lipoid-soluble

Convulsions

are more frequent

OP compounds

mus-

and central in case of

which easily cross

barrier [ 17,181. severity of the clinical manifestations

the blood-brain The ultimate pends

and of other respiratory

life-threatening.

on the compound

involved,

de-

and on the level, the

frequency, the duration, and the route of exposure. After oral intake, which is most often the case in suicide attempts, prolonged absorption of OP agents can continue for several days, even with concomitant gastric lavage [19]. Toxicokinetics of the individual OP compounds also plays an important role [ 161. Individual variations in toxicity with the same compound may largely be explained by altered metabolism and excretion rates [20] and by changes in cardiovascular or other systemic functions by the actual poisoning

itself.

drome (IMS) [15], emerging a few days after successful treatment of an acute cholinergic poisoning, again boosted the scientific work on OP compounds.

Management

This paper reviews the neurological aspects of OP poisoning, especially in the subacute and chronic stages with brief reference to therapeutic measures in the acute phase.

Clinical management of moderate or severe OP agent poisoning implies: 1. Intensive care supportive therapy with artificial ventilation.

The acute cholinergic crisis

2. Removal of the toxic compound. 3. Symptomatic therapy: atropine administration. 4. Causal therapy: cholinesterase reactivating drugs.

Clinical aspects

5. Drug treatment of acute and subacute e.g. convulsions, bronchopneumonia.

of’ acute OP poisoning

complications,

6. Its prevention. Poisoning

with anticholinesterase

OP agents results in

accumulation of endogenous acetylcholine (ACh) at all cholinergic transmission sites in the peripheral and central nervous system. Table 1 summarizes the main symptoms of acute cholinergic poisoning which constitute a typical syndrome composed of muscarinic, nicotinic, and central nervous signs. Respiratory depression due to paralysis of central respiratory centers combined with muscarinic bronchoconstriction and laryngospasm, excessive tracheobroncheal and salivary secretions, and nicotinic

Intensive care supportive

therapy

As acute respiratory failure is the main cause of death, early symptomatic treatment of hypoxia by artificial ventilation is often lifesaving. In a personal series of 19 consecutive patients, delay in ventilation facilities was a major cause of persistent hypoxic encephalopathy (unpublished observation). Besides this urgent respiratory support, several other acute and subacute direct or indirect effects of OP poisoning often require intensive care

9.5 facilities.

Acid-base

and electrolyte

often acidosis

and hypokalemia

tored closely.

Cardiovascular

of cardiac

rhythm

disturbances,

most

[21-231, are to be monimonitoring

or conduction

and treatment

alterations

may

be

of the toxic compound

After oral ingestion,

gastric

lowed by administration of activated

is performed

of a salt laxative

charcoal

into the stomach.

moved every 3 h and replaced contains

the OP compound.

toxicant

in the stomach,

been mentioned

fol-

and instillation The latter is re-

as long as the lavage fluid

Long-term

persistence

of the

even for more than 4 days, has

by several authors

Besides these techniques

[ 19,22,26].

to eliminate

unabsorbed

1

SIGNS

AND

SYMPTOMS

ASE INHIBITOR

OF ACUTE

CHOLINESTER-

and unfavorable

Systemic remains

treatment:

unclear

cholinergic and

sup-

in the management

of

atropine administration symptoms,

mainly

effects, are antagonized whether

symptoms

a protective zures

evidence

is

[ 161.

muscarinic

lar and bronchial

results

from these case reports

nor does experimental

victims

atropine

cardiovascuby atropine.

also antagonizes

It

CNS

in man. Rat studies demonstrated

effect of atropine

on the occurrence

on histopathological

Few dose-effect sub-

stance, removal of the already absorbed compound has also been attempted using hemodialysis and hemoperfuTABLE

still inconclusive,

issuing

port the use of these techniques

Symptomatic lavage

with favorable

[27,28]. The evidence

OP-poisoned

needed [24,25]. Removal

sion techniques

or human

CNS

damage

pharmacokinetic

of sei[29,30].

studies

are

available, with different conclusions [ 161. A loading-dose depending on the severity of the poisoning [31] followed by a titrated maintenance dose keeping the heart rate at or above 80 beatsimin proved useful in clinical practice [19,32]. A&opine overdose, resulting in agitation, confusion, and other signs of delirium should be avoided [33].

POISONING

Causal therapll: oxime administration Oximes reactivate

Muscarinic symptoms

Bronchial tree Tightness of the chest, wheezing, dyspnea, increased secretions, cough, pulmonary edema. cyanosis Gastrointestinal system Nausea,

vomiting.

abdominal

tightness

and cramps,

di-

arrhoea, tenesmus, fecal incontinence Cardiovascular system Bradycardia, fall in blood pressure Exocrine glands Increased sweating. salivation and lacrimation Urinary system Frequency, urinary incontinence Eyes Miosis,

blurred vision, headache

Nicotinic manifestations Cardiovascular system Pallor, tachycardia, elevation of blood pressure Striated muscle Muscular twitching, fasciculations, cramps, weakness. neuromuscular paralysis Central nervous system manifestations Giddiness, anxiety. restlessness, emotional

from ref. 10)

complex.

Among

the

recent years, HI-6 has been tested in experimental animals [34]. Early initiation of oxime treatment is of utmost importance. Less unanimity is found concerning dose and duration of administration. Generally, pulse doses are injected

until serum cholinesterase

activity has recov-

ered and is steady [33]. Studies are underway in our hospital to evaluate the role of continuous low-dose perfusion in reactivating AChE and reducing oxime-induced toxicity

[ 161.

Drug treatment

of other complications

Convulsions pam. Whether

are usually treated by intravenous diazediazepam, independent from its anticon-

vulsant

effect, also improves

final outcome

in man has

not been systematically investigated. In animals, positive [35,36] as well as negative [37] results have been reported. Bronchopneumonia is treated with antibiotics of which some, e.g. aminoglycosides, may influence neuromuscular transmission [3841]. Whether this potential side-ef-

lability, excessive

dreaming, insomnia, tremor, apathy, withdrawal and depression, drowsiness, confusion, ataxia, coma with areflexia, Cheyne-Stokes respiration, convulsions, depression of respiratory and circulatory centers (16, modified

the OP-AChE

oximes used in clinical practice are pralidoxime chloride, pralidoxime methylsulphate and obidoxime chloride. In

fect of aminoglycosides

is of any importance

in the treat-

ment of OP-poisoned patients is unknown. We did not observe any aggravation in our patients’ condition after aminoglycosides had been started. The use of respiratory stimulants cholinergic

(e.g., prethcamide; doxepram) in the acute phase is not recommended [42].

96

Fig. 2. Myophagocytosis and waxy degeneration in the diaphragm of a paraoxon-poisoned rat killed 24 h after subcutaneous injection (H&E, x 100).

Prophylaxis

In case of occupational exposure to OP agents, prophylaxis relies on correct working procedures and general hygienic and safety measures. In military research, drugs that may protect soldiers from warfare nerve agents are under intensive investigation. Long-term use of oximes produces undesirable neurobehavioral side-effects in rats [43]. Carbamate prophylaxis is more promising. Carbamate compounds reversibly inhibit AChE for a short time and so protect it from irreversible inhibition by OP phosphorylation. With these carbamate compounds, especially with pyridostigmine and more recently with physostigmine, a centrally acting carbamate more readily crossing the blood-brain barrier, good results are reported in animals [44-46]. Tolerance studies in soldiers are also promising [47]. The acute myopathy

Ariens et al. [48] were the first to describe a myopathy in rats a few hours after i.v. injection of several OP com-

pounds. A segmental muscle fiber necrosis emerges within the first few hours of the cholinergic poisoning (Fig. 2) [49-511. Diaphragms are constantly far more involved than limb muscles. Neurotomy prevents necrosis [48,52-541 whereas electrical stimulation enhances the number of necrotizing fibers [48]. Hindleg immobilization is protective, while exercise has no aggravating effect on paraoxon-induced myopathy. We observed that paralytic rats under continuous barbiturate anaesthesia had no limb muscle necrosis and only mild diaphragm involvement (unpublished observation). The first human case of OP-induced myopathy was described by De Reuck and Willems [55]. Lesions similar to those in rats were abundantly found in the diaphragm of a parathion-poisoned man. Similar muscle fiber alterations were subsequently reported after diazinon [56], trichlornate [57], and combined malathion and diazinon poisoning [58]. ACh overflow with overstimulation of the postsynaptic muscle fiber membrane leading to excess calcium influx and subsequent muscle fiber degeneration is thought

97 to be the underlying mechanism. In animals, several drugs have been reported to be myoprotective (Table 2). Although postsynaptic receptor protection appears to be the most common mechanism through which they act, the protective action of so widely different drugs suggests that the mechanisms underlying OP-induced myopathy might be multiple. In man no separate treatment to prevent myonecrosis has been tried out.

found in severely poisoned subjects, one after trichlornate and one after dimethoate ingestion [57]. Reversible chorea-athetosis was observed in chlorpyrifos intoxication [59]. Atypical ocular bobbing was noticed after diazinon ingestion [60]. Opsoclonus in the acute stage was reported by Pullicino and Aquilana [61], and we personally observed it in combined parathion and methylparathion poisoning.

Acute CNS manifestmtions

Usual CNS manifestations during the acute cholinergic phase have been listed in Table 1. In addition, a Wernicke-like distribution of neuropathological lesions was

TABLE 2 DRUGS REPORTED ED MYOPATHY

TO PROTECT

FROM

OP-INDUC-

Drug

Chemomechanism

Reference

Hemicholinium

inhibitor

52

(+)-Tubocurarine

postsynaptic nicotinic ceptor blocker

Atropine

muscarinic onist

Pralidoxime

(P2S)

HI-6

of ACh synthesis

receptor

ChE reactivating

re-

antag-

oxime

48,117

117,118

48, 119, 120

ChE reactivating oxime and mild nicotinic gan-

119

glion blocker Hexamethonium

nicotinic

ganglion

Pyridostigmine

reversible

EGTA

intracellular

blocker

119

AChE inhibitor

120

Chronic PNS involvement: the organophosphate-induced delayed polyneuropathy (OPIDN) History

In 1889, nearly 50 years before the toxic properties of OP insecticides became used in insecticides and nerve gases, ataxia and polyneuropathy had been reported in patients with tuberculosis in whom treatment was intended with phosphocreosote, containing several phosphoric esters among which tri-ortho-cresyl phosphate (TOCP) [59,62]. In 1930, a strange paralytic illness afflicted some 20 00040 000 ‘southern and midwestern U.S. natives lo-14 days after drinking a popular illicit alcoholic beverage, Jamaica ginger extract or “jake”. An impurity in the illegitimately commercialized beverage, more precisely the OP compound TOCP, caused a predominantly motor polyneuropathy with rapidly developing bilateral flaccid paralysis of distal arm and leg muscles [64-691. In the 1930s several women who had used Apiol, a TOCP-containing abortificient agent, suffered from a similar disease [70]. Recent outbreaks of TOCPrelated polyneuropathy have been reported from Morocco [71], Bombay [72], Durban [73], Sri Lanka [74,75] and the Fiji Islands [76], all due to contaminated cooking oils, beverages or food. Clinical feature

calcium chela-

121

tor Diltiazem

calcium channel

blocker

122

Gentamycin

aminoglycoside

antibiotic

118

a-Bungarotoxin

inactivation of post-synaptic ACh receptors

121

Diazepam

facilitates GABA-mediated neurotransmission spinal cord and brain

117 in

Symptoms of OPIDN start l-3 weeks after acute exposure to the toxic substance, with a symptom-free interval. Cramping muscle pain in the legs, followed by progressive leg weakness and depressed tendon reflexes are the initial symptoms. Sensory disturbances are usually mild. Later, pyramidal signs may superimpose on the initial polyneuropathy [77]. The prognosis depends largely on the severity of the neurological deficit. After approximately a one-year period, functional improvement occurs in most cases with mild, purely neuropathic damage. In severe cases, however, especially in those

98 with concomitant

pyramidal

sist. In 1978, Morgan

signs, the latter

and Penovich

often per11

[78] interviewed

and examined

4 victims of the 1930 Jamaica

ysis epidemic, ron syndrome

and found that a spastic upper motor had persisted.

Neuroputhology of OPIDN

ginger paralneu-

Cavanagh tensively

and his co-workers

study TOCP-induced

tal “dying-back”

[96] were the first to exlesions in the hen. A dis-

axonopathy

was found

involving

most distal and largest fibers. The proximal Puthogenesis

axon and the nerve cell body was initially of Wallerian

Initially, involved

TOCP

was the compound

in OPIDN.

bolites able to inhibit

It is neither

most

frequently

in itself nor by its meta-

cholinesterase

enzymes

[79,80] as it

has no leaving group. Later, several other OP compounds - with and without anticholinesterase capacity also proved among them [83], triclorfon

able to induce

a similar

figuring leptophos [84], methamidophos

polyneuropathy,

[8 1,821, trichloronate [85], malathion [86],

clorpyriphos [87], and isofenphos [88]. Johnson [89] found that all OP compounds with delayed neurotoxic capability inhibited the same esterase which he called Neuropathy Target Esterase (NTE). He also demonstrated that phosphorylation of NTE was only part of the story. After phosphorylation, a side-chain “R” group is lost from the phosphorus atom leaving a negatively charged phosphoryl-enzyme complex. This time-depend-

degeneration,

however,

ered in het lateral and dorsal columns cervical Using Bouldin

cord

technique

and Cavanagh

degeneration,

spared.

initially

of the lumbar

tal end of the axon, was actually They suggested a “chemical focal distal - but not terminal itates Wallerian

and

poisoning.

in cat phrenic

[97] discovered suspected

Signs

were also discov-

some 21 days after the initial

the teased-fiber

the

part of the

nerve,

that the axonal

to begin at the most disfocal and non-terminal.

transsection” producing a ~ axonal lesion that precip-

degeneration.

The few human nerve or muscle biopsy reports mainly confirmed the animal findings [83,84,98-l 001. No autopsies with spinal cord examination

are available.

Chronic CNS manifestations

ent process is called “aging”. Only compounds capable of undergoing the aging process after sufficient NTE phosphorylation (around 70% of hen brain NTE activ-

Several chronic CNS disturbances due to acute or chronic OP agent poisoning have been reported in isolated cases or in worker cohorts [loll. The syndromes

ity) induce OPIDN. NTE has been found in most tissues assayed, including brain, peripheral nerves, and lymphocytes. In human poisoning it is determined in peripheral

vary widely and include parkinsonian and pseudobulbar signs, alterations in affect, libido and memory, psychiatric or more insiduous neuropsychological dysfunction

blood lymphocytes [90,91]. It proved a useful tool in the predictive monitoring of OPIDN development in OPpoisoned man [92]. The adult hen proved to be the animal most sensitive to OPIDN. An excellent correlation between hen brain NTE inhibition and clinical ataxia has been found [93]. This hen model is now used to find out probable delayed neurotoxic side-effects of newly synthesized OP com-

[14,102-1041,

and a cerebellar

Original report

Despite the excellent correlation between NTE inhibition and OPIDN development in both man and experi-

Senanayake new syndrome

mental animals, several criticisms were raised against the NTE theory. First of all, no physiologic role for NTE is demonstrated in normal conditions. Moreover, no ac-

in human OP poisoning. Asian origin who were

ripheral nerves. Other recent hypotheses include the OP compound interaction with Ca/calmoduline kinase II

[951.

[105]. No con-

The intermediate syndrome

pounds before they can be considered for registration and commercialization as insecticides [94].

ceptable hypothesis has been formulated to explain how NTE inhibition actually damages neurones and/or pe-

syndrome

stant common affected CNS sites can be derived from those clinical reports, and systematic neuropathological studies have not yet been carried out.

and Karalliedde in 1987 [15] described a they believed to be a distinct clinical entity They observed admitted with

10 patients of a well-defined

cholinergic crisis. and with rapid favorable outcome after treatment with atropine and oximes. After apparent recovery from the cholinergic crisis, they developed an “intermediate syndrome” (IMS) (2496 h after the acute poisoning) during the interval between the acute crisis and before the usual onset of OPIDN.

99 The most

threatening

tory failure requiring ventilation.

Apart

ness in muscles present

symptom

innervated

in 8 patients.

flexes were absent pattern

limb muscles.

decreased.

in the development

order. Cranial

nerve palsies ~ palatal, order

followed

improvement

proximal

muscle

recover.

followed

a characteristic

function

Neck flexion

days. In one methamidophos-poisoned

of

was the last to

ranged

from patient,

the causative

outcome

in 2 of them. The authors presence

of the pesticide

slow restoration

of the plasma

activities

compound,

remained

either

demonstrated

in blood

pro-

and fat, and a

and erythrocyte

with

severely

Prolonged

from

metabolism

likely explanation. tient

of res-

with lethal

AChE

over several weeks. In our cases, too, cholinest-

activities

paired

symptoms,

fat reserves

and/or IMS

throughof the OP

or because

excretion,

We studied

prolonged

inhibited

circulation seems

of im-

the most

a parathion-poisoned (unpublished

delayed

crosis, and hepatic failure. Delayed removal of parathion _ known to be far less fat-soluble than the other IMScausing compounds [ 116]- turned out to be the cause of

OP compound

was

anuria

pa-

observation).

This man had persistent

known: fenthion in 4, dimethoate in 2, monocrotophos 2, and methamidophos in 1. Assay of cholinesterase tivity was not available. EMG showed activity and normal motor and sensory

failure and of muscarinic

longed

with diclofenthion

5 to 18

polyneuropathy occurred consequently. Two patients died on the 3rd and 5th day from respiratory failure. In 9 of the subjects

piratory

5 patients

They suffered from several recurrences

out the IMS period.

Then and

et al. [116] studied

erase

facial, and external

of respiratory of recovery

re-

There was no

- were the first to regress.

strength.

The period

of neck

of the symptoms.

their

in that

regression

nerves was

Deep tendon

Davies

poisoning.

weak-

had weakness

Nevertheless, ocular,

paralysis,

by several cranial

All subjects

or markedly

respira-

and positive-pressure

from the respiratory

flexors and of proximal distinct

was sudden

re-intubation

due to acute tubular

ne-

the IMS.

in ac-

normal muscle conduction ve-

Conclusions

locities. Tetanic stimulation revealed a marked fade at 20 and 50 Hz. Trains of 4 stimuli at 2 Hz produced no

Apart from their acute anticholinesterase action, OP agents can also produce several other neurological syn-

changes. atropine

dromes in the acute or chronic stage. Every neurologist in a western country is likely to be occasionally con-

Treatment was symptomatic. did not influence the IMS.

Reinstoration

of

fronted Review of IMS literature

Several cases with similar

features

were returned

from

with them,

and in Third

World

countries

epi-

demic outbreaks emerge regularly. OPIDN has been well studied in the past decades. The hen mode1 is able to predict fairly reliably which new

in the literature. The largest group was presented by Wadia et al. [106] in diazinon-poisoned subjects. These authors divided the symptoms into type I (those present on admission) and type II (those appearing 24 h after the

compounds are unlikely to have delayed neurotoxic effects. The recently described IMS requires further study

onset of the poisoning).

disturbances

The type I signs, including

im-

paired consciousness and fasciculations, responded to atropine therapy, whereas type II signs, including proximal limb weakness,

areflexia,

and cranial

as to its nosology and as to whether or not it bears a separate structure-activity relationship. Chronic CNS in worker cohorts

have been poorly

studied

until present.

nerve palsies,

were not influenced by atropine. Some type I patients developed type II signs after an initial recovery. Several case reports of fenthion-poisoned patients

References

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