Intravenous

ATP

infusions

can

be

safely

administered

in

the

home

setting

a

study

in

pre-terminal

cancer

patients

Summary

Introduction

In

recent

years

favorable

effects

of

adenosine

triphosphate

-LRB-

ATP

-RRB-

on

nutritional

and

functional

status

and

survival

in

cancer

patients

were

reported

-LSB-

-RSB-

However

ATP

-LSB-

-RSB-

and

its

breakdown

product

adenosine

-LSB-

-RSB-

given

either

as

a

continuous

intravenous

infusion

or

by

intravenous

bolus

administration

were

also

reported

to

have

side

effects

which

might

hamper

administration

especially

in

an

outpatient

setting

In

cancer

patients

ATP

was

administered

as

continuous

intravenous

infusions

over

several

hours

in

doses

varying

from

to

μg

kg

min

In

a

Phase

I

study

-LSB-

-RSB-

patients

with

advanced

cancer

received

infusions

of

ATP

once

per

month

for

a

total

of

at

least

three

infusions

as

tolerated

by

the

patient

In

the

first

three

patients

ATP

was

given

at

a

dose

of

μg

kg

min

If

well

tolerated

subsequent

dose

escalations

were

planned

in

groups

of

three

patients

in

increments

of

μg

kg

min

until

the

maximally

tolerated

dose

-LRB-

MTD

-RRB-

was

reached

Patients

who

completed

therapy

without

serious

toxicity

and

later

progressed

were

eligible

for

retreatment

at

a

higher

dose

of

ATP

Fourteen

patients

received

a

total

of

ATP

infusions

patients

received

infusions

at

a

dose

of

μg

kg

min

six

patients

received

ATP

infusions

at

a

dose

of

μg

kg

min

and

three

patients

who

had

tolerated

μg

kg

min

very

well

were

reconsented

and

received

one

cycle

each

at

a

dose

of

μg

kg

min

In

total

adverse

events

were

reported

whether

or

not

these

could

be

ascribed

to

ATP

The

majority

of

side

effects

-LRB-

dyspnea

chest

pain

hypotension

gastrointestinal

side

effects

dizziness

headache

fever

and

local

injection

site

reaction

-RRB-

were

minor

-LRB-

adverse

events

grade

-LRB-

-RRB-

and

adverse

events

grade

-LRB-

-RRB-

based

on

the

US

National

Cancer

Institute

Toxicology

Criteria

Dose-limiting

toxicities

of

ATP

were

reported

in

seven

patients

i.e.

asymptomatic

electrocardiographic

evidence

of

cardiac

ischemia

-LRB-

n

-RRB-

grade

cardiac

toxicity

-LRB-

angina

without

evidence

of

infarction

-RRB-

and

grade

pulmonary

toxicity

-LRB-

dyspnea

at

rest

-RRB-

usually

occurring

as

a

characteristic

cardiopulmonary

syndrome

including

an

initial

feeling

of

chest

tightness

and

a

sensation

of

needing

to

take

a

deep

breath

-LRB-

n

-RRB-

Dose-limiting

cardiopulmonary

toxicity

appeared

in

all

three

μg

kg

min

ATP

infusions

in

four

-LRB-

-RRB-

μg

kg

min

infusions

and

in

five

-LRB-

-RRB-

μg

kg

min

infusions

In

a

subsequent

uncontrolled

phase

II

study

-LSB-

-RSB-

previously

untreated

patients

with

stage

IIIB/IV

non-small-cell

lung

cancer

-LRB-

NSCLC

-RRB-

received

infusions

of

ATP

at

doses

of

-LRB-

first

course

-RRB-

and

μg

kg

min

-LRB-

subsequent

courses

-RRB-

for

h

every

weeks

Reported

side

effects

were

in

decreasing

frequency

chest

pain

dyspnea

coughing

anxiety

injection

site

pain

chest

tightness

headache

insomnia

and

hot

flushes

According

to

the

authors

six

patients

reported

severe

adverse

events

of

which

CTC

dyspnea

occurred

in

two

patients

this

led

to

the

cessation

of

treatment

in

five

patients

-LSB-

-RSB-

In

the

first

randomized

clinical

trial

with

ATP

-LSB-

-RSB-

patients

with

stage

IIIB/IV

NSCLC

received

a

total

of

intravenous

ATP

courses

at

doses

of

maximally

μg

kg

min

-LRB-

tailored

to

the

maximum

tolerance

of

each

patient

-RRB-

for

h

every

weeks

Twenty-nine

percent

of

the

infusions

were

given

at

rates

of

μg

kg

min

at

μg

kg

min

and

at

μg

kg

min

-LSB-

-RSB-

The

most

frequent

side

effects

were

chest

discomfort

-LRB-

-RRB-

and

the

urge

to

take

a

deep

breath

-LRB-

-RRB-

both

of

which

resolved

within

minutes

after

lowering

the

ATP

dose

Electrocardiography

-LRB-

ECG

-RRB-

was

performed

in

patients

with

chest

pain/discomfort

during

the

ATP

infusions

but

no

ECG

changes

suggestive

of

myocardial

ischemia

were

detected

-LSB-

-RSB-

In

all

of

the

above

studies

ATP

was

administered

on

an

inpatient

basis

under

medical

supervision

Based

on

the

previously

reported

favorable

effects

of

ATP

on

quality

of

life

nutritional

status

and

survival

-LSB-

-RSB-

we

initiated

a

new

randomized

clinical

trial

to

investigate

whether

these

effects

of

ATP

could

be

confirmed

in

patients

with

different

types

of

cancer

in

the

pre-terminal

stage

of

disease

-LRB-

life

expectancy

months

-RRB-

In

view

of

the

short

life

expectancy

of

these

patients

and

based

on

the

favorable

safety

profile

of

ATP

we

decided

to

administer

ATP

in

the

home

setting

The

aim

of

the

present

study

was

to

investigate

the

safety

of

ATP

administration

at

home

in

pre-terminal

cancer

patients

We

hypothesized

that

side

effects

of

ATP

infusions

would

occur

mainly

during

the

first

ATP

infusion

especially

during

assessment

of

the

MTD

of

ATP

We

also

hypothesized

that

the

presence

of

cardiac

disorders

and/or

lung

cancer

would

lead

to

a

lower

MTD

and

a

higher

frequency

of

side

effects

Patients

and

methods

Study

population

and

design

Patients

were

recruited

through

the

Departments

of

Medical

Oncology

and

Pulmonology

of

five

hospitals

in

different

regions

in

The

Netherlands

-LRB-

Maastricht

Eindhoven

Utrecht

and

Heerlen

-RRB-

and

through

general

practitioners

in

the

region

of

Maastricht

Eligible

were

patients

with

cytologically

or

histologically

confirmed

cancer

for

whom

medical

treatment

options

were

restricted

to

supportive

care

who

had

a

life

expectancy

months

had

a

World

Health

Organization

-LRB-

WHO

-RRB-

performance

status

or

and

who

at

the

time

of

inclusion

suffered

from

at

least

one

of

the

following

complaints

fatigue

anorexia

or

weight

loss

in

the

previous

months

Exclusion

criteria

were

symptomatic

angina

pectoris

symptomatic

heart

failure

atrio-ventricular

block

-LRB-

checked

by

standard

ECG

in

all

patients

before

inclusion

-RRB-

life

expectancy

of

less

than

weeks

concurrent

palliative

chemotherapy

at

the

time

of

inclusion

cognitive

dysfunction

and

the

presence

of

other

diseases

hampering

adequate

follow

up

The

eligibility

of

patients

was

evaluated

by

a

medical

oncologist

or

pulmonologist

After

baseline

measurements

patients

were

randomly

allocated

to

ATP

or

control

treatment

The

present

report

on

the

safety

of

ATP

administration

is

restricted

to

patients

randomized

to

ATP

treatment

The

study

was

approved

by

the

Ethical

Committee

of

University

Hospital

Maastricht

and

Maastricht

University

and

all

patients

signed

written

informed

consent

prior

to

the

study

Details

of

the

trial

design

have

been

published

elsewhere

-LSB-

-RSB-

Intervention

Adenosine

triphosphate

-LRB-

-RRB-

of

purity

was

purchased

from

Pharma

Waldhof

GmbH

and

co.

KG

-LRB-

Düsseldorf

Germany

-RRB-

For

each

infusion

g

of

ATP

were

dissolved

in

ml

NaCl

sterilized

by

ultrafiltration

-LRB-

Minisart

μM

-RRB-

and

supplied

in

sterile

containers

Patients

received

weekly

intravenous

ATP

infusions

of

h

over

a

period

of

weeks

All

ATP

infusions

were

started

at

a

dose

of

μg

kg

min

and

then

increased

in

steps

of

μg

kg

min

every

min

until

a

maximum

dose

of

μg

kg

min

or

the

MTD

if

this

was

lower

had

been

reached

Thereafter

ATP

was

infused

at

a

continuous

rate

If

any

side

effects

occurred

the

dose

was

reduced

until

side

effects

disappeared

Blood

pressure

and

pulse

were

registered

before

starting

the

infusion

at

min

after

determining

the

MTD

and

just

before

the

infusion

was

stopped

Since

initiation

of

ATP

infusions

under

medical

supervision

in

a

clinical

setting

would

facilitate

the

treatment

of

possible

side

effects

the

first

two

ATP

infusions

were

given

at

the

day

care

center

of

the

participating

hospitals

Based

on

evaluation

of

safety

data

in

the

first

patients

in

view

of

the

mild

character

of

the

noted

side

effects

during

the

first

two

infusions

in

these

patients

the

Ethical

Committee

granted

permission

to

administer

only

the

first

ATP

infusion

at

the

day

care

center

and

all

subsequent

infusions

at

home

The

description

below

applies

to

the

procedures

in

case

of

only

one

hospital

infusion

At

the

end

of

the

first

infusion

the

safety

and

tolerated

dose

of

ATP

was

evaluated

for

each

individual

patient

Subsequent

infusions

were

given

at

the

patients

home

by

an

experienced

and

trained

nurse

of

a

specialized

infusion

team

usually

embedded

in

the

regional

Community

Care

Organization

The

MTD

as

determined

during

the

first

infusion

at

the

day

care

center

was

also

the

maximum

dose

for

this

patient

for

the

next

infusions

at

home

The

same

rule

was

applied

for

subsequent

home

infusions

so

that

the

infusion

rate

in

any

subsequent

ATP

infusion

course

was

never

higher

than

the

MTD

during

the

previous

ATP

infusion

Patients

and

their

partners

were

instructed

extensively

regarding

the

infusion

procedures

also

they

were

instructed

to

immediately

call

the

involved

infusion

team

in

case

of

any

side

effects

Documentation

of

side

effects

and

adverse

events

Side

effects

of

ATP

infusions

Side

effects

of

all

ATP

infusions

adjustments

of

dosage

schedules

and

any

other

events

occurring

during

the

infusions

were

registered

by

the

infusion

nurse

either

a.

during

the

infusions

or

b.

on

completion

of

each

infusion

In

addition

the

researcher

called

all

patients

after

each

infusion

to

ask

whether

any

side

effects

had

occurred

Side

effects

were

scored

using

the

NCI

Common

Toxicity

Criteria

-LSB-

-RSB-

on

a

four-point

scale

according

to

seriousness

In

this

system

dyspnea

is

graded

as

follows

no

change

not

defined

dyspnea

on

significant

exertion

dyspnea

at

normal

activity

dyspnea

at

rest

Since

most

terminal

cancer

patients

are

at

rest

dyspnea

would

in

these

cases

automatically

be

classified

as

CTC

grade

which

would

misrepresent

the

actual

severity

of

the

symptoms

and

disregard

the

intention

of

the

NCI

Common

Toxicity

Criteria

-LRB-

i.e.

CTC

grade

life-threatening

-RRB-

For

this

reason

we

decided

to

apply

the

general

toxicity

grading

of

the

CTC

also

for

dyspnea

i.e.

mild

moderate

severe

and

life-threatening

Based

on

Agteresch

et

al.

-LSB-

-RSB-

we

pre-defined

side

effects

chest

discomfort

urge

to

take

a

deep

breath

nausea

flushing

light-headedness

dyspnea

headache

sweating

mood

alteration-anxiety

palpitations

epistaxis

symptoms

of

cardiac

ischemia

injection

side

reaction

or

other

-LRB-

to

be

specified

-RRB-

In

case

of

persistent

or

severe

chest

pain

suspect

for

potential

cardiac

ischemia

an

ECG

was

made

in

order

to

exclude

this

Statistical

analysis

Data

were

entered

in

a

database

using

Microsoft

Access

and

checked

for

errors

by

means

of

double

data

entry

by

two

independent

persons

Data

were

analyzed

using

SPSS

for

Windows

Changes

in

blood

pressure

and

heart

rate

over

time

were

tested

for

statistical

significance

by

Student

's

paired

t

test

To

test

our

hypothesis

that

side

effects

would

especially

occur

during

the

first

infusion

we

calculated

the

average

number

of

side

effects

per

infusion

over

all

infusions

To

investigate

whether

the

MTD

and

frequency

of

side

effects

were

dependent

on

the

presence

of

cardiac

disorders

and/or

lung

cancer

linear

regression

models

were

fitted

As

dependent

variables

we

used

mean

MTD

per

patient

over

all

courses

and

frequency

of

side

effects

per

infusion

As

independent

variables

we

included

dummy

variables

for

the

presence

of

cardiac

disorders

-LRB-

yes/no

-RRB-

and

lung

cancer

-LRB-

yes/no

-RRB-

To

investigate

the

relation

between

the

seriousness

of

side

effects

-LRB-

CTC

grades

vs.

CTC

grade

-RRB-

and

the

presence

of

cardiac

disorders

and/or

lung

cancer

Fisher

's

exact

test

was

used

P

values

of

less

than

indicated

significance

Results

Study

population

Fifty-one

patients

with

different

types

of

pre-terminal

cancer

were

included

in

the

present

study

Baseline

characteristics

of

the

patients

are

listed

in

Table

Mean

age

was

years

-LRB-

range

years

-RRB-

and

the

majority

of

patients

were

male

-LRB-

-RRB-

The

most

frequent

diagnosis

was

lung

cancer

-LRB-

-RRB-

followed

by

colon

cancer

-LRB-

-RRB-

The

majority

of

patients

-LRB-

-RRB-

had

WHO

performance

status

and

WHO

status

Twelve

patients

-LRB-

-RRB-

suffered

from

cardiac

disorders

Table

characteristics

of

ATP-treated

patients

-LRB-

n

-RRB-

NumberPercent

-LRB-

-RRB-

Age

-LRB-

years

-RRB-

-LRB-

-RRB-

aGender

performance

scoreb

type

Gastro-intestinal

of

cardiac

-LRB-

range

-RRB-

bWHO

restricted

in

physically

strenuous

activity

but

ambulatory

and

able

to

do

light

work

WHO

ambulatory

-LRB-

not

more

than

in

bed

-RRB-

and

capable

of

self-care

but

unable

to

carry

out

any

work

Out

of

patients

six

patients

died

during

the

intervention

period

because

of

disease

progression

-LRB-

Fig.

-RRB-

Three

patients

did

not

start

because

of

rapid

deterioration

of

their

condition

and

patients

stopped

with

the

ATP

infusions

Reasons

to

stop

were

deterioration

in

medical

condition

-LRB-

n

-RRB-

fear

of

side

effects

-LRB-

n

-RRB-

or

being

unsatisfied

with

the

effect

of

ATP

-LRB-

n

-RRB-

Fig.

diagram

of

the

study

Over

the

study

period

of

weeks

a

total

of

ATP

infusions

were

administered

in

patients

Fifteen

patients

-LRB-

-RRB-

received

one

to

three

ATP

courses

nine

patients

-LRB-

-RRB-

received

four

to

seven

courses

and

patients

-LRB-

-RRB-

completed

all

eight

ATP

infusions

Eleven

infusions

-LRB-

-RRB-

of

infusions

were

given

at

the

lowest

dose

of

μg

kg

min

infusions

-LRB-

-RRB-

at

a

dose

of

μg

kg

min

and

-LRB-

-RRB-

at

the

highest

dose

of

μg

kg

min

Heart

rate

and

blood

pressure

Heart

rate

decreased

from

-LRB-

mean

SEM

-RRB-

at

baseline

to

at

min

after

reaching

the

MTD

-LRB-

p

-RRB-

and

thereafter

remained

constant

at

beats/min

as

measured

at

h

of

ATP

administration

-LRB-

comparison

with

baseline

p

-RRB-

Systolic

blood

pressure

decreased

from

at

baseline

to

at

min

-LRB-

p

-RRB-

but

then

increased

to

mm

Hg

at

h

of

ATP

infusion

-LRB-

comparison

with

baseline

p

-RRB-

Diastolic

blood

pressure

also

initially

decreased

from

mmHg

to

mmHg

-LRB-

p

-RRB-

but

then

increased

to

mm

Hg

at

h

of

ATP

infusion

-LRB-

comparison

with

baseline

p

-RRB-

Side

effects

Ten

patients

out

of

had

no

side

effects

during

any

of

the

infusions

Out

of

infusions

infusions

-LRB-

-RRB-

were

without

any

side

effects

In

infusions

-LRB-

-RRB-

side

effect

occurred

in

infusions

-LRB-

-RRB-

side

effects

and

in

infusions

-LRB-

-RRB-

side

effects

In

total

side

effects

were

reported

-LRB-

Fig.

-RRB-

side

effects

-LRB-

-RRB-

were

reported

to

the

nurse

of

which

during

the

infusions

and

afterwards

and

-LRB-

-RRB-

to

the

researcher

when

specifically

asked

for

The

average

number

of

side

effects

per

infusion

was

-LRB-

i.e.

side

effects

in

infusions

-RRB-

Fig.

side

effects

of

ATP

according

to

location

-LRB-

day

care

centre

vs.

home

-RRB-

time

of

reporting

side

effects

-LRB-

during

vs.

after

the

infusion

-RRB-

and

person

to

whom

the

side

effects

were

reported

-LRB-

nurse

vs.

researcher

-RRB-

At

the

day

care

center

side

effects

were

reported

in

infusions

-LRB-

side

effect

per

infusion

-RRB-

Of

these

side

effects

-LRB-

-RRB-

were

reported

to

the

nurse

of

which

during

the

infusions

and

afterwards

and

-LRB-

-RRB-

to

the

researcher

when

specifically

asked

for

At

home

side

effects

were

reported

in

infusions

-LRB-

side

effect

per

infusion

-RRB-

of

these

-LRB-

-RRB-

were

reported

to

the

nurse

of

which

during

the

infusions

and

afterwards

and

-LRB-

-RRB-

to

the

researcher

when

specifically

asked

for

All

side

effects

were

transient

and

resolved

within

minutes

after

lowering

the

ATP

infusion

rate

In

a

total

of

infusions

one

or

more

side

effects

were

reported

by

patients

In

the

infusions

with

one

or

more

side

effects

reported

during

ATP

administration

the

infusion

was

stopped

in

infusions

-LRB-

-RRB-

lowered

in

infusions

-LRB-

-RRB-

and

not

changed

in

infusions

-LRB-

-RRB-

Of

the

latter

eight

infusions

the

side

effects

had

already

disappeared

before

lowering

the

infusion

rate

in

four

infusions

whereas

in

three

infusions

the

side

effects

had

already

been

present

before

the

start

of

the

ATP

infusions

in

one

infusion

extravasation

occurred

and

the

ATP

infusion

was

temporarily

interrupted

In

out

of

the

total

of

infusions

with

one

or

more

side

effects

the

side

effects

were

reported

by

patients

to

the

nurse

or

researcher

only

after

completion

of

the

infusion

and

the

infusion

rate

was

therefore

not

adapted

The

frequency

of

specific

side

effects

observed

during

the

ATP

infusions

is

shown

in

Table

Dyspnea

was

the

most

frequent

side

effect

appearing

in

out

of

infusions

-LRB-

-RRB-

followed

by

chest

discomfort

-LRB-

-RRB-

and

the

urge

to

take

a

deep

breath

-LRB-

-RRB-

No

symptoms

of

cardiac

ischemia

occurred

in

any

of

the

infusions

Table

effects

during

a

total

of

intravenous

ATP

cycles

in

patients

CTC-gradingNo

side

effectsSide

effects

according

to

CTC

gradeTotal

side

grade

unspecifiedNumberPercent

of

inf

-LRB-

-RRB-

Cardiac

side

to

take

a

deep

some

courses

more

than

one

side

effect

was

observedaThe

side

effects

classified

as

Other

were

cold

shivering

feelings

of

coldness

pain

in

infusion

arm

dry

eyes

sleepiness

burning

sensation

of

the

throat

vomiting

diarrhea

pain

neck

general

discomfort

and

unspecified

From

the

side

effects

one

side

effect

-LRB-

lightheadedness

-RRB-

occurred

at

the

day

care

center

and

was

scored

by

the

nurse

as

CTC

because

of

prolonged

stay

-LRB-

one

night

-RRB-

at

the

hospital

after

the

first

infusion

there

were

no

abnormalities

on

ECG

Four

side

effects

were

scored

as

CTC

-LRB-

in

all

cases

chest

discomfort

-RRB-

and

side

effects

as

CTC

Two

CTC

side

effects

occurred

at

the

day

care

center

in

two

patients

with

no

abnormalities

on

ECG

Of

these

one

patient

decided

to

stop

with

the

ATP

infusions

The

other

patient

wanted

to

continue

for

safety

reasons

all

subsequent

infusions

in

this

patient

were

given

at

the

day

care

center

The

remaining

two

CTC

side

effects

occurred

at

home

one

in

a

patient

during

the

normal

procedure

of

stepwise

increasing

the

infusion

rate

by

the

nurse

according

to

protocol

in

the

other

patient

during

constant

ATP

infusion

after

the

nurse

had

left

in

the

latter

case

the

nurse

was

called

by

telephone

by

the

patient

or

informal

caregiver

and

immediately

arrived

In

both

cases

the

infusions

were

stopped

immediately

for

that

very

day

The

first

patient

decided

to

continue

the

ATP

infusions

in

this

patient

all

four

subsequent

infusions

until

the

end

of

the

study

were

given

at

the

day

care

center

at

the

highest

ATP

dose

-LRB-

μg

kg

min

-RRB-

and

no

further

side

effects

occurred

The

second

patient

decided

to

stop

the

ATP

infusions

The

following

CTC

side

effects

were

reported

by

patients

To

the

nurse

during

the

infusions

by

seven

patients

in

seven

infusions

Urge

to

breathe

deeply

headache

sweating

and

cold

shivering

in

one

patient

at

the

day

care

center

-LRB-

the

same

patient

with

the

CTC

chest

discomfort

and

CTC

lightheadedness

-RRB-

Sweating

in

one

patient

at

the

day

care

center

at

the

end

of

the

infusion

due

to

flushing

the

infusion

line

-LRB-

violation

of

the

administration

protocol

-RRB-

Pain

in

the

infusion

arm

-LRB-

one

patient

-RRB-

and

dyspnea

-LRB-

one

patient

-RRB-

both

at

the

day

care

centerUrge

to

breathe

deeply

headache

and

sweating

in

one

patient

at

home

during

the

period

of

stepwise

increasing

the

infusion

rate

by

the

nurseChest

discomfort

-LRB-

once

-RRB-

and

lightheadedness

-LRB-

twice

-RRB-

at

home

in

two

patients

who

called

the

home

nurseOut

of

these

seven

patients

with

CTC

side

effects

two

patients

decided

to

stop

the

ATP

infusions

for

the

rest

of

the

study.To

the

nurse

after

completion

of

the

infusion

by

three

patients

-LRB-

four

infusions

-RRB-

To

the

researcher

when

specifically

asked

for

by

one

patient

-LRB-

five

infusions

-RRB-

These

nine

CTC

side

effects

-LRB-

eight

times

urge

to

breathe

deeply

once

nausea

-RRB-

were

probably

not

sufficiently

serious

to

call

the

home

nurse

All

of

these

patients

continued

the

ATP

infusions

Timing

of

side

effects

Side

effects

were

not

only

present

during

the

first

infusion

but

also

during

subsequent

infusions

even

though

the

number

of

side

effects

per

infusion

appeared

to

be

lower

during

the

last

three

infusions

-LRB-

Fig.

-RRB-

At

the

day

care

center

of

the

side

effects

reported

during

the

infusions

-LRB-

-RRB-

were

reported

during

MTD

assessment

and

side

effects

-LRB-

-RRB-

after

MTD

assessment

had

been

completed

-LRB-

Fig.

-RRB-

At

home

side

effects

were

reported

during

the

infusion

side

effects

-LRB-

-RRB-

during

MTD

assessment

and

side

effects

-LRB-

-RRB-

after

MTD

assessment

had

been

completed

In

the

latter

cases

of

side

effects

the

nurse

-LRB-

and

once

the

general

practitioner

-RRB-

was

called

by

the

patient

and

visited

the

patient

to

lower

or

stop

the

infusion

rate

Fig.

number

of

side

effects

per

ATP

infusion

in

subsequent

infusions

Effect

of

cardiac

or

lung

disorders

on

MTD

and

frequency

of

side

effects

Mean

MTD

was

-LRB-

mean

SEM

-RRB-

μg

kg

min

in

patients

without

cardiac

disorders

and/or

lung

cancer

-LRB-

Table

-RRB-

In

the

presence

of

cardiac

disorders

mean

MTD

was

μg

kg

min

lower

-LRB-

p

-RRB-

and

μg

kg

min

lower

in

the

presence

of

lung

cancer

-LRB-

p

-RRB-

The

mean

number

of

side

effects

per

infusion

was

in

patients

without

cardiac

disorders

and/or

lung

cancer

In

the

presence

of

cardiac

disorders

the

number

of

side

effects

was

significantly

higher

-LRB-

p

-RRB-

The

presence

of

lung

cancer

had

no

significant

impact

on

the

frequency

of

side

effects

-LRB-

-RRB-

Neither

the

presence

of

cardiac

disorders

nor

the

presence

of

lung

cancer

had

a

significant

impact

on

the

frequency

of

specific

complaints

-LRB-

chest

discomfort

urge

to

breathe

deeply

nausea

lightheadedness

or

dyspnea

-RRB-

However

in

the

presence

of

cardiac

disorders

the

number

of

other

side

effects

was

significantly

higher

-LRB-

p

-RRB-

The

proportion

of

CTC

grade

side

effects

in

the

presence

of

cardiac

disorders

and/or

lung

cancer

-LRB-

CTC

grades

out

of

side

effects

i.e.

-RRB-

was

similar

to

patients

without

such

disorders

-LRB-

seven

CTC

grades

out

of

side

effects

i.e.

-RRB-

Table

independent

effect

of

the

presence

of

cardiac

disorders

and/or

lung

cancer

on

MTD

and

frequency

of

side

effectsMeanNo

cardiac

disorders

and/or

lung

cancerCardiac

disordersLung

All

side

Chest

Urge

to

breathe

Reference

group

patients

with

no

cardiac

disorders

and/or

lung

cancer

p

p

p

Continuation

of

infusions

after

completion

of

the

study

Of

the

patients

who

completed

all

eight

ATP

infusions

decided

to

continue

ATP

administration

-LRB-

nine

patients

with

lung

cancer

one

with

prostate

cancer

one

with

a

malignant

melanoma

one

with

liver

cancer

-RRB-

Until

the

censoring

date

these

patients

had

received

a

total

of

ATP

infusions

after

completion

of

the

regular

study

period

-LRB-

range

additional

infusions

-RRB-

Of

these

infusions

infusions

-LRB-

-RRB-

reached

a

dose

of

μg

kg

min

infusions

-LRB-

-RRB-

were

given

at

a

dose

of

μg

kg

min

and

-LRB-

-RRB-

reached

a

dose

of

μg

kg

min

ATP

A

total

of

side

effects

were

reported

over

infusions

-LRB-

side

effects

per

infusion

-RRB-

a

number

significantly

lower

-LRB-

p

-RRB-

than

in

the

first

infusions

in

the

same

patients

Discussion

The

aim

of

this

study

was

to

investigate

whether

ATP

can

be

safely

administered

to

patients

with

pre-terminal

cancer

in

the

home

setting

A

total

of

infusions

were

administered

for

h.

Although

statistically

significant

changes

in

blood

pressure

and

heart

rate

were

observed

these

were

minor

and

clinically

irrelevant

corroborating

earlier

results

-LSB-

-RSB-

In

total

side

effects

were

reported

during

the

ATP

infusions

i.e.

an

average

of

side

effects

per

infusion

Most

side

effects

were

mild

and

transient

presumably

due

to

the

short

plasma

half-life

of

ATP

and

adenosine

-LRB-

s

-RRB-

-LSB-

-RSB-

We

saw

more

side

effects

than

in

a

previous

study

in

lung

cancer

patients

by

Agteresch

et

al.

-LSB-

-RSB-

These

authors

observed

side

effects

during

a

total

of

ATP

cycles

of

h

-LRB-

side

effects

per

infusion

-RRB-

even

though

these

infusions

were

administered

for

a

longer

period

of

time

-LRB-

h

vs

h

in

our

study

-RRB-

One

possible

explanation

of

this

discrepancy

may

be

the

different

procedures

of

data

collection

in

these

two

studies

For

safety

reasons

the

safety

procedure

adopted

in

the

present

study

was

that

the

researcher

contacted

the

patients

after

each

home

infusion

to

ask

for

side

effects

specifically

naming

a

number

of

the

most

common

potential

side

effects

-LRB-

based

on

side

effects

listed

by

Agteresch

et

al.

-LSB-

-RSB-

Our

results

clearly

demonstrate

that

this

procedure

lead

to

a

higher

frequency

of

reported

side

effects

in

our

study

out

of

a

total

number

of

side

effects

side

effects

-LRB-

-RRB-

were

reported

only

afterwards

to

the

researcher

when

specifically

asked

for

If

these

side

effects

-LRB-

i.e.

side

effects

which

had

not

spontaneously

been

reported

to

the

nurse

during

or

after

the

infusion

-RRB-

are

excluded

the

frequency

of

the

remaining

side

effects

per

infusion

in

the

present

study

-LRB-

-RRB-

is

remarkably

similar

to

the

report

by

Agteresch

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

in

which

trained

research

nurses

in

a

dedicated

clinical

research

unit

registered

the

side

effects

In

both

our

study

and

the

studies

by

Haskell

et

al.

-LSB-

-RSB-

and

Agteresch

et

al.

-LSB-

-RSB-

chest

discomfort/pain

dyspnea

and

the

urge

to

take

a

deep

breath

were

frequent

side

effects

Results

showed

that

in

out

of

infusions

-LRB-

-RRB-

with

side

effects

reported

during

ATP

administration

the

infusion

rate

was

lowered

or

stopped

according

to

protocol

Reasons

for

not

lowering

the

infusion

rate

in

eight

infusions

were

the

fact

that

in

four

infusions

complaints

disappeared

automatically

in

three

infusions

the

reported

complaints

were

already

present

before

the

start

of

the

infusion

and

in

one

infusion

extravasation

occurred

with

a

temporary

interruption

of

the

ATP

infusion

In

infusions

with

side

effects

side

effects

had

only

been

reported

after

completion

of

the

concerned

ATP

infusion

and

the

infusion

rate

was

therefore

not

adapted

One

potential

explanation

for

this

finding

may

be

that

patients

were

eager

to

receive

ATP

at

the

highest

possible

dose

as

some

patients

expressed

their

worry

that

the

potential

effectiveness

of

ATP

could

fade

in

case

of

lowering

the

dose

-LRB-

similar

to

chemotherapy

-RRB-

despite

our

explicit

explanation

to

patients

prior

to

the

study

that

there

is

currently

no

evidence

that

the

efficacy

of

ATP

would

be

better

at

higher

ATP

doses

Another

possible

explanation

is

that

patients

in

our

study

population

were

used

to

experiencing

far

more

serious

complaints

caused

by

progression

of

the

disease

and/or

previous

antitumor

treatment

One

CTC

side

effect

four

CTC

side

effects

and

CTC

score

were

observed

The

CTC

side

effect

-LRB-

see

Results

-RRB-

and

two

CTC

side

effects

-LRB-

chest

discomfort

-RRB-

occurred

at

the

day

care

center

with

no

abnormalities

on

ECG

The

other

two

CTC

side

effects

occurred

at

home

one

with

the

nurse

still

being

present

and

in

the

other

case

the

nurse

immediately

arrived

Side

effects

were

not

limited

to

the

period

of

MTD

assessment

nor

were

they

limited

to

the

first

ATP

infusion

The

implication

of

this

finding

is

that

alertness

with

regard

to

potential

side

effects

of

ATP

administration

is

necessary

during

all

subsequent

ATP

infusions

and

not

just

during

the

first

infusion

or

MTD

assessment

The

lower

MTD

found

in

the

presence

of

cardiac

disorders

or

lung

cancer

indicates

that

patients

with

these

disorders

tolerate

lower

doses

of

ATP

without

side

effects

than

patients

without

these

disorders

Moreover

even

at

the

lower

MTD

side

effects

tend

to

be

more

frequent

in

the

presence

of

cardiac

disorders

Because

all

patients

with

presence

of

COPD

also

had

cardiac

disorders

or

lung

cancer

this

subgroup

was

not

analyzed

separately

Based

on

our

findings

we

conclude

that

ATP

administration

at

home

is

safe

First

the

majority

of

infusions

-LRB-

-RRB-

are

without

side

effects

and

second

our

results

confirm

a

previous

study

in

lung

cancer

patients

-LSB-

-RSB-

showing

that

side

effects

that

do

appear

are

mild

and

transient

resolving

within

minutes

after

lowering

the

ATP

infusion

rate

Nevertheless

it

remains

possible

that

some

side

effects

could

be

prevented

by

encouraging

patients

to

report

any

side

effects

without

delay

This

emphasizes

the

need

for

careful

instruction

and

facilitating

patients

reporting

and

monitoring

of

side

effects

when

ATP

infusions

are

administered

at

home

As

patients

with

cardiac

disorders

and

lung

cancer

appear

to

have

a

lower

MTD

and

more

side

effects

these

patients

should

be

monitored

with

special

care

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 B 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 B I 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 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 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 B 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 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 B O O O O B I 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 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 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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 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 B O O O O O O O O O O O B 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 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 B 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 B O O O O O 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 B O O O O O O O O O O O O O O B I 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 B I 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 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 B 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 B I O O O B I O O O B I O B O B I 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 B I 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 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 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 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 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 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 B 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 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 B 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 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 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 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 B O O O O O O O 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 B I 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 B I 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 B I O O O O O O O B I 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 B I 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 B I O O O O O O O O O O O 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 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 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 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 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 B 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 B 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 B I 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 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 O O O O B I B I 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 B I 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 B I O O O O O O O B I 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 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 B I O B 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 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 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 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 B I 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 B I 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 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O O O O B I O O O O O O O O O O B I 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 B I O O O O O O O O O O O B I O O B I O O O O O O O O O O O O O O O O O O B I 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 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 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 B I O O O O O O O O O O O O O O O B I 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 B O O O O O O B I O B I 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 B 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 B 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 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 B I 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 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Eye -- hand coordination during manual object transport with the affected and less affected hand in adolescents with hemiparetic cerebral palsy In the present study we investigated eye -- hand coordination in adolescents with hemiparetic cerebral palsy -LRB- CP -RRB- and neurologically healthy controls . Using an object prehension and transport task , we addressed two hypotheses , motivated by the question whether early brain damage and the ensuing limitations of motor activity lead to general and/or effector-specific effects in visuomotor control of manual actions . We hypothesized that individuals with hemiparetic CP would more closely visually monitor actions with their affected hand , compared to both their less affected hand and to control participants without a sensorimotor impairment . A second , more speculative hypothesis was that , in relation to previously established deficits in prospective action control in individuals with hemiparetic CP , gaze patterns might be less anticipatory in general , also during actions performed with the less affected hand . Analysis of the gaze and hand movement data revealed the increased visual monitoring of participants with CP when using their affected hand at the beginning as well as during object transport . In contrast , no general deficit in anticipatory gaze control in the participants with hemiparetic CP could be observed . Collectively , these findings are the first to directly show that individuals with hemiparetic CP adapt eye -- hand coordination to the specific constraints of the moving limb , presumably to compensate for sensorimotor deficits . Introduction Cerebral palsy -LRB- CP -RRB- is an umbrella-term describing a group of disorders of movement and posture leading to activity limitations , and that are caused by damage to the fetal or infant brain -LRB- Bax et al. 2005 -RRB- . In this study , we focused on the most common subtype of cerebral palsy , spastic hemiparesis , which typically occurs after unilateral lesions to the cerebral cortex or corticospinal pathways -LRB- Kwong et al. 2004 -RRB- . This condition is characterized by impaired control of muscle tone and spasticity in the upper and lower limbs of the contralesional , `` affected '' , side of the body -LRB- Albright 1996 -RRB- , generally progressing from proximal to distal -LRB- Freund 1987 ; Steenbergen et al. 2000b -RRB- , and often accompanied by sensory deficits of proprioception and tactile perception -LRB- Cooper et al. 1995 -RRB- . These symptoms induce limitations on manual actions performed with the affected hand -LRB- AH -RRB- , in particular related to fine motor skills such as fingertip force control -LRB- Eliasson et al. 1991 -RRB- . These limitations are further amplified by more central deficits in the integration of different modalities , such as matching proprioceptive and visual spatial information -LRB- Wann 1991 -RRB- , and integrating sensory information with motor output -LRB- Gordon et al. 2006 -RRB- . While the less affected hand -LRB- LAH -RRB- is usually spared from severe sensorimotor impairments -LRB- but see , Steenbergen and Meulenbroek 2006 for subtle deficits at the less affected body side -RRB- , there is converging evidence for more high-level deficits in prospective control , or motor planning , in particular , in individuals with right hemiparesis -LRB- Mutsaarts et al. 2005 , 2006 ; Steenbergen et al. 2000a , 2004 ; te Velde et al. 2005 -RRB- . These studies on manual control have advanced our knowledge about the different levels at which the motor system affects CP as well as the behavioural reorganisation during the performance of actions -LRB- e.g. , van Roon et al. 2005b -RRB- . Yet , up to date , eye -- hand coordination has not been investigated , despite preliminary evidence suggesting that it may contribute to deficits in action performance in individuals with CP -LRB- van der Meer et al. 1995 ; van der Weel et al. 1996 -RRB- . Even indirect evidence regarding the role of visual feedback for manual action performance in CP is scarce . Wann -LRB- 1991 -RRB- investigated visuo-proprioceptive integration in adolescents with CP . Comparing arm postures in a bimanual position-matching task under different conditions of sensory feedback , he found that , in contrast to adult controls , participants with CP employed very similar end postures -LRB- joint angle configurations -RRB- with the left and right arm in conditions in which vision of one or both arms was prevented . This was interpreted as evidence that they relied more strongly on purely proprioceptive information rather than on a shared visuospatial-proprioceptive representation and that the encoding of visual and proprioceptive information into a common egocentric frame may be problematic in these individuals . This would suggest that individuals with CP more strongly depend on continuous visual feedback for guiding manual actions to visual targets , compared to neurologically healthy adults . Moreover , as the severity of the motor impairment , and concomitant proprioceptive impairment , increases from proximal to distal -LRB- e.g. , Steenbergen et al. 2000b -RRB- , it may be expected that actions with the affected-hand involving more fine motor control , such as grasping , need closer visual monitoring to provide additional feedback . In line with this , Steenbergen and colleagues -LRB- 1996 -RRB- , studying bimanual actions in participants with hemiparetic CP , made the anecdotal observation that -LRB- overt -RRB- visual attention seemed to be drawn to the affected side of the body . However , in contrast to the reasoning above , a recent study that scrutinized the effect of removing visual information of the moving limb on end-point accuracy in a straight-line drawing task -LRB- van Roon et al. 2005a -RRB- found no specific adverse effect of this manipulation in participants with tetraparetic cerebral palsy when using their relatively less-impaired hand compared to control participants . Thus , up to date , there is no consensus on the role of visual guidance for the control of manual actions in CP . Besides the sensorimotor impairments of the AH , more high-level aspects of action control , such as motor planning and prospective control , have been shown to be compromised as well in hemiparetic CP . In research on motor planning in individuals with CP , the LAH is used , as this hand has no -LRB- or small -RRB- movement restrictions , as is often the case with the AH . Hence , the higher-order process of motor planning can be studied without the confounding effects of possible movement restrictions . Atypical performance with the LAH was found for instance in tasks involving planning of the hand 's posture at the end of the action -LRB- Steenbergen and Gordon 2006 ; Steenbergen et al. 2000a -RRB- , in particular , in individuals with right hemiparesis -LRB- Steenbergen et al. 2004 -RRB- . In these tasks , individuals have to pick up objects and place them in another orientation on a designated target . Ample evidence in controls suggest that individuals pick-up objects with a grip that allows them to end the task with a comfortable posture , even when this means that they have to sacrifice comfort of the start grip -LRB- see Steenbergen and Gordon 2006 -RRB- . This `` end state comfort '' effect was not present in individuals with CP , indicating a higher-level impairment of movement planning . Prospective control in individuals with hemiparetic CP was recently investigated in a collision avoidance task -LRB- te Velde et al. 2005 -RRB- . This study found later , hand-movement initiation in individuals with right as compared to left hemiparesis , again indicating reduced anticipation of action requirements . The extent to which deficits in motor planning or prospective control may be related to deviations in visual monitoring , with its typically anticipatory role for action control -LRB- Johansson et al. 2001 -RRB- has not been investigated yet in individuals with CP . In the present study , we examined eye -- hand coordination in an unconstrained object prehension task in individuals with hemiparetic CP and neurologically healthy controls . To manipulate task difficulty , an obstacle was present in half of the trials , inducing a more complex transport trajectory . Participants performed the task with each hand separately . Based on the registration of eye and hand movements , we calculated several measures of temporal and spatial aspects of eye -- hand coordination . Besides giving a first descriptive account of gaze patterns during object manipulation in a population with congenital hemiparesis , we addressed two hypotheses . Our first and main research question concerned the way in which individuals with hemiparetic CP adapt eye -- hand coordination to the sensorimotor impairments of their affected hand . We hypothesized that individuals with CP would use increased visual monitoring when they perform the task with their AH as compared to performance with the LAH and to performance of control participants . Second , we examined eye -- hand coordination when the task was performed with the LAH in participants with CP . Based on the previously established deficits in action planning , we hypothesized that gaze patterns are less anticipatory in general , in individuals with CP . Given the limited knowledge on visumotor control in CP and on the role of eye-movements for action planning , this second research question was much more exploratory than the first . Methods Participants In total , 16 individuals took part in the study . Six participants with hemiparetic CP constituted the experimental group and ten participants with no known history of neurological disorders served as controls . Control participants were all right handed -LRB- Dutch version of the Edinburgh handedness inventory , Oldfield 1971 -RRB- University students -LRB- 9 females , 20 -- 25 years -RRB- . The six participants of the experimental group -LRB- 5 females , 14 -- 19 years -RRB- were students at the Werkenrode Institute -LRB- Groesbeek , The Netherlands -RRB- , where they followed an adapted educational programme . They had been asked to take part in the study based on their condition -LRB- viz. congenital spastic hemiparesis -RRB- . Additional requirements were no known oculomotor disturbance -LRB- such as nystagmus -RRB- , and having the motor , cognitive and attentional capacities to perform the experimental task as assessed by initial screening . All were able to walk and sit independently , and able to read and write with their LAH . Consent was obtained prior to the experiment , both in verbal form from the participants during the initial screening session , as well as in written form from their parents or caregivers . In a separate session taking place after the experiment , the participants with CP performed two standardised dexterity tests , the Box and Block test for gross dexterity -LRB- Mathiowetz et al. 1985 -RRB- and the Purdue pegboard test for fine dexterity -LRB- Tiffin 1968 -RRB- . One of the participants was not available for the manual dexterity testing afterwards . Table 1 shows the results of these tests as well as other participant information . For the Purdue -- Pegboard test , the norm score for individuals at the age of 16 -- 17 years is 49.5 for the preferred hand . Standardised norm scores for the Box and Block test are not available for individuals younger than 20 years . For the youngest age group available , individuals between 20 and 24 , the norm score is 88.2 for the preferred hand . The performance of the participants with CP was consistently below these norms , even when using the LAH . Table 1Participant information for the participants with cerebral palsyParticipantAgeParetic sideB and Ba , cPPb , cCP115Right15/380/33CP217Left24 / 520/42CP317Left16/326 / 27CP415Right15/430/33CP514Left18 / 423/33CP619RightNAdNAdaBox and Blocks testbPurdue -- Pegboard testcAffected hand/less affected handdNot available for testing All participants received the same reimbursement -LRB- $ 6 per hour -RRB- for taking part . The study was approved by the local ethics committee and performed in accordance with the standards laid down in the 1964 Declaration of Helsinki . Setup and procedure The experimental setup is depicted in Fig. 1 . Participants were comfortably seated on a chair approximately centered at the midline of the table , which constituted the working region for the experiment . Two objects -LRB- blue and green -RRB- , two target regions , and an optional obstacle were placed on the table , as well as a fixation target -LRB- see Fig. 1 and caption for details -RRB- . Two loudspeakers , placed below the table , were used to verbally instruct the participant through a pre-recorded voice . The experimenter sat facing the participant at a separate table . From this position he was able to supervise the experiment by instructing the participant , starting and terminating the trials , and monitoring participants ' performance -LRB- directly and via a computer monitor that showed the eye movement recording system 's output in real time -RRB- . Fig. 1Experimental setup -LRB- top view -RRB- . The participant is seated at the table , with the right hand resting at the starting position . Positions of objects -LRB- blue and green cylinder , 6 cm in height , 3 cm in diameter , with an enlarged stabilizing basis of 6 cm in diameter -RRB- , target regions -LRB- blue and green disc , 10 cm in diameter , contralateral to the corresponding object -RRB- , optional obstacle -LRB- cylinder , 15 cm in height , 6 cm in diameter -RRB- , and the pre-trial fixation target -LRB- red ball 2 cm in diameter mounted on a frame at about eye height -RRB- are shown . The experimenter was seated at a separate desk facing the participant . The dashed line represents the object transport movement from object to target region in a `` blue '' trial . The x - and z-axis of the Optotrak system were approximately aligned to the axes indicated here , the y-axis was orthogonal to both -LRB- vertical axis -RRB- For each participant , the experiment consisted of eight conditions in a 2 × 2 × 2 factorial design , with the factors hand -LRB- AH/LAH for the participants with CP , NPH/PH for controls -RRB- , obstacle -LRB- present , absent -RRB- and side -LRB- blue , green -RRB- . In each of these conditions , five trials were performed , yielding a total of 40 trials per subject . The factors hand and obstacle were blocked while side was randomized within blocks . The order of the blocks was partially counterbalanced between participants . Prior to each trial , the participant was instructed to rest the `` inactive '' hand in his/her lap , such that it did not interfere with the task . Each trial started with the task-hand resting at the starting position , and with gaze directed to the fixation target . After a variable delay -LRB- 500 -- 1,500 ms -RRB- , the pre-recorded instruction `` green '' or `` blue '' -LRB- in Dutch -RRB- was played , upon which , the participant was to grasp the corresponding object and transport it to and place it on the contralateral target region of the same color . When an obstacle was present , the object had to pass in front of it , that is , between obstacle and participant -LRB- see Fig. 1 , dashed arrow-line -RRB- . After placing the object on the target region , the participant moved his/her hand back to the starting position and the experimenter put the cylinder back to its original location . When a trial failed , for instance because the cylinder slipped out of the participant 's hand , it was immediately repeated . This never occurred more than twice in a single participant . Data acquisition During the experiment , hand and head movements were recorded using an Optotrak 3020 system -LRB- sampling rate set at 125 Hz -RRB- . Four Optotrak markers were located on the Eyelink helmet -LRB- see below -RRB- to monitor position and orientation of the head . Hand movements were recorded by means of a marker placed on the back , each of the participant 's hands near the head of the second metacarpal . For two participants with CP , this position did not guarantee sufficient visibility of the marker on the AH due to individual grasping patterns -LRB- excessive arm pronation leading to a thumb-down grasping posture -RRB- . In these instances , the marker was placed more laterally on the hand . As we were mainly interested in the temporal aspects of the movements kinematics , this adjustment did not affect the measurement in a relevant way . The coordinate frame of the Optotrak system was oriented such that x , y and z axes roughly corresponded to the horizontal , vertical and posterior -- anterior dimension with respect to the participant 's position -LRB- see Fig. 1 -RRB- . Gaze direction was assessed using a head mounted Eyelink II system -LRB- sampling frequency 500 Hz -RRB- , which was calibrated twice during the experiment , before each of the main blocks that corresponded to the obstacle present/absent conditions . To calibrate the system , the subject was asked to look at 10 -- 15 points covering the frontal working plane . These points were manually indicated by the experimenter by using a stick on the end of which both a fixation target -LRB- small red ball with a diameter of 13 mm -RRB- and an Optotrak marker were attached . This `` interactive '' calibration method was chosen because pilot recordings revealed that two participants with CP failed to follow the instructions of the standard calibration procedure -LRB- employing a calibration board with LEDs -RRB- . In addition , the `` interactive '' method allowed for constant monitoring of the Eyelink system 's output by the experimenter -LRB- see `` Setup and procedure '' -RRB- . The position of the fixation target and the position of the eye relative to the Eyelink helmet were used to compute gaze direction . Gaze direction was subsequently transformed to a 2D signal by projecting it to the xy-plane . Linear regression between this direction and the raw Eyelink data was used to calibrate the system . Although calibration error -LRB- deviation between actual and reconstructed gaze direction for the calibration targets -RRB- was relatively large -- on average , 5 ° of visual angle , increasing towards the periphery -- it was well within the precision requirements needed to answer our research questions . Particular care was taken in the analysis of eye movements -LRB- see `` Eye movements '' -RRB- to minimize the effect of this inaccuracy . Preprocessing The raw Optotrak data were partially interpolated with cubic spline interpolation -LRB- up to ten successive samples , corresponding to 80 ms -RRB- and low-pass filtered -LRB- third order Butterworth filter with cut-off frequency of 10 Hz -RRB- . Hand velocity was computed by 3-point numerical differentiation . The raw Eyelink signal was transformed to relative gaze direction and integrated with the helmet position and orientation to yield absolute gaze direction . Approximate fixations were computed as the intersection of gaze direction with the plane parallel to the xy-plane -LRB- see Fig. 1 -RRB- and containing the centers of objects and target regions . Only data from one eye -LRB- selected by visual inspection for each individual participant -RRB- were used for further analysis . Gaze data were partially interpolated -LRB- up to four successive samples , corresponding to 8 ms , using cubic spline interpolation -RRB- and low-pass filtered -LRB- third order Butterworth with cut-off frequency of 20 Hz -RRB- . Subsequently , gaze velocity , acceleration , and jerk -LRB- second time differential of velocity -RRB- were computed by repeated 3-point numeric differentiation . Data reduction Hand movements Hand movements were identified using an absolute velocity threshold -LRB- 0.20 m/s -RRB- and a direction criterion -LRB- start of a new movement indicated by a reversal of horizontal direction -RRB- . These criteria provided the algorithms for the semi-automatic custom-written selection routines for the segmentation of the trials . Based on this segmentation , the grasp time -LRB- interval between the hand reaching and leaving the object region -RRB- and hand movement duration -LRB- interval between the hand leaving the object and reaching the target region -RRB- were determined . Analysis of eye -- hand coordination was confined to the object transport phase that is from onset of the hand movement away from the object region till the end , reaching the target region . The duration of this movement was determined . Eye movements Saccades were detected using a jerk -LRB- second time differential of velocity -RRB- criterion , which has been shown to be more reliable than methods based purely on gaze velocity or acceleration , especially for head-free eye movement recordings . A saccade was scored whenever jerk exceeded 200.000 ° / s3 , with an additional velocity requirement -LRB- 50 ° / s -RRB- -LRB- see Wyatt 1998 , for similar analaysis -RRB- . Saccade termination was determined as the first moment after saccade onset at which velocity dropped below 50 ° / s . The total number of saccades registered in the experiment was 4,613 . Saccade initiation/termination time was determined when none of the first or last eight samples -LRB- 16 ms -RRB- were missing . Saccade peak velocity was determined , when in addition no more than four samples were missing in a row throughout the entire saccade . According to these criteria , saccade initiation and termination time could not be determined in 5.5 % of all saccades , and peak velocity could not be determined in 10.5 % of all saccades . To test for potential group differences in basic eye movement kinematics , saccade main sequences were plotted , based on the saccades for which the peak velocity could be determined . Main sequences showed , for both groups , the typical linear relationship between amplitude and duration -LRB- e.g. , Carpenter 1988 -RRB- , and the log-linear relationship between amplitude and peak velocity for all participants of both groups . No significant group differences were found in gradient or intercept of linear regressions of these relationships -LRB- all p > 0.05 , Welch 's unpaired t-test -RRB- . Subsequently , for each trial the `` object-leaving '' and the `` target-reaching '' saccade were determined -LRB- in many trials these saccades coincided since there was a single gaze shift from object to target -RRB- . Automatic detection of these saccades was complicated by the fact that precision of gaze data was not sufficient for a procedure based on landmark regions around object and target . Therefore , the following semi-automatic two-step procedure was adopted . First , fixations to object and target were determined automatically , assuming that these occurred before -LRB- up to − 600 ms -RRB- the beginning and at the end of object transport . Fixation periods were defined as intervals of at least 200 ms , during which , the standard deviation of absolute gaze fixation was smaller than 5 mm . Note that this automatic procedure did not use absolute landmark regions but relative position information -- this was possible because the object and target were placed at the lateral extremes of the working region of the experiment . For the obstacle , an analogous procedure was not possible . Choices of this first step were inspected trial by trial and manually corrected if necessary . Obstacle fixations were not taken into account since it was not always possible to reliably distinguish them from other , frequently occurring intermediate fixations between object and target . Second , an automatic routine was used to detect the object-leaving saccade , defined as the first saccade , at the end of which , gaze had moved more than 10 ° horizontally relative to the object fixation . Based on an analogous 10 ° criterion , the target-reaching saccade was determined at the end of object transport . Thus , small -LRB- < 10 ° -RRB- corrective saccades at the end of object transport were ignored in the definition of the target-reaching saccade . Eye -- hand coordination Visual monitoring during object transport was quantified by the number of intermediate fixations , that is , the number of gaze shifts minus one occurring between the object-leaving and the target-reaching saccade . Note that this number does not include potential small corrective saccades at the end of object transport , since the target-reaching saccade was defined as the last saccade of horizontal amplitude > 10 ° reaching the target region . To examine temporal coordination between eye and hand at the beginning and end of object transport , two variables were computed : the movement onset asynchrony -LRB- MOA -RRB- and the movement termination asynchrony -LRB- MTA -RRB- . The MOA was defined as the interval between the start of the object transport movement and the onset of the object-leaving saccade , with larger -LRB- positive -RRB- values corresponding to later gaze departure . Similarly , the MTA was determined by the delay between the termination of the object transport movement and the end of the target-reaching saccade , with smaller -LRB- negative -RRB- values corresponding to earlier target fixation . To eliminate a potential confounds with hand kinematics -LRB- in particular in the comparison of AH and LAH in participants with CP -RRB- , both MOA and MTA were normalized with respect to hand movement duration -LRB- expressed as percentage of the latter -RRB- . With respect to our experimental hypotheses , we predicted that closer visual monitoring would be reflected in greater gaze-hand proximity -LRB- smaller average angular distance -RRB- , larger number of intermediate gaze fixations , and delayed gaze departure from the object region -LRB- that is , a longer MOA -RRB- . Regarding prospective control , we assumed that less anticipatory gaze patterns would be reflected in delayed departure from the object region -LRB- longer MOA -RRB- and delayed arrival on target -LRB- shorter/less negative MTA -RRB- . Statistical analysis Data from one control participant were excluded due to insufficient quality of the Eyelink data , leaving data from six experimental and nine control subjects for statistical analysis . For each of the five variables of hand kinematics and eye -- hand coordination introduced in `` Data reduction '' , the means averaged across all replications in each condition were submitted to a three-way repeated measures ANOVA with one between-subject factor -LRB- group : CP/control -RRB- and two within-subject factors -LRB- hand : AH/LAH , NPH/PH ; obstacle : present/absent -RRB- . Subsequent analyses of simple effects were performed using paired t-tests for within-subject factors , and Welch 's unpaired t-test -LRB- no equal variance assumed -RRB- for the between-subject factor . To correct for multiple -LRB- five -RRB- ANOVAs , the critical significance level was set to 0.01 . Results Of the total 15 × 40 = 600 trials , seven trials were entirely rejected due to insufficient data quality -LRB- no more than two trials in any individual participant -RRB- . Sample trials Figures 2 and 3 show representative trials from participants with CP and control participants . Horizontal components of head and hand position and gaze fixation -LRB- see `` Data reduction '' -RRB- are plotted on the vertical axis , as a function of time . The intervals and durations of the -LRB- non-normalized -RRB- MOA and MTA are indicated by vertical arrows and numerically in the plots . To allow comparisons between the plots , all data shown are from obstacle present trials . Visual inspection indicates qualitatively similar patterns -LRB- saccadic gaze shifts to future hand targets -RRB- in all conditions , and for both participant groups . Complete visual tracking of the trajectory of the hand was found only in a few trials -LRB- detected by visual inspection -RRB- in two participants with CP when using their AH . For these trials , MOA and/or MTA could not be determined . Fig. 2Sample trials of two control participants , using their PH -LRB- a , c -RRB- and NPH -LRB- b , c -RRB- in trials with the obstacle present . Interpolated data points are represented by dashed lines . Vertical arrows at the top and bottom of the plots specify the intervals defining the MOA and MTA -LRB- beginning/end of hand and eye movement -RRB- , with numerical values of these measures addedFig . 3Sample trials of two participants with CP , using their LAH -LRB- a , c -RRB- and AH -LRB- b , d -RRB- in trials with the obstacle present . Note the delayed gaze departure -LRB- longer MOA -RRB- and increased number of intermediate fixations for the AH compared to the LAH and to both hands of control participants -LRB- Fig. 2 -RRB- . Interpolated data points are represented by dashed lines . Vertical arrows at the top and bottom of the plots specify the intervals defining the MOA and MTA -LRB- beginning/end of hand and eye movement -RRB- , with numerical values of these measures added The representative trials shown in Fig. 2 -LRB- control participants using their PH and NPH -RRB- and Fig. 3 -LRB- participants with CP using their LAH and AH -RRB- illustrate some general trends when participants with CP use their AH . These are a prolonged MOA , a larger number of intermediate fixations and a greater gaze-hand proximity compared to the other combinations of group and task hand . These observations are in agreement with the hypothesis of increased visual monitoring -LRB- see Eye -- hand coordination '' -RRB- , and this is corroborated by the statistical analysis presented below . In contrast , no clear pattern with respect to the MTA is obvious from these data plots , nor from the statistical analysis . Dependent variables Values for the different dependent variables are summarized in Table 2 . Due to missing samples , some of the measures reported below could not be determined in a number of trials . This number did not exceed 40 out of 600 trials -LRB- never more than five out of ten in a single condition and participant -RRB- for any of the variables . Table 2Mean and standard deviation -LRB- between participants -RRB- of dependent variablesDependent variableParticipants with CPControl participantsLAHaAHbPHcNPHdNo obstacleObstacleNo obstacleObstacleNo obstacleObstacleNo obstacleObstacleHand movement duration -LRB- s -RRB- Mean0 .811.051.051.600.610.83 0.650.87 SEM0 .030.050.030.150.010.020.020.03 Object grasp time Mean0 .220.251.071.160.0630.0710.0860.094 SEM0 .030.040.140.160.0090.010.0170.015 Number of intermediate fixations Mean0 .240.820.76 1.300.06 0.73 0.07 0.61 SEM0 .090.340.241.210.040.220.060.26 Movement onset asynchrony -LRB- % hand movement duration -RRB- Mean − 6.881.5313.4 14.62 − 4.45 0.02 − 3.143.84 SEM5 .814.964.372.124.844.214.844.37 Movement termination asynchrony -LRB- % hand movement duration -RRB- Mean − 76.8 − 61.2 − 49.5 − 51.4 − 75.7 − 65.6 − 71.5 − 62.2 SEM5 .396.872.843.644.393.784.643.56 aLess affected handbAffected handcPreferred handdNon-preferred hand Grasp time showed main effects of group , hand as well as a group -- hand interaction -LRB- ANOVA , all p-values < 0.0001 -RRB- . Both , with the AH and the LAH participants with CP showed a longer grasp time than controls using either hand . The simple effect of hand was only present in participants with CP -LRB- longer grasp time with the AH compared to the LAH -RRB- . Hand movement durations for object transport showed main effects of group , hand , and obstacle , as well as a group -- hand interaction -LRB- ANOVA , all p-values < 0.0001 -RRB- . Simple effect analysis revealed that the effect of hand was present in both groups , but more pronounced in participants with CP . Moreover , the movement duration was longer in participants with CP and in the presence of an obstacle -LRB- Fig. 4 -RRB- . Fig. 4Mean ± SEM of the movement onset asynchrony -LRB- MOA -RRB- as a function of participant group , task hand and obstacle presence . MOA was normalized with respect to hand movement duration Regarding the number of intermediate fixations during object transport , a main effect of obstacle -LSB- F -LRB- 1,13 -RRB- = 15.06 , p < 0.002 -RSB- was found , as well as a group -- hand interaction -LSB- F -LRB- 1,13 -RRB- = 12.36 , p < 0.005 -RSB- . Analysis of simple effects showed that the number of intermediate fixations was larger in the obstacle present condition than in the obstacle absent condition . With respect to the group -- hand interaction , significant differences were found between participants with CP using their AH and control participants using either hand -LRB- higher number of intermediate fixations for CP using AH -RRB- , but not between the AH versus LAH of participants with CP . Temporal eye -- hand coordination at the beginning of object transport , as quantified by MOA -LRB- see Fig. 4 -RRB- , showed main effects of hand -LSB- F -LRB- 1,13 -RRB- = 17.25 , p < 0.002 -RSB- and a group -- hand interaction -LSB- F -LRB- 1,13 -RRB- = 12.55 , p < 0.005 -RSB- . The simple effect of hand was present in participants with CP , with longer MOA in the AH condition , but not in control participants . Moreover , there was a significant difference -LRB- prolonged MOA -RRB- between participants with CP using their AH and control participants using either hand . With respect to MTA , a main effect of hand -LSB- F -LRB- 1,13 -RRB- = 25.68 , p < 0.0005 -RSB- , a group -- hand interaction -LSB- F -LRB- 1,13 -RRB- = 14.189 , p < 0.005 -RSB- were found , as well as a marginally significant group -- hand -- obstacle interaction -LSB- F -LRB- 1,13 -RRB- = 8.19 , p = 0.013 -RSB- . The simple effect of hand was present only in participants with CP , with a shorter -LRB- less negative -RRB- MTA when using the AH . Also the difference between participants with CP using the AH and control participants using either hand was significant -LRB- shorter MTA in participants with CP using the AH -RRB- . Discussion The main question we pursued in the present study was whether and in which way individuals with hemiparetic CP adapt eye -- hand coordination to their sensorimotor impairments , in particular , when actions are performed with the affected hand -LRB- AH -RRB- . We hypothesized that participants with CP would more closely monitor actions performed with their AH , compared to actions performed with their less affected hand -LRB- LAH -RRB- and compared to neurologically healthy control participants using either hand . Qualitatively , eye -- hand coordination patterns were similar among control participants and participants with CP , regardless of the hand used to perform the task . That is , anticipatory saccadic gaze shifts were used to fixate future `` action sites '' -- such as object , target , or intermediate fixations -- in advance . Notwithstanding these qualitative resemblances , a more fine-grained analysis of temporal and spatial aspects of eye -- hand coordination did confirm our hypothesis of increased visual monitoring when moving with the AH . Depending on the measure employed , this effect was present when comparing performance with the AH to control participants using either hand -LRB- increased number of intermediate fixations -RRB- , or in addition for comparing performance with the AH to performance with the LAH in participants with CP -LRB- delayed gaze departure from object and hand , i.e. , a longer MOA -RRB- . It is important to note that our main result regarding visual monitoring is an interaction effect of group and task hand -LRB- effect of task hand was present only in the experimental group -RRB- . Therefore , it can not be explained by potential group differences in oculomotor control or gaze data quality . Moreover , despite previous findings that did not find a strong relationship between gaze-exit time relative to hand action and task speed -LRB- Flanagan and Johansson 2003 -RRB- , we decided to normalize our measures of temporal eye -- hand coordination in order to exclude any potential confounding effects of hand kinematics . This normalization may be considered rather conservative . Without normalizing , the effects of task and participant group on MOA may have even been stronger . A second , and more speculative hypothesis of the present study was that in general , gaze patterns might be less anticipatory in participants with CP , contributing to deficits in prospective control and action planning that have been reported in this population -LRB- Steenbergen et al. 2000a , 2004 ; te Velde et al. 2005 -RRB- , in particular , individual with right hemiparesis . The present study found no evidence in support of this hypothesis . Although participants with CP did show a prolonged MOA , that is , a delayed gaze departure that may indicate less anticipation , this effect was restricted to the AH . No significant differences in the MOA were found between actions of participants with CP using their LAH and control participants using their PH. Similarly , for our measure of temporal eye -- hand coordination at the end of object transport -LRB- the movement termination asynchrony , MTA -RRB- , a delayed gaze arrival on target was only present in participants with CP using their AH , not as a general group effect . In addition , preliminary analyses had shown no difference between individuals with left and right hemiparesis with respect to any of our dependent variables . Thus our results suggest that deficits in prospective action control found in CP are not directly related to atypical eye -- hand coordination . However , this statement is made with caution as we only tested a small number of participants -LRB- n = 6 in total , n = 3 for each left and right hemiparesis -RRB- . An unexpected finding of the present study was that gaze frequently departed from the object region only after the hand movement had started , in particular , in the presence of the obstacle . This was also the case in control participants and is in contrast to the results of Johansson et al. -LRB- 2001 -RRB- , who reported that in the majority of the trials gaze departure from the grasp site occurred even before the fingertips had reached the object . These contrasting findings may in part be explained by differences in the experimental set-up . In the present study the distance between initial object position and the target was much larger compared to the one used by Johansson et al. -LRB- 2001 -RRB- , leading to longer hand movement durations . This potential confounding effect of hand movement duration needs to be addressed in future research , for instance , by systematically manipulating hand movement distance in order to disentangle components of online and prospective control in the MOA . Also , task complexity might play a role . In a block-stacking task , Flanagan and Johansson -LRB- 2003 -RRB- found gaze to depart on average just before hand movement onset , which is more consistent with our present findings . In sum , we found evidence in support the hypothesis of increased visual monitoring of manual actions of individuals with hemiparetic CP performing actions with their AH , both at the beginning and during object transport . This may reflect a strategy of visual compensation for sensorimotor deficits -LRB- see also , Mulder et al. 2001 -RRB- . However , since the functional significance of the observed gaze patterns was not addressed in the present study , the question whether and by which neurophysiological mechanisms vision enhances manual performance requires further research . Generalizability of our results is certainly limited by the fact that our experimental group was relatively small -LRB- n = 6 -RRB- and highly selective , considering the high variability in the CP population regarding intellectual and motor abilities . In particular , the null-findings on anticipatory control and the comparison of individuals with left and right hemiparesis should be considered preliminary and require further investigation . On the other hand , the fact that we did find significant effects with respect to online visual control -LRB- number of intermediate fixations and MOA -RRB- despite the small number of participants suggests that the observed effects are robust .

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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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

sensorimotor impairment
visuomotor control
prehension
affected side