Jonathan Newmark

M Victoria Ingram

Margaret M Swanberg

Yince Loh

CiteSeerX

NeuroToxicology 31 (2010) 244–246Case report
Case report: Long-term cognitive sequelae of sarin exposure
Yince Loh a,*, Margaret M. Swanberg b, M. Victoria Ingram c, Jonathan Newmark d
a Neurology Section, Department of Medicine, Madigan Army Medical Center, Bldg 9040, Fitzsimmons Dr., Tacoma, WA 98431, USA
b Department of Neurology, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Washington, DC 20307, USA
c Psychology Service, Womack Army Medical Center, 2132 Reilly St, Fort Bragg, NC 28310, USA
d Chemical Casualty Care Division, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA
A R T I C L E I N F O
Article history:
Received 31 July 2009
Accepted 7 December 2009
Available online 29 December 2009
Keywords:
Sarin
Neurocognition
Neuropsychological
Organophosphate
Weaponized
A B S T R A C T
The long-term sequelae of acute sarin exposure are not well understood. The largest clinical cohort
resulted from the 1994 and 1995 attacks in Japan. Observers noted mostly psychiatric sequelae, with a
high prevalence of post-traumatic stress disorder (PTSD). We describe neurocognitive findings that may
represent sequelae of low-level sarin exposure in Iraq.
Published by Elsevier Inc.
Contents lists available at ScienceDirect
NeuroToxicology1. Introduction
Nerve agent exposure has garnered public attention in the
recent decade. Sarin, an organophosphate acetylcholinesterase
inhibitor, first became a household term after the Tokyo subway
bombing by Aum Shinriyko in 1995. Since then, the world has seen
a rash of chemical and biological terrorist activity to include the
anthrax release into the US postal system. A result is the increasing
awareness of the potential for smaller organizations to turn to
chemical and biological agents as their weapon of choice. These are
cheap, can be delivered in mass quantities and may have the added
psychological impact of contagious or delayed effects.
The US invasion of Iraq was driven partly by the fear of such
effects and consequently the decision to deter a suspected nuclear,
biological, and chemical threat. Although US forces never found
production or storage facilities, the first cases of exposure with
weaponized sarin emerged in the summer of 2004. The insurgency
made public news with these first chemical casualties when two
soldiers were exposed to sarin gas by means of an improvised
explosive device (IED).
The long-term neurologic sequelae of sarin exposure remain
unclear. What little literature exists comes almost entirely from
the Japanese healthcare system’s experience with the casualties
and healthcare workers of the Tokyo subway bombing. The
majority of this body of literature encompasses only the
psychiatric sequelae, given the high prevalence of post-traumatic* Corresponding author. Tel.: +1 206 829 9876; fax: +1 253 968 0443.
E-mail address: yincer@yahoo.com (Y. Loh).
0161-813X/$ – see front matter . Published by Elsevier Inc.
doi:10.1016/j.neuro.2009.12.004stress disorder. We describe the neurocognitive sequelae of one of
the two incipient cases of exposure in Iraq, which is, to our
knowledge, the first description of sarin exposure since 1995 and
the first ever report of a sarin combat casualty.
2. Case report
A 34-year-old right-handed Caucasian male senior Army
explosive ordnance disposal (EOD) sergeant was exposed to sarin
in May of 2004 while deployed to Iraq. The patient was called to
disarm an IED after a blast was reported. Upon arrival, he and his
assistant picked up the IED and rapidly loaded it in their enclosed
vehicle in an effort to evacuate the area, which was still under
enemy fire. Several minutes later, while driving towards their
headquarters, the patient and his assistant had the onset of
confusion, dyspnea, blurred vision, and severe headache. Upon
arrival to their headquarters, they were immediately given oxygen
and observed. Initial serologies and chemistries were drawn
normal. In the meantime, the IED was inspected and 3–5 cm3 of a
colorless liquid was discovered inside the vehicle, which was later
identified as sarin. The patient demonstrated erythrocyte cholin-
esterase (RBC-ChE) activity of 2.88 U/ml (0.46 delta pH unit/h),
which represented a 39% depression from a baseline of 0.75 delta
pH unit/h (drawn prior to deployment to Iraq).1 After 2 days of
observation and supportive care, they were allowed to convalesce
for the ensuing 2 weeks and subsequently returned to duty.1 The conversion method was established by the US Army Center for Health
Promotion and Preventive Medicine.
Table 1
Neuropsychological Testing assessment results 8 months after exposure.
Score Score
Intelligence/achievement/effort Attention and executive function
WAIS-III Full Scale IQ 100 Auditory consonant trigrams-900 T 40
Verbal IQ 95 (VCI = 105) 1800 T 38
Performance IQ 106 3600 T 34
Processing speed index 86
WRAT-III Reading 103 WAIS-III Subtest Scaled-Arithmetic 6
Digit span 8
Word memory test Type I Seashore rhythm 51
Psychomotor Trail making test T-scores A: 53; B: 54
Finger tapping T-scores 43 (R); 54 (L) Wisconsin card sort categories (raw) 6
FTMS (raw) 0
Grooved pegboard T-scores 32 (R); 29 (L) CVLT trial 1 (raw) 4
Language Memory
Boston naming (60 item) T-score 51 Wechsler memory scale-III
Logical memory T-scores LMI: 55; LMII: 55
Visual reproduction T-scores VRI: 42; VRII: 48
Thurstone verbal Fluency T-score 39 Rey complex figure recall T-scores 30: 43; 300: 42
Visuoperceptual CVLT Trail 2 z-scores SDFR: 1.0; LDFR: 0.5
Rey complex figure copy (raw) 33/36
Hooper visual organization (raw) 28/30
Note: Impairments/inefficiencies in this individual are bold; WAIS-III = Weschler Adult Intelligence Scale, 3rd edition; WRAT-III = Wide Range Achievement Test, 3rd edition;
CVLT = California Verbal Learning Test; SDFR = short delay free recall; LDFR = long delay free recall; LM = logical memory I & II; VR = visual reproduction I & II; FTMS = failure to
maintain sets.
Y. Loh et al. / NeuroToxicology 31 (2010) 244–246 245Despite subjective fatiguability, the patient continued to serve
as an EOD expert without problems. His unit returned to the U.S. 3
months after his exposure. No testing of butylcholinesterase levels
was performed, but 1-month following exposure, RBC-ChE activity
was normal. Gradually over the 2 months following his return, he
began to complain of progressively worsening short-term memory
loss, dyscoordination and episodic imbalance, none of which
objectively limited his performance. Eight months later, following
a non-diagnostic neurological and neurophysiological evaluation
in his hometown, he was sent to our tertiary care center for its PET,
EMG, and neuropsychological testing capabilities.
He complained of short-term memory loss, mostly involving
names and tasks that he intended to complete. He also noted
episodic dyscoordination and imbalance. He had fallen several times
for no reason and would weave down straight hallways on occasion.
These episodes would occur without any precipitating factors. He
had not experienced any weakness, numbness or tingling.
He complained of headaches that were post-exertional and
mild. He denied any constitutional symptoms, malaise, nausea,
vomiting, or diarrhea. He denied any difficulties with swallowing,
speaking, or double vision. He admitted to some difficulty with
sleep, but denied mood changes or lability, irritability, or
personality changes. He had no significant past history except
for sinus, hemorrhoid, and arthroscopic knee surgery. There was no
significant family history. He denied tobacco, alcohol, or illicit drug
use. He was a father of one healthy child. He took no medications.
On physical examination, he was a well-developed, well-
nourished male in no acute distress. His vitals were stable. He was
well-groomed and his mood appeared good and his affect was full.
On neurological examination, he was fully oriented and his
language was normal. His cranial nerve examination was
unremarkable. His motor, reflex, sensation, and gait examinations
were normal, but he had some difficulty with rapid alternative
finger-tapping. He was not able to recall one of three words at
3 min, but was able to with prompting. He was only able to recall
six digits in a forward sequence and four in reverse (low for age).
He was only able to name 11 words beginning with the letter ‘‘F’’ in
1 min (low for age), and could only remember five words of a nine-
word list without any improvement with up to three repetitions
(impaired).Basic chemistry, hematology and toxicology screens were
negative. MRI examination of the brain and spine was normal, and
electromyography/nerve conduction was normal. Electroenceph-
alography and positron emission tomography (PET) were normal.
His neuropsychological test demonstrated a mild cluster of
impairments (Table 1). Despite full effort, he demonstrated
reduced speed of information processing (Wechsler Adult Intelli-
gence Scale [WAIS] Processing Speed Index [PSI] subtest) and poor
focused and divided attention (Auditory Consonant Trigrams (ACT)
and the Trial 1 of the California Verbal Learning Test [CVLT]).
Testing also revealed difficulty in speeded, bilateral manual motor
coordination (grooved pegboard test). While his problem solving,
mental flexibility, naming, new learning, recall, and visuopercep-
tual integration was normal, he showed delays on timed tasks that
required rapid mental processing of information. Certain aspects of
attention were affected, with greatest impairment on divided
attention tasks. Finally, results of the Minnesota Multiphasic
Personality Inventory (MMPI-2, a test for psychopathology) did not
reveal the presence of significant emotional distress or any
significant mood, anxiety, or thought disorder. Further, it validated
the results of his neuropsychological testing.
3. Discussion
There have been few reports on the long-term neurologic
sequelae of acute sarin exposure. The few clinical observations in
humans are limited to post-exposure victims of the Tokyo subway
attack. A delayed cerebellar syndrome and has been described
(Yokoyama et al., 1998), in which exposed patients demonstrated
an increased postural instability as documented by computerized
posturography. Cognitive deficits in the Tokyo subway victims are
mostly limited to descriptions of impairment in working memory
such as backward digit span, which was observed to be persistent
in up to 3 years (Nishiwaki et al., 2001).
The cognitive deficits in our patient demonstrated reduced
information processing speed, poor focused and divided attention,
and difficulty in speeded, bilateral manual motor coordination. He
performed abnormally in the ACT, the CVLT, the WAIS-PSI, and the
grooved pegboard test. The ACT task measures divided attention
and information processing ability by requiring the individual to
Y. Loh et al. / NeuroToxicology 31 (2010) 244–246246count out loud backwards for a specified delay period and then
recall a consonant trigram that was verbally given to them prior to
the delay period (Spreen and Strauss, 1998). The CVLT is a measure
of new verbal learning and recall in which a series of 16 words are
presented over five learning trials and the individual is later
required to produce those words after a distraction task and a
longer delayed period. The Trial 1 score is an indicator of the
individual’s ability to attend novel information without repetition
(Spreen and Strauss, 1998). The WAIS (3rd edition) is a measure
that provides information on the individual’s overall intellectual
abilities and identifies areas of potential intellectual weakness or
disability. The PSI subtest is a measure of one’s ability to quickly
and accurately process and act on visual information (Kaufman and
Lichtenberger, 1999). The grooved pegboard test measures manual
fine motor speed and coordination by requiring the patient to
rapidly place small metal pegs into alternating slotted holes of
alternating positions on a board (Lezak, 1995). These deficits are
similar in nature to those present in US soldiers exposed to sarin
during the 1991 Gulf War (Proctor et al., 2006).
The entire body of medical literature describing the neuroana-
tomical and neuropathological substrate of long-term sarin effects is
composed solely of experimental studies in the animal model. These
have demonstrated that there may be permanent alterations in the
density of cholinergic receptor subtypes after subclinical sarin
exposure. These changes may be a potential mechanism by which
memory dysfunction can result from sarin (Henderson et al., 2001).
Behavioral changes following low-level sarin exposure have
been described, though the evidence for delayed or long-term
effects is discordant. In one study, rats exposed to sarin showed
behavioral abnormalities, specifically decreased open field explo-
ration and increased acoustic startle that persist despite normali-
zation of cholinesterase dysfunction up to 16 weeks post-exposure
(Scremin et al., 2003). However, acute and repeated low levels of
sarin can impair rat spatial memory acutely, but this resolves 3
weeks after exposure (Kassa et al., 2001). Several studies have
demonstrated persistent EEG changes up to 1 year after exposure
(van Helden et al., 2004). In non-human primates, however, acute
or delayed behavioral changes have not yet been correlated to
levels of RBC-ChE inhibition similar to that seen in our patient.
Acute, low-level sarin exposure in monkeys did not impair their
cognitive performance on several cognitive tasks (Pearce et al.,
1999; Genovese et al., 2007).
Pathologically, Wallerian degeneration as well as neuronal
apoptosis is seen in chronic exposure, while higher acute doses of
sarin increase the permeability of the blood–brain barrier.
Selective injury is seen in the thalamus, piriform cortex and
hippocampus as well as degeneration of cerebellar Purkinje cells
(Abou-Donia, 2003; Abdel-Rahman et al., 2002; Kadar et al., 1995).
Proposed mechanisms of these degenerative pathways include
decreases in endothelial barrier antigen (EBA) and microtubule-
associated protein (MAP-2). The clinical relevance of the cerebellar
involvement may explain the delayed-onset ataxia syndrome that
was first described in the Tokyo subway victims (Yokoyama et al.,
1998). Human observations of delayed morphological changes
following acute sarin exposure have demonstrated quantifiable
reduction in both overall white matter volume and hippocampal
volume, a memory-encoding structure well-known to inter-relate
with cholinergic brain centers (Heaton et al., 2007; Yamasue et al.,
2007).
In summary, this is the first human sarin exposure documented
since the 1995 Tokyo subway incident and the first US sarin
battlefield casualty. We are not aware of other reports of exposure
during the ongoing conflict in the Middle East. Although there is no
way to exclude the possibility of a sole or concurrent psychiatric
component, our patient neither endorsed subjective complaints
suggestive of PTSD nor exhibited any objective evidence asassessed by neuropsychometrics. Although the neuropsychologi-
cal battery administered is accepted as a valid and reproducible
measure, there is some inherent margin of error for what is
considered a deviation from the norm. In addition, conclusion of a
causal relationship between sarin exposure and his subtle deficits
is not substantiated, though his deficits do suggest the possibility
of long-term organic brain dysfunction despite normalization of
RBC-ChE activity. Interestingly, his impairments tended to be more
apparent on tests of motor tasks and attention, both reliant on
cholinergic neurotransmission. Since animal experiments impli-
cate an effect of sarin on various neuroanatomical structures that
are integral to memory and attention, a similar mechanism could
occur following exposure in humans. The advent of higher
resolution imaging techniques and functional mapping such as
fMRI may help define the neuroanatomical substrate of the post-
sarin syndrome as a future topic of study.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgements
The views expressed in this article are those of the authors and
do not reflect the official policy or position of the Department of the
Army, the Department of Defense, or the United States Govern-
ment.
References
Abou-Donia MB. Organophosphorus ester-induced chronic neurotoxicity. Arch Environ
Health 2003;58(8):484–97.
Abdel-Rahman A, Shetty AK, Abou-Donia MB. Acute exposure to sarin increases blood
brain barrier permeability and induces neuropathological changes in the rat brain:
dose–response relationships. Neuroscience 2002;113(3):721–41.
Kaufman AS, Lichtenberger EO. Essentials of WAIS-III assessment. New York: John
Wiley and Sons; 1999.
Genovese RF, Oubre JL, Jakubowski EM, Fleming PJ, Saxena A, Rockwood GA, Tipparaju
P, Willmore CB. Evaluation of cognitive and biochemical effects of low-level
exposure to sarin in rhesus and African green monkeys. Toxicology 2007;
231(1):11–20.
Heaton KJ, Palumbo CL, Proctor SP, Killiany RJ, Yurgelun-Todd DA, White RF. Quantita-
tive magnetic resonance brain imaging in US army veterans of the 1991 Gulf War
potentially exposed to sarin and cyclosarin. Neurotoxicology 2007;28(4):761–9.
Henderson RF, Barr EB, Blackwell WB, Clark CR, Conn CA, Kalra R, et al. Response of
F344 rats to inhalation of subclinical levels of sarin: exploring potential causes of
Gulf War illness. Toxicol Ind Health 2001;17:294–7.
Kadar T, Shapira S, Cohen G, Sahar R, Alkalay D, Raveh L. Sarin-induced neuropathology
in rats. Hum Exp Toxicol 1995;14(3):252–9.
Kassa J, Koupilova M, Vachek J. The influence of low-level sarin inhalation exposure on
spatial memory in rats. Pharmacol Biochem Behav 2001;70(1):175–9.
Lezak M. Neuropsychological assessment. New York: Oxford University Press; 1995.
Nishiwaki Y, Maekawa K, Ogawa Y, Asukai N, Minami M, Omae K. Sarin Health Effects
Study GroupEffects of sarin on the nervous system in rescue team staff members
and police officers 3 years after the Tokyo subway sarin attack. Environ Health
Perspect 2001;109(11):1169–73.
Spreen O, Strauss E. A compendium of neuropsychological tests: administration, norms
and commentary. New York: Oxford University Press; 1998.
Pearce PC, Crofts HS, Muggleton NG, Ridout D, Scott EA. The effects of acutely
administered low dose sarin on cognitive behaviour and the electroencephalogram
in the common marmoset. J Psychopharmacol 1999;13(2):128–35.
Proctor SP, Heaton KJ, Heeren T, White RF. Effects of sarin and cyclosarin exposure
during the 1991 Gulf War on neurobehavioral functioning in US army veterans.
Neurotoxicology 2006;27(6):931–9.
Scremin OU, Shih TM, Huynh L, Roch M, Booth R, Jenden DJ. Delayed neurologic and
behavioral effects of subtoxic doses of cholinesterase inhibitors. J Pharmacol Exp
Ther 2003;304(3):1111–9.
van Helden HP, Vanwersch RA, Kuijpers WC, Trap HC, Philippens IH, Benschop HP. Low
levels of sarin affect the EEG in marmoset monkeys: a pilot study. J Appl Toxicol
2004;24(6):475–83.
Yamasue H, Abe O, Kasai K, Suga M, Iwanami A, Yamada H, et al. Human brain
structural change related to acute single exposure to sarin. Ann Neurol
2007;61(1):37–46.
Yokoyama K, Araki S, Murata K, Nishikitani M, Okumura T, Ishimatsu S, et al. A
preliminary study on delayed vestibulo-cerebellar effects of Tokyo Subway Sarin
Poisoning in relation to gender difference: frequency analysis of postural sway. J
Occup Environ Med 1998;40(1):17–21.


Case report Case report: Long-term cognitive sequelae of sarin exposure

http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=CB771FB8B181DEE25624396E102A9138?doi=10.1.1.1047.9237&rep=rep1&type=pdf

Case report Case report: Long-term cognitive sequelae of sarin exposure

Abstract

Similar works

Full text

Available Versions

CiteSeerX