Concordance

between

school

outcomes

and

developmental

follow-up

results

of

very

preterm

and/or

low

birth

weight

children

at

the

age

of

years

Introduction

Long-term

follow-up

studies

have

revealed

a

high

frequency

of

developmental

disturbances

in

preterm

survivors

of

neonatal

intensive

care

who

were

formerly

considered

to

be

non-disabled

These

developmental

disturbances

interfere

with

the

acquisition

of

everyday

skills

and

in

particular

with

normal

school

functioning

Introduction

The

survival

rate

of

very

preterm

-LRB-

VPT

completed

weeks

of

gestation

-RRB-

and

very

low

birth

weight

-LRB-

VLBW

g

-RRB-

children

has

steadily

improved

during

the

last

decades

but

the

prevalence

of

major

disabilities

or

handicaps

in

these

children

has

remained

stable

Follow-up

studies

have

shown

that

VPT

and

VLBW

infants

are

at

risk

with

regard

to

neurological

dysfunctioning

such

as

cerebral

palsy

and

mental

retardation

-LSB-

-RSB-

Even

more

children

of

these

groups

experience

difficulties

in

intellectual

speech

and

language

skills

as

well

as

clumsiness

and

attention

and

behaviour

problems

all

of

which

can

affect

school

functioning

-LSB-

-RSB-

Significant/severe

neurosensory

dysfunctioning

is

usually

detected

early

with

the

result

that

children

with

major

handicaps

often

attend

a

school

for

special

education

from

school

entry

Minor

developmental

impairments

and

disabilities

however

frequently

go

undetected

until

school

age

-LRB-

years

in

The

Netherlands

-RRB-

These

children

start

their

school

career

in

mainstream

education

Once

at

school

however

certain

learning

problems

may

become

apparent

during

the

first

years

-LRB-

the

kindergarten

years

-RRB-

but

more

often

these

appear

only

when

the

children

start

formal

academic

training

-LSB-

-RSB-

Several

reasons

may

explain

this

phenomenon

of

growing

into

educational

deficits

-LSB-

-RSB-

Mild

developmental

disturbances

usually

pose

no

problem

for

the

child

until

greater

demands

have

to

be

met

at

school

or

when

more

detailed

evaluations

are

made

In

addition

the

cumulative

effect

of

the

failure

to

acquire

basic

skills

and

the

resulting

declining

motivation

may

play

an

important

role

In

The

Netherlands

schools

are

focused

strongly

on

the

early

detection

of

children

who

need

special

assistance

After

year

of

education

at

the

age

of

teachers

usually

have

a

good

impression

of

both

the

cognitive

and

language

development

of

their

children

and

of

their

motor

skills

and

behaviour

Standardized

tests

are

used

to

assess

children

who

are

not

doing

well

at

school

and

the

data

from

these

tests

are

used

to

underpin

the

need

for

special

help

for

these

children

Additionally

many

neonatal

intensive

care

units

-LRB-

NICUs

-RRB-

have

follow-up

programmes

for

premature

children

in

which

standardized

assessments

of

different

domains

enable

an

overall

evaluation

of

the

child

's

development

Within

the

framework

of

follow-up

research

we

assessed

a

group

of

VPT

and

VLBW

children

at

the

age

of

years

in

different

developmental

domains

Perinatal

social

and

economic

data

as

well

as

information

on

school

functioning

were

available

This

provided

the

opportunity

to

compare

school

outcomes

and

developmental

follow-up

outcomes

assuming

that

developmental

skills

mediate

the

effects

of

biological

and

social

risk

factors

on

school

performance

-LSB-

-RSB-

We

studied

the

degree

of

agreement

between

follow-up

assessments

and

school

outcomes

as

well

as

the

most

important

characteristics

of

the

children

-LRB-

perinatal

developmental

and

socio-economic

-RRB-

in

this

context

Our

aim

was

to

obtain

a

understanding

of

the

-LRB-

potential

-RRB-

developmental

disturbances

in

order

to

facilitate

an

adequate

and

timely

signalling

of

children

who

need

special

help

to

meet

their

developmental

capacities

Methods

Study

population

The

study

population

consisted

of

infants

of

less

than

weeks

of

gestation

and/or

weighing

less

than

g

who

were

born

between

October

and

December

and

treated

in

three

Dutch

neonatal

intensive

care

units

the

Radboud

University

Nijmegen

Medical

Centre

the

Academic

Medical

Centre

Amsterdam

and

the

Máxima

Medical

Centre

Veldhoven

Mortality

before

the

age

of

years

was

-LRB-

-RRB-

Forty-six

children

-LRB-

-RRB-

were

excluded

because

they

had

participated

in

another

study

Thirty-three

children

-LRB-

-RRB-

with

severe

or

moderate

cerebral

palsy

blindness

mental

retardation

chromosomal

abnormalities

inborn

errors

of

metabolism

personality

developmental

disorders

and/or

attendance

at

special

schools

or

institutions

were

excluded

Sixty

children

-LRB-

-RRB-

of

non-Dutch

parents

were

excluded

from

the

analyses

since

school

problems

could

be

caused

by

language

and

cultural

problems

As

a

result

children

-LRB-

-RRB-

qualified

for

the

study

School

performance

and

socio-economic

situation

A

questionnaire

was

mailed

to

the

parents

of

the

participating

children

month

before

follow-up

assessments

were

to

be

carried

out

these

were

returned

when

the

family

attended

the

outpatient

clinic

for

the

assessment

The

paediatrician

initiated

the

follow-up

assessment

by

checking

the

questionnaire

and

exploring

the

answers

with

the

family

in

more

depth

Within

the

framework

of

the

present

study

we

analysed

questions

addressing

school

performance

and

educational

level

of

the

parents

-LRB-

low

middle

high

-RRB-

School

outcome

was

defined

in

two

categories

-LRB-

-RRB-

normal

-LRB-

mainstream

education

without

problems

which

means

no

remedial

teaching

or

other

forms

of

extra

help

-RRB-

or

-LRB-

-RRB-

problematic

-LRB-

mainstream

education

with

remedial

teaching

or

special

mainstream

education

i.e.

schools

for

children

with

mild

learning

behavioural

or

cognitive

problems

-RRB-

The

parents

were

asked

to

fill

in

the

school

items

together

with

the

schoolteacher

The

educational

level

of

the

parents

was

used

in

this

study

as

a

measure

of

the

social

and

economic

situation

-LRB-

SES

-RRB-

because

it

is

the

best

indicator

in

predicting

school

outcomes

in

The

Netherlands

-LSB-

-RSB-

Perinatal

data

Perinatal

data

were

prospectively

collected

during

admission

in

the

NICU

stored

in

the

NICU

databases

and

retrieved

for

data

analysis

The

following

individual

characteristics

and

perinatal

variables

were

considered

gender

multiple

birth

gestational

age

birth

weight

small

for

gestational

age

-LRB-

SGA

birth

weight

below

the

centile

-RRB-

low

Apgar

score

-LRB-

-RRB-

intracranial

haemorrhage

grade

and

-LRB-

ICH

-RRB-

-LSB-

-RSB-

periventricular

leucomalacia

-LRB-

PVL

-RRB-

bronchopulmonary

dysplasia

-LRB-

BPD

oxygen

dependency

at

weeks

postconceptional

age

or

at

days

of

life

-RRB-

ante

or

postnatal

use

of

steroids

and

length

of

stay

in

NICU

Assessment

at

the

age

of

years

Clinical

assessments

were

carried

out

on

the

health

and

neurological

functioning

of

the

children

-LRB-

not

reported

in

this

article

-RRB-

and

four

developmental

domains

cognition

language

motor

functioning

and

behaviour

A

paediatrician

a

child

psychologist

and

a

paediatric

physical

therapist

assessed

the

children

Appointments

were

scheduled

at

random

Cognitive

development

was

assessed

with

the

Revised

Amsterdam

Children

's

Intelligence

Test

-LRB-

RAKIT

-RRB-

for

children

aged

years

-LRB-

short

version

-RRB-

This

version

has

a

correlation

of

with

the

full-scale

test

The

concurrent

validity

with

the

Wechsler

Intelligence

Scale

for

Children-Revised

-LRB-

WISC-R

-RRB-

is

for

total

IQ

-LRB-

Intelligent

Quotient

-RRB-

-LSB-

-RSB-

This

test

included

logical

reasoning

word

knowledge

visual-motor

integration

and

word

fluency

It

also

included

visual

synthesis

for

children

younger

than

years

and

visual

analysis

and

memory

for

children

aged

years

or

older

The

norm

score

-LRB-

IQ

score

-RRB-

of

the

test

is

with

a

standard

deviation

-LRB-

SD

-RRB-

of

All

scores

higher

or

equal

to

are

classified

as

normal

while

scores

below

or

SD

's

are

classified

as

mild

or

severe

cognitive

problems

respectively

The

Dutch

Language

Screening

Test

assessed

language

and

speech

This

test

consists

of

items

covering

the

use

of

vocabulary

comprehension

memory

and

production

of

language

use

of

plurals

prepositions

and

pronunciations

The

total

score

varies

from

to

with

a

score

considered

to

be

normal

that

of

considered

to

indicate

mild

problems

and

that

of

to

indicate

severe

problems

-LSB-

-RSB-

The

Movement

Assessment

Battery

for

Children

-LRB-

Movement

ABC

-RRB-

was

used

to

assess

motor

skills

A

total

motor

impairment

score

-LRB-

range

-RRB-

was

computed

by

summing

the

scores

on

all

motor

tasks

A

total

score

-LRB-

centile

-RRB-

was

considered

to

be

normal

from

through

to

-LRB-

centile

-RRB-

considered

to

indicate

children

at

risk

and

to

indicate

abnormal

motor

development

-LSB-

-RSB-

To

assess

behavioural

outcomes

we

used

the

Child

Behaviour

Checklist

for

children

aged

years

-LRB-

CBCL

-RRB-

This

is

a

standardized

parental

questionnaire

used

to

describe

the

skills

and

behavioural

problems

of

children

It

comprises

descriptions

of

behavioural

problems

with

each

description

scored

as

-LRB-

not

true

-RRB-

-LRB-

somewhat

or

sometimes

true

-RRB-

or

-LRB-

very

true

or

often

true

-RRB-

A

total

problem

score

is

obtained

by

summing

all

items

The

severity

of

the

behaviour

problems

can

be

the

borderline

and

clinical

cut-off

point

corresponding

with

standardized

norm

scores

of

and

respectively

-LSB-

-RSB-

A

normal

score

is

a

mild

problematic

score

is

and

and

a

severe

problem

score

is

Statistical

analysis

In

order

to

compare

the

results

of

the

follow-up

assessments

and

school

outcomes

we

cross-tabulated

categorical

data

originating

from

the

individual

developmental

test

results

of

the

children

with

school

outcomes

-LRB-

normal

or

problematic

-RRB-

Normal

follow-up

outcomes

were

defined

as

four

normal

developmental

scores

or

only

one

mild

developmental

problem

score

Problematic

follow-up

outcomes

were

defined

as

two

mild

developmental

problem

scores

one

severe

developmental

problem

score

or

two

or

more

severe

developmental

problem

scores

Cross-tabulation

was

also

used

to

describe

the

relation

between

the

follow-up

assessment

outcomes

and

the

school

outcomes

and

the

nominal

variables

-LRB-

chi-square

for

testing

-RRB-

A

one-way

analysis

of

variance

was

used

to

assess

within

each

of

the

follow-up

outcomes

the

differences

between

the

two

types

of

school

outcomes

on

the

interval

variables

-LRB-

F

test

for

testing

-RRB-

The

general

linear

model

-LRB-

GLM

-RRB-

was

used

for

multivariate

testing

of

the

differences

between

the

two

school

outcome

groups

within

each

of

the

two

follow-up

outcome

groups

Results

Of

the

children

included

in

this

follow-up

study

-LRB-

-RRB-

were

not

assessed

for

various

reasons

-LRB-

Table

-RRB-

Consequently

all

outcome

data

including

developmental

data

were

collected

on

children

at

the

age

of

years

No

significant

differences

were

found

in

perinatal

data

between

assessed

partly

assessed

and

unassessed

children

with

the

exception

of

multiple

births

in

that

they

were

overrepresented

in

the

assessed

group

-LSB-

-RSB-

Table

and

assessed

children

nPercentagenPercentageCohort

Excluded

because

of

participation

in

an

other

Excluded

because

of

severe

handicap

and/or

in

Special

Children

of

non-Dutch

Address

Moved

outside

the

Treated

in

another

Impossibility

to

make

a

convenient

Refusal

by

the

Assessment

not

fully

Mutual

correlations

between

child

characteristics

and

perinatal

variables

were

present

but

rather

low

The

percentage

of

children

with

all

follow-up

assessment

results

being

normal

or

with

only

one

mild

developmental

problem

score

was

-LRB-

n

-RRB-

-LRB-

n

-RRB-

of

the

children

had

at

least

two

mild

problems

or

one

or

more

severe

problems

according

to

the

four

developmental

tests

No

school

problems

were

reported

for

children

-LRB-

-RRB-

while

children

-LRB-

-RRB-

were

reported

to

school

problems

as

reflected

in

the

need

for

special

help

-LRB-

remedial

teaching

or

other

forms

of

extra

help

or

specialized

mainstream

education

-RRB-

One

hundred

and

seventy-five

children

-LRB-

of

the

study

group

-RRB-

had

normal

school

outcomes

and

normal

follow-up

outcomes

and

children

-LRB-

of

the

study

group

-RRB-

had

problematic

follow-up

outcomes

and

problematic

school

outcomes

These

results

show

that

for

-LRB-

n

-RRB-

of

the

children

there

was

a

positive

relation

between

school

outcomes

and

the

results

of

the

follow-up

assessments

Fifty-three

children

-LRB-

of

the

study

group

-RRB-

had

school

problems

while

their

developmental

test

scores

were

normal

and

children

-LRB-

of

the

study

group

-RRB-

did

not

receive

any

extra

help

at

school

although

they

had

test

scores

that

fell

in

the

problematic

range

However

for

children

-LRB-

-RRB-

there

was

no

concordance

between

the

school

outcomes

and

follow-up

assessment

results

-LRB-

Table

-RRB-

A

significant

difference

-LRB-

χ2

p

-RRB-

was

found

between

the

two

school

outcome

groups

with

more

developmental

problems

in

the

school

problem

group

Children

who

received

special

help

at

school

although

they

had

obtained

normal

follow-up

assessment

results

differed

significantly

from

the

children

with

normal

follow-up

results

without

special

assistance

This

subgroup

comprised

more

boys

and

SGA

children

who

had

lower

Movement

ABC

scores

-LRB-

motor

skills

-RRB-

and

in

particular

lower

language

screening

test

scores

Table

outcomes

versus

school

outcomesSchool

outcomes

Normal

n

-LRB-

-RRB-

Problematic

n

-LRB-

-RRB-

Total

n

-LRB-

-RRB-

Follow-up

outcomes

Normal

n

-LRB-

-RRB-

Four

normal

developmental

-LRB-

-RRB-

-LRB-

-RRB-

One

mild

developmental

problem

-LRB-

-RRB-

-LRB-

-RRB-

Problematic

n

-LRB-

-RRB-

Two

mild

developmental

problem

-LRB-

-RRB-

-LRB-

-RRB-

One

severe

developmental

problem

-LRB-

-RRB-

-LRB-

-RRB-

Two

or

more

severe

developmental

problem

-LRB-

-RRB-

-LRB-

-RRB-

For

children

who

did

not

receive

any

extra

help

at

school

even

though

problematic

follow-up

assessments

were

found

the

results

differed

significantly

from

those

who

did

receive

extra

help

This

subgroup

was

less

preterm

had

higher

Apgar

scores

had

had

BPD

less

often

and

was

treated

less

frequently

with

steroids

during

the

neonatal

period

Their

scores

on

the

Movement

ABC

the

language

screening

test

and

in

particular

on

the

RAKIT

-LRB-

intelligence

test

-RRB-

were

better

-LRB-

Tables

and

-RRB-

Within

each

of

the

follow-up

assessment

groups

-LRB-

normal

or

problematic

assessment

results

-RRB-

the

MANOVA

showed

significant

differences

between

the

two

school

outcome

groups

-LRB-

F

p

df

and

F

p

df

respectively

-RRB-

Table

standard

deviations

-LRB-

SD

-RRB-

and

one-way

analyses

of

variance

for

normal

and

problematic

school

outcomes

Follow-up

outcomesSchool

outcomesNormalProblematicFMeanSDMeanSDGestational

Birth

NICU

RAKIT

Movement

Language

CBCL

Total

problem

p

p

Table

of

child

's

characteristics

perinatal

data

and

parents

education

with

normal

and

problematic

school

outcomes

Follow-up

outcomesSchool

outcomesχ2NormalProblematicPercentagePercentageMaleNormal42574

Multiple

Apgar

Neonatal

Parents

Parents

Parents

p

p

Discussion

The

developmental

skills

of

children

are

largely

expressed

in

school

functioning

-LSB-

-RSB-

Therefore

it

would

be

expected

that

there

is

a

great

concordance

between

the

assessments

of

the

NICU

follow-up

teams

and

school

teams

with

respect

to

the

identification

of

children

who

need

special

assistance

at

school

The

results

of

this

study

support

this

expectation

with

respect

to

children

with

good

developmental

outcome

assessments

and

those

with

obvious

problematic

developmental

outcomes

While

the

latter

group

mainly

consisted

of

children

with

very

low

gestational

ages

and/or

serious

perinatal

problems

some

were

being

faced

with

the

direct

adverse

consequences

of

the

use

of

neonatal

steroids

-LSB-

-RSB-

It

is

likely

that

the

problems

of

these

children

and

the

genuine

concern

of

parents

and

teachers

has

offered

them

the

extra

attention

and

assistance

they

required

Children

with

relatively

normal

developmental

outcomes

who

notwithstanding

this

received

extra

help

at

their

schools

still

had

language

and/or

motor

problems

that

apparently

interfered

with

school

functioning

thereby

causing

schoolteachers

to

provide

them

with

extra

attention

and

help

The

overrepresentation

of

boys

in

this

group

as

in

both

groups

with

problematic

developmental

outcomes

is

a

frequent

finding

-LSB-

-RSB-

and

because

their

behavior

is

often

more

demonstrative

there

is

a

stronger

need

to

deal

with

More

children

who

were

SGA

were

also

found

in

this

group

A

number

of

these

were

still

small

at

the

age

of

years

which

may

have

led

to

overprotection

or

the

conviction

that

the

child

needs

more

time

or

help

to

be

ready

for

reading

writing

or

arithmetic

-LSB-

-RSB-

Further

research

should

reveal

if

the

problems

of

this

latter

group

of

children

are

attributable

to

not

being

ready

for

learning

-LRB-

pre

-RRB-

academic

skills

or

to

still

being

too

playful

or

whether

it

concerns

serious

learning

and

developmental

problems

The

limited

number

of

children

with

developmental

problems

who

were

not

signalled

by

the

school

did

not

have

special

characteristics

with

the

exception

of

having

slightly

better

developmental

outcomes

and/or

having

not

been

born

extremely

premature

having

not

been

subjected

to

neonatal

steroids

and/or

having

had

a

somewhat

less

complicated

neonatal

period

It

is

possible

that

their

developmental

problems

did

not

interfere

with

school

functioning

or

they

were

able

to

compensate

for

them

but

it

is

also

possible

that

their

parents

and/or

teachers

did

not

signal

their

problems

adequately

Parents

are

sometimes

very

relieved

that

the

first

difficult

and

worrisome

years

are

over

and

unconsciously

cut

themselves

off

from

new

problems

or

both

parents

and

teachers

lower

their

expectations

and

demands

because

of

overprotection

We

did

not

find

that

less

well-educated

parents

had

more

difficulties

in

mobilizing

extra

help

for

their

children

than

relatively

well-educated

parents

Children

of

the

former

displayed

developmental

problems

more

often

but

they

received

extra

help

and

assistance

in

the

same

ratio

as

children

of

relatively

more

highly

educated

parents

Based

on

this

line

of

reasoning

a

possible

overrepresentation

of

children

of

less

well-educated

parents

in

the

unassessed

group

would

not

change

the

degree

of

concordance

between

the

follow-up

results

and

school

outcomes

One

may

question

whether

our

developmental

tests

were

sensitive

enough

to

register

minor

neurological

signs

In

the

overall

study

the

paediatrician

did

a

neurological

examination

-LRB-

the

modified

Touwen

examination

-RRB-

-LSB-

-RSB-

This

examination

classified

-LRB-

-RRB-

of

the

children

participating

in

this

study

with

neurological

problems

-LRB-

disabling

cerebral

palsy

non-disabling

cerebral

palsy

minimal

neurological

dysfunction

and

gross

motor

retardation

-RRB-

Ninety-five

-LRB-

-RRB-

of

these

children

were

also

classified

as

problematic

by

one

or

more

of

the

other

instruments

While

these

neurological

data

provide

a

more

complete

picture

they

do

not

improve

the

degree

of

concordance

between

school

outcome

and

follow-up

outcome

-LRB-

-RRB-

Of

the

preterm

children

tested

at

age

years

one-half

were

found

to

have

problems

in

the

developmental

assessments

or

in

school

functioning

This

outcome

confirms

the

findings

of

others

that

follow-up

research

in

more

than

one

developmental

domain

in

combination

with

school

outcomes

shows

a

more

problematic

outcome

picture

-LSB-

-RSB-

Schools

are

doing

quite

well

in

identifying

children

with

and

without

developmental

problems

but

the

need

for

longitudinal

multidisciplinary

follow-up

programmes

in

different

developmental

domains

remains

Information

that

promotes

the

understanding

of

the

development

of

these

children

during

their

school

career

provides

schools

and

parents

with

more

tools

for

early

detection

and

will

facilitate

the

design

and

evaluation

of

intervention

programmes

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

developmental outcome
low birth weight children
premature children
school outcome
school performance


Mucopolysaccharidosis type II -LRB- Hunter syndrome -RRB- : a clinical review and recommendations for treatment in the era of enzyme replacement therapy Mucopolysaccharidosis type II -LRB- MPS II ; Hunter syndrome -RRB- is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase , leading to progressive accumulation of glycosaminoglycans in nearly all cell types , tissues and organs . Clinical manifestations include severe airway obstruction , skeletal deformities , cardiomyopathy and , in most patients , neurological decline . Death usually occurs in the second decade of life , although some patients with less severe disease have survived into their fifth or sixth decade . Until recently , there has been no effective therapy for MPS II , and care has been palliative . Enzyme replacement therapy -LRB- ERT -RRB- with recombinant human iduronate-2-sulphatase -LRB- idursulfase -RRB- , however , has now been introduced . Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II . This paper provides an overview of the clinical manifestations , diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT . The issue of treating very young patients and those with CNS involvement is also discussed . ERT with idursulfase has the potential to benefit many patients with MPS II , especially if started early in the course of the disease . Introduction First described by Major Charles Hunter in 1917 -LSB- 15 -RSB- , mucopolysaccharidosis type II -LRB- MPS II or Hunter syndrome ; OMIM +309900 -RRB- is an X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase -LRB- I2S -RRB- . This enzyme cleaves O-linked sulphate moieties from the glycosaminoglycans -LRB- GAGs -RRB- dermatan sulphate and heparan sulphate as the first step in their degradative pathway . The clinical phenotype of MPS II -LRB- Fig. 1 -RRB- is characterised by progressive pathological lysosomal storage of GAGs in nearly all cell types , tissues and organs . Fig. 1Appearance of a child with mucopolysaccharidosis type II -LRB- Hunter syndrome -RRB- at -LRB- a -RRB- 6 years of age and -LRB- b -RRB- 12 years of age , illustrating the ` typical ' clinical phenotype at the more severe end of the disease spectrum . The manifestations of the syndrome and the rate of progression , however , may vary widely among individual patients Oropharyngeal and tracheo-bronchial deposition of GAGs leads to severe airway obstruction due to macroglossia , supraglottic narrowing , and tracheomalacia . This obstructive anatomy and physiology leads to sleep apnoea and airway obstruction . As the disease progresses , the respiratory system is further compromised by pulmonary restriction secondary to the effects of the disease on the thoracic skeleton . Deposition of GAGs in the heart , liver and spleen leads to cardiomyopathy , cardiac valve dysplasia and hepatosplenomegaly . Bone and joint involvement results in severe skeletal deformities and limitations of joint mobility . In patients with CNS involvement , severe learning difficulties and progressive neurological decline occur . The clinical manifestations of MPS II generally lead to death in the first or second decade of life , although in the more attenuated form of MPS II , death may occur in early adulthood , and some patients have survived into their fifth and sixth decades of life . Until recently , there has been no effective therapy for MPS II . Care has been palliative , focusing on management of the multiple clinical symptoms . Haematopoietic stem cell therapy -LRB- HSCT -RRB- has been attempted in some patients -LSB- 36 -RSB- , but the long-term results have been unsatisfactory . The recent introduction of enzyme replacement therapy -LRB- ERT -RRB- with recombinant human I2S -LRB- idursulfase -RRB- , however , has raised the possibility that the burden of GAG storage can be reduced and that the progressive tissue and organ damage associated with MPS II can be slowed or even prevented . The availability of ERT thus requires a greater awareness and understanding of the disease amongst a range of medical specialists and primary care physicians , so that early diagnosis can be made and treatment started before organ damage becomes irreversible . This article gives an overview of the clinical manifestations , diagnosis and symptomatic management of patients with MPS II and provides , for the first time , recommendations for the use of ERT . Incidence and inheritance Data from The Netherlands and Germany indicate that the incidence of MPS II is 1.3 per 100,000 male live births -LSB- 1 , 23 -RSB- . Two-thirds of patients present with CNS involvement , representing the more severe end of the disease phenotype . There have been very few reports of recurrent or common mutations within the gene encoding I2S . As a consequence , genotype -- phenotype correlations have been difficult to establish , with the exception of those patients who present with large deletions , which are most often associated with more severe disease -LSB- 38 -RSB- . As MPS II is an X-linked recessive condition , it would not be expected to affect females . Despite this , a few girls have been reported with MPS II -LSB- 35 -RSB- . Affected females generally have low levels of I2S activity and an attenuated clinical phenotype , although the somatic abnormalities can be severe in some individuals . In affected heterozygous females , skewed inactivation of the X-chromosome prevents expression of the normal allele -LSB- 35 -RSB- . Molecular basis of MPS II MPS II is the only known X-linked MPS disorder . The human gene encoding I2S has been mapped to Xq28 . It contains nine exons spread over 24 kb . Individuals with major deletions or rearrangements in the gene usually have severe MPS II . An I2S-like pseudogene , comprising copies of exons 2 and 3 and intron 7 , is located about 20 kb from the active gene -LSB- 34 -RSB- . A recurring rearrangement is due to recombination between the intron region of the gene and a homologous region near exon 3 of the pseudogene , with inversion of the intervening DNA -LSB- 3 -RSB- . Very large deletions of the I2S locus may extend to adjoining genes , as the neighbouring DNA is gene rich . A contiguous gene syndrome involving fragile X mental retardation -LRB- FMR1 and FMR2 -RRB- genes could possibly explain the unusual phenotypes seen in some severely affected patients -LSB- 33 -RSB- . Over 150 different mutations , resulting in a spectrum of disease phenotypes , have been described . General disease manifestations and diagnosis Treatment of possible disease complications can greatly improve quality of life . Early diagnosis is therefore essential , particularly with the recent introduction of ERT . Table 1 shows the common presenting features of patients with MPS II , together with the range of specialists who are likely to be involved in diagnosis and care . Table 1Presenting features of patients with mucopolysaccharidosis type II -LRB- Hunter syndrome -RRB- and the specialists likely to be involved in diagnosis and treatmentPresenting featureSpecialistRecurrent upper respiratory tract infections , recurrent otitis media , developmental delay , hepatosplenomegaly , joint restriction , coarse faciesPaediatricianPaediatric neurologistOtolaryngologistRecurrent ear infections , abdominal distension , stiff jointsPrimary care physicianUmbilical and inguinal hernias with recurrenceSurgeonHip dysplasia , arthropathyOrthopaedic specialistUpper airway obstruction , sleep apnoea , recurrent ear infections requiring tube placementOtolaryngologistPapilloedema in the absence of raised intracranial pressureOphthalmologistValvular thickening on echocardiographyCardiologistJoint pain and restrictionRheumatologistPapular pearly rash across the scapulaeDermatologistRestrictive joint range of motionPhysiotherapistCarpal tunnel syndromeHand surgeonCervical myelopathyNeurosurgeon Clinical spectrum of MPS II MPS II is a variable , progressive , multisystem disorder . In most patients , symptoms are severe and death occurs at an early age . In other patients the disease has a more chronic and protracted course . The age of presentation of MPS II is also variable , as are the presenting signs and disease complications . Figure 2 shows the age at onset of the main signs and symptoms of the disease in a cohort of 82 patients enrolled in HOS , the Hunter Outcome Survey . This is a multinational long-term outcomes survey to investigate the natural history of MPS II and the safety and efficacy of ERT with idursulfase -LSB- 8 -RSB- . Fig. 2Reported age at onset and prevalence of clinical features in 82 patients with mucopolysaccharidosis type II -LRB- Hunter syndrome -RRB- enrolled in HOS , the Hunter Outcome Survey The traditional classification of patients into ` mild ' or ` severe ' subtypes , on the basis of length of survival and the presence or absence of CNS disease , is a gross simplification . The disorder should rather be regarded as a continuum between two extremes -LRB- severe and attenuated -RRB- . It is important to note that individuals who are diagnosed with an attenuated form of the disease may still have symptoms and complications that lead to significant morbidity and disability , and may present with mild to moderate learning difficulties . Although the clinical course for the more severely affected patients is relatively predictable , there is considerable variability in the clinical phenotype and progression of the more attenuated form of the disease . Individuals with attenuated MPS II are most often diagnosed between the ages of 4 and 8 years . For the majority of these affected patients , the clinical course is very similar to the intermediate form of MPS I -LRB- MPS IH/S , Hurler -- Scheie disease -RRB- . Survival to adulthood is common , but death often occurs between the ages of 20 and 30 years from cardiac or respiratory disease -LRB- Fig. 3 -RRB- . A few patients are less severely affected . In these , life expectancy can be near normal , and such affected males may have children -LSB- 9 -RSB- . Fig. 3Mortality by age of patients with mucopolysaccharidosis type II -LRB- Hunter syndrome -RRB- in the UK . Data are from the Society for Mucopolysaccharide Diseases -LRB- MPS Society -RRB- and are based on patients registered with the MPS Society between 1950 and October 2006 Patients with the more severe form of MPS II exhibit a chronic and progressive disease involving multiple organs and tissues . They appear normal at birth , although they tend to be heavy , some have inguinal or umbilical hernias and there is an increased incidence of Mongolian blue spots -LSB- 25 -RSB- . The age at diagnosis is usually between 18 and 36 months , compared with 9 months for severe MPS I -LSB- 6 -RSB- . Death from a combination of neurological deterioration and cardiorespiratory failure usually occurs in the mid-teenage years . Physical appearance The typical patient with attenuated MPS II is short with some change of facial features . Significant arthropathy and connective tissue involvement lead to joint contractures . A combination of hepatomegaly and lax abdominal muscles leads to abdominal prominence . In the more severely affected patients , the typical facial features become apparent in the first 3 years . They are most likely caused by a combination of storage in the soft tissues of the orofacial region and underlying facial bone dysostosis . Thickening of the alae nasi , lips , ear lobules and tongue becomes progressively more obvious . The patients often develop a plethoric , rosy-cheeked appearance . Thickening of the calvaria results in macrocephaly . Facial and body hypertrichosis is often seen and the scalp hair becomes coarse , straight and thatch-like . Patients also develop specific , pearly , papular skin eruptions , which are usually first seen around the scapulae , but then spread to involve the trunk and upper thighs . These skin eruptions , first noted in Hunter 's original presentation , are said to be pathognomic for MPS II -LSB- 32 -RSB- . Development Infants with MPS II appear normal at birth , and early developmental milestones may also be normal , even in the presence of significant somatic disease . Developmental outcomes , however , are highly variable . Significant psychosocial problems occur in affected teenagers and young adults -LSB- 40 -RSB- . Even in patients with attenuated disease , cranial magnetic resonance imaging -LRB- MRI -RRB- scans are often grossly abnormal , with extensive white matter changes as well as dilated perivascular spaces , despite apparently normal intellectual skills -LSB- 27 -RSB- . Patients with more severe MPS II also appear normal at birth , and early developmental milestones may be normal . Some patients fail hearing screening tests in the first year , and speech delay is not unusual in more severely affected patients . By 18 -- 24 months , developmental delay is usually apparent . Most patients make very slow progress after this stage , with a developmental plateau beginning between 3 and 5 years of age . Unlike children with severe MPS I , who are usually placid , more severely affected children with MPS II can be hyperactive and aggressive . By the time of death in their second decade , most patients with CNS involvement are severely mentally handicapped and dependant on care providers for all their needs . Biochemical diagnosis Assessing urinary GAGs -LRB- heparan and dermatan sulphates -RRB- is the usual first screening test for MPS II , and can be quantitative -LRB- measurement of total urinary uronic acid -RRB- or qualitative -LRB- GAG electrophoresis -RRB- . Although neither test can offer a definitive diagnosis , abnormal measurements indicate the likely presence of an MPS disorder . The sensitivity of these tests , however , is not perfect , particularly when measurements are made on samples of dilute urine . Definitive diagnosis is established by enzyme assay in leukocytes , fibroblasts or plasma , using substrates specific for I2S . Another sulphatase should be measured in conjunction , in order to exclude multiple sulphatase deficiency . This is a much rarer disorder than MPS II and is generally associated with a very poor prognosis . It should be noted that the amount of enzyme activity measured in vitro from cellular extracts does not indicate where an individual falls within the MPS II spectrum of disease severity . Prenatal diagnosis Prenatal testing is available for foetuses at risk of MPS II . This is generally carried out by enzyme assay of I2S in uncultured chorionic villi , allowing early testing and rapid diagnosis of affected foetuses . Very low activities have been measured in some pregnancies with a -LRB- heterozygous -RRB- female foetus , emphasising the need to combine an enzyme assay with foetal sex determination -LSB- 7 -RSB- . Molecular-genetic prenatal testing can be performed if the mutation is known in the family . Carrier testing Previous methods of carrier detection based on an I2S assay in either plasma or hair roots are now known to be unreliable , as there is considerable overlap between the normal and heterozygous ranges . The only definitive test for determining carrier status is based on DNA analysis . In a small number of families , however , the mutation remains elusive , despite full sequencing of the I2S locus . Symptomatic treatment Even with the introduction of ERT , patients with MPS II still require supportive symptomatic treatment from a wide range of specialists . A comprehensive initial assessment of each patient at diagnosis should therefore be undertaken , and should be followed by regular reviews . Supportive management and the anticipation of possible complications can greatly improve the quality of life of affected individuals and their families . Family members should be offered genetic counselling , and contact with other affected families , patients and support groups can be helpful . Skeletal abnormalities Orthopaedic complications , caused by a combination of direct bone involvement and severe arthropathy , can lead to significant disability . The destructive arthropathy , which especially affects the hip joints , is a feature of the skeletal disease in some patients and may be due to secondary events occurring within chondrocytes and/or osteoblasts as a result of storage . Progressive arthropathy may affect all joints and leads to severe restriction of motion . The hip joints appear to be particularly vulnerable and severe erosive hip dysplasia can be especially disabling . Poor hand function , due to the characteristic claw-hand deformity , carpal tunnel syndrome and interphalangeal joint stiffness , is also common . Abnormal joint function is largely a result of both metaphyseal deformities and thickened joint capsules . Secondary erosive joint disease is particularly disabling and is extremely difficult to manage medically and/or surgically . The deformed acetabulum and pelvis makes prosthetic surgery a challenge , and many patients become wheelchair-bound because of hip pain . The role of physical therapy in MPS II is not well studied , but range-of-motion exercises appear to offer some benefit in preserving joint function and should be started at an early age . If significant restriction of joint movement has already occurred , range-of-motion exercises may slow further progression . Cardiovascular system Cardiac abnormalities detected by echocardiography are common in patients with MPS II . Valvular involvement , with thickening and stiffening of the valve leaflets , commonly leads to mitral and aortic regurgitation and/or stenosis -LSB- 24 -RSB- . Cardiomyopathy is much less common but may be associated with an increased risk of cardiac arrhythmia -LSB- 14 -RSB- . Valve replacement surgery may be necessary , and annual cardiac evaluation with echocardiography is essential . Bacterial endocarditis prophylaxis should be used where appropriate . The prevalence and age at onset of the main cardiovascular signs and symptoms as reported in HOS are shown in Table 2 . Table 2Prevalence and reported age at onset -LRB- median and 10th -- 90th percentiles -RRB- of the main cardiovascular manifestations of mucopolysaccharidosis type II -LRB- Hunter syndrome -RRB- in a cohort of 82 patients in HOS , the Hunter Outcome SurveyCardiac manifestationnPrevalence -LRB- % -RRB- Age at onset -LRB- years -RRB- Valvular disease34536 .2 -LRB- 2.9 -- 13.8 -RRB- Murmur32526 .4 -LRB- 3.7 -- 12.3 -RRB- Cardiomyopathy497 .6 -LRB- 5.2 -- 27.3 -RRB- Any cardiovascular sign/symptom49726 .0 -LRB- 2.9 -- 13.7 -RRB- Respiratory disease and upper airway manifestations Chronic recurrent rhinitis and persistent copious nasal discharge without obvious infection are common . Enlargement of the tonsils and adenoids , a narrowed trachea , tracheomalacia , thickened vocal cords , redundant tissue in the upper airway , and an enlarged tongue can contribute to upper airway complications -LSB- 4 , 26 , 39 -RSB- . The upper airway involvement leads to noisy breathing , particularly at night , and is probably a major component of obstructive sleep apnoea , which is a common complication in the later stages of the disease -LSB- 16 -RSB- . Because of the airway disease , there is a high risk associated with anaesthesia in these patients -LSB- 17 -RSB- . In patients with attenuated MPS II , rhinorrhoea tends to improve with age , but upper airway obstruction and sleep apnoea become more troublesome with increasing age . A progressive restrictive respiratory defect also becomes apparent with increasing age , mainly due to progressive changes in the thoracic skeleton . Sleep studies should form part of the regular assessment schedule , and significant episodes of hypoxia should be managed by continuous or bilevel positive airway pressure devices . Severely affected patients often find such treatment difficult to tolerate . In these patients , supplemental oxygen alone may be an acceptable alternative , but should be used with caution in patients with documented hypercapnia . Tonsillectomy and adenoidectomy are frequently performed to correct Eustachian tube dysfunction and to decrease airway obstruction . Severely affected patients also tend to have frequent ear infections and constant rhinorrhoea . Early placement of ventilating tubes is recommended in severely affected individuals . Gastrointestinal system Protuberance of the abdomen and hernias caused by progressive hepatosplenomegaly are common . Although organ size can become massive , storage of GAGs in the liver and spleen does not lead to either liver or splenic dysfunction . Patients are prone to periodic bouts of watery diarrhoea , which occur without apparent cause and are not associated with malabsorption . Rectal biopsies in affected patients have demonstrated storage within gut neural cells , and an autonomic cause for episodes of diarrhoea has been postulated -LSB- 10 -RSB- . With age , loss of muscle strength and physical inactivity lead to constipation . Abdominal hernias should be repaired surgically , though recurrence can occur . Diarrhoea can be controlled by diet and the use of antimotility drugs . Central nervous system Communicating high pressure hydrocephalus , which is common in MPS I , is rare in MPS II . Other CNS complications , such as seizures , are more common . They are usually tonic -- clonic in nature and respond to standard anticonvulsant treatment . Progressive compression of the spinal cord with resulting cervical myelopathy due to thickening of the dura -LRB- hypertrophic pachymeningitis cervicalis -RRB- and hyperplasia of the transverse ligament is common -LSB- 21 -RSB- . In addition , MRI scans of the craniocervical junction will often show deposition of GAG around the tip of the odontoid process . Most patients have a well-formed odontoid process and atlanto-axial subluxation is usually not a feature of MPS II . Cervical myelopathy may initially present as reduced activity , exercise intolerance or difficulty in rising from a sitting position . If it remains untreated , irreversible cord damage can occur . Hypertrophic pachymeningitis cervicalis and cervical compression secondary to hyperplasia of the transverse ligaments should be quickly and aggressively treated in patients with attenuated disease . Early and careful cervical decompression performed by an experienced team may prevent severe and devastating consequences . Peripheral nervous system Carpal tunnel syndrome is common in patients with attenuated forms of MPS II and should be promptly investigated and treated . Nerve conduction studies should be conducted to monitor patients , as the typical symptoms of compression -LRB- pain , tingling or numbness -RRB- do not occur -LSB- 13 -RSB- . Surgical decompression of the median nerve at an early stage of involvement results in either partial or complete improvement in most patients . Visual problems Although corneal opacity has been reported -LSB- 31 -RSB- , it is not generally a feature of MPS II and helps to distinguish the disorder clinically from severe MPS I and MPS VI . In addition glaucoma is rarely present , even in severely affected patients . Retinal degeneration resulting in decreased peripheral vision and poor dark adaptation is common , but often difficult to investigate fully in a severely affected patient . Disc oedema , uveal effusions and epiretinal membranes have all been reported as part of the variable ocular pathology -LSB- 2 , 20 , 37 -RSB- . Electroretinography confirms retinal degeneration in many patients , but a disturbance of vision apart from nyctalopia -LRB- ` night blindness ' -RRB- is rare . Chronic papilloedema without evidence of raised intracranial pressure is common and may be due to deposition of GAGs within the sclera causing pressure on the optic nerve at the interscleral level -LSB- 2 -RSB- . Regular , annual , ophthalmological assessment is required and should include a measure of intraocular pressure . Spectacles should be prescribed as appropriate . Hearing Hearing loss is common in patients with severe MPS II and is correlated with the severity of somatic disease . Manifestations leading to hearing loss include frequent middle ear disease secondary to Eustachian tube dysfunction , dysostosis of the ossicles of the middle ear , scarring of the tympanic membrane , and damage to the eighth nerve . Audiological abnormalities usually consist of conductive deafness early in the course of the disease but as the child ages a sensorineural element appears and most patients have combined deafness once the disease is fully established -LSB- 29 -RSB- . Moderate to severe hearing loss develops in most adults with attenuated MPS II . In most patients there is a mixture of both conductive and sensorineural deafness -LSB- 22 -RSB- . Appropriate regular audiology assessment and provision of the correct auditory aids are required . Education and behaviour Given the intellectual involvement in the more severely affected patients , it is important that infants with MPS II are provided with a stimulating environment to encourage as much learning as possible during the early stages , as some skills may be retained during the later period of general deterioration . For patients with more attenuated forms of the disease , deafness and physical limitations may impact on education . Educational assessments of special needs should be undertaken to ensure that an appropriate educational environment is provided . This may be in a mainstream school with additional help or within a special school system . Many patients with severe MPS II exhibit hyperactivity and aggression . Psychological assessment , behaviour management and the use of medication should be considered in these patients . The hyperactivity generally responds poorly to methylphenidate , and over-sedation is a risk with other forms of medication . Anaesthetic complications All patients with MPS II present major anaesthetic risks , and death can result if appropriate precautions are not taken -LSB- 12 -RSB- . Patients should only undergo general anaesthesia in centres staffed with anaesthesiologists experienced in these disorders . The most important complications relate to the following . Dysostosis multiplex leading to rigidity of the neck and spine . Although instability of the spine is rare , significant cervical compression may be present in patients with attenuated disease . This can result in sudden neurological deterioration if excessive neck manipulation is performed during attempts to intubate the patient.Induction may be difficult because of an inability to maintain an adequate airway.Intubation may require smaller-than-anticipated endotracheal tubes and a narrow trachea and thickened vocal cords will impede view . It is recommended that a paediatric pulmonologist or ear , nose and throat specialist should be present during intubation . Fibre-optic laryngotracheoscopy is usually essential.Extubation can also be hazardous for these patients , and there is an increased incidence of post-obstructive pulmonary oedema.Recovery from anaesthesia may be slow , and post-operative airway obstruction is always a risk . Enzyme replacement therapy Recombinant I2S -LRB- idursulfase ; Elaprase , Shire Human Genetic Therapies , Cambridge , MA , USA -RRB- has recently been licensed for treatment of patients with MPS II in the United States , European Union and Switzerland . Idursulfase is produced in a continuous human cell line and is a purified form of the natural lysosomal enzyme I2S . Mannose-6-phosphate -LRB- M6P -RRB- residues on the oligosaccharide chains of the glycoprotein enzyme allow specific binding of idursulfatase to M6P receptors on the cell surface , leading to cellular internalisation and targeting of the enzyme to lysosomes , and subsequent catabolism of accumulated GAGs . Phase I/II trial Twelve patients were enrolled in a randomized , double-blind , placebo-controlled trial of idursulfase for 24 weeks , followed by an open-label extension study . Urinary GAGs were reduced within 2 weeks of initiating idursulfase treatment and remained low for the 48 weeks of the study -LRB- P < 0.0001 -RRB- . Both liver and spleen volumes were decreased at 24 weeks -LRB- P < 0.01 -RRB- and 48 weeks -LRB- P < 0.001 -RRB- . The distance that patients could walk in 6 min -LRB- 6-min walk test -RRB- increased by an average of 48 m after 48 weeks -LRB- P = 0.013 -RRB- . Six patients developed IgG antibodies that did not appear to influence the clinical response to idursulfase -LSB- 18 -RSB- . Phase II/III trial A multinational , randomized , double-blind , placebo-controlled trial was performed to evaluate the safety and efficacy of idursulfase , 0.5 mg/kg administered weekly , compared with placebo . Additionally , the trial evaluated idursulfase , 0.5 mg/kg every other week , compared with placebo . Ninety-six patients were randomized to one of three groups with each patient receiving a total of 52 infusions of either idursulfase , idursulfase alternating weekly with placebo , or placebo . The primary efficacy endpoint of the trial was a composite of two clinical measures -- forced vital capacity and the 6-min walk test . Patients receiving the weekly dosing regimen of idursulfase showed a statistically significant improvement in the primary efficacy endpoint -LRB- P < 0.005 -RRB- compared with placebo . Patients receiving the alternate-week dosing regimen of idursulfase also showed a statistically significant improvement -LRB- P < 0.05 -RRB- compared with placebo -LSB- 19 -RSB- . Treatment with idursulfase was generally well tolerated . The most common adverse events observed were associated with the clinical manifestations of MPS II . Of the adverse events considered possibly related to idursulfase , infusion-related reactions were the most common and were generally mild . There were two patient deaths during the study , both of which were considered unrelated to treatment with idursulfase . IgG and IgM antibodies were observed in the idursulfase-treated patients at some point during the course of the study . When antibodies occurred , there was a transient increase in urinary GAGs , presumably due to a neutralising effect . This did not correlate with any of the clinical variables measured -LRB- Shire HGT , data on file -RRB- . No IgE antibodies were observed and no patient withdrew from the trial due to an adverse event considered related to idursulfase -LSB- 19 -RSB- . Current treatment with idursulfase Idursulfase is given by weekly intravenous infusion over 3 h at a dose of 0.5 mg/kg diluted in an appropriate volume of saline -LRB- according to weight -RRB- . Patients may receive premedication with antipyretics and/or antihistamines at the discretion of the prescribing physician . Patients who have experienced infusion-related reactions should be premedicated for subsequent infusions . Consideration should be given to the possibility of sodium overload in small infants , and , if necessary , the total volume of the infusion can be decreased to 50 ml . Although the treatment is generally safe and infusion-related reactions are no more frequent than with other protein-based therapies , anaphylactoid reactions have been reported . Early response to ERT The response to ERT appears to depend on the severity of the individual 's condition and the age at which the treatment begins . In our experience , the first sign of efficacy in most young -LRB- prepubertal -RRB- patients is usually an enhanced feeling of wellbeing and greater energy , manifesting as an increased ability to take part in normal daily activities . By 2 months , most patients have urinary GAG levels approaching the normal range and there is usually evidence of a reduction in size of the liver and spleen . After a further month of therapy there is often an improvement in soft-tissues joint contractures and the beginning of a growth spurt . By 6 months of treatment , most patients have improved the distance that they can achieve in the 6-min walk test and most show stabilisation -LRB- if not improvement -RRB- in pulmonary function tests . Most of the improvement occurs in the first 12 -- 18 months of treatment . After this period of time , gains are very slow and the condition of most patients will generally have stabilised , although physicians still need to be vigilant and look actively for possible disease-related complications . ERT for particular patient groups Treating very young patients Experience of treating children under the age of 5 years with idursulfase is limited , as the clinical trials enrolled patients above this age so that the patients would be able to comply with and be able to cooperate with repeated pulmonary function and endurance testing . The following is therefore based on our personal clinical experience . Treating patients at a very young age leads to practical problems with the infusions . These may be resolved with indwelling vascular access devices . Outcomes are likely to be better in patients treated from a very young age , but there are currently no recommendations on how to monitor the response to treatment , especially in patients either too young to cooperate with the tests used in the clinical trials -LRB- pulmonary function tests and 6-min walk test -RRB- or in patients who are not yet showing symptoms of the disease . This situation would be improved by identifying a suitable biomarker that would reflect the disease burden and that would respond promptly to therapy . We believe that these challenges should not prevent the introduction of treatment in patients under the age of 5 years after discussion with parents . Careful clinical follow-up , however , will be necessary in these patients , accompanied by regular -LRB- annual -RRB- developmental assessments . As of October 2006 , there were 12 patients below 5 years of age in HOS . Treating patients with severe CNS involvement Idursulfase is not expected to cross the blood -- brain barrier and therefore would not be expected to lead to any improvement in CNS dysfunction in patients with severe MPS II . In most patients there is likely to be some initial benefit in terms of enhanced respiratory function due to airway improvement and reduction in size of the liver and spleen . In addition , joint mobility may improve as a result of ERT on peri-articular soft tissue . The burden of weekly intravenous therapy may be significant in some patients with very severe CNS disease . The authors believe that patients with severe CNS involvement may be offered the possibility of treatment for a ` trial ' period of 12 -- 18 months , after which time a decision should be made as to whether to continue . Decisions on whether to start and continue treatment should be made only after detailed discussion with the parents . Home therapy More than 90 % of patients treated with idursulfase have had no infusion-related reactions and , in those who do , the reactions are mostly minor and respond promptly to reducing the rate of infusion and using antipyretics and antihistamines for future treatments . Under these circumstances , it would appear that idursulfase is a therapy that could be administered safely in the patient 's home after a minimum of 12 infusions in hospital . Depending on the labelling and clinical practices in particular countries , a logical approach would appear to be to consider home therapy for those patients with minimal or no obstructive airway disease -LRB- as judged by sleep study and pulmonary function tests -RRB- . It should be stressed , however , that ERT during respiratory infections or other intercurrent illnesses are contraindicated . Treatment should be postponed under such circumstances , regardless of whether treatment is given in the hospital or home setting . Management of infusion reactions Infusion-related reactions appear to be of two types : those occurring during the infusion and ` late ' reactions occurring 12 h or more after the infusion . The classic reactions occurring during the infusion , with fever , chills and urticaria , respond to temporarily stopping the infusion , administering paracetamol -LRB- acetominophen -RRB- and antihistamines , and restarting the infusion after at least 30 min but at a slower rate . Before subsequent infusions , patients should be premedicated with acetominophen and antihistamines 1 h before the infusion . If the reactions continue despite this premedication , consideration should be given to pretreatment with corticosteroids ; for example , prednisolone , 1 mg/kg , 12 h and 1 h before infusion . Late reactions typically consist of a sunburn-type rash and mild wheezing . The rash can be managed as above , but the wheezing requires bronchodilator treatment and , possibly , oxygen supplementation . All patients who have significant infusion-associated reactions should have specific immune testing . Reducing the rate of infusion is mandatory in these patients . To assess the efficacy of ERT in individual patients and to ensure the appropriate management of possible infusion-related reactions , it is recommended that the treatment of patients receiving ERT is overseen by experienced physicians in centres with expertise in treating lysosomal storage diseases . Haematopoietic stem cell therapy The potentially beneficial effect of HSCT on lysosomal storage diseases is thought to be due to the replacement of deficient macrophages with marrow-derived donor macrophages -LRB- Kupffer cells -- pulmonary , splenic , nodal , tonsillar and peritoneal macrophages -- and microglial cells -RRB- which constitute an ongoing source of enzyme capable of gaining access to various storage sites . HSCT has been successful in modifying the course of the disease in patients with severe MPS I and MPS VI . In a single small study of HSCT in MPS II , however , the results of treatment were not positive , with nine of ten patients continuing to exhibit progressive neurodegeneration -LSB- 36 -RSB- . The future Whilst ERT is likely to benefit many patients with MPS II , the problems associated with severe CNS involvement are unlikely to be solved by intravenous ERT . Other methods of treatment , including alternative routes of enzyme administration , will therefore need to be studied . Direct administration of enzyme into the cerebrospinal fluid , either into the ventricle or lumbar space , has not prevented progressive neurological deterioration in another lysosomal storage disorder , type II Gaucher disease -LSB- 28 -RSB- . This approach has not been attempted in MPS II , and formal studies are required , perhaps with the addition of immunosuppression to prevent antibody formation . Currently , there are no suitable methods for infusion directly into the brain , and repeated intracerebral injections would not be practical . It may be that to treat CNS disease more effectively , peripheral ERT may have to be combined with other approaches , such as cell-based therapies , perhaps involving gene enhancement or replacement . Gene therapy is the logical approach for treating disorders of the CNS , and animal work on other MPS disorders is beginning to show promise -LSB- 5 , 30 -RSB- . Choice of vector , the use of immunosuppression and the route of administration are all issues that need addressing before the first human clinical trials of gene therapy involving MPS disorders are performed . Use of nanoparticles containing engineered myoblasts expressing I2S has been reported . Scaling-up studies , however , are required to evaluate the feasibility of such devices -LSB- 11 -RSB- . Conclusion MPS II -LRB- Hunter syndrome -RRB- is a severe progressive multisystemic disorder that has the potential to cause disease in most body systems and is usually fatal in the second or third decade of life . Ideally , management should be centralised in major medical centres with access to all medical specialties . Management is multidisciplinary and a holistic approach to the patient is required , especially for those who have severe neurological involvement . ERT is an important new therapy that has the potential to help many patients , providing that it is started early in the course of the disease . CNS disease remains a major challenge and an innovative approach to treatment will be needed if this is to be addressed fully .

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

mucopolysaccharidosis type ii
hunter syndrome
enzyme replacement therapy
idursulfase


Insulinoma misdiagnosed as juvenile myoclonic epilepsy We report a girl presenting with drug-refractory myoclonia and generalized tonic-clonic seizure -LRB- GTCS -RRB- on awakening who , initially , was misdiagnosed as having juvenile myoclonus epilepsy -LRB- JME -RRB- before insulinoma was detected . Many conditions may mimic or cause epileptic seizures , including psychiatric and movement disorders , cardiac arrhythmias and metabolic abnormalities . Toxic and metabolic causes are potentially curable , are refractory to antiepileptic drugs , and may be fatal if untreated . Insulinoma is a rare and treatable cause of hypoglycemic seizures which might be misdiagnosed as intractable epilepsy . Case report In May 2001 a 13-year-old girl was referred to the hospital because of GTCS on awakening . The family history was unremarkable and her personal history revealed one simple febrile seizure at age 3 years . One month before admission two episodes of confusional states were reported which lasted 5 and 30 min and were characterized by unresponsiveness and psychomotor slowing . Physical and neurological examinations were normal , weight was 62 kg -LRB- 97th centile -RRB- , height 162 cm -LRB- 90th centile -RRB- , and menarche was at age 13 years -LRB- March 2001 , 1 month before the first seizure -RRB- . Awake EEG the day after GTCS revealed normal background activity , bilateral synchronous and asynchronous high-amplitude delta waves over the parietotemporal regions , and right frontal sharp-slow waves . Blood count , blood chemistry -LRB- glucose 4.5 mmol/l , calcium 2.4 mmol/l , potassium 4.0 mmol/l -RRB- , and magnetic resonance imaging -LRB- MRI -RRB- of the brain were normal . Confusional states were interpreted as complex partial seizures and GTCS as a secondary generalization . Low-dose carbamazepine -LRB- 6.3 mg/kg per day -RRB- was introduced . Two weeks later , a second GTCS on awakening occurred , followed by two short episodes of unresponsiveness before breakfast in front of the television . Another few days later , perioral and eyelid myoclonus and jerks in the arms and legs were noticed early in the morning . After sleep deprivation a series of myoclonic jerks at awakening in the morning and after several naps were registered coinciding with generalized low-amplitude spikes or polyspikes . JME was diagnosed and carbamazepine replaced by valproate -LRB- 20 mg/kg per day -RRB- which was not effective . Blood glucose was normal -LRB- 4.2 mmol/l 4 h after food intake -RRB- . Two months later -LRB- August 2001 -RRB- a second overnight long-term video-EEG revealed generalized discharges of spikes or polyspikes and slow waves in the second part of the night . Again myoclonic jerks in the hands and legs with a single generalized low-amplitude spike and slow waves were registered on awakening -LRB- Fig. 1 -RRB- . Fig. 1Ictal EEG on awakening : generalized low-amplitude spike with simultaneous registration of myoclonic jerks of the hands and legs . Although the EEG pattern is not so typical for JME , together with the history and the clinical symptoms this EEG seemed compatible with this diagnosis In September 2001 , 6 months after the manifestation of the first seizures , low preprandial blood glucose -LRB- 1.8 mmol/l , normal 3.8 -- 6.1 -RRB- and high insulin -LRB- 31 μU/ml , normal 1.9 -- 2.3 -RRB- were detected because the patient was sluggish and dizzy -LRB- glucose and insulin were measured by routine methods -RRB- . Inappropriate insulin secretion was suspected and confirmed by pre - and postprandial glucose and insulin measurements -LRB- preprandial : glucose 2.8 mmol/l , insulin 33 μU/ml and 50 min after food intake : glucose 3.1 mmol/l , insulin 153 μU/ml -RRB- ; therefore , a 72-h fasting test was not done . Abdominal ultrasound -LRB- US -RRB- and MRI revealed a round and circumscribed hypoechoic lesion -LRB- 2.1 × 1.8 × 1.9 cm -RRB- with sharp but uneven borders in the pancreatic body without evidence of metastases . Insulinoma was suspected . Because multiple endocrine neoplasia type I syndrome -LRB- MEN I -RRB- is associated in 5 -- 10 % of the cases with insulinoma -LSB- 5 , 9 -RSB- , prolactin , thyroid-stimulating hormone , parathyroid hormone , and thyroxin -LRB- T3 , T4 -RRB- were determined , which were all normal ; therefore , mutation analysis of exons 2 -- 10 of the MENIN gene was not done . Valproate was stopped and the patient was advised to have food intake every 2 h and three times during the night . Since then she has been seizure free , but myoclonic jerks recurred occasionally when meals were delayed by > 5 h during the night . Her weight had increased from 62 to 84 kg within the last 10 months before surgery . Surgery was performed 5 months later -LRB- March 2002 -RRB- in Moscow and two insulinomas were revealed by intraoperative US : one located on the superior-posterior surface between the head and body -LRB- diameter 2.5 cm -RRB- and the other on the anterior surface of the pancreas -LRB- diameter 0.7 -- 0.9 cm -RRB- . Before the surgery , US and MRI disclosed only one lesion . Both insulinomas were removed in toto and the endocrine pancreas was suppressed by Sandostatin -LRB- octreotide -RRB- for 4 days . Histology confirmed the diagnosis of two benign beta-cell adenomas . The patient fully recovered , remained seizure free during the next 4 years , has a current weight of 62 kg -LRB- 75th centile -RRB- , and is mentally normal . Discussion Myoclonus and GTCS after awakening are hallmarks of JME , especially when adolescents are affected -LSB- 2 -RSB- . Hence , in our patient the interpretation of the clinical symptoms together with spike waves was indicative of JME . Confusional states and drug-refractory seizures on the other side are less compatible with the diagnosis of JME , but fit well with hypoglycemic events . The latter , however , were erroneously thought to be excluded by two normal blood glucose measurements . Furthermore , hypoglycemia in nondiabetic adolescents is much rarer than JME . Insulinoma , responsible for the profound hypoglycemia in our patient , has its onset usually in middle -LSB- 10 -RSB- or older age -LSB- 4 -RSB- and is very rare in children -LSB- 9 -RSB- . Symptoms are prominent following prolonged fasting states , especially in the morning as in our patient , but also in the late afternoon -LSB- 4 -RSB- . Hypoglycemia can cause loss of consciousness , sluggishness , confusion , asthenia , deep coma , dizziness , disturbances in vision , and epilepsy . An international review of 1,067 cases -LSB- 10 -RSB- showed such neuropsychiatric symptoms in 92 % of the patients . Irreversible damage of the central nervous system occurred in 6.8 % of the cases -LSB- 10 -RSB- . Forty-one percent of the patients have amnesia during the hypoglycemic event -LSB- 4 -RSB- . Therefore , the history has to be obtained from family members or friends . Clinical details about the onset , duration , and type of symptoms as well as temporal association with fasting and the relief of symptoms after food intake are helpful information for making the diagnosis . Considerable weight gain as in our patient was reported in 39 % of the patients -LSB- 4 -RSB- . Taking into account that an actually normal glucose level does not exclude episodes of hypoglycemia , a prolonged fasting test up to 72 h under close monitoring is recommended to assess inappropriate insulin secretion -LSB- 3 -RSB- . The median interval from the onset of symptoms to the diagnoses of insulinoma is 2 years , with a wide range of 1 month to 30 years -LSB- 4 -RSB- . Initial misdiagnosis is frequent . In a series of 59 patients with insulinoma , prior diagnosis included neurological disorders in 39 -LRB- 64 % -RRB- and especially epilepsy in 23 -LRB- 39 % -RRB- patients . Seven patients -LRB- 12 % -RRB- were treated with antiepileptic drugs -LSB- 4 -RSB- . The seizure symptoms are variable . During severe hypoglycemia generalized and focal seizures occurred in children -LSB- 6 -RSB- . In patients with insulinoma , shaking of all four limbs at night -LSB- 8 -RSB- , jerking and twitching -LSB- 1 -RSB- , and symptoms suspicious for partial and complex partial seizures with and without secondarily generalized seizures are reported -LSB- 3 , 5 -RSB- . Varying degrees of EEG changes and sometimes massive spiking were recorded during hypoglycemia -LSB- 7 -RSB- . In patients with insulinoma , focal and widespread EEG slowing -LSB- 1 , 3 -RSB- combined with epileptic activity -LSB- 5 -RSB- are mentioned . Conclusions The combination of seizures and episodic confusional states should prompt the search for hyperinsulinism , especially when the episodes occur in fasting states and when they are refractory to antiepileptic treatment . Inappropriately high insulin with low blood glucose is diagnostic ; this constellation has to be investigated resolutely -LRB- e.g. , by the classic 72-h fasting test -RRB- but with caution under strict clinical and chemical monitoring . Timely diagnosis of an insulinoma is of paramount importance to prevent sequelae for such patients .

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

hypoglycemia
insulinoma
juvenile myoclonic epilepsy
myoclonus