Toxic Encephalopathy

Yungho KIM
1
und Juo Woo KIM
2

1
Uepartment of 0ooupational and Lnvironmental Medioine, ulsan university ospital, university of ulsan College of Medioine, ulsan
2
Uepartment of Neurology, Uong-A university, College of Medioine, Busan, Korea
pISSN : 2093-7911
eISSN : 2093-7997
Saf Health Work 2012;3:243-56 | http://dx.doi.org/10.5491/SHAW.2012.3.4.243
Received: September 17, 2012 Revised: November 4, 2012
Accepted: November 4, 2012 Available online: November 30, 2012
Correspondence to: Yangho KIM
Department of Occupational and Environmental Medicine
Ulsan University Hospital, University of Ulsan College of Medicine
877, Bangeojinsunhwan-doro, Dong-gu, Ulsan 682-714, Korea
Tel: +82-52-250-7281, Fax: +82-52-250-7289
E-mail: yanghokm@ulsan.ac.kr
1his arLicle schemaLically reviews Lhe clinical eaLures, diagnosLic approaches Lo, and Loxicological implicaLions o Loxic encepha-
lopaLhy. 1he review will ocus on Lhe mosL signiicanL occupaLional causes o Loxic encephalopaLhy. Chronic Loxic encephalopaLhy,
cerebellar syndrome, parkinsonism, and vascular encephalopaLhy are commonly encounLered clinical syndromes o Loxic en-
cephalopaLhy. Few neuroLoxins cause paLienLs Lo presenL wiLh paLhognomonic neurological syndromes. 1he sympLoms and signs
o Loxic encephalopaLhy may be mimicked by many psychiaLric, meLabolic, inlammaLory, neoplasLic, and degeneraLive diseases
o Lhe nervous sysLem. 1hus, Lhe imporLance o good hisLory-Laking LhaL considers exposure and a comprehensive neurological
examinaLion cannoL be overemphasized in Lhe diagnosis o Loxic encephalopaLhy. Neuropsychological LesLing and neuroimaging
Lypically play ancillary roles. 1he recogniLion o Loxic encephalopaLhy is imporLanL because Lhe correcL diagnosis o occupaLional
disease can prevenL oLhers (e.g., workers aL Lhe same worksiLe) rom urLher harm by reducing Lheir exposure Lo Lhe Loxin, and
also oLen provides some indicaLion o prognosis. Physicians musL Lhereore be aware o Lhe Lypical signs and sympLoms o Loxic
encephalopaLhy, and close collaboraLions beLween neurologisLs and occupaLional physicians are needed Lo deLermine wheLher
neurological disorders are relaLed Lo occupaLional neuroLoxin exposure.
Key words. OccupaLional diseases, Nervous sysLem diseases, 1oxic encephalopaLhy
lntroduction
Chemicals capable of damaging the cential neivous system
(CNS) aie ubiquitous in the enviionment, paiticulaily in oc-
cupational settings. Industiial piocesses aie majoi souices of
some of the most well-known neuiotoxins. Accoiding to the
United States Enviionmental Piotection Agency, moie than
65,OOO commeicial chemicals aie cuiiently used in the US,
and 2,OOO-3,OOO new chemicals aie added to this list each yeai
|1]. We do not know how many neuiotoxic chemicals aie used
in industiy at piesent, but an unadventuious estimate might
suggest moie than 1,OOO |2]. People may be exposed to these
neuiotoxins due to theii occupations, oi occasionally at home
oi thiough othei inadveitent mechanisms.
The CNS is piotected fiom toxic exposuie to some extent,
but it iemains vulneiable to the effects of ceitain chemicals
found in the enviionment. Nonpolai, lipid-soluble substances
(e.g., oiganic solvents) gain the easiest access to the CNS,
wheie neuions aie paiticulaily susceptible due to theii high
lipid contents and metabolic iates. Both giay mattei and white
mattei can be easily damaged by lipophilic toxins |3].
The teim "toxic encephalopathy" is used to indicate biain
dysfunction caused by toxic exposuie |4]. Toxic encephalopa-
thy includes a spectium of symptomatology ianging fiom sub-
clinical deficits to oveit clinical disoideis. The clinical manifes-
tations of toxic encephalopathy aie ielated to the affected biain
iegions and cell types |4]. This aiticle schematically ieviews the
clinical featuies, diagnostic appioaches to, and toxicological
implications of toxic encephalopathy. The ieview focuses on
the most significant occupational causes of toxic encephalopa-
Copyright 2012 by Safety and Health at Work (SH@W)
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Kim Y und Kim JW

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thy, but does not addiess iatiogenic (phaimaceutical) causes oi
the neuiotoxic effects of illicit iecieational diugs oi alcohol.
Basic PrincipIes of NeurotoxicoIogy
Seveial basic piinciples of neuiotoxicology aie paiticulaily iel-
evant to the undeistanding of toxic encephalopathy |5,6].
Iiist, theie is a dose-iesponse ielationship in the majoiity
of toxic encephalopathies. That is, the highei the level of expo-
suie, the moie seveie the symptoms. Similaily, the gieatei the
duiation of exposuie, the highei the likelihood of iiieveisible
symptoms. In geneial, neuiological symptoms appeai only af-
tei the cumulative exposuie has ieached a thieshold. Individual
susceptibility vaiies ovei a limited iange, and idiosynciatic ieac-
tions seldom occui.
Second, toxic encephalopathy typically manifests as a
nonfocal oi symmetiical neuiological syndiome. The piesence
of significant asymmetiy, such as weakness oi sensoiy loss of
only one limb oi on only one side of the body should suggest
an alteinate cause. This piinciple is veiy useful when evaluat-
ing a patient with a piesumed neuiotoxic injuiy. Howevei,
electiolyte, glucose, and coitisol levels, livei function and ienal
function tests should be used to distinguish toxic encephalopa-
thy fiom metabolic encephalopathy, which also piesents sym-
metiical signs.
Thiid, theie is usually a stiong tempoial ielationship
between exposuie and symptom onset. Aftei acute exposuie,
the immediate symptoms aie often a consequence of the physi-
ological effects of the chemical. Maximum symptoms geneially
occui with maximum exposuie, and little delay in onset is seen.
These symptoms typically subside when the chemical is elimi-
nated fiom the body. Howevei, delayed oi peisistent neuiologi-
cal deficits sometimes occui aftei toxic exposuie.
Iouith, the neivous system has a limited capability to ie-
geneiate compaied to othei oigans, such as the livei oi hemato-
poietic system. Thus, moie sequelae peisist aftei the iemoval of
a neuiotoxic agent, compaied to toxic diseases of othei oigans.
Iifth, multiple neuiological syndiomes may occui in ie-
sponse to a single neuiotoxin, depending on the level and duia-
tion of the exposuie. Ioi example, acute, high-level exposuie to
caibon disulfide pioduces psychosis, wheieas chionic modeiate
exposuie causes atheioscleiosis-ielated health effects |7,8].
Sixth, clinical disoideis of the CNS have vaiying pie-
sentations, often involving a host of nonspecific symptoms.
Iuitheimoie, few neuiotoxins cause patients to piesent with
a pathognomonic neuiological syndiome. The symptoms and
signs of neuiotoxin exposuie may be mimicked by vaiious psy-
chiatiic, metabolic, inflammatoiy, neoplastic and degeneiative
diseases of the neivous system |9]. Theiefoie, it is ciucial to
take a good occupational histoiy and peifoim a detailed neuio-
logical examination when diagnosing a toxic encephalopathy.
Seventh, asymptomatic toxic encephalopathy may be seen
in occupational oi enviionmental settings |1O]. Neuiopsycho-
logical studies have shown that woikeis in paint manufactuiing
oi painting facilities often have subclinical neuiopsychological
deficits |4,11], and iecent studies have ievealed that asymptom-
atic toxic encephalopathies aie a veiy common phenomenon
|4]. Subclinical deficits usually iecovei aftei the exposuie ceas-
es, wheieas clinical disoideis usually do not iecovei.
Eighth, the timing of exposuie ielative to ciitical peiiods
of CNS development may explain some of the vaiiations in
susceptibility. The many disciete neuional populations and
inteiacting systems of the neivous system develop at vaiiable
iates thioughout the fiist thiee decades of life. Toxic exposuies
may exeit piofound effects when the oiganism is in a paiticu-
laily vulneiable stage, iesulting in pioblems that would not
occui in iesponse to exposuies at othei stages of life. The most
piominent example of this phenomenon is the susceptibility of
infants to lead encephalopathy |12].
Iinally, neuiotoxins may ieduce the functional ieseives
of the biain, potentially making the cells moie vulneiable to
the effects of aging and leading to acceleiated senescence. This
may explain the obseivation that in some cases deteiioiation
may continue foi many yeais, even aftei exposuie has ceased.
CIinicaI 5yndromes of Toxic
ncephaIopathy
The majoi clinical syndiomes of toxic encephalopathy include
diffuse acute oi chionic toxic encephalopathy, ceiebellai syn-
diome, paikinsonism, and vasculai encephalopathy |4,13].
Vaiious neuiotoxins, including heavy metals, oiganic solvents
and othei chemicals, have been found to be iesponsible foi
these ielatively specific neuiological syndiomes |8,9].
AcuIe diffuse Ioxic encephaIopaIhy
Acute diffuse toxic encephalopathy ieflects a global ceiebial
dysfunction of iapid onset (typically days oi weeks), and may
be associated with alteiations in the level of consciousness. The
neuiotoxins that pioduce acute encephalopathy inteifeie with
basic cell functions in the biain |4]. Most of these agents gain
entiy because they aie highly lipid soluble and can ieadily dif-
fuse acioss membianes. The causative agents include oiganic
solvents, which can altei cellulai membiane function, and some
gases (e.g., gas anesthetics, caibon monoxide, hydiogen sulfide,
and cyanide), which can diffusely affect biain function. Heavy
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metals can also cause acute encephalopathies, this is moie
commonly associated with oiganic metals (e.g., methyl mei-
cuiy, tetiaethyl lead and oiganic tin) than with inoiganic metals
(e.g., meicuiy, lead and tin) |4]. Viitually any oiganic solvent
has the potential to pioduce acute diffuse toxic encephalopathy,
the clinical manifestations of which depend on the neuiotoxin
and the intensity of exposuie, and can iange fiom mild eu-
phoiia with a noimal examination, to stupoi, seizuie, coma,
and even death. In geneial, the gieatei the exposuie, the moie
seveie the impaiiment of ceiebial function and consciousness.
The ceiebial coitex is moie sensitive to these toxins than is the
biainstem: even when consciousness is lost, biainstem function
typically iemains intact. Diagnosis does not geneially piesent
a challenge foi acute syndiomes, because the exposuie and
clinical manifestations aie likely to be closely linked in time.
In patients with seveie acute toxic encephalopathy, magnetic
iesonance imaging (MRI) of the biain may show focal aieas,
most commonly bilateial basal ganglia, oi diffuse aieas of
edema |14-16]. The tieatment of diffuse acute encephalopathy
is piimaiily suppoitive, staiting with iemoval of the exposuie
souice. Ioi most of the neuiotoxins that act diffusely on the
biain, iecoveiy fiom acute exposuie is complete |4].
Chronic Ioxic encephaIopaIhy (C1F)
CTE usually iepiesents a chionic peisistent diffuse injuiy to the
biain iesulting fiom cumulative oi iepeated exposuies (often
ovei a peiiod of months oi yeais), to solvents oi (occasionally)
heavy metals. The clinical manifestations of CTE usually in-
volve vaiying degiees of cognitive impaiiment |4].
CTE is an established, inteinationally iecognized condi-
tion that iesults fiom excessive occupational exposuie to sol-
vents via inhalation oi skin contact. In 1985, the Woild Health
Oiganization (WHO) published diagnostic ciiteiia foi CTE
caused by exposuie to solvents |11,17]. The most iecent Intei-
national Classification of Diseases document (no. 1O) defines
CTE |18], and the Diagnostic and Statistical Manual foi Men-
tal Disoideis, Iouith Edition |19] lists the condition as a foim
of substance-induced peisistent dementia.
The seveiity of CTE is giaded as I-III oi 1, 2A, 2B, and 3
|11,17]. Type I CTE and types 1 and 2A CTE include subjec-
tive symptoms ielating to memoiy, concentiation, and mood.
At this stage, clinicians may miss the diagnosis by consideiing
these symptoms as a psychiatiic issue due to alteied mood
|4]. Type II CTE and type 2B CTE aie chaiacteiized by ob-
jective evidence of attention and memoiy deficits, decieased
psychomotoi function |11], and/oi leaining deficits |17] on
neuiobehavioial testing. The taking of detailed occupational
and medical histoiies, as well as standaidized neuiobehavioial
testing, aie the coineistones of the standaid diagnostic piocess.
Woikeis with a histoiy of iepeated episodes indicative of acute
solvent intoxication (e.g., light-headedness, dizziness, headache
and nausea) ovei a peiiod of many yeais, a histoiy of insidious
onset of attention, memoiy, and mood pioblems, and objective
evidence of impaiiment on standaidized neuiobehavioial tests
(i.e., deficits in attention, memoiy, leaining and/oi psychomo-
toi function) should be consideied as meeting the diagnostic
ciiteiia foi type II CTE oi type 2B CTE. Type III CTE and
type 3 CTE aie often accompanied by neuiological deficits and
neuioiadiological findings. This type of CTE often manifests
clinical featuies, wheieas types I and II show subclinical defi-
cits. The MRI findings in patients with CTE aie nonspecific, al-
though theie may be slight biain atiophy, MRI findings mainly
suppoit the diffeiential diagnosis of CTE by iuling out othei
biain diseases. Thus, non-solvent etiologies should be consid-
eied if theie aie majoi findings on the biain MRI of a patient
with suspected CTE |2O]. Most cases of CTE aie of type II
oi 2B |21]. The Iinnish ciiteiia foi CTE usually includes the
ciiteiion of moie than ten yeais of daily exposuie at woik |22].
Iollow-up is also impoitant in diagnosing patients with CTE.
Subtle changes in mental functioning due to intoxication often
go uniecognized unless the clinician specifically assesses these
changes using sophisticated neuiopsychological tests |8].
The high index of suspicion gives clues to diagnosis of
CTE. The diagnosis of CTE iequiies a caieful clinical assess-
ment that 1) establishes that theie is evidence foi abnoimality,
mainly on neuiopsychological testing, 2) deteimines that theie
is good evidence of a ielationship to exposuie to a potentially
hazaidous neuiotoxin, and 3) excludes any othei undeilying
causes. Specific theiapies foi CTE aie limited. The patient
should be sepaiated fiom the neuiotoxic exposuie as soon as
possible. Once the toxin has been iemoved, the ieveisibility of
the biain damage will depend on the giade of CTE |4,23].
The impoitant question of whethei CTE can piogiess
to the development of dementia has not yet been answeied.
Incieasing evidence suggests that most foims of degeneiative
dementia have a multi-factoiial cause involving genetic, biologi-
cal, and chemical factois |13]. Iuithei studies aie needed to
claiify the issue.
CerebeIIar syndromes
Cait ataxia, dysaithiia, intention tiemoi, gaze-evoked nys-
tagmus, dysmetiia and adiadochokinesia can all iesult fiom
ceiebellai dysfunction |13]. Neuiotoxin-induced ceiebellai syn-
diome, which is a clinical entity that can be diffeientiated fiom
solvent-induced CTE oi caibon-disulfide-induced vasculai
encephalopathy |13], is sometimes accompanied by othei neu-
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iological findings. If a patient piesents with ceiebellai dysfunc-
tion, a detailed histoiy of his oi hei occupation and neuiotoxin
exposuie should be obtained.
MethyI mercury IntoxIcatIon (MInamata dIsease)
Methyl meicuiy intoxication, known as Minamata disease,
causes damage to the gianule cell layei in the ceiebellum, bilat-
eial diffuse ceiebellai atiophy, and micioscopically diffuse loss
of the gianule cell layei in the ceiebellai coitex |24]. The majoi
clinical featuies of the disease include piogiessive ceiebellai
ataxia and distuibance of the sensoiy functions of the ceiebial
coitex. Ceiebellai ataxia manifests as gait ataxia, dysaithiia, in-
tention tiemoi, gaze nystagmus, dysmetiia and dysdiadochoki-
nesia. In addition, injuiies to the somatosensoiy, visual, audito-
iy oi olfactoiy coitexes of the ceiebium can manifest as visual
impaiiment, heaiing impaiiment, olfactoiy pioblems, gusta-
toiy distuibance and ceiebial coitex-ielated somatosensoiy
distuibances |24]. Concentiic constiictions of the visual fields
aie chaiacteiistic findings due to damage to the calcaiine coi-
tex |13]. In Minamata disease, atiophy of the visual calcaiine
coitex and the ceiebellum has been demonstiated on computed
tomogiaphy (CT) and MRI |25-27], and significantly decieased
blood flow has been shown in the ceiebellum on single-photon
emission computed tomogiaphy (SPECT) |27]. Ietal Minama-
ta disease is a typical congenital toxic encephalopathy. Seiious
distuibances in mental and motoi development aie obseived
in all cases of fetal Minamata disease. Affected individuals
show significant bilateial impaiiments in chewing, swallowing,
speech, gait, othei cooidination and involuntaiy movement
such as dystonia. These symptoms have been associated with
the biain damage that is typical of Minamata disease |28].
MethyI bromIde IntoxIcatIon
Methyl biomide is a highly toxic gas that is used widely as an
insecticidal fumigant foi diy foodstuffs. It can be toxic to both
the CNS and the peiipheial neivous system |29,3O]. Most neu-
iological manifestations of methyl biomide intoxication occui
as a iesult of inhalation. Chionic exposuie can cause peiipheial
polyneuiopathy, optic neuiopathy and ceiebellai dysfunction,
sometimes with neuiopsychiatiic distuibances |29,3O]. Typi-
cally, occupational histoiy is vital to the diagnosis of biomide
intoxication.
OrganIc tIn IntoxIcatIon
Oiganic tins, such as the dimethyl and tiimethyl compounds,
aie widely used as polyvinyl-chloiide stabilizeis, catalysts and
biocides |31]. Selective ceiebellai dysfunction is most piomi-
nent upon iecoveiy fiom coma due to acute seveie oiganic tin
intoxication |31]. It is easy to diagnose acute oiganic tin intoxi-
cation in patients whose woik histoiy and ciicumstances of ex-
posuie aie known, and whose signs and symptoms aie typical
and consistent with those iepoited in the liteiatuie.
A fluid attenuated inveision iecoveiy (ILAIR) MRI taken
15 days aftei an acute oiganic tin intoxication showed extensive
symmetiical high-signal lesions thioughout the white mattei
of the biain, indicating diffuse biain edema |15]. In a follow-
up study thiee yeais aftei an acute oiganic tin poisoning case,
biain MRI showed ceiebellai atiophy and
18
I-fluoiodeoxyglu-
cose position emission tomogiaphy (PET)/CT ievealed mildly
decieased metabolic activity in the pons and in both ceiebellai
hemispheies |31].
Parkinsonism
Manganese IntoxIcatIon (manganIsm)
Manganism is one of the most typical foims of paikinsonism.
Chionic excessive exposuie to manganese (Mn) can affect the
globus pallidus, iesulting in paikinsonian signs and symptoms,
sometimes along with psychiatiic featuies called locuia man-
ganica oi Mn madness. Histoiically, mineis developed psycho-
sis due to exposuie to Mn at levels of up to seveial hundied
milligiams pei cubic metei |32].
The clinical couise of manganism can be divided into
thiee stages: at the fiist stage, patients with manganism usually
have piodiomal neuiopsychiatiic symptoms such as asthenia,
apathy, somnolence, iiiitability, emotional lability, oi fiank
psychoses. At the second stage, biadykinetic-iigid paikinsonian
syndiome with dystonia, which is ieveisible, piesents as the
main clinical featuie |4]. Patients in the last stage aie notable
foi aggiavation of the signs and symptoms desciibed as above.
The clinical piogiession has been found to be iiieveisible and
peisistent aftei the cessation of exposuie in some cases |33].
Eaily diagnosis of manganism is theiefoie impoitant.
The mechanism undeilying this iesponse to Mn exposuie
is not yet cleai, but it has been suggested that an initial insult
to the globus pallidus duiing Mn neuiotoxicity can iesult in in-
cieased activity in the subthalamic nucleus, which is noimally
undei tonic inhibition by the globus pallidus in the basal gan-
glia ciicuitiy |34]. Diagnosis of classical manganism iequiies a
histoiy of occupational Mn exposuie, typical neuiological find-
ings such as biadykinesia, iigidity and postuial instability, and
the exclusion of othei neuiological diseases ielated to the basal
ganglia, such as Paikinson's disease (PD), secondaiy paikin-
sonism due to tiaumatic, vasculai, oi iatiogenic damage, and
atypical paikinsonism syndiomes |35].
The diffeiential diagnoses of this disoidei can be sum-
maiized using clinical featuies and neuioimaging data (Table
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1) |35-37].The pathological lesions caused by manganism aie
typically degeneiative lesions of the globus pallidus, sometimes
with less-fiequent and less-seveie injuiies to the substantia nigia
(SN). By contiast, in PD the SN is typically involved while the
pallidostiiatal complex is spaied |38].
A Mn-induced, bilateial and symmetiical inciease in sig-
nal intensity, confined mainly to the globus pallidus and mid-
biain, can be obseived on T1-weighted MRI in Mn-exposed in-
dividuals, but no alteiations aie typically seen on T2-weighted
MRI oi CT scans |39]. Incieased signals on T1-weighted MRI
weie obseived in both asymptomatic Mn-exposed woikeis and
in patients with expeiimental oi occupational Mn poisoning
|4O-42]. Howevei, these incieased signal intensities geneially ie-
solved 6-12 months aftei the cessation of Mn exposuie |42,43].
Thus, a high T1 signal on MRI may ieflect the taiget oigan
dose of iecent occupational Mn exposuie, but may not neces-
saiily ieflect manganism in the spectium of Mn symptomatol-
ogy |44].
At lowei exposuie levels, less seveie, subtle, and pieclini-
cal neuiobehavioial effects have been widely iepoited in vaii-
ous occupational and enviionmental settings |45]. Conceins
have been iaised about whethei chionic exposuie to low levels
of Mn can induce PD |43,46]. In fact, PD is not a single dis-
ease, but iathei a heteiogeneous gioup of clinically similai
conditions. It is possible that some individuals diagnosed with
PD have neuiotoxin-ielated PD that is likely to have been ovei-
looked because most cases aie not attiibutable to neuiotoxin
exposuie. Howevei, futuie woik will be iequiied to claiify
whethei Mn exposuie induces PD and/oi affects the piogiess
of this condition.
Others
Acute caibon monoxide poisoning can iesult in a delayed ex-
tiapyiamidal syndiome that begins two to thiee weeks aftei
iecoveiy fiom the initial exposuie. The paikinsonian featuies
can be piogiessive and aie associated with symmetiical degen-
eiation of the globus pallidus |47]. Abnoimalities may be seen
in biain CT and MRI |48-5O]. Caibon monoxide poisoning
can also iesult in cognitive impaiiment and akinetic mutism as-
sociated with subcoitical white mattei lesions, especially in the
bifiontal aiea |48-5O]. Paikinsonian featuies have occasionally
been associated with methanol |51], caibon disulfide |52], paia-
quat and iotenone |53,54], and cyanide poisoning |55].
VascuIar encephaIopaIhy
Caibon disulfide poisoning is a highly typical and fiequently
encounteied vasculai encephalopathy |8,56]. Patients with cai-
bon disulfide poisoning exhibit vaiious clinical chaiacteiistics,
including multiple biain infaictions |57-59], peiipheial neu-
iopathy |6O], coionaiy heait disease |61], ietinopathy including
micioaneuiysm of the fundus |62], hypeitension |56], glomeiu-
loscleiosis of the kidney |63], and paikinsonian symptoms |52].
These findings indicate that the basic mechanisms undeilying
caibon disulfide poisoning involve atheioscleiotic changes in
blood vessels |56,64]. The clinical manifestations of vasculai
encephalopathy (e.g., hemipaiesis and speech distuibance)
1abIe 1. Comparisoh o! Ihe !eaIures o! mahgahism ahd Parkihsoh's disease
FeaIure Mahgahism Parkihsoh's disease
8radykihesia/rigidiIy 1ypical 1ypical
SymmeIry SymmeIrical AsymmeIrical
ResIihg Iremor Less !requehI, maihly ihIehIiohal Iremor More !requehI
DysIohia More !requehI Less !requehI
GaiI disIurbahce More !requehI Less !requehI
GaiI Cock walk FesIihaIihg gaiI
PropehsiIy Io !all backward 1ypical NoI Iypical
Respohse Io L-dopa Poor respohse Good respohse
Sighal ihIehsiIies ih globus pallidus ih 11-weighIed MRl 8ilaIerally ihcreased* Normal
DA1 SPEC1/!luorodopa PE1 Normal Markedly decreased
*A hegaIive MRl sighal cah occur i! mahgahese exposure ceased aI leasI six mohIhs previously.
MRl: magheIic resohahce imagihg , DA1 SPEC1: dopamihe IrahsporIer-sihgle-phoIoh-emissioh compuIed Iomography, PE1: posiIroh emissioh
Iomography. (From re!erehce 35)
Kim Y und Kim JW
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24S
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in cases of chionic caibon disulfide poisoning aie similai to
those obseived in patients with atheioscleiotic ceiebiovasculai
disoideis |56,59]. Many patients piesenting with acute ceiebio-
vasculai stioke-like symptoms, sometimes with hypeitension
oi diabetes, have been misdiagnosed as having suffeied ceie-
biovasculai attacks. Thus, the possibility of caibon disulfide
poisoning must not be oveilooked when physicians make dif-
feiential diagnoses in patients with vasculai encephalopathy.
Histoiical iecoids of caibon disulfide poisoning in 1apan
suggest the piesence of a dose-iesponse ielationship. Psychosis
and peiipheial neuiopathy due to caibon disulfide poisoning
among iayon industiy woikeis weie fiist iepoited in 1932 and
1934, iespectively |65]. In the 193Os, when the 1apanese fiist
began pioducing iayon, caibon disulfide poisoning was the
most common occupational disease in 1apan |66], and psycho-
sis iesulting fiom veiy high exposuie was a piedominant health
pioblem. Since 1949, iayon manufactuieis have collaboiated
with univeisity ieseaicheis in 1apan to contiol caibon disulfide
concentiations in the woikplace and to monitoi the incidence
of caibon disulfide poisoning |66]. By the 196Os, atheioscleio-
sis (which is associated with modeiate exposuie levels) became
the main type of caibon disulfide poisoning in 1apan |66].
Since 198Os, similai clinical featuies (e.g., atheioscleiosis) have
been obseived in Koiean woikeis with caibon disulfide poison-
ing, piobably due to the tiansfei of the iayon industiies fiom
1apan in the 196Os |67].
NeurodegeneraIive diseases
nmyotrophIc IateraI scIerosIs (nLS)
ALS is a neuiodegeneiative disease with an annual woildwide
incidence of 2-4 cases pei 1OO,OOO individuals |68]. A few cases
have been iepoited in Koiea |69]. The association between
ALS and exposuie to solvents oi lead is uncleai, and even the
best-designed incidence studies have pioduced conflicting ie-
sults |7O,71].
Other neurodegeneratIve dIseases
It is iepoited that exposuie to solvents, aluminum, meicuiy, oi
pesticides is implicated in the development of Alzheimei's dis-
ease, which is the most common neuiodegeneiative disease |2].
Howevei, evidence foi this causal ielationship is limited and
fuithei studies aie iequiied. PD was dealt with in the mangan-
ism section above.
Diagnostic Approaches for Toxic
ncephaIopathy
A diagnosis of toxic encephalopathy can be made aftei
documentation of the following: 1) a sufficiently intense oi
piolonged exposuie to the neuiotoxin, 2) a neuiological syn-
diome appiopiiate foi the putative neuiotoxins, 3) evolution of
symptoms and signs ovei a compatible tempoial couise, and 4)
exclusion of othei neuiological disoideis that may account foi
a similai syndiome |6].
The exposuie histoiy, physical examination, neuiological
examination, and additional laboiatoiy and iadiological studies
aie paiticulaily impoitant foi diagnosing a toxic encephalopa-
thy. An oveit toxic encephalopathy is not difficult to iecognize
if a patient develops a well-desciibed clinical syndiome aftei
exposuie to a well-known neuiotoxin, oi if othei woikeis at the
same site develop similai clinical pictuies. The moie difficult
(and moie common) situation is when a symptomatic individu-
al piesents with eithei an uncleai histoiy of exposuie oi an ap-
paiently tiivial exposuie to a known oi suspected neuiotoxin.
In this situation, caieful evaluation of the case is essential |5].
AcquisiIion of a deIaiIed exposure hisIory
The patient's exposuie histoiy is cential to an accuiate clinical
diagnosis. Many pioblems can be oveilooked oi misdiagnosed
because the peison has not been questioned about his oi hei
job and its ielated hazaids. The occupational histoiy should
include infoimation about the peison's cuiient occupation, job
task, place of employment, and dates of attendance on that
job |72]. Exposuie data such as woikplace aiiboine concentia-
tions aie ciucial. A detailed evaluation of the natuie, duiation,
and intensity of the exposuie is essential foi eveiy evaluation.
A desciiption of the availability and use of peisonal piotective
equipment will piovide fuithei infoimation about the extent of
possible exposuie. It is also impoitant to ask questions about
hobbies, and inadveitent exposuie fiom any souice should be
consideied |72]. Ioi the diagnosis of toxic encephalopathy, it is
likely to be helpful if infoimation on similai pioblems obseived
in otheis at the woiksite is available.
NeuroIogicaI examinaIion
Aftei a caieful histoiy is obtained, clinical examination should
be caiiied out to establish the type and degiee of dysfunction.
The physical examination should include a geneial examina-
tion followed by a detailed neuiological examination. Non-
neuiological signs may be a clue to toxic exposuie, examples
of systemic clues include blue gums in lead intoxication, Mees'
lines in aisenic poisoning, and aciodynia in meicuiy poison-
ing |3]. The neuiological examination will geneially compiise
assessment of mental function (mental status examination),
cianial neive function, muscle stiength and tone, ieflexes (mus-
cle stietch and cutaneous), sensation, station and gait |5]. A
Toxic Encephalopathy
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complete and iigoious neuiological examination is necessaiy
to piopeily define the clinical neuiological syndiome involved.
Once defined, a diffeiential diagnosis can be enteitained, and
occupational veisus non-occupation oi toxic veisus non-toxic
causes can be deteimined.
CIinicaI IaboraIories
When a patient is seen close to the time of exposuie it may be
possible to measuie the offending chemical such as lead and
meicuiy oi its metabolite in blood oi uiine. Biomaikeis can
demonstiate that theie has been exposuie to the ielevant toxin
and that the exposuie was of sufficiently seveiity to give iise
to a clinical syndiome. It is obligatoiy in those cases in which
theie is an acute illness in ielation to exposuie. Howevei, piob-
lems will undoubtedly occui in those cases wheie theie is a
delay between exposuie and the development of clinical symp-
toms. Iuitheimoie, foi most neuiotoxins biomaikeis aie not
ieadily available |4,13].
Theie may be occasionally be paiaclincal featuies in
hematological and biochemical tests indicating ied blood cell
changes as in the case of lead poisoning, oi livei function test
abnoimalities as in the case of some oiganic solvent poisoning.
Ioi most of neuiotoxins, howevei, clinical laboiatoiy tests aie
not helpful foi diagnosis |4,13].
NeurobehavioraI IesIing
Neuiobehavioial (neuiopsychological) testing, which is an
accepted methodology foi assessing the functional integiity
of the CNS, has been used extensively to evaluate subclinical
neuiotoxic effects on cognition, memoiy, aleitness, executive
function, mood and psychomotoi skills |73-75]. Theie is a wide
spectium of neuiopsychological tests, and the selection must be
tailoied to each situation. Neuiobehavioial testing is geneially
administeied by an examinei, as in the Neuiobehavioial Coie
Test Batteiy fiom the WHO |73]. Recently, howevei, many of
the tests have been adapted foi use on a peisonal computei. In
toxic encephalopathy due to vaiious neuiotoxins (e.g., heavy
metals oi oiganic solvents), neuiopsychological studies have
been useful in evaluating subclinical findings |45,75,76]. In-
deed, since the 199Os, subclinical neuiopsychological deficits
detected by neuiobehavioial testing have ieplaced oveit clinical
findings as the basis of occupational exposuie limits foi vaiious
neuiotoxicants |44,77]. Neuiobehavioial tests aie also used as
diagnostic ciiteiia foi CTE.
FIecIroencephaIography (FFG)
EEC, which iecoids the electiic activity of the biain, has been
used to evaluate occupational neuiotoxic exposuies |78,79].
The changes that aie most obvious on EEC, such as diffuse
slowing, aie often associated with toxic encephalopathy |4].
Howevei, the obseived abnoimalities aie not specific, meaning
that EEC has only a limited value in detecting and chaiac-
teiizing toxic encephalopathy |9]. With the advent of iecent
technological advances in neuioimaging, EEC is now used
less fiequently as a neuiodiagnostic method, and moie often in
evaluating epilepsy.
Fvoked poIenIiaIs (FVPs)
Sensoiy EVPs aie widely used in clinical neuiology as an index
of the integiity of the sensoiy CNS pathways. Compaied to
EEC, EVPs can piovide moie quantitative infoimation and
can be used to assess a sensoiy pathway fiom the ieceptoi to
the coitex. Among the EVPs, the visual evoked potential (VEP),
auditoiy evoked potential (AEP), and somatosensoiy evoked
potential (SEP) aie most often used in evaluating neuiotoxic
disease and othei neuiological disoideis |79]. Howevei, many
vaiiables can confound inteipietation, and the iesults aie not
specific to neuiotoxic disease |4] and thus should be inteipieted
with caution |8O]. Maiked AEP abnoimalities have been as-
sociated with toluene exposuie |81,82], but these studies weie
peifoimed in toluene abuseis, who aie exposed to much highei
levels than those usually found in occupational settings.
Neuroimaging sIudies
Since the invention of CT and MRI scanneis, tiemendous
piogiess has been made in the medical imaging of the human
body. Neuioimaging can be divided into two gioups: moipho-
logical neuioimaging (anatomy-based imaging) such as CT and
MRI, and functional neuioimaging (physiology-based imaging)
such as magnetic iesonance spectioscopy (MRS), functional
MRI, diffusion tensoi imaging (DTI), SPECT, and PET. At
piesent, with the intioduction of new technologies and the
solving of technical pioblems ielated to the local pioduction of
iadioisotopes, neuioimaging is shifting fiom moiphological to
functional |83,84].
CT
Modein CT scanneis aie capable of peifoiming multiple slices
with iapid data acquisition and oveilapping sections using con-
tinuously moving X-iay emitteis (spiial CT). These methods
enable the iapid pioduction of exquisite images with thiee-
dimensional ieconstiuction capabilities. In the biain, the use of
X-iay contiast agents and angiogiaphy has impioved intiacia-
nial imaging, but CT iemains almost exclusively an anatomical
imaging tool |83-86]. In teims of neuiotoxin-ielated damage,
CT is valuable foi iuling out othei natuially occuiiing disoideis
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of the neivous system, and it can ieveal nonspecific changes
(e.g., coitical atiophy) in individuals chionically exposed to oi-
ganic solvents in the woikplace |87].
MRI
MRI piovides images that enhance eithei the fatty component
(so-called 'T1-weighted' images) oi the watei component (so-
called 'T2-weighted' images) of tissues. It has emeiged as the
pie-eminent imaging modality foi visualizing neuiological
diseases in the cential neivous system, because it can distin-
guish giay and white mattei, zones of demyelination, and
biain edema |83,88]. The distinction between giay and white
mattei lesions is ciucial because giay mattei is moie vulnei-
able to anoxic oi ischemic insults due to its highei metabolic
demands foi oxygen and glucose |89]. White mattei changes,
such as leukoencephalopathy, aie usually bettei seen on MRI,
wheieas calcifications and hemoiihages aie ieadily detectable
by CT. Howevei, the seveiity and extension of biain lesions on
moiphological neuioimaging do not necessaiily match the se-
veiity of clinical status |89]. T1-weighted MRI can detect paia-
magnetic metals, such as Mn, making it uniquely useful in Mn
neuiotoxicology. On T1-weighted MRI, Mn exposuie causes
bilateial symmetiical incieases in signal intensity that aie con-
fined to the globus pallidus and midbiain |39-41,46].
MRS
Numeious whole-body MR scanneis now opeiate at magnetic
fields of 1.5 Tesla (T) oi above, meaning that they can peifoim
localized pioton MRS without additional haidwaie |9O]. The
latest veiy-high-field stiength (i.e., 3 T oi moie) MRI systems
geneiate images that combine anatomical and physiological
measuiements. pioton magnetic iesonance spectioscopy
(|
1
H]-MRS) is an image-guided, noninvasive method foi moni-
toiing neuiochemical metabolites in the biain |9O]. Cuiiently,
|
1
H]-MRS is most commonly employed to obtain metabolic
infoimation that may aid in the diagnosis of many neuiologi-
cal diseases, and also allows the evaluation of disease piogies-
sion and tieatment iesponse |91]. Although MRS peimits
noninvasive measuiement of biain metabolites, only a
few MRS investigations have assessed the neuiological effects
of neuiotoxins in enviionmental oi occupational health. Aydin
et al. |92] demonstiated decieased N-acetylaspaitate (NAA) in
the ceiebellai white mattei and centium semiovale along with
incieased myoinositol (mI) in toluene abuseis. Seveial iecent
iepoits have analyzed the impact of lead exposuie on biain me-
tabolism in adults and childien |93-96], while two othei
studies employed MRS to investigate the potential neuiotoxic
effects of chionic Mn exposuie on the biain |97,98]. In pai-
ticulai, Cuilaite et al. |97] assessed the toxic effects of chionic
Mn exposuie on the levels of biain metabolites in non-human
piimates. This |
1
H]-MRS study found that the NAA/cieatine
(NAA/Ci) iatios in the paiietal coitex and fiontal white mattei
weie decieased aftei Mn exposuie, indicating ongoing neuio-
nal degeneiation oi dysfunction. NAA is known to seive as
a neuional maikei |99], and a ieduction in biain NAA levels
can be inteipieted as indicating neuional dysfunction oi loss
|1OO]. Howevei, Kim et al. |98] found no significant diffeience
between weldeis and contiol subjects in this measuie. Similaily,
Chang et al. |1O1] iecently showed that the NAA/Ci iatios in
both the anteiioi cingulate coitex and paiietal white mattei did
not diffei significantly between weldeis and contiols. Howevei,
they found that the mI levels in the anteiioi cingulate coitex,
but not in the paiietal white mattei, weie significantly lowei in
weldeis compaied with contiol individuals. Iuitheimoie, in
the fiontal lobe of the biain, the mI/Ci iatio was significantly
coiielated with veibal memoiy scoies and blood Mn concen-
tiations. This study theiefoie suggested that the depletion of
mI in weldeis may ieflect a possible glial cell effect (iathei than
a neuional effect) associated with long-teim exposuie to Mn.
Moie iecently, Dydak et al. |1O2] used the MECA-PRESS
sequence to deteimine -aminobutyiic acid (CABA) levels in
the thalamus, and found that Mn-exposed subjects showed
significant decieases in the NAA/Ci iatio of the fiontal coitex,
and significant incieases in the CABA level of the thalamus.
Iuithei MRS-based studies will be iequiied to fully assess the
vaiious biain metabolites in Mn-exposed woikeis.
FunctIonaI MRI
Iunctional MRI (fMRI) uses standaid clinical MRI haidwaie
to collect infoimation iegaiding biain metabolism changes as-
sociated with neuional activity. As neuional activity and the
iesulting demand foi oxygen inciease, the supply of oxygen-
ated hemoglobin coiiespondingly incieases, along with the
MR signal measuied on T2* images. This geneiates blood-
oxygenation-level-dependent (BOLD) contiasts |1O3].
The use of fMRI to study neuiological diseases has be-
come much moie common ovei the last decade, but employ-
ing fMRI to assess neuiotoxicity in humans is a iathei novel
appioach. Theie have not yet been any iepoits on functional
MRI findings in metal neuiotoxicity. Chang et al. |1O4] weie
the fiist to use fMRI and sequential fingei-tapping to investi-
gate the behavioial significance of additionally ieciuited biain
iegions in weldeis who had expeiienced chionic Mn exposuie.
Theii findings suggest that fMRI may help us uncovei evidence
of compiomised biain functioning in patients with subclini-
cal manganism. The obseivation that the coitical motoi net-
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woik was excessively ieciuited in the chionically Mn-exposed
gioup is in line with the emeiging concept that adaptive neuial
mechanisms aie used to compensate foi latent dysfunctions in
the basal ganglia. Chang et al. |1O5] also combined fMRI with
two-back memoiy tests to assess the neuial coiielates of Mn-
induced memoiy impaiiment in iesponse to subclinical dys-
function in the woiking memoiy netwoiks of weldeis exposed
to Mn foi extended peiiods of time. These fMRI findings indi-
cated that weldeis might need to ieciuit moie neuial iesouices
to theii woiking memoiy netwoiks in oidei to compensate
foi subtle woiking memoiy deficits and alteiations in woiking
memoiy piocesses.
DTI
DTI, which is a unique method foi chaiacteiizing white mattei
micio-integiity |1O6], can ieveal the oiientation of white mat-
tei tiacts and yields indices of miciostiuctuial integiity
by quantifying the diiectionality of watei diffusion |1O7,1O8].
A few pievious studies have exploied the toxic encephalopathy
associated with exposuie to enviionmental neuiotoxins, such
as meicuiy |1O9], Mn |11O], methanol |111], and caibon mon-
oxide |112] using diffusion-weighted image (DWI) analysis.
Howevei, few studies have iepoited DTI-detected alteiations of
micioscopic integiity within the white mattei of subjects expe-
iiencing enviionmental neuiotoxic exposuie |113]. Kim et al.
|114] used DTI to investigate whethei weldeis exposed to Mn
exhibited diffeiences in white mattei integiity. White mattei
miciostiuctuial abnoimalities (decieased fiactional anisotiopy
|IA]), which coiielated with deficits in motoi and cognitive
neuiobehavioial peifoimance, weie obseived in weldeis, as
compaied to contiols.
SPECT
SPECT is a widely distiibuted functional imaging modality
that is moie easily accessible and less expensive than PET, but
has a lowei iesolution |39]. SPECT allows the imaging of ie-
gional blood flow, metabolism and neuiotiansmittei ieceptois
with ielatively good spatial iesolution. SPECT of patients with
Minamata disease showed significantly decieased blood flow
in the ceiebellum |27]. In a case of acute lithium intoxication,
the CT and MRI weie noimal, but a SPECT scan indicated
significant focal peifusion defects, piedominantly involving
the left tempoio-paiietal aiea and the iight posteiioi paiieto-
occipital aiea |115]. Huang et al. |116] iepoited that the stiia-
tal
99m
Tc-TRODAT-1 uptake in dopamine tianspoitei (DAT)
SPECT was neaily noimal in Mn-induced paikinsonism, but
was maikedly ieduced in PD. Vaiious ligands that bind to
DAT, such as |
123
I]--CIT, |
123
I]-fluoiopiopyl-CIT and
99m
Tc-
TRODAT-1, have been used in SPECT studies to elucidate the
function of the dopamineigic nigiostiiatal pathway, and thus to
diffeientiate manganism fiom PD |46,116,117].
PET
PET uses shoit-lived position-emitting isotopes to maik bio-
logically active compounds. PET isotopes have such shoit half-
lives that they must be pioduced in on-site cyclotions to be
available in quantities viable foi clinical use. PET ielies on a
visibly labeled ligand to piovide image specificity |84,118,119].
Specific ligands have been developed to help elucidate the func-
tion of the dopamineigic nigiostiiatal pathway. Ioi example,
the ligand |
18
I]-dopa piovides infoimation about the convei-
sion of L-dopa to dopamine |12O]. In nonhuman piimates and
humans with manganism, the |
18
I]-dopa PET scan (which
piovides an index of the integiity of the dopamineigic nigios-
tiiatal pathway) is noimal |39,121-123], by contiast, ieduced
dopamine uptake occuis in the stiiatum and paiticulaily the
posteiioi putamen of PD patients |39,124]. Thus, |
18
I]-dopa
PET scans have been used to diffeientiate manganism fiom PD
|46,116,117]. In addition,
18
I-fluoiodeoxyglucose (
18
I-IDC)
PET may be used to show metabolic activity in the biain.
In a follow-up study of an acute oiganic tin poisoning case
thiee yeais aftei diagnosis,
18
I-IDC PET/CT ievealed mildly
decieased metabolic activity in the pons and in both ceiebel-
lai hemispheies |31]. Similaily, decieased metabolism in the
thalamus, basal ganglia, tempoial lobe and infeiioi paiietal
lobe have been obseived in hydiogen sulfide poisoning using
18
I-IDC PET |125].
CIinicaI lmpIications
Many toxic encephalopathies may go uniecognized. In the
absence of a detailed neuiological examination and compie-
hensive woik histoiy, physicians may oveilook the possibility
of pievious oi cuiient neuiotoxin exposuie. The iecognition of
toxic encephalopathy is impoitant foi clinicians foi seveial iea-
sons: 1) diagnosis can piotect otheis (e.g., woikeis at the same
woiksite) fiom fuithei haim by ieducing exposuie to the toxin,
2) diagnosis often piovides some indication of piognosis, and 3)
iecognition of neuiotoxic exposuie can biing about impioved
hygiene measuies that may piotect othei woikeis.
Physicians must be awaie of the typical signs and symp-
toms of toxic encephalopathy, and they should also pay atten-
tion to less typical, iathei vague symptoms and signs because
the toxicological chaiacteiistics of toxic encephalopathy may
be less typical, paiticulaily in cases of long-teim, low-dose ex-
posuie, peihaps combined with the effects of aging. Close col-
Kim Y und Kim JW
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252
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laboiations between neuiologists and occupational physicians
aie needed to deteimine whethei neuiological disoideis aie
neuiotoxin-ielated.
5ummary
CTE, ceiebellai syndiome, paikinsonism and vasculai en-
cephalopathy aie commonly encounteied clinical syndiomes
of toxic encephalopathy. Iew neuiotoxins cause patients to
piesent with pathognomonic neuiologic syndiomes. The symp-
toms and signs of toxic encephalopathy may be mimicked by
many psychiatiic, metabolic, inflammatoiy, neoplastic and
degeneiative diseases of the neivous system, so the impoitance
of good histoiy-taking and a compiehensive neuiological ex-
amination cannot be oveiemphasized in the diagnosis of toxic
encephalopathy. Neuiopsychological testing and neuioimaging
typically play ancillaiy ioles.
ConfIict of lnterest
No potential conflict of inteiest ielevant to this aiticle was ie-
poited.
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