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Perspective

Organophosphate (OP)pesticides contribute toa substantial burden of

mortality and morbidity from self-poisoning, particularly in developingcountries. Such poisonings areassociated with several syndromes,including acute cholinergic crises, theintermediate syndrome (IMS), andorganophosphate-induced delayedneuropathy. In a study publishedin PLoS Medicine, Jayawardane andcolleagues begin to scientificallycharacterize a specific constellationof signs and symptoms seen afterpoisoning with organophosphates [1].Specifically, they aim to define thepathophysiology of IMS, which wasinitially described in 1987 as an illnessoccurring after the resolution of acute

cholinergic crises and associated withproximal muscle weakness [2]. Sincethis seminal article was published,there has been tremendous controversyin the toxicology world concerningthe true definition and existenceof IMS as an isolated entity [3,4].Here, Jayawardane and colleaguesfurther elucidate the nature of IMSby systematically recording repetitivenerve stimulation (RNS) patterns atthe neuromuscular junction in patientspoisoned with OPs.

The Initial Definition of IMS

In 1987, Senanayake and Karallieddereported on ten patients whopresented 2496 hours after acutecholinergic crises from exposureto methamidophos, fenthion,dimethoate, and monocrotophos.

These patients had acute muscleparalysis in the proximal limb muscles,neck flexors, motor cranial nerves,and respiratory muscles, and somerequired ventilatory support [2]. Thisparticular constellation of signs wasdesignated the intermediate syndrome.Over the ensuing years, other patientshave presented with similar findings

within 2496 hours after exposureto organophosphates, and there hasbeen substantial debate as to whetherIMS, the syndrome defined on the

basis of this group of patients, is a truesyndrome or represents subtherapeuticoxime therapy. Although the clinicalpicture is well-defined, changes in theneurophysiology at the neuromuscular

junction in IMS are poorly delineated.Jayawardane and colleagues haveclearly described a large cohort of OP-poisoned patients and delineated theelectrophysiological abnormalities thatoccur at the neuromuscular junction inconjunction with the clinical entity ofIMS [1].

Electrophysiological Recordings in

Organophosphate Poisoning: The

New Study

In the paper published in PLoSMedicine[1], the researchers describeresults of a prospective observational

study of 78 patients with symptomaticOP poisoning presenting to twohospitals in the Central Province ofSri Lanka between May 2005 andDecember 2006. All patients weretreated under the same protocol,receiving a 1015 mg bolus of atropineintravenously followed by 1015 mgatropine infusion over 12 hours.

Additional atropine was used to controlsigns and symptoms of muscarinicexcess. Pralidoxime was given as a 1g infusion every 6 hours for 48 hours.

All patients were assessed daily witha focused neurological exam. RNS ofthe right and left median and ulnarnerves was done at the bedside within

Organophosphate PoisoningInduced

Intermediate Syndrome:

Can Electrophysiological Changes HelpPredict Outcome?Cynthia K. Aaron

Funding: The author received no specific funding forthis article.

Competing Interests:The author has seen andcommented on other manuscripts by Dr. Dawsonand Dr. Buckley (co-authors of the related article)before publication, and has spent time observing thework of Dr. Dawson in Sri Lanka.

Citation: Aaron CK (2008) Organophosphatepoisoninginduced intermediate syndrome:

Can electrophysiological changes help predictoutcome? PLoS Med 5(7): e154. doi:10.1371/journal.pmed.0050154

Copyright: 2008 Cynthia K. Aaron. This is anopen-access article distributed under the termsof the Creative Commons Attribution License,which permits unrestricted use, distribution, andreproduction in any medium, provided the originalauthor and source are credited.

Abbreviations: IMS, intermediate syndrome; OP,organophosphate; RNS, repetitive nerve stimulation

Cynthia K. Aaron is Program Director, MedicalToxicology, Regional Poison Center, ChildrensHospital of Michigan, Detroit, Michigan, United Statesof America. E-mail: CAaron@dmc.org

Linked Research Article

This Perspective discusses the followingnew study published in PLoS Medicine:

Jayawardane P, Dawson AH, WeerasingheV, Karalliedde L, Buckley NA, et al. (2008)

The spectrum of intermediate syndromefollowing acute organophosphatepoisoning: A prospective cohort studyfrom Sri Lanka. PLoS Med 5(7): e147.doi:10.1371/journal.pmed.0050147

Jayawardane and colleaguesevaluate a cohort of 78 patients withorganophosphate poisoning from SriLanka, and identify changes in repetitivenerve stimulation that precede, and mayhelp predict, the onset of intermediatesyndrome.

The Perspective section is for experts to discuss the

clinical practice or public health implications of a

published article that is freely available online.

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24 hours of presentation in 69 of 78patients and then repeated daily untilall abnormalities resolved.

The Main Findings

Ten of 78 patients were diagnosed withIMS by the authors diagnostic criteria.

An additional 30 of 78 patients showedvarying degrees of weakness from

electrophysiological changes and weredesignated as having an incomplete, or

forme frustevariant of IMS. From thesedata, the researchers identified a seriesof stereotypic electrophysiologicalchanges associated with IMS, and

were able to correlate the progressionof muscle weakness with theelectrophysiological changes, includingan alteration in the pattern whenpatients developed respiratory musclefailure. During the recovery phase,electrophysiological improvementpreceded patient recovery on thebasis of clinical findings. Motor nerveconduction velocity was normal in 60patients regardless of clinical weakness.The researchers were able to documentno difference in treatment regimensbetween those who developed IMSor theforme frustevariant, and those

who did not. Since one of ten patientswith IMS and six of 30 patients withthe spectrum disorder did not receivepralidoxime, and the remainder ofpatients did receive the standard doseof 1 g intravenously every 6 hours for

48 hours, these data may suggest thatpralidoxime dosing has less impacton the development of IMS thanpreviously suggested.

What Do These Findings Mean?

In this study, a large cohort of OP-poisoned patients were studied

with electrophysiological tracingsof sequential RNS in the proximalmuscle groups. The data showthat there is clear progressionof electrophysiological changes

that parallel the development ofIMS, followed by a resolution ofelectrophysiological changes that may

precede clinical improvement. Thesedata help to document the existenceof IMS as a clinical entity. If thesedistinctive electrophysiological changesare subsequently validated in furtherstudies, they should lead to improveddiagnostic and prognostic tools forclinical use in OP-poisoned patients.

Limitations of the StudyAlthough this study shows that theIMS spectrum disorder is associated

with a continuum of stereotypic RNSchanges and is distinct from acutemuscarinic cholinergic crises, it stilldoes not clearly define the underlyingcause of the disorder. There is a largecontingent of clinicians who feel thatoximes are not necessary to treat ill OP-poisoned patients, and these physicianstend to use high-dose atropine andsupportive care [5]. In this study, allpatients received atropine, and sevenof 78 patients received only atropine

without pralidoxime. It is not clearwhether the specific RNS findings inthe atropine-only group differed fromother individuals in the atropine plusoxime group The electrophysiologicalfindings suggest that IMS representsa complex series of interactionsand cannot be classified as a simplereceptor block on one side of thesynaptic cleft. Although beyond thescope of the study, sequential RNStracings of patients before and after

administration of high-dose oximesmight delineate acetylcholines effecton the neuromuscular junction duringIMS.

What Research Remains To Be

Done?

The authors provide limited datato help establish the existence ofIMS as a clinical entity distinct fromthe muscarinic cholinergic crises.One individual enrolled in thestudy was clearly cholinergic during

development of clinical IMS findings,and several other patients developedtransient muscarinic findings during

development of IMS. The RNS tracingsin these patients were no different fromother patients without overt muscarinicfindings.

The study did not address theissue of oxime treatment on thedevelopment of IMS. There is atleast one other study that has shownimproved neck flexor function,

morbidity, and mortality in patientsreceiving high-dose pralidoximeinfusions [6]. All of the patientsincluded were treated either withoutoximes or with low-dose intermittentoximes. A large randomized trial ofOP-poisoned patients receiving nooximes, low-dose oximes, or high-doseoximes would be useful in establishingappropriate treatment in relationto reducing muscle weakness andmortality. In such a trial, studyingadditional outcomes such as RNS andnerve conduction, particularly phrenicnerve conduction velocity, would goa long way towards answering thequestion of whether IMS is a clearlydefined entity, and whether oximestruly make a difference to patientoutcome.

References

1. Jayawardane P, Dawson AH, WeerasingheV, Karalliedde L, Buckley NA, et al. (2008)The spectrum of intermediate syndromefollowing acute organophosphate poisoning:

A prospective cohort study from Sri Lanka.PLoS Med 5: e147. doi:10.1371/journal.pmed.0050147

2. Senanayake N, Karalliedde L (1987)

Neurotoxic effects of organophosphorusinsecticides: An intermediate syndrome. NEngl J Med 316: 761-763.

3. Curry SC (1994) Organophosphate-associatedintermediate syndrome; For real? ACCT ClinToxicol Update 7: 1-2.

4. DeBleeker JL (1995) The intermediatesyndrome in organophosphate poisoning:

An overview of experimental and clinicalobservations. J Toxicol Clin Toxicol 33:683-686.

5. Cherian AM, Peter JV, Samuel J, Jeydevan R,Peter S, et al. (1997) Effectiveness of 2-PAM inthe treatment of organophosphorus poisoning.

A randomized, double blind placebo controlledtrial. J Assoc Physicians India 45: 22-24.

6. Pawar KS, Bhoite RR, Pillay CP, Chavan SC,Malshikare DS, et al. (2006) Continuous

pralidoxime infusion versus repeated bolusinjection to treat organophosphorus pesticidepoisoning: A randomized controlled trial.Lancet 368: 2136-2141.