Prenatal

Methylmercury

Exposure

and

Developmental

Outcomes

Review

of

the

Evidence

and

Discussion

of

Future

Directions

I

conducted

a

review

of

the

published

literature

to

assess

the

strength

of

the

evidence

for

an

association

between

prenatal

exposure

to

methylmercury

-LRB-

MeHg

-RRB-

and

subsequent

child

development

I

identified

studies

on

this

subject

published

since

Of

these

were

longitudinal

studies

conducted

in

the

Seychelle

Islands

and

in

the

Faroe

Islands

Nine

were

cross-sectional

studies

conducted

in

different

countries

where

seafood

a

source

of

MeHg

constituted

a

major

part

of

the

diet

The

ages

of

the

children

studied

ranged

from

weeks

to

years

The

results

of

the

longitudinal

studies

were

contradictory

Researchers

in

the

Faroe

Islands

identified

an

association

between

MeHg

exposure

and

developmental

effects

whereas

those

in

the

Seychelle

Islands

identified

no

such

association

This

inconsistency

was

mirrored

in

the

results

of

the

cross-sectional

studies

where

there

were

some

positive

and

some

negative

findings

It

was

concluded

that

it

was

not

possible

from

currently

available

data

to

determine

whether

there

is

an

association

between

prenatal

MeHg

exposure

and

adverse

developmental

effects

in

children

In

advance

of

future

research

consideration

should

be

given

to

resolving

the

uncertainties

surrounding

exposure

assessment

and

outcome

measurement

as

both

elements

varied

between

studies

It

was

suggested

that

questions

of

exposure

assessment

would

benefit

from

the

application

of

an

expert

review

process

Outcome

assessment

would

benefit

from

the

development

of

theoretically

based

measures

of

specific

aspects

of

cognitive

functioning

to

replace

the

relatively

crude

measures

of

attainment

and

IQ

currently

employed

in

most

studies

This

would

assist

in

the

development

of

classic

longitudinal

studies

by

allowing

repeated

assessment

over

the

full

age

range

and

providing

data

that

are

more

readily

interpretable

and

comparable

between

studies

Organic

compounds

of

mercury

have

a

variety

of

industrial

uses

and

most

of

the

data

relating

to

the

neurotoxic

effects

of

mercury

exposure

have

been

derived

from

occupational

populations

-LRB-

Chipman

et

al.

-RRB-

However

in

the

a

potential

risk

to

the

wider

community

was

highlighted

when

large

numbers

of

people

living

in

the

Minamata

Bay

area

of

Kyushu

Island

Japan

developed

symptoms

of

mercury

poisoning

This

well-documented

incident

was

traced

to

a

factory

using

mercuric

chloride

as

a

catalyst

in

the

production

of

vinyl

chloride

and

discharging

effluent

into

the

sea

-LRB-

Harada

-RRB-

In

aquatic

environments

mercury

is

methylated

by

the

action

of

common

bacteria

and

methylmercury

-LRB-

MeHg

-RRB-

then

passes

up

the

food

chain

and

becomes

concentrated

in

fish

and

sea

mammals

The

heavy

dependence

of

the

Minamata

inhabitants

on

a

fish

diet

meant

that

they

were

subject

to

high

levels

of

MeHg

exposure

Both

marine

and

freshwater

fish

routinely

contain

low

levels

of

MeHg

as

a

result

of

mercury

leaching

from

the

earth

's

crust

Cases

of

frank

poisoning

have

not

been

recorded

in

fish-eating

populations

other

than

those

in

Minamata

where

special

circumstances

prevailed

However

the

Minamata

findings

raised

questions

about

whether

less

severe

neurologic

effects

might

occur

at

lower

levels

of

exposure

in

populations

whose

diets

were

rich

in

seafood

Given

the

high

level

of

fetal

abnormalities

observed

in

Minamata

-LRB-

Harada

-RRB-

particular

concern

focused

on

the

potentially

hazardous

effects

of

prenatal

exposure

This

concern

increased

after

an

outbreak

of

mercury

poisoning

in

Iraq

in

when

large

numbers

of

people

consumed

bread

made

from

grain

treated

with

a

mercury-based

fungicide

Subsequent

neurologic

examination

of

children

born

to

mothers

who

had

eaten

the

affected

bread

over

a

to

period

suggested

an

increase

in

neurologic

abnormalities

-LRB-

Amin-Zaki

et

al.

-RRB-

Animal

and

other

data

have

indicated

that

the

developing

fetus

is

more

vulnerable

both

to

exposure

to

neuro-toxicants

such

as

heavy

metals

and

to

the

effects

of

such

exposure

-LRB-

Hanson

-RRB-

Any

adverse

effects

are

likely

to

be

structurally

and

functionally

different

from

those

seen

in

the

exposed

adult

Thus

in

addition

to

the

obvious

concern

for

the

health

of

those

with

diets

high

in

seafood

this

issue

has

wider

public

health

implications

in

terms

of

the

general

advisability

of

consuming

seafood

during

pregnancy

The

systematic

investigation

of

potential

developmental

effects

in

children

after

prenatal

exposure

to

MeHg

began

in

the

Since

that

time

two

major

longitudinal

programs

of

work

and

a

number

of

smaller

cross-sectional

studies

have

been

conducted

These

investigations

assessed

levels

of

prenatal

exposure

to

MeHg

in

seafood-eating

populations

and

examined

subsequent

developmental

outcomes

in

children

of

varying

ages

However

despite

considerable

research

effort

over

a

period

of

years

there

remains

a

lack

of

consensus

on

the

central

issue

of

whether

exposure

to

MeHg

derived

from

the

routine

diets

of

pregnant

women

presents

a

risk

to

their

unborn

children

This

article

contributes

to

the

current

debate

on

this

subject

with

a

brief

description

of

the

currently

available

data

some

possible

explanations

for

the

inconclusive

results

that

have

so

far

emerged

and

suggestions

for

potential

ways

forward

in

this

contentious

area

of

research

Current

Evidence

A

search

of

relevant

databases

-LSB-

Medline

-LRB-

-RRB-

Toxfile

-LRB-

-RRB-

Embase

-LRB-

-RRB-

Cancerlit

-LRB-

-RRB-

Biosis

Previews

-LRB-

-RRB-

SciSearch

-LRB-

-RRB-

and

the

Web

of

Science

-LRB-

-RRB-

-RSB-

using

keywords

such

as

methylmercury

prenatal

exposure

child

development

and

neurobehavior

revealed

that

investigations

have

been

published

thus

far

on

this

subject

all

of

which

have

been

conducted

since

These

investigations

have

used

either

neurologic

examinations

developmental

rating

scales

or

psychological

tests

to

evaluate

postnatal

neurologic

effects

in

children

prenatally

exposed

to

MeHg

Nine

of

the

studies

were

cross-sectional

-LRB-

Table

-RRB-

in

the

sense

that

a

sample

of

children

was

tested

on

one

occasion

and

associations

between

test

results

and

a

measure

of

prenatal

exposure

to

MeHg

were

examined

-LRB-

Cordier

et

al.

Grandjean

et

al.

Kjellstrom

Marsh

et

al.

McKeown-Eyssen

et

al.

Murata

et

al.

Steuerwald

et

al.

Stewert

et

al.

Weihe

et

al.

-RRB-

Of

these

cross-sectional

studies

however

one

consisted

of

a

form

of

follow-up

in

that

children

were

tested

at

years

of

age

and

divided

into

comparison

groups

on

the

basis

of

exposure

data

collected

from

their

mothers

soon

after

birth

-LRB-

Crump

et

al.

Kjellstrom

-RRB-

In

addition

the

study

of

Stewert

et

al.

-LRB-

-RRB-

comprised

a

cross-sectional

element

of

a

larger

longitudinal

investigation

concerned

primarily

with

the

adverse

effects

of

prenatal

exposure

to

polychlorinated

biphenyls

-LRB-

PCBs

-RRB-

During

the

course

of

this

investigation

possible

interactions

between

PCB

and

MeHg

exposure

as

determinants

of

adverse

health

effects

were

also

investigated

Sample

sizes

in

the

cross-sectional

studies

ranged

from

to

and

response

rates

from

to

-LRB-

Table

-RRB-

Three

studies

were

longitudinal

in

design

-LRB-

Table

-RRB-

and

followed

children

from

birth

at

intervals

for

several

years

Of

these

the

Faroe

Islands

study

-LRB-

Budtz-Jorgensen

et

al.

Grandjean

et

al.

Murata

et

al.

Weihe

et

al.

-RRB-

commenced

in

with

a

cohort

of

newborn

infants

who

were

subsequently

tested

at

ages

months

years

and

years

Two

further

longitudinal

studies

were

carried

out

in

the

Seychelle

Islands

The

first

commenced

in

with

a

sample

of

newborn

infants

who

were

followed

up

at

age

weeks

months

and

months

-LRB-

Cernichiari

et

al.

Davidson

et

al.

Marsh

et

al.

Myers

et

al.

Shamlaye

et

al.

-RRB-

This

was

considered

a

pilot

study

by

the

authors

although

a

large

amount

of

data

was

collected

of

a

good

standard

and

was

therefore

reported

A

subsequent

study

commenced

in

the

Seychelle

Islands

in

with

a

sample

of

newborns

who

were

followed

up

at

ages

months

months

months

months

and

months

-LRB-

Axtell

et

al.

Cernichiari

et

al.

Cox

et

al.

Crump

et

al.

Davidson

et

al.

Myers

et

al.

Palumbo

et

al.

-RRB-

Sample

sizes

in

the

longitudinal

studies

were

larger

than

those

in

the

cross-sectional

studies

-LRB-

Tables

and

-RRB-

although

there

was

inevitable

attrition

over

the

periods

of

longitudinal

investigation

-LRB-

Table

-RRB-

Exposure

assessment

With

the

exception

of

the

longitudinal

Faroe

Islands

study

and

the

study

of

Steuerwald

et

al.

-LRB-

-RRB-

all

studies

used

maternal

hair

as

the

vehicle

for

measuring

prenatal

exposure

In

the

case

of

the

two

longitudinal

Seychelle

Islands

studies

and

six

of

the

cross-sectional

studies

-LRB-

Kjellstrom

Marsh

et

al.

McKeown-Eyssen

et

al.

Steuerwald

et

al.

Stewert

et

al.

Weihe

et

al.

-RRB-

hair

samples

were

taken

from

the

mothers

at

parturition

However

three

of

the

cross-sectional

studies

used

hair

samples

taken

from

the

mother

and/or

the

child

at

the

time

the

child

was

tested

-LRB-

Cordier

et

al.

Grandjean

et

al.

Murata

et

al.

-RRB-

In

the

study

by

Grandjean

et

al.

-LRB-

-RRB-

for

example

exposure

was

assessed

by

reference

to

MeHg

concentrations

in

maternal

hair

samples

and

where

this

was

not

available

by

reference

to

concentrations

in

the

child

's

hair

at

the

time

of

testing

Dietary

habits

and

social

circumstances

had

changed

little

in

the

community

during

the

previous

years

For

this

reason

maternal

hair

samples

were

judged

likely

to

be

representative

of

parturition

samples

In

addition

child

and

maternal

hair

concentrations

were

highly

correlated

Thus

where

it

was

necessary

to

use

child

hair

samples

these

were

also

regarded

as

representing

an

adequate

proxy

measure

for

maternal

exposure

at

parturition

The

longitudinal

Faroe

Islands

study

and

the

cross-sectional

study

of

Steuerwald

et

al.

-LRB-

-RRB-

used

samples

of

cord

blood

as

well

as

maternal

hair

to

assess

levels

of

prenatal

exposure

All

studies

reported

details

of

quality

control

measures

for

the

analysis

of

samples

However

the

specific

form

of

mercury

included

in

the

measurement

was

not

always

clear

and

a

number

of

different

exposure

metrics

were

employed

-LRB-

Tables

and

-RRB-

Outcome

measurements

A

variety

of

outcome

measures

were

used

that

included

neurologic

examination

developmental

rating

scales

neuropsychological

tests

and

attainment

tests

Although

this

variety

was

accounted

for

partly

by

the

differing

ages

of

the

children

necessitating

different

forms

of

assessment

variation

also

occurred

between

studies

in

terms

of

the

tests

used

for

children

of

the

same

age

group

All

studies

used

tests

or

rating

scales

that

were

established

published

assessment

tools

With

the

exception

of

the

Seychelle

Islands

studies

information

on

testing

procedures

provided

in

the

published

reports

was

rather

limited

and

therefore

difficult

to

evaluate

All

studies

reported

control

of

some

potential

effect

modifiers

such

as

socioeconomic

status

ethnicity

and

parental

IQ

but

the

particular

factors

selected

for

inclusion

varied

between

studies

All

studies

used

multivariate

analysis

techniques

Three

of

the

studies

namely

the

longitudinal

Faroe

Islands

study

and

the

studies

of

Kjellstrom

-LRB-

-RRB-

and

Grandjean

et

al.

-LRB-

-RRB-

reported

a

statistically

significant

relationship

between

prenatal

exposure

to

MeHg

and

at

least

one

developmental

outcome

In

the

case

of

the

Faroe

Islands

study

significant

associations

were

observed

for

the

group

as

a

whole

at

years

of

age

between

MeHg

in

cord

blood

and

some

but

not

all

of

the

outcome

measures

on

six

neurobehavioral

tests

Many

of

these

associations

were

of

borderline

statistical

significance

However

a

dose

response

relationship

between

cord

blood

MeHg

and

some

test

outcomes

was

demonstrated

in

a

subgroup

with

the

highest

MeHg

levels

Initial

analysis

in

the

Kjellstrom

study

-LRB-

-RRB-

did

not

indicate

any

significant

associations

between

test

outcomes

and

MeHg

However

exclusion

of

one

outlier

whose

mother

had

particularly

high

MeHg

levels

resulted

in

the

emergence

of

associations

between

MeHg

and

six

test

outcomes

-LRB-

Crump

et

al.

Kjellstrom

-RRB-

In

the

study

by

Grandjean

et

al.

-LRB-

-RRB-

an

association

between

MeHg

exposure

was

observed

for

three

test

outcomes

No

discernible

pattern

was

evident

in

these

results

in

terms

of

effects

on

particular

tests

Three

further

studies

reported

some

positive

associations

between

MeHg

exposure

and

developmental

outcomes

although

all

qualify

their

conclusions

and

express

some

reservations

about

the

strength

of

their

findings

In

two

of

these

studies

children

were

under

years

of

age

and

assessments

were

in

the

form

of

neurologic

examination

Steuerwald

et

al.

-LRB-

-RRB-

reported

that

examination

of

children

at

weeks

of

age

showed

that

those

with

higher

prenatal

exposures

had

slightly

lower

overall

neurologic

scores

although

there

was

no

discernible

pattern

of

suboptimal

findings

Similarly

McKeown-Eyssen

et

al.

-LRB-

-RRB-

carried

out

neurologic

examinations

on

Cree

Indian

children

between

and

months

of

age

and

found

an

association

between

MeHg

exposure

and

the

prevalence

of

abnormal

muscle

tone

reflexes

in

males

only

The

authors

note

the

mildness

of

the

abnormality

which

they

consider

to

be

of

doubtful

clinical

significance

Cordier

et

al.

-LRB-

-RRB-

in

a

study

of

children

to

years

of

age

found

an

association

between

scores

on

one

test

and

MeHg

exposure

but

this

did

not

appear

in

separate

analysis

of

the

highest

exposure

subgroup

Moreover

results

from

one

test

showed

a

positive

association

with

MeHg

exposure

This

type

of

counterintuitive

result

also

occurred

in

a

study

of

children

years

of

age

-LRB-

Weihe

et

al.

-RRB-

and

in

the

main

Seychelle

Islands

study

when

children

were

assessed

at

months

-LRB-

Davidson

et

al.

-RRB-

Neither

of

these

studies

or

the

first

Seychelle

Islands

study

report

associations

between

other

test

results

and

MeHg

exposure

Similarly

the

results

of

Marsh

et

al.

-LRB-

-RRB-

and

Murata

et

al.

-LRB-

-RRB-

with

children

between

and

years

of

age

indicated

no

associations

between

psychological

test

scores

and

MeHg

exposure

Murata

et

al.

-LRB-

-RRB-

however

demonstrated

an

effect

of

MeHg

exposure

on

two

neurophysiologic

measures

Finally

the

study

of

Stewert

et

al.

-LRB-

-RRB-

of

younger

children

and

months

of

age

reported

an

interactive

effect

of

MeHg

and

PCB

exposure

as

an

incidental

finding

that

emerged

in

the

course

of

a

study

to

investigate

the

adverse

effects

of

PCB

exposure

A

finding

of

this

nature

although

interesting

should

perhaps

be

regarded

as

speculative

only

and

requiring

further

investigation

Our

relatively

brief

review

of

the

literature

highlights

the

current

uncertainty

in

this

field

of

enquiry

The

two

major

longitudinal

investigations

report

contradictory

findings

and

a

number

of

cross-sectional

studies

have

similarly

produced

inconsistent

results

This

data

set

has

already

been

subjected

to

much

examination

-LSB-

National

Research

Council

-LRB-

NRC

-RRB-

-RSB-

and

further

analysis

in

an

attempt

to

derive

appropriate

environmental

exposure

limits

for

pre-natal

MeHg

-LRB-

Office

of

Environmental

Health

Rice

et

al.

-RRB-

The

generally

assumed

superiority

of

longitudinal

over

cross-sectional

designs

has

tended

to

focus

most

attention

on

the

studies

conducted

in

the

Faroes

and

the

Seychelle

Islands

which

are

of

high

methodologic

quality

-LRB-

Jacobson

-RRB-

However

it

should

be

noted

that

given

the

complex

and

challenging

nature

of

this

type

of

research

the

majority

of

the

cross-sectional

studies

are

also

of

relatively

good

quality

and

would

normally

be

taken

into

account

in

a

systematic

review

The

results

of

these

cross-sectional

studies

in

fact

mirror

the

general

inconsistency

evident

in

the

results

of

the

longitudinal

investigations

One

is

therefore

drawn

to

the

conclusion

that

it

is

not

possible

from

currently

available

data

to

determine

whether

prenatal

exposure

to

MeHg

at

levels

routinely

experienced

by

populations

whose

diets

are

rich

in

seafood

results

in

adverse

effects

on

the

nervous

system

of

the

developing

child

Discussion

A

primary

objective

of

the

review

process

is

the

derivation

of

conclusions

from

the

available

data

to

guide

future

policy

In

this

case

however

the

development

of

such

a

policy

would

appear

to

be

hindered

by

the

existence

of

directly

contradictory

results

obtained

from

research

of

equal

quality

As

noted

above

the

data

from

the

studies

contained

in

this

review

have

already

been

the

subject

of

extensive

evaluation

-LRB-

NRC

Rice

et

al.

-RRB-

and

continue

to

excite

controversy

that

is

so

far

unresolved

-LRB-

Davidson

et

al.

Grandjean

and

White

Stern

and

Gochfeld

-RRB-

A

secondary

objective

of

the

review

process

the

identification

of

data

gaps

in

the

literature

appears

inappropriate

in

circumstances

where

so

much

research

has

been

carried

out

to

date

Although

the

contribution

of

existing

published

research

is

unquestioned

it

may

be

time

to

concede

that

there

is

little

further

that

can

be

drawn

from

these

data

or

one

suspects

from

repeated

studies

of

a

similar

type

Experience

from

other

fields

-LRB-

Spurgeon

-RRB-

suggests

that

further

cross-sectional

studies

employing

similar

neurobehavioral

outcomes

will

serve

only

to

increase

rather

than

reduce

the

uncertainty

surrounding

this

issue

In

the

remainder

of

this

article

therefore

I

discuss

some

of

the

possible

reasons

for

the

inconsistency

in

the

existing

data

and

indicate

some

areas

where

alternative

approaches

might

be

required

to

achieve

some

progress

in

this

field

The

common

objective

of

the

investigations

reviewed

above

was

to

establish

whether

there

is

an

association

between

prenatal

exposure

to

MeHg

and

developmental

effects

Although

the

various

studies

had

many

elements

in

common

perhaps

the

most

noticeable

feature

of

the

studies

as

a

group

was

the

variation

in

the

methods

used

to

assess

the

two

basic

elements

of

the

association

namely

the

exposure

and

the

effect

It

is

not

surprising

that

research

using

different

combinations

of

biological

and

psychological

measures

produces

inconsistent

results

The

debate

surrounding

each

of

these

elements

although

undoubtedly

complex

merits

resolution

in

advance

of

any

further

research

Exposure

In

terms

of

the

most

appropriate

biological

marker

of

prenatal

exposure

opinion

is

divided

between

maternal

hair

and

cord

blood

as

the

biological

sample

of

choice

Studies

that

have

attempted

to

define

the

relationship

between

different

biological

indices

have

produced

inconsistent

and

somewhat

wide-ranging

results

and

conversion

from

one

set

of

values

to

another

appears

to

involve

a

number

of

questionable

assumptions

-LRB-

Office

of

Environmental

Health

-RRB-

Other

difficulties

in

the

interpretation

of

the

data

set

arise

as

a

result

of

the

use

of

different

units

of

measurement

and

a

lack

of

clarity

in

some

studies

about

whether

the

measure

is

of

organic

inorganic

or

total

mercury

concentration

Thus

there

is

continuing

uncertainty

about

the

association

between

elements

of

the

diet

and

concentrations

in

child

hair

maternal

hair

cord

blood

and

maternal

blood

as

well

as

uncertainty

about

the

strength

of

any

relationship

between

each

of

these

elements

and

the

relationship

between

each

and

the

actual

exposure

of

the

fetus

Elements

of

the

debate

about

hair

versus

blood

samples

must

be

linked

to

a

large

number

of

other

unanswered

questions

surrounding

prenatal

exposure

measurement

These

relate

particularly

to

the

relative

importance

of

exposure

at

different

periods

of

gestation

the

relationship

between

these

and

average

exposures

and

the

importance

of

peak

exposures

The

development

of

the

central

nervous

system

is

time

related

and

unidirectional

The

inhibition

of

one

stage

of

development

tends

to

cause

alterations

to

subsequent

processes

with

limited

capacity

for

compensation

for

cell

loss

-LRB-

Annau

and

Eccles

Trask

and

Kosofsky

-RRB-

Both

the

dose

and

timing

of

any

environmental

insult

are

important

in

terms

of

the

specific

nature

of

any

adverse

effects

How

far

do

our

current

methods

of

prenatal

exposure

assessment

reflect

the

need

to

take

this

into

account

The

present

enthusiasm

for

evidence-based

policy

and

practice

appears

to

offer

an

ideal

opportunity

to

address

these

types

of

questions

either

through

the

medium

of

an

expert

workshop

or

that

of

a

written

systematic

review

The

important

issues

in

either

process

include

a

-RRB-

definition

of

the

important

questions

to

be

addressed

to

achieve

valid

and

reliable

assessment

of

prenatal

exposure

b

-RRB-

identification

of

available

data

that

could

be

used

to

answer

these

questions

and

c

-RRB-

identification

of

new

research

required

to

fill

any

identified

data

gaps

In

advance

of

some

consensus

on

these

issues

further

research

is

likely

to

provoke

more

controversy

rather

than

lead

to

any

resolution

of

the

current

uncertainty

Outcomes

The

outcomes

used

in

these

studies

were

predominantly

psychological

tests

Use

of

such

tests

in

environmental

and

occupational

health

research

which

began

in

the

early

has

always

been

controversial

and

the

apparent

inconsistencies

in

the

data

produced

has

provoked

much

debate

in

both

environmental

and

occupational

health

research

-LRB-

Koller

et

al.

Levy

et

al.

-RRB-

Results

relating

to

prenatal

MeHg

exposure

represent

a

particular

example

of

a

wider

problem

and

highlight

a

number

of

questions

related

to

the

more

general

field

of

neurobehavioral

toxicology

Specifically

two

main

areas

are

of

concern

The

first

and

perhaps

the

more

straightforward

relates

to

the

control

of

variables

that

either

represent

potential

confounders

or

may

act

as

modifiers

of

the

effects

under

investigation

-LRB-

Spurgeon

and

Gamberale

-RRB-

They

are

perhaps

best

considered

under

the

broad

headings

of

situational

variables

-LRB-

physical

testing

conditions

and

test

procedures

-RRB-

tester

variables

-LRB-

reliability

of

the

examiners

-RRB-

and

subject

variables

-LRB-

individual

characteristics

such

as

age

gender

and

socioeconomic

group

-RRB-

In

all

epidemiologic

research

involving

psychological

testing

the

list

of

these

variables

is

potentially

very

long

and

researchers

appear

divided

about

which

to

include

In

research

on

MeHg

the

majority

of

studies

consider

important

subject

characteristics

such

as

age

ethnic

and

socioeconomic

group

and

aspects

of

parental

lifestyle

However

for

a

number

of

other

variables

-LRB-

e.g.

aspects

of

the

caregiving

environment

-RRB-

inclusion

is

patchy

For

many

of

these

variables

useful

literature

is

available

on

their

effects

on

children

's

abilities

or

on

test

performance

and

it

may

be

possible

to

reach

an

evidence-based

consensus

on

their

inclusion

or

exclusion

For

other

mainly

procedural

factors

data

appear

relatively

scarce

A

systematic

review

that

encompasses

other

areas

of

psychology

for

example

that

pertaining

to

human

computer

interaction

might

reveal

relevant

information

For

example

how

much

does

the

size

of

the

screen

affect

performance

on

a

computer-administered

test

How

much

does

the

physical

location

of

testing

-LRB-

home

laboratory

hospital

-RRB-

affect

test

performance

Existing

data

on

the

effects

of

time

of

day

-LRB-

Smith

-RRB-

for

example

indicate

that

in

epidemiologic

studies

this

factor

should

always

be

controlled

Intuitively

it

would

seem

appropriate

that

the

physical

testing

situation

and

procedures

should

be

standardized

for

all

subjects

as

far

as

is

practically

possible

regardless

of

whether

firm

evidence

exists

about

the

influence

of

heating

lighting

noise

control

or

the

arrangement

of

furniture

Less

well-researched

aspects

of

the

test

situation

can

be

explored

usefully

within

the

researchers

data

Is

there

for

example

a

significant

difference

between

test

scores

obtained

at

the

beginning

and

at

the

end

of

the

week

or

at

different

times

of

the

year

The

effects

of

the

tester

particularly

where

tests

are

not

computer-administered

may

be

important

not

only

because

of

different

interactions

with

different

subjects

but

also

because

of

the

examiner

's

variable

moods

motivation

levels

of

fatigue

and

tendency

to

introduce

systematic

errors

into

the

testing

procedure

It

can

not

be

assumed

that

confining

testing

to

one

examiner

or

using

examiners

who

have

undergone

a

single

period

of

training

removes

tester

variation

In

terms

of

reliability

it

may

be

advantageous

to

employ

more

than

one

tester

in

some

circumstances

Measures

such

as

the

videotaping

of

testing

procedures

double

scoring

and

examination

of

the

test

data

for

trends

related

to

some

of

these

factors

have

all

been

used

to

account

for

or

eliminate

this

potential

source

of

variation

-LRB-

Harvey

et

al.

-RRB-

Similarly

some

estimation

albeit

a

subjective

rating

of

the

child

's

level

of

co-operation

with

the

testing

procedure

is

important

to

include

Potentially

this

is

a

major

source

of

variation

in

test

performance

rarely

alluded

to

in

published

reports

Ideally

tests

should

also

include

parallel

forms

or

practice

trials

to

ensure

that

maximal

performance

level

is

recorded

for

each

subject

All

except

one

of

the

studies

in

the

field

of

research

under

discussion

here

present

detailed

accounts

of

quality

control

procedures

in

relation

to

MeHg

assessment

It

is

relatively

rare

to

find

equally

detailed

discussion

of

procedures

for

outcome

assessment

This

is

a

situation

that

occurs

frequently

in

neurobehavioral

investigations

Lack

of

reference

to

quality

control

does

not

necessarily

imply

that

control

was

limited

but

may

suggest

something

about

the

attitude

of

researchers

toward

its

importance

The

implications

for

further

research

are

First

systematic

work

is

needed

on

the

effects

of

factors

considered

likely

to

affect

test

performance

including

both

a

review

of

the

available

data

and

if

necessary

further

investigative

work

Second

consensus

must

be

reached

on

good

practice

such

as

that

available

in

some

other

areas

of

toxicology

notably

animal

experimentation

Although

this

consensus

may

exist

at

an

informal

level

in

the

field

the

considerable

methodologic

variations

between

different

neurobehavioral

studies

suggest

that

many

aspects

are

currently

opinion

based

rather

than

evidence

based

A

second

and

fundamental

issue

in

terms

of

outcome

measures

relates

to

the

types

of

tests

used

and

by

implication

the

interpretation

of

the

results

they

provide

and

the

comparability

of

these

between

studies

The

tests

employed

in

the

studies

described

above

are

mainly

tests

of

intellectual

functioning

However

those

used

in

different

studies

and

sometimes

within

the

same

study

derive

from

a

number

of

separate

traditions

of

intellectual

assessment

each

of

which

was

developed

for

a

different

purpose

and

different

client

group

Although

each

has

some

advantages

were

developed

specifically

for

neurotoxicity

research

and

is

entirely

appropriate

for

this

type

of

application

Attainment

tests

are

attractive

in

the

sense

that

they

offer

the

opportunity

to

benchmark

the

performance

of

children

in

basic

skills

such

as

literacy

and

numeracy

against

that

of

their

peers

However

such

tests

tend

to

reflect

the

use

of

abilities

rather

than

the

underlying

abilities

themselves

Given

the

range

of

social

and

educational

factors

interacting

with

the

ability

to

produce

attainment

this

effectively

introduces

additional

variables

into

the

equation

-LRB-

Gadzella

et

al.

-RRB-

In

contrast

the

neuropsychological

approach

characterized

for

example

by

tests

such

as

the

Trailmaking

test

used

in

the

Seychelle

Islands

study

or

the

Bender

Gestalt

test

used

in

the

Faroes

Islands

study

was

developed

to

provide

detailed

evaluation

of

patients

with

suspected

damage

to

the

brain

Such

damage

might

have

resulted

from

head

injury

or

other

insult

or

from

a

degenerative

disease

of

the

nervous

system

In

these

circumstances

the

purpose

of

assessment

is

to

provide

detailed

information

about

the

nature

of

the

problem

in

functional

terms

and

thus

provide

a

basis

for

rehabilitation

and

progress

monitoring

Assessment

in

a

clinical

setting

tends

to

be

a

flexible

process

that

draws

as

much

on

the

qualitative

aspects

of

the

interaction

between

psychologist

and

client

as

it

does

on

the

numerical

test

scores

The

clinician

is

interested

in

the

patient

as

an

individual

and

reaches

a

professional

judgment

on

the

basis

of

a

number

of

sources

of

information

There

is

a

risk

that

tests

of

this

nature

lose

much

of

their

value

when

applied

in

a

routine

fashion

to

large

groups

of

people

Many

who

work

in

the

field

of

clinical

neuropsychology

appear

to

be

deeply

uneasy

about

the

transfer

of

these

techniques

to

an

epidemiologic

setting

-LRB-

British

Psychological

Society

-RRB-

Particular

concern

arises

when

tests

designed

for

administration

by

a

psychologist

are

adapted

for

computer

presentation

Researchers

with

a

neuropsychological

background

tend

to

adopt

a

clinical

approach

by

administering

a

very

large

battery

of

tests

to

cover

all

aspects

of

functioning

-LRB-

Davidson

et

al.

Grandjean

et

al.

Kjellstrom

-RRB-

In

an

epidemiologic

setting

this

can

be

inappropriate

resulting

in

multiple

comparisons

and

the

possibility

of

chance

findings

Moreover

it

often

leads

to

confusion

from

a

psychological

point

of

view

where

the

results

appear

as

a

collection

of

apparently

unconnected

findings

with

no

discernible

meaningful

pattern

Where

studies

use

the

same

tests

it

is

common

for

significant

associations

to

appear

in

both

studies

but

in

relation

to

different

outcomes

-LRB-

Grandjean

et

al.

-RRB-

Finally

there

are

questions

about

the

ability

of

tests

designed

for

more

severely

affected

patient

groups

to

detect

relatively

subtle

effects

in

community

samples

-LRB-

Spurgeon

Stollery

-RRB-

Tests

derived

from

a

psychometric

tradition

are

concerned

with

the

assessment

of

intelligence

quotients

-LRB-

IQ

-RRB-

in

the

general

population

and

were

originally

developed

to

describe

normal

distributions

of

cognitive

functioning

The

Wechsler

Scale

-LRB-

Wechsler

-RRB-

represents

the

most

widely

used

test

battery

in

this

respect

Developmental

scales

for

very

young

children

fit

within

this

tradition

replacing

formal

testing

where

this

is

impractical

although

it

should

be

noted

that

maternal

reports

of

developmental

milestones

are

subject

to

numerous

sources

of

error

such

as

inaccurate

recall

differing

definitions

of

certain

behaviors

and

presentational

bias

-LRB-

Axelson

and

Rylander

-RRB-

The

measurement

of

IQ

is

a

reassuringly

familiar

concept

supported

by

a

wealth

of

normative

data

and

experience

built

up

over

many

years

Unfortunately

IQ

tests

were

originally

developed

within

a

theoretical

framework

of

cognitive

functioning

that

prevailed

more

than

a

half-century

ago

Such

tests

reflected

a

contemporary

need

to

categorize

individuals

on

a

quantitative

scale

to

predict

future

performance

an

approach

now

considered

somewhat

crude

and

simplistic

Although

such

tests

maintain

their

predictive

validity

in

some

settings

-LRB-

Neisser

et

al.

-RRB-

they

are

relatively

blunt

instruments

that

combine

a

number

of

different

abilities

within

each

test

-LRB-

Lezak

-RRB-

This

aspect

limits

the

information

that

can

be

derived

from

the

assessment

and

makes

interpretation

difficult

when

conflicting

results

emerge

from

different

studies

When

placed

in

the

context

of

more

recent

theoretical

developments

in

cognitive

psychology

established

IQ

tests

do

not

provide

results

that

can

be

easily

linked

to

current

models

of

cognitive

processes

A

primary

objective

of

neurobehavioral

research

is

the

detection

of

subtle

effects

on

cognitive

functioning

in

community

samples

after

neurotoxicant

exposure

For

epidemiologic

purposes

tests

should

be

quick

and

easy

to

administer

The

results

should

be

interpretable

at

group

level

and

comparable

between

different

studies

Given

these

criteria

of

the

tests

currently

in

use

appear

to

be

entirely

fit

for

this

purpose

Speed

and

ease

of

administration

do

not

represent

major

challenges

in

an

age

of

advanced

information

technology

However

improvements

in

interpretability

and

comparability

are

more

complex

issues

likely

to

require

a

radical

change

of

approach

In

recent

years

a

number

of

authors

have

pointed

to

the

overemphasis

on

empiricism

in

this

field

and

the

lack

of

a

strong

theoretical

underpinning

for

the

assessment

tools

employed

-LRB-

Stephens

and

Barker

Stollery

Williamson

-RRB-

The

development

of

tests

grounded

in

well-established

cognitive

theory

would

allow

results

to

be

discussed

in

terms

of

the

specific

aspects

of

cognitive

processing

under

investigation

rather

than

simply

by

reference

to

broad

and

largely

uninformative

categories

of

effect

such

as

memory

or

attention

Modern

approaches

to

the

study

of

memory

processes

for

example

have

long

distinguished

between

several

elements

that

contribute

to

the

final

outcome

-LRB-

initial

registration

of

information

encoding

transfer

to

long-term

store

loss

of

information

by

decay

or

interference

and

use

of

cues

for

retrieval

-RRB-

-LRB-

Baddeley

-RRB-

Each

may

be

differentially

susceptible

to

neurotoxic

insult

but

effects

on

one

specific

process

can

not

be

uncovered

by

most

current

tests

that

provide

a

simple

global

outcome

score

Moreover

overall

scores

may

mask

specific

effects

where

subjects

employ

compensatory

strategies

among

different

processes

to

achieve

maximum

performance

The

development

of

tests

for

both

children

and

adults

based

on

techniques

currently

available

to

separate

and

measure

these

specific

processes

would

provide

much

more

useful

information

about

the

nature

and

size

of

any

observed

effect

This

type

of

approach

would

ultimately

pave

the

way

for

much

greater

comparability

between

the

results

of

different

investigations

and

for

the

development

of

comparable

assessment

techniques

for

children

at

different

ages

during

longitudinal

investigations

Despite

much

international

effort

during

the

last

years

agreement

on

a

universally

approved

set

of

tests

has

proved

elusive

-LRB-

World

Health

Oganization

-RRB-

At

the

same

time

the

pursuit

of

the

goal

to

achieve

comparability

over

time

and

between

studies

has

tended

to

inhibit

the

development

of

new

techniques

It

seems

unlikely

that

consensus

on

appropriate

assessment

tools

will

be

achieved

in

advance

of

a

consensus

on

the

theoretical

basis

for

those

tools

Fortunately

much

of

the

information

required

for

these

new

developments

is

readily

available

in

the

existing

cognitive

experimental

and

developmental

psychology

literature

Conclusion

Reviews

of

the

data

relating

to

the

developmental

effects

of

prenatal

MeHg

exposure

have

highlighted

the

inconsistency

of

the

currently

available

evidence

The

size

and

nature

of

the

risk

to

children

that

is

associated

with

seafood

consumption

by

their

mothers

remains

uncertain

and

a

source

of

considerable

controversy

It

has

been

argued

here

that

the

present

uncertainty

derives

from

the

variation

between

studies

in

the

methods

used

to

measure

both

the

exposure

and

the

effect

Each

element

would

merit

further

consideration

in

advance

of

any

future

research

in

this

field

Although

consensus

is

required

on

the

appropriate

biological

marker

of

exposure

there

is

also

a

particular

need

to

address

issues

of

both

procedure

and

content

in

psychological

assessment

Discussion

of

these

issues

particularly

those

relating

to

psychological

tests

may

have

implications

that

go

well

beyond

the

immediate

needs

of

this

field

of

inquiry

Investigation

of

the

effects

of

MeHg

provides

one

particular

example

of

the

difficulties

in

data

interpretation

that

occur

repeatedly

in

neurobehavioral

studies

and

threaten

to

undermine

confidence

in

this

methodology

The

increasing

international

anxiety

about

potential

adverse

effects

of

low-level

neurotoxicant

exposure

in

the

environment

underlines

the

importance

of

addressing

these

concerns

as

psychological

methods

currently

represent

one

of

the

main

tools

of

research

in

this

field

O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

developmental outcomes
methylmercury
neurobehavioral tests
prenatal exposure


Twenty-Four Hour Tonometry in Patients Suspected of Chronic Gastrointestinal Ischemia Background and aims Gastrointestinal tonometry is currently the only clinical diagnostic test that enables identification of symptomatic chronic gastrointestinal ischemia . Gastric exercise tonometry has proven its value for detection of ischemia in this patients group , but has its disadvantages . Earlier studies with postprandial tonometry gave unreliable results . In this study we challenged -LRB- again -RRB- the use of postprandial tonometry in patients suspected of gastrointestinal ischemia . Introduction In patients presenting with postprandial pain , especially when associated with weight loss and positive history for cardiovascular diseases , chronic gastrointestinal ischemia -LRB- CGI -RRB- should be among the differential diagnosis -LSB- 1 -- 3 -RSB- . Vascular anatomic abnormalities can be demonstrated with duplex ultrasound or angiography . However , a stenosis does not necessarily imply ischemia , due to the abundant collateral circulation . We have recently demonstrated that gastric exercise tonometry -LRB- GET -RRB- allows differentiation between patients with and without gastrointestinal ischemia . GET showed an accuracy of 87 % in detection of gastrointestinal ischemia . The patients selected for treatment using GET , are likely to benefit from revascularization techniques -LSB- 4 -- 9 -RSB- . Gastric -LRB- exercise -RRB- tonometry is not widely accepted as a diagnostic technique for gastrointestinal ischemia due to the lack of familiarity with this approach and its time-consuming nature . Twenty-four hour gastrointestinal tonometry with meals is more familiar -LRB- resembling 24-h pH measurement -RRB- and easier to perform . Over 90 % of CGI patients report postprandial , while only 60 % report exercise-related , complaints . Ischemic pain after meals in CGI is caused by insufficient increase of postprandial blood flow to balance the increased metabolic demand of the gastrointestinal tract -LSB- 10 -RSB- . This indicates that tonometry directly after meals would be the most physiologic approach of measuring ischemia in these patients . However , earlier studies showed unreliable results using tonometry after meals , related to insufficient suppression of gastric acid secretion and dilution effects -LSB- 11 -- 13 -RSB- . We therefore started by testing standard meals in vitro and performed a study with healthy subjects using these meals and high-dose proton pump inhibition -LRB- PPI -RRB- as an optimal gastric acid suppressant -LSB- 14 -RSB- . In this study we retrospectively evaluated the additional value of prolonged gastrointestinal tonometry in a group of patients suspected for possible CGI . Methods Patients with unexplained chronic abdominal symptoms who were referred for suspected CGI were included in this study . More-common causes of chronic abdominal symptoms had been excluded previously by appropriate diagnostic evaluation . All patients had imaging of the splanchnic arteries -LSB- intra-arterial digital substraction multiplane abdominal angiography -LRB- DSA -RRB- and duplex ultrasound scanning -RSB- and GET . Along with this standard diagnostic work up , patients had twenty-four hour -LRB- 24 h -RRB- tonometry testing , directly following GET . Gastric exercise tonometry -LRB- GET -RRB- GET was performed using a standardized protocol , before , during , and after 10 min of submaximal exercise , as described previously with both gastric and jejunal catheters -LSB- 15 -RSB- . A maximal gradient was calculated between stomach and arterial PCO2 . The criteria for a positive GET -LRB- all three required -RRB- , established in healthy volunteers and a patient cohort , were : -LRB- 1 -RRB- a gradient of > 0.8 kPa in the stomach after exercise , -LRB- 2 -RRB- an increase in gastric PCO2 , and -LRB- 3 -RRB- an arterial lactate < 8 mmol/l -LSB- 8,15 -RSB- . Twenty-four hour tonometry testing A gastric and jejunal tonometer catheter -LRB- 8 French , Datex Ohmeda , Helsinki , Finland -RRB- and a gastric pH meter -LRB- pHersaflexTM , internal reference , Medical Measurement Systems , Enschede , the Netherlands -RRB- were inserted nasogastrically using fluoroscopy . Intravenous infusion of omeprazole was started with a bolus of 80 mg in 30 min , followed by 8 mg/h , using an infusion pump -LRB- Perfusor compact ® , B Braun Melsungen AG , Melsungen , Germany -RRB- . The catheters were connected , respectively , to the Tonocap -LRB- Datex Ohmeda , Helsinki , Finland -RRB- and the pH recording device -LRB- Medical Measurement Systems , Enschede , the Netherlands -RRB- . The Tonocaps were connected to a computer on which a data-collection program automatically registered the gastric and jejunal PCO2 level every 10 min . The gastric pH was automatically recorded and stored in a datalogger -LRB- Medical Measurement Systems , Enschede , the Netherlands -RRB- , which also allows for real-time reading of the gastric pH. As soon as the gastric pH was > 4.0 for ≥ 30 min , the first meal was started -LRB- t = 0 min -RRB- . All patients had meals at standard times : breakfast I -LRB- 08:00 -RRB- , dinner -LRB- 12:00 -RRB- , liquid compound meal I -LRB- 15:00 -RRB- , bread meal -LRB- 18:00 -RRB- , liquid compound meal II -LRB- 21:00 -RRB- , and breakfast II -LRB- 08:00 the next day -RRB- . The breakfast , bread , and dinner meals were standardized . The liquid compound meal consisted of two packages of 200 ml each -LRB- Nutridrink ® , Nutricia , The Netherlands -RRB- . The contents and caloric density of each meal used are presented in Table 1 . The patients were instructed to eat their meals within 15 min . The consumption of small amounts of liquids -LRB- noncarbonated -RRB- was allowed and noted , consumption of alcohol - , acid - , and CO2-containing beverages was strictly prohibited . Due to the limited length of the catheters , the subjects were only capable of performing very minor exercise and were allowed to lie down in supine position from 22:00 . Table 1Composition characteristics of the various standard mealsMealCompositionkcal/gBreakfast Fat -LRB- 16 % -RRB- , proteins -LRB- 22 % -RRB- , carbohydrates -LRB- 62 % -RRB- 1.7 DinnerFat -LRB- 16 % -RRB- , proteins -LRB- 47 % -RRB- , carbohydrates -LRB- 37 % -RRB- 2.2 Bread mealFat -LRB- 10 % -RRB- , proteins -LRB- 19 % -RRB- , carbohydrates -LRB- 71 % -RRB- 1.8 Compound solutionFat -LRB- 35 % -RRB- , proteins -LRB- 16 % -RRB- , carbohydrates -LRB- 49 % -RRB- 1.5 Percentages of delivered energy -LRB- En % -RRB- ; kcal = kilocalories ; g = gram . Diagnosis and treatment The results of all diagnostic procedures were discussed in a multidisciplinary team . In this team a gastroenterologist , a vascular surgeon , and an interventional radiologist discussed the symptoms , medical history , physical examination , and all diagnostic evaluations , with the exception of the results on 24-h tonometry . The latter therefore did not influence the consensus diagnosis . The multidisciplinary team decided for every patient : -LRB- 1 -RRB- no splanchnic stenosis , -LRB- 2 -RRB- splanchnic stenosis and no ischemia or -LRB- 3 -RRB- splanchnic stenosis and ischemia -LRB- i.e. chronic gastrointestinal ischemia , CGI -RRB- . The gold standard for the diagnosis of chronic gastrointestinal ischemia was a positive outcome after successful revascularization at -LRB- long-term -RRB- follow-up . The outcome of GET , and consensus diagnosis of the multidisciplinary team were compared to the results of the 24-h tonometry testing . Definition of a positive -LRB- abnormal -RRB- 24 h tonometry The cut-off values established in the previous healthy subjects study were used to define the criteria for the results on 24-h tonometry -LSB- 9 -RSB- . These cut-off values were , for the stomach : 12.1 , 11.4 , and 11.3 kPa for the breakfast -LRB- or bread meal -RRB- , dinner , and compound solution meals , respectively ; in the jejunum these threshold values were , respectively , 12.0 , 13.6 , and 10.6 kPa . The criteria for a positive finding -LRB- abnormal result -RRB- on 24-h tonometry were : -LRB- 1 -RRB- pathologic responses after three or more -LRB- standard -RRB- meals , or -LRB- 2 -RRB- a combination of one or two pathologic responses after -LRB- standard -RRB- meals combined with a median PCO2 > 8.0 kPa , measured in between meals . Statistics Data were expressed as mean -LRB- standard deviation -RRB- or median -LRB- range -RRB- when appropriate . The data of the ischemic and non-ischemic patients were compared using Student 's t-test or χ2 testing . Sensitivity , specificity as well as positive and negative predicted values of 24-h tonometry were calculated with the consensus diagnosis as the gold standard . Results Patient characteristics In a period of three years -LRB- 2002 -- 2005 -RRB- , in 37 patients referred for suspected of CGI , 24-h tonometry along with the standard work-up was performed . Of these , 33 -LRB- 89 % -RRB- patients had complete work-up and were included in this study . Mean age was 54 -LRB- 22 -- 82 -RRB- years , with eight males and 25 females . Significant splanchnic stenosis were found in 23/33 -LRB- 69 % -RRB- patients . A significant single vessel splanchnic stenosis was found in 14/33 -LRB- 42 % -RRB- patients -LSB- 13 celiac artery -LRB- CA -RRB- and one superior mesenteric artery -LRB- SMA -RRB- -RSB- . A significant stenosis of two splanchnic arteries was found in 9/33 -LRB- 27 % -RRB- patients -LRB- all CA and SMA stenosis -RRB- . All 33 patients had chronic abdominal pain for a mean of 35 months -LRB- range 3 -- 120 -RRB- , 24/33 -LRB- 73 % -RRB- patients had pain following meals , 11/33 -LRB- 33 % -RRB- patients reported pain during or after exercise , 9/33 -LRB- 27 % -RRB- patients reported both pain following meals and during , or after , exercise , and 23/33 -LRB- 70 % -RRB- patients reported weight loss . The mean weight loss was 11 kg -LRB- range 3 -- 28 kg -RRB- in 17 months -LRB- range 2 -- 120 months -RRB- ; see Table 1 . Gastric exercise tonometry In 18/31 -LRB- 58 % -RRB- patients a gradient of > 0.8 was found by GET . In 14/18 -LRB- 78 % -RRB- patients this increased gradient was defined as abnormal using the three criteria as previously defined . In four patients a gradient > 0.8 kPa was not caused by ischemia : three patients had persistent acid production , and one performed excessive exercise -LRB- leading to false positive findings -RRB- -LSB- 8 -RSB- . Consensus diagnosis of the multidisciplinary team and results after treatment According to the team the diagnosis of no stenosis -LRB- and no ischemia -RRB- , stenosis but no ischemia , and stenosis with ischemia -LRB- CGI -RRB- was diagnosed in , respectively , 12 -LRB- 36 % -RRB- , four -LRB- 12 % -RRB- and 17 -LRB- 52 % -RRB- patients . Fifteen patients diagnosed with CGI had treatment : 10 patients surgical and five patients stent-placement therapy . Three patients had no treatment : two patients preferred a conservative approach and one patient proved inoperable due to comorbidity . After a mean follow-up of 55 months -LRB- 49 -- 85 -RRB- , 12 out of 15 -LRB- 80 % -RRB- patients were free of complaints , one patient died immediately after surgical revascularization -LRB- multiple organ failure -RRB- , one patient had partial improvement , and one patient had persistent complaints . The latter patient had a celiac artery release , and was diagnosed as having no CGI after follow-up ; this patient had no abnormalities on 24-h tonometry testing ; see Table 2 . Table 2Patient characteristics , results of diagnostic tests and conclusionNrAgeSexStenosisPP painPE painGET resultsConsensus diagnosisTreatmentOutcome complaintsFinal conclusion24-h tono results161FNone + − 0,5 No stenosis , no ischemia -- No stenosis , no ischemiaNormal236MCA + − 0,4 No ischemia -- No ischemiaNormal355FCA + − 0,7 aCGISurgeryFreeCGIAbnormal476MNone − − 0,6 No stenosis , no ischemia -- No stenosis , no ischemiaNormal547MNone − +1,6 bNo stenosis , no ischemia -- No stenosis , no ischemiaNormal642FCA + SMA − − 1,5 CGISurgeryFreeCGIAbnormal765FCA + SMA − − 2,0 CGIConservativeCGIAbnormal877FCA + SMA + − 2,2 CGISurgeryDied post-op . CGIAbnormal972FSMA + +1,8 CGIStentFreeCGIAbnormal1041MNone + − 2,8 cNo stenosis , no ischemia -- No stenosis , no ischemiaNormal1172FCA + − 1,4 CGIStentPartial relieveCGIAbnormal1267FCA − − 0,9 cNo stenosis , no ischemia -- No ischemiaNormal1340FCA − +1,1 cCGISurgeryUnchangedNo ischemiaNormal1482MCA + SMA + +1,0 CGIConservativeCGINormal1554FCA + +0,9 CGIConservativeCGINormal1626MCA + +1,0 CGISurgeryFreeCGIAbnormal1758MNone + +2,2 cNo stenosis , no ischemia -- No stenosis , no ischemiaNormal1822FCA + − 0,7 No ischemia -- No ischemiaNormal1942FNone + − 1,1 dNo stenosis , no ischemia -- No stenosis , no ischemiaNormal2048FCA + − 1,7 CGISurgeryFreeCGINormal2151FCA + − 0,7 No ischemia -- No ischemiaNormal2243FCA + SMA + +0,5 eCGISurgeryFreeCGIAbnormal2354FCA + SMA − − 1,5 CGISurgeryFreeCGINormal2476FCA + SMA + − 0,6 fCGIStentFreeCGIAbnormal2553MNone + − 2,0 cNo stenosis , no ischemia -- No stenosis , no ischemiaNormal2653FCA + +1,1 CGIStentFreeCGIAbnormal2750FCA − − 1,3 CGISurgeryFreeCGIAbnormal2861FCA + SMA + +1,7 CGIStentFreeCGIAbnormal2963FNone + − 0,8 No stenosis , no ischemia -- No stenosis , no ischemiaNormal3024FCA + +1,3 CGISurgeryFreeCGIAbnormal3174FCA + SMA − − 0,8 No ischemia -- No ischemiaNormal3241FNone + − 1,2 dNo stenosis , no ischemia -- No stenosis , no ischemiaNormal3363FNone + − 0,0 No stenosis , no ischemia -- No stenosis , no ischemiaAbnormalPP = postprandial , PE = post-exercise , M = male , F = female ; CA = celiac artery , SMA = superior mesenteric artery ; GET = gastric exercise tonometry , result presented as gradient -LRB- in kPa -RRB- ; 24-h tono = twenty-four hour tonometry ; CGI = chronic gastrointestinal ischemia.a false negative GETb acid production during GETc false positive GETd no CO2 raise during GETe abnormal jejunal gradient during GETf minor exercise during GET Twenty-four hour tonometry The 24-h tonometry was well tolerated in all patients , no medical or technical problems occurred . In 28/33 -LRB- 85 % -RRB- patients tonometric measurements were performed in both stomach and jejunum , in 5/33 -LRB- 15 % -RRB- patients only stomach measurements were performed -LRB- in all five patients placement of jejunal tonometry catheter failed -RRB- ; see Fig. 1 . In 8/33 -LRB- 24 % -RRB- patients a dose reduction of the compound solution was necessary , due to patient 's inability to consume the normal dosage . The overall gastric acid suppression was good , with a gastric pH > 4 during 94.8 % -LRB- range 71 -- 100 % -RRB- of the time . Pathological peaks during 24-h tonometry coexisting with periods of pH < 4 , were defined as non-pathologic peaks . Fig. 1 Individual curves of results of 24-h tonometry in a non-ischemic -LRB- A -RRB- and an ischemic patient -LRB- B -RRB- . Individual curves of a non-ischemic patient -LRB- A -RRB- and an chronic gastrointestinal ischemia patient -LRB- B -RRB- ; on the horizontal axis the time from 0 to 24 h , on the vertical axis PCO2 from 0 to 20 in kilopascal -LRB- kPa -RRB- ; curves : PCO2 values measured every 10 min in stomach -LRB- □ -RRB- , jejunum -LRB- × -RRB- and four meals spread over the 24 h period -LRB- * -RRB- The fasting baseline of stomach and jejunal PCO2 measurements were significantly higher in the ischemic patients compared to the non-ischemic patients group . The jejunal PCO2 peaks after breakfast and dinner were significantly higher in the ischemic patients compared to the non-ischemic patients ; see Tables 3 and 4 . Table 3Results of 24-h tonometry in ischemic and non-ischemic patientsCGI pts.Non-ischemic pts.PeakΔ-peakMean PCO2PeakΔ-peakMean PCO2StomachB10 .6 -LRB- 3.9 -RRB- 4.0 -LRB- 3.4 -RRB- -- 8.5 -LRB- 2.7 -RRB- 2.6 -LRB- 2.0 -RRB- -- D9 .9 -LRB- 1.9 -RRB- 3.7 -LRB- 1.5 -RRB- -- 8.5 -LRB- 2.3 -RRB- 3.3 -LRB- 2.5 -RRB- -- CS10 .4 -LRB- 3.0 -RRB- 3.3 -LRB- 2.2 -RRB- -- 8.1 -LRB- 2.6 -RRB- 1.8 -LRB- 1.2 -RRB- -- Fasting -- -- 7.7 -LRB- 1.4 -RRB- a -- -- 6.8 -LRB- 0.7 -RRB- Day -- -- 6.9 -LRB- 1.1 -RRB- -- -- 6.5 -LRB- 0.7 -RRB- Night -- -- 8.2 -LRB- 1.8 -RRB- -- -- 6.9 -LRB- 0.8 -RRB- JejunumB11 .6 -LRB- 3.2 -RRB- b3 .2 -LRB- 1.5 -RRB- -- 8.8 -LRB- 1.4 -RRB- 2.1 -LRB- 0.8 -RRB- -- D12 .2 -LRB- 3.4 -RRB- c3 .7 -LRB- 2.0 -RRB- -- 9.0 -LRB- 1.7 -RRB- 2.2 -LRB- 0.7 -RRB- -- CS10 .6 -LRB- 2.2 -RRB- 2.5 -LRB- 1.6 -RRB- -- 9.0 -LRB- 1.9 -RRB- 1.5 -LRB- 1.0 -RRB- -- Fasting -- -- 8.9 -LRB- 1.6 -RRB- d -- -- 7.4 -LRB- 0.7 -RRB- Day -- -- 8.8 -LRB- 1.3 -RRB- -- -- 7.5 -LRB- 0.9 -RRB- Night -- -- 8.9 -LRB- 1.9 -RRB- -- -- 7.5 -LRB- 0.8 -RRB- CGI = chronic gastrointestinal ischemia ; PCO2 = carbon dioxide in kilopascal ; B = breakfast , D = dinner , CS = compound solution meal ; a P = 0.02 , b P = 0.005 , c P = 0.04 , d P = 0.03 Table 4Results of different tests compared to final diagnosisPatientsFinal diagnosisGET24-h tonometryCombination GET -- -- 24-h tonometryCGI 1714 -LRB- 82 % -RRB- 13 -LRB- 76 % -RRB- 17 -LRB- 100 % -RRB- No ischemia1611 -LRB- 69 % -RRB- 15 -LRB- 94 % -RRB- 16 -LRB- 100 % -RRB- Data presented as number of patients with positive predictive value -LRB- PPV -RRB- and negative predictive value -LRB- NPV -RRB- ; GET = gastric exercise tonometry ; CGI = chronic gastrointestinal ischemia ; GET = gastric exercise tonometry Using the previously defined criteria , 13/17 patients with CGI and 15/16 patients without ischemia were correctly identified with 24-h tonometry . The calculated test properties show a sensitivity of 76 % and a specificity of 94 % , a positive predictive value -LRB- PPV -RRB- of 76 % and a negative predictive value -LRB- NPV -RRB- of 94 % for detection of ischemia by 24-h tonometry alone . Combining the results of GET and 24-h tonometry , 17/17 patients with CGI and 16/16 patients without ischemia could be correctly identified -LRB- sensitivity of 100 % and specificity of 100 % -RRB- . Comparing patients with single - and multi-vessel ischemia , or patients with or without postprandial and/or exercise-related complaints , no significant differences in diagnostic accuracy were found . Discussion The results of this retrospective study indicate that 24-h gastrojejunal tonometry is feasible and may be clinically useful in diagnosing chronic gastrointestinal ischemia . The measurements were easy to perform , generally well tolerated and no complications occurred . The fasting baseline PCO2 in both stomach and jejunum was significantly higher in the ischemic patients group compared to the non-ischemic patients . This difference might be explained by the continuous compromised arterial blood flow of the mucosa of the stomach -LRB- and/or jejunum -RRB- in the ischemic patients group . The significant higher maximum peak after the breakfast and dinner and the borderline significant higher peak after the compound solution meal -LRB- P = 0.07 and 0.052 for stomach and jejunum , respectively -RRB- support the theory that , with a maximal metabolic oxygen demand , mucosal ischemia is apparent and detectable using tonometry . Using the cut-off values predicted by the previously performed healthy subjects study , the positive predictive value of 24-h tonometry seems very promising -LSB- 14 -RSB- . Comparing the results of detection of ischemia for 24-h tonometry and GET , no significant differences were found . Theoretically it might be expected that 24-h tonometry is more accurate in patients with postprandial complaints , and GET in patients with exercise-predominant complaints , but this was not found in this small patient series . In five patients the results of GET were incorrect -LRB- four false-positive and one false-negative result -RRB- , whereas the 24-h tonometry -LRB- retrospectively -RRB- correctly predicted the presence -LRB- one patient -RRB- or absence -LRB- four patients -RRB- of gastrointestinal ischemia in these patients . One of the major advantages of 24-h tonometry over GET is the fact that all patients are suitable for 24-h tonometry , in contrast to GET , where patients have to perform submaximal exercise , which is not always possible due to age , concomitant disease , and/or compromised general condition of the patient . Another advantage of the 24-h tonometry is the familiarity with 24-h pH measurement , which is a widely accepted diagnostic tool in gastroenterology . Moreover 24-h tonometry testing is more easily standardized than GET , especially regarding the level of exercise , which is difficult to manage and may cause false positive findings during or after excessive exercise -LSB- 15 -RSB- . In this study , the 24 h tonometry was not repeated in a standard fashion after treatment . In two patients who had successful , anatomical and clinical , revascularization 24-h tonometry was repeated , and showed normalization in both patients . In theory , the compound solution meal -LRB- low volume , high calorie content -RRB- should be the ideal test meal for provocation of gastrointestinal ischemia . The use of standard meals with large metabolic demand , like the compound solution meal , called for a dose reduction in several patients . These patients already had severely impaired food intake and could hardly tolerate -LRB- larger -RRB- meals . This dose reduction might have influenced the outcome of the 24-h tonometry , the borderline significant differences between CGI and non-ischemic patients after compound solution meals might be explained by this effect . The results of tonometry after meals have to be interpreted with care . Unsuccessful suppression of acid production and meal-related production of CO2 may influence the results of tonometry . Using optimal acid suppression medication and standardized meals , these effects can be minimized , but not completely ruled out . In this study gastric pH measurement was used to control acid suppression . Furthermore , duodenogastric reflux of jejunal contents and/or pancreatic juices are quite common and might theoretically influence intragastric and - jejunal PCO2 levels in a major way , leading to false positive tonometry findings -LSB- 16 -RSB- . In conclusion , this retrospective study shows that 24-h tonometry is feasible , safe , and has a very promising diagnostic accuracy for the detection of gastrointestinal ischemia . Using high-dose PPI acid suppression and standard meals , and previously established normal values , 24-h tonometry identifies gastrointestinal ischemia with an acceptable accuracy . The definitive role of 24-h tonometry in the diagnosis of chronic gastrointestinal ischemia has to be established in -LRB- future -RRB- prospective studies .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

chronic splanchnic syndrome
chronic mesenteric ischemia
gastric tonometry
small bowel tonometry