(PDF) Guillain-Barr?? syndrome: Pathogenesis, diagnosis, treatment and prognosis

Diagnosis,

treatment

and

prognosis

of

Guillain-Barré

syndrome

(GBS)

Pieter

A.

van

Doorn

Erasmus

MC,

Department

of

Neurology,

Rotterdam,

The

Netherlands

Correspondence:

Pieter

A.

van

Doorn,

Erasmus

MC,

Department

of

Neurology’s-Gravendijkwal

230,

3015CE

Rotterdam,

The

Netherlands.

p.a.vandoorn@erasmusmc.nl

Available

online:

28

April

2013

Presse

Med.

2013;

42:

e193–e201

on

line

on

ß

2013

Elsevier

Masson

SAS

All

rights

reserved. www.em-consulte.com/revue/lpm IMMUNE-MEDIATED

NEUROPATHIES

www.sciencedirect.com

Quarterly

Medical

Review

e193

Summary

Guillain-Barré

syndrome

(GBS)

is

an

acute

polyneuropathy

with

a

variable

degree

of

weakness

that

reaches

its

maximal

severity

within

4

weeks.

The

disease

is

mostly

preceded

by

an

infection

and

generally

runs

a

monophasic

course.

Both

intravenous

immunoglobulin

(IVIg)

and

plasma

exchange

(PE)

are

effective

in

GBS.

Rather

surprisingly,

steroids

alone

are

ineffective.

Mainly

for

practical

reasons,

IVIg

usually

is

the

preferred

treatment.

GBS

can

be

subdivided

in

the

acute

inflammatory

demyelinating

polyneuropathy

(AIDP),

the

most

frequent

form

in

the

western

world;

acute

motor

axonal

neuropathy

(AMAN),

most

frequent

in

Asia

and

Japan;

and

in

Miller-Fisher

syndrome

(MFS).

Additionally,

overlap

syndromes

exist

(GBS-MFS

overlap).

About

10%

of

GBS

patients

have

a

secondary

deterioration

within

the

first

8

weeks

after

start

of

IVIg.

Such

a

treatment-related

fluctuation

(TRF)

requires

repeated

IVIg

treatment.

About

5%

of

patients

initially

diagnosed

with

GBS

turn

out

to

have

chronic

inflammatory

demyelinating

polyradiculoneuropathy

(CIDP)

with

acute

onset

(A-CIDP).

It

is

yet

unknown

whether

GBS

patients

who

remain

able

to

walk

(‘mildly

affected

GBS

patients’),

or

patients

with

MFS,

also

benefit

from

IVIg.

Despite

current

treatment,

GBS

remains

a

severe

disease,

as

about

25%

of

patients

require

artificial

ventilation

during

a

period

of

days

to

months,

about

20%

of

patients

are

still

unable

to

walk

after

6

months

and

3–10%

of

patients

die.

Additionally,

many

patients

have

pain,

fatigue

or

other

residual

complaints

that

may

persist

for

months

or

years.

Pain

can

also

be

very

confusing

in

making

the

diagnosis,

especially

when

it

precedes

the

onset

of

weakness.

Advances

in

prognostic

modelling

resulted

in

the

development

of

a

simple

prognostic

scale

that

predicts

the

chance

for

artificial

ventilation,

already

at

admission;

and

in

an

outcome

scale

that

can

be

used

to

determine

the

chance

to

be

able

to

walk

unaided

after

1,

3

or

6

months.

GBS

patients

with

a

poor

prognosis

potentially

might

benefit

from

a

more

intensified

treatment.

A

larger

increase

in

serum

IgG

levels

after

standard

IVIg

treatment

(0.4

g/kg/day

for

5

consecutive

days)

seems

to

be

an

improved

outcome

after

GBS.

This

was

one

of

the

reasons

to

start

the

second

course

IVIg

trial

(SID-GBS

trial)

in

GBS

patients

with

a

poor

prognosis.

This

study

is

currently

going

on.

The

international

GBS

outcome

study

(IGOS)

is

a

new

worldwide

prognostic

study

that

aims

to

get

further

insight

in

the

(immune)pathophysiology

and

outcome

of

GBS,

both

in

children

and

adults.

Hopefully

these

and

other

studies

will

further

help

to

improve

the

understanding

and

especially

the

outcome

in

patients

with

GBS.

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http://dx.doi.org/10.1016/j.lpm.2013.02.328

Almost

a

century

ago,

the

French

neurologists

Guillain,

Barré

and

Strohl

described

two

soldiers

who

developed

acute

paralysis

with

areflexia

that

spontaneously

recovered

[1].

They

reported

the

combination

of

increased

protein

concen-

tration

with

a

normal

cell

count

in

the

CSF,

or

albuminocyto-

logical

dissociation,

which

differentiated

the

condition

form

poliomyelitis.

Despite

the

fact

that

Landry

had

already

repor-

ted

similar

cases

in

1859,

the

combination

of

these

clinical

and

laboratory

features

became

known

as

Guillain-Barré

syndrome

(GBS)

[2].

GBS

most

frequently

is

a

post-infectious

disorder,

mostly

with

Campylobacter

jejuni,

cytomegalovirus,

Epstein-

Barr

virus

or

M.

pneumoniae

[3–6].

In

typical

cases,

among

the

first

symptoms

are

pain,

numbness,

paraesthesia,

or

weakness

in

the

limbs.

The

main

features

of

GBS

however

are

rapidly

progressive

bilateral

and

relatively

symmetric

weakness

of

the

limbs

with

or

without

involvement

of

respiratory

or

cranial

nerve-innervated

muscles.

By

definition,

maximal

weakness

is

reached

within

4

weeks,

but

most

patients

have

reached

their

maximal

weakness

already

within

2

weeks

[7].

Patients

then

have

a

plateau

phase

of

variable

duration

ranging

from

days

to

several

weeks

or

months.

This

phase

is

followed

by

a

recovery

phase

of

variable

duration

(figure

1).

Despite

the

positive

effect

of

intravenous

immunoglobulin

(IVIg)

or

plasma

exchange

(PE),

about

20%

of

the

patients

unable

to

walk

unaided

(‘severely

affected

patients’)

remain

unable

to

do

so

after

half

a

year.

Moreover,

many

patients

remain

other-

wise

disabled

or

severely

fatigued.

Even

3–6

years

after

onset,

GBS

had

great

impact

on

social

life

and

the

ability

to

perform

activities

[8,9].

It

is

clear

that

GBS

often

remains

a

severe

disease

for

which

better

treatment

is

required,

at

least

in

a

proportion

of

patients

[10].

Diagnosis

of

Guillain-Barré

syndrome

(GBS)

[7]

Clinical

features

The

diagnosis

of

GBS

is

often

straightforward,

especially

when

weakness

is

preceded

with

an

infection

within

1–3

weeks

from

onset

(box

1).

In

some

patients

however,

the

diagnosis

can

be

more

difficult

especially

when

pain

is

present

already

before

the

onset

of

weakness,

or

when

weakness

initially

is

only

present

in

the

legs

[11].

Also

in

children,

the

presence

of

pain

may

initially

suggest

other

disorders

like

discitis,

which

may

seriously

delay

the

diagnosis

and

may

even

be

very

troublesome

because

progressive

respiratory

weakness

may

be

missed

[12].

Therefore,

several

features

especially

should

raise

doubt

about

the

diagnosis

(box

2).

Several

disorders

or

conditions

that

may

mimic

GBS

need

to

be

excluded

or

made

unlikely

before

the

diagnosis

of

GBS

can

be

made

(box

3).

Cerebrospinal

fluid

(CSF)

examination

CSF

examination

is

especially

helpful

to

rule

out

other

causes

of

weakness,

for

example

Lyme

disease

or

HIV-related

radiculitis,

both

associated

with

increased

number

of

mononuclear

cells.

If

there

is

an

increased

cerebrospinal

fluid

total

protein

(without

cellular

reaction),

this

may

help

making

the

diagnosis,

espe-

cially

when

there

are

some

none-typical

features.

It

is

impor-

tant

to

realise

however

that

about

50%

of

GBS

patients

still

have

a

normal

CSF

protein

in

the

first

week

after

onset

of

weakness,

and

that

the

absence

of

an

increased

CSF

protein

does

not

rule

out

the

diagnosis.

EMG

examination

EMG

is

especially

helpful

when

it

shows

signs

of

a

polyneuro-

pathy

in

clinically

not

yet

involved

areas,

for

example

when

it

e194

Figure

1

Course

of

Guillain-Barré

syndrome

(GBS),

antecedent

infections

and

anti-ganglioside

antibodies

PA

van

Doorn

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shows

signs

of

a

polyneuropathy

in

the

arms

in

patients

with

weakness

only

in

the

legs.

It

also

enables

to

differentiate

GBS

in

AMAN

(axonal

features)

and

AIDP

(demyelinating

features)

[13].

Anti-ganglioside

antibodies

Anti-ganglioside

antibodies,

as

monomer

or

as

complexes,

can

be

found

in

a

proportion

of

GBS

patients,

however

especially

in

patients

with

AMAN

(especially

IgG

anti-GM1

antibodies),

and

in

patients

with

MFS

(anti-GQ1b

antibodies)

that

cross-react

with

Campylobacter

[4,10,14–20].

Especially

the

presence

of

anti-GQ1b

antibodies

can

be

helpful

in

making

the

diagnosis

in

patients

with

MFS

(table

I).

The

results

of

these

anti-ganglioside

antibody

essays

however

may

last

several

days

or

weeks

making

these

tests

not

always

very

suitable

for

use

in

clinical

practise.

A

recent

paper

based

on

yet

published

and

well-discussed

data

proposed

new

criteria

for

GBS

and

Miller-Fisher

syndrome.

These

criteria

are

mainly

suggested

to

be

helpful

in

immuniza-

tion

safety

or

epidemiological

studies

[21].

Three

levels

of

diagnostic

certainty

about

the

diagnosis

of

GBS

are

categorized

based

on

the

presence

of

absence

of

clinical,

EMG

and

CSF

studies

(table

II).

Whether

these

Brighton

criteria

also

work

in

clinical

practise

now

needs

further

evaluation.

It

is

assumed

that

rare

variants

of

GBS

consisting

about

1%

of

the

total

population

are

not

captured

within

these

criteria.

To

further

move

on

with

the

criteria

for

GBS,

it

especially

would

be

helpful

to

have

access

to

new

carefully

prospectively

gathe-

red

data

on

a

large

group

of

well-described

and

followed

GBS

patients.

This

preferentially

includes

both

mildly

and

severely

affected

GBS

patients,

both

children

and

adults,

and

patients

e195

Box

2

Features

that

should

raise

doubt

about

the

diagnosis

Marked

persistent

asymmetry

of

weakness.

Bladder

or

bowel

dysfunction

at

onset.

Persistent

bladder

or

bowel

dysfunction.

Sharp

sensory

level.

Severe

pulmonary

dysfunction

with

limited

limb

weakness

at

onset.

Severe

sensory

signs

with

limited

weakness

at

onset.

Fever

at

onset

of

neurological

symptoms.

Increased

number

of

mononuclear

cells

in

CSF

(>

50



10

6

/L).

Polymorphonuclear

cells

in

CSF.

Box

1

Criteria

for

the

diagnosis

of

typical

Guillain-Barré

syndrome

(GBS)

(adapted

from

Asbury

[7])

Features

required

for

diagnosis:

progressive

weakness

in

both

arms

and

both

legs;

areflexia.

Features

strongly

supporting

diagnosis:

progression

of

symptoms

over

days

to

4

weeks;

relative

symmetry

of

symptoms;

mild

sensory

symptoms

or

signs;

cranial

nerve

involvement,

especially

bilateral

weakness

of

facial

muscles;

recovery

beginning

2–4

weeks

after

progression

ceases;

autonomic

dysfunction;

absence

of

fever

at

onset;

high

concentration

of

protein

in

cerebrospinal

fluid,

with

fewer

cells

than

10



10/L;

typical

electrodiagnostic

features;

pain

(is

often

present).

Features

excluding

diagnosis:

diagnosis

of

botulism,

myasthenia,

poliomyelitis,

or

toxic

neuropathy;

abnormal

porphyrin

metabolism;

recent

diphtheria;

purely

sensory

syndrome,

without

weakness.

Box

3

Differential

diagnosis

of

Guillain-Barré

syndrome

(GBS)

Intracranial/spinal

cord:

brain

stem

encephalitis,

meningitis

carcinomatosis/

lymphomatosis,

transverse

myelitis,

cord

compression.

cells:

poliomyelitis,

West

Nile

virus.

Spinal

nerve

roots:

compression,

inflammation

(e.g.

Cytomegalovirus),

CIDP,

meningitis

carcinomatosis/lymphomatosis.

Peripheral

nerves:

drug-induced

neuropathy,

acute

intermittent

porphyria,

critical

illness

polyneuropathy,

vasculitic

neuropathy,

diphtheria,

vitamin

B1

deficiency

(Beri-beri),

heavy

metal

or

drug

intoxication,

tick

paralysis,

metabolic

disturbances

(hypokalaemia,

hypophosphatemia,

hypermagnesia,

hypoglycemia).

Neuromuscular

junction:

myasthenia

gravis,

botulism,

organophosphate

poisoning.

Muscle:

critical

illness

polyneuromyopathy,

polymyositis,

dermatomyositis,

acute

rhabdomyolysis.

Diagnosis,

treatment

and

prognosis

of

Guillain-Barré

syndrome

(GBS) IMMUNE-MEDIATED

NEUROPATHIES

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from

various

regions

around

the

globe

(so

to

include

reasonable

large

numbers

of

both

AIDP

and

AMAN

cases).

These

new

data

potentially

give

relevant

information,

also

on

less

frequently

encountered

clinical

subgroups,

including

on

patients

who

do

not

fulfil

all

standard

diagnostic

criteria

usually

required

to

be

randomized

in

controlled

trials,

e.g.

on

patients

with

a

pro-

gressive

phase

of

4–6

weeks,

having

(near)

normal

reflexes,

or

on

those

having

over

50

CSF

WBC/ul

or

on

patients

having

only

weakness

of

their

legs.

This

would

help

to

have

better

insight

in

the

complete

spectrum

of

GBS.

Treatment

Importance

of

general

care

in

Guillain-Barré

syndrome

(GBS)

Patients

with

GBS

especially

need

excellent

multidisciplinary

care

to

prevent

and

manage

the

potential

fatal

complications.

This

indicates

the

need

for

careful

monitoring

of

cardiac

and

respiratory

function

and

the

prevention

of

infections

[22].

Since

about

25%

of

severely

involved

patients

require

ventilation,

the

need

for

this

needs

carefully

and

regularly

be

evaluated.

This

means

at

least

the

regular

measurement

of

vital

capacity

and

respiratory

frequency,

and

timely

transfer

to

an

intensive

care

unit

when

indicated

(box

4).

A

new

simple

scale

that

can

be

used

already

at

hospital

admission

helps

to

predict

the

chance

that

a

particular

patient

needs

artificial

ventilation

[23].

Among

other

issues

that

need

attention

already

early

in

the

course

of

disease

are

prophylaxis

for

deep

vein

thrombosis,

cardiac

and

hemodynamic

monitoring

(among

other

symptoms

of

autonomic

dysfunction),

pain

management,

management

of

possible

bladder

and

bowel

dysfunction,

psychosocial

support

and

rehabilitation.

Many

patients

and

their

relatives

benefit

from

joining

a

patient

organisation

such

as

The

GBS/CIDP

Foundation

International

(www.GBS-CIDP.org).

The

beneficial

effect

of

immunotherapy

It

has

been

shown

that

plasma

exchange

(PE)

is

beneficial

when

applied

within

the

first

4

weeks

from

onset,

but

the

largest

effect

was

seen

when

started

early

(within

the

first

2

weeks)

[24–28].

The

usual

regimen

is

a

five

times

PE

during

2

weeks,

with

a

total

exchange

of

about

five

plasma

volumes.

A

French

PE

trial

showed

that

two

PE

sessions

is

more

effective

than

no

PE

in

patients

being

mildly

affected

form

GBS

[29].

The

first

RCT

on

the

use

of

IVIg

(0.4

g

IVIg/kg

bodyweight/day

for

five

consecutive

days)

was

published

in

1992,

demonstrating

that

IVIg

is

as

effective

as

PE

[30].

After

these

results

were

published,

IVIg

has

replaced

PE

as

the

preferred

treatment

in

many

centres,

mainly

because

of

its

greater

convenience

and

availability

[23].

The

Cochrane

review

on

the

use

of

IVIg

in

GBS

e196

Table

I

Spectrum

of

Guillain-Barré

syndrome

(GBS)

and

serum

anti-

ganglioside

antibodies

GBS

subgroup

Antibodies

Acute

inflammatory

demyelinating

polyneuropathy

(AIDP)

Unknown

Acute

motor

(and

sensory)

axonal

neuropathy

(AMAN

or

AMSAN)

GM1,

GM1b,

GD1a,

GalNac–GD1a

Miller-Fisher

syndrome/GBS

overlap

syndrome

GQ1b,

GD3,

GT1a

Table

II

Criteria

for

Guillain-Barré

syndrome

(GBS)

for

vaccinations

or

epidemiological

research

[21]

Items

that

are

fulfilled/requested Levels

of

diagnostic

certainty

1

2

3

1.

Bilateral

and

flaccid

weakness

of

the

limbs

+

2.

Decreased

or

absent

tendon

reflexes

in

weak

limbs

+

3.

Monophasic

illness

pattern

+

4.

Onset

to

nadir

of

weakness:

12

h–28

days

+

subsequent

plateau

+

5.

Cytoalbuminologic

dissociation

#

(i.e

elevation

CSF

protein

level

and

CSF

white

cells

<

50



10

6

/L)

+

+/#

6.

Electrophysiological

(EMG)

findings

consistent

with

GBS

+

#

7.

Absence

of

identified

alternative

diagnosis

for

weakness

+

#

+

Levels

of

diagnostic

certainty

range

from

1

(most

likely)

to

3

(least

likely).

Level

1:

is

the

highest

level

(diagnosis

of

GBS

is

most

likely).

All

items

positive.

Level

2:

items

1–4

positive;

#

5

(CSF)

positive,

or

when

CSF

is

not

collected/available:

6

(EMG)

and

7

(absence

of

identified

alternative

diagnosis

for

weakness)

positive.

Level

3:

items

1–4

and

7

positive.

PA

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showed

that

there

was

no

difference

between

IVIg

and

PE

with

respect

to

the

improvement

in

disability

grade

after

4

weeks,

the

duration

of

mechanical

ventilation,

mortality,

or

residual

disability

[31].

The

combination

of

PE

followed

by

IVIg

was

not

significantly

better

than

PE

or

IVIg

alone

[26].

It

appeared

that

oral

steroids

(or

intravenous

methylprednisolone

500

mg/day

for

five

consecutive

days)

alone

are

not

beneficial

in

GBS

[32].

The

combination

of

IVIg

and

intravenous

metylprednisolone

was

not

more

effective

than

IVIg

alone,

but

there

might

be

some

additional

short-term

effects

of

this

combined

treatment

when

a

correction

was

made

for

known

prognostic

factors

[33].

The

overall

conclusion

is

that

according

to

moderate

quality

evidence,

corticosteroids

given

alone

do

not

significantly

has-

ten

recovery

from

GBS

or

affect

the

long-term

outcome.

According

to

low

quality

evidence,

oral

corticosteroids

may

even

delay

recovery

[34].

In

a

pilot-study,

we

studied

the

additional

effect

of

a

6-week

treatment

of

mycophenolate

in

GBS,

which

did

not

show

a

positive

effect

[35].

There

definitely

is

an

effect

of

immunotherapy

on

the

course

of

GBS,

but

new

studies

improving

also

the

final

outcome

of

GBS

remain

urgently

needed

[27].

An

ongoing

RCT

(SID-GBS)

studies

the

effect

of

a

second

course

of

IVIg

given

shortly

after

the

first

IVIg

course

only

in

GBS

patients

with

a

poor

prognosis.

This

study

is

currently

running

in

The

Netherlands.

An

international

obser-

vational

study

on

the

effect

of

a

second-dose

IVIg

in

GBS

patients

with

a

poor

prognosis

(I-SID-GBS)

has

just

started.

This

study

is

linked

to

the

International

GBS

Outcome

Study

(IGOS),

a

study

performed

by

the

Inflammatory

Neuropathy

Consortium

(INC).

When

should

treatment

be

started?

The

North-American

PE

trial

showed

an

effect

of

PE

when

applied

within

the

first

4

weeks

after

onset/weakness.

Most

effect

however

was

observed

when

PE

was

started

within

the

first

2

weeks

form

onset.

After

the

publication

of

this

trial,

most

RCT’s

have

enrolled

patients

being

within

the

time

window

of

2

weeks

from

onset

of

weakness

and

unable

to

walk

without

assistance

[27].

Should

mildly

affected

patients

be

treated?

Mildly

affected

is

arbitrarily

often

defined

as

being

able

to

walk,

with

or

without

assistance.

A

retrospective

study

demonstrated

that

these

patients

frequently

have

residual

disabilities.

The

RCT’s

evaluating

the

effect

of

IVIg

did

not

study

the

effect

in

e197

Box

4

Management

of

Guillain-Barré

syndrome

(GBS)

during

course

of

disease

Diagnosis:

diagnosis

of

GBS

is

mainly

based

on

clinical

features

and

CSF;

laboratory

investigations

include

blood

studies

and

EMG.

Give

good

general

care:

monitor

progression,

and

prevent

and

manage

potential

fatal

complications,

especially:

–

regular

monitor

pulmonary

function

(vital

capacity,

respiration

frequency)

initially

every

2–4

hours,

in

stable

phase

every

6–12

hours,

–

check

for

autonomic

dysfunction

(blood

pressure,

heart

rate,

pupils,

ileus),

–

check

for

swallowing

dysfunction,

–

recognize

and

treat

pain

(WHO

guideline).

Try

to

avoid

opioids,

–

prevent

(and

treat)

infections

and

pulmonary

embolism,

–

prevent

decubitus

and

contractures.

Consider

specific

treatment

with

IVIg

or

PE:

indication

to

start

IVIg

or

PE;

severely

affected

patients

(inability

to

walk

unaided

=

GBS

disability

scale



3);

start

preferable

within

first

2

weeks

from

onset;

IVIg:

0.4

g/kg

for

5

days

(unknown

whether

1.0

g/kg

for

2

days

is

superior);

PE:

standard

5x

PE

with

total

exchange

of

five

plasma

volumes;

unknown

whether

IVIg

is

effective

in

mildly

affected

patients

(GBS

disability

scale



2)

or

MFS

patients;

indication

for

re-treatment

with

IVIg:

secondary

deterioration

after

initial

improvement

or

stabilization

(treatment-related

fluctuation):

treat

with

0.4

g/kg

for

5

days;

no

proven

effect

of

re-treatment

with

IVIg

in

patients

who

continue

to

worsen.

Is

there

an

indication

for

ICU

admission?

Rapidly

progressive

severe

weakness

often

with

impaired

respiration

(vital

capacity

<

20

ml/kg)

[23].

Need

for

artificial

ventilation.

Insufficient

swallowing

with

high

chance

for

pulmonary

infection.

Severe

autonomic

dysfunction.

Use

prognostic

model

to

determine

change

for

artificial

ventilation

[23].

Fluctuations

during

course

of

disease

or

continued

slow

progression?

Consider

treatment-related

fluctuation

(TRF):

repeat

treatment.

Consider

acute

onset

CIDP

(A-CIDP)

and

treat

accordingly.

Rehabilitation

and

fatigue:

start

physiotherapy

early

during

course

of

disease;

start

rehabilitation

as

soon

as

improvement

starts;

Box

4

(Continued)

consider

a

physical

training

program

for

severe

fatigue;

consider

to

contact

patient

organization

for

additional

information

and

help.

Diagnosis,

treatment

and

prognosis

of

Guillain-Barré

syndrome

(GBS) IMMUNE-MEDIATED

NEUROPATHIES

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mildly

affected

patients.

One

large

French

trial

studied

the

effect

of

PE

also

in

patients

who

could

walk

with

or

without

aid,

but

not

run.

Onset

of

motor

recovery

was

faster

in

patients

who

received

two

PE

sessions

compared

to

no

PE

[29].

Based

on

this

study

there

seems

to

be

an

indication

also

to

treat

mildly

affected

GBS

patients

with

PE,

but

one

must

keep

in

mind

that

yet

no

randomized

placebo

controlled

studies

have

evaluated

the

effect

of

PE

or

IVIg

in

these

mildly

affected

GBS

patients

[10,27].

Should

patients

with

Miller-Fisher

syndrome

(MFS)

be

treated?

No

RCT’s

have

been

performed

on

the

effect

of

PE

or

IVIg

in

patients

with

MFS.

Observational

studies

suggested

that

the

final

outcome

in

patients

with

MFS

generally

is

good

[36].

From

a

large

Japanese

uncontrolled

observational

study,

it

was

found

that

IVIg

slightly

hastened

the

amelioration

of

ophthalmoplegia

and

ataxia,

but

the

times

of

disappearances

of

these

symptoms

were

similar

among

the

IVIg,

PE

and

no-treatment

group.

It

was

concluded

that

IVIg

and

PE

seem

not

to

have

influenced

MFS

patients’

outcome,

presumably

because

of

good

natural

reco-

very

[37–39].

What

to

do

if

a

patient

continues

to

deteriorate

after

treatment?

A

proportion

of

GBS

patients

continue

to

deteriorate

after

PE

or

a

standard

course

of

IVIg.

In

these

cases,

it

is

unknown

what

would

be

the

best

option:

wait

and

see,

or

to

start

additional

treatment.

The

reason

why

some

patients

continue

to

dete-

riorate

and

may

be

paralytic

for

months

is

not

known.

These

patients

might

have

a

severe

or

prolonged

immune

attack

causing

severe

axonal

degeneration.

Treatment

might

act

insufficiently

in

these

individuals.

It

is

presently

not

known

how

to

treat

patients

who

continue

to

deteriorate.

Do

these

patients

need

PE

after

they

have

been

treated

with

IVIg?

This

has

not

been

investigated,

but

it

has

been

shown

that

the

combination

of

PE

followed

with

IVIg

is

not

superior

compared

to

PE

or

IVIg

alone

[26].

A

small

open

study

suggested

that

a

repeated

course

of

IVIg

may

be

effective

in

severe

unrespon-

sive

GBS

patients

[40].

Additionally

it

has

been

shown

that

a

larger

increase

in

serum

IgG

levels,

2

weeks

after

starting

a

first

IVIg

course,

was

associated

with

a

better

outcome

[41].

The

international

trial

studying

the

effect

of

a

second

IVIg

dose

in

patients

with

a

poor

prognosis

(I-SID-GBS),

based

upon

the

modified

Erasmus

Guillain-Barré

Outcome

score

(mEGOS),

is

currently

running

[42].

What

to

do

if

a

patient

deteriorates

after

initial

improvement?

About

5

to

10%

of

GBS

patients

deteriorate

after

initial

improvement

or

stabilization

following

IVIg

treatment,

a

condi-

tion

named

‘‘treatment-related

clinical

fluctuation’’

[43,44].

Although

no

RCT

has

evaluated

the

effect

of

a

repeated

IVIg

dosage

in

this

condition,

it

is

common

practise

to

give

a

second

IVIg

course

(2

g/kg

in

2–5

days),

since

these

patients

are

likely

to

improve

after

re-initiating

this

treatment

[27].

It

is

conside-

red

that

these

patients

may

have

a

prolonged

immune-res-

ponse

that

causes

ongoing

nerve

damage

needing

treatment

for

a

longer

period

of

time.

Some

of

these

GBS

patients

may

even

have

several

episodes

of

deterioration.

This

often

raises

the

question

whether

these

patients

may

have

chronic

inflam-

matory

demyelinating

polyneuropathy

with

acute

onset

(A-

CIDP)

(figure

2)

[45].

How

many

deteriorations

would

alter

the

diagnosis

from

GBS

to

A-CIDP?

This

is

an

important

question,

but

the

answer

is

not

fully

known

yet.

We

have

evaluated

our

series

of

patients

and

concluded

that

the

diagnosis

of

A-CIDP

should

be

suspected

when

patients

initially

diagnosed

with

GBS,

do

have

three

or

more

of

these

deteriorations

or

when

they

have

a

subsequent

deterioration

after

9

weeks

from

onset

of

GBS

[45]

(box

5).

It

is

important

to

look

for

these

secondary

deteriorations

because

GBS

patients

may

improve

after

a

new

course

of

IVIg

and

some

of

these

patients

turn

out

to

have

a

variant

of

CIDP

with

acute

onset

(A-CIDP)

needing

chronic

maintenance

treatment

[45].

Importance

of

pain

in

the

acute

and

chronic

phase

of

GBS

Pain

is

a

common

and

severe

symptom

in

patients

with

GBS.

Recognition

of

pain

is

important,

especially

in

patients

unable

to

communicate

due

to

intubation.

Pain

as

a

presenting

symp-

tom

of

GBS,

before

the

onset

of

weakness,

may

be

misleading

in

making

the

diagnosis

of

GBS.

Pain

has

been

described

in

up

to

89%

of

patients

with

GBS.

Recognition

of

the

presence

and

type

e198

Figure

2

Guillain-Barré

syndrome

(GBS),

treatment-related

fluctuations

(GBS-TRF)

and

acute

onset

CIDP

(A-CIDP)

PA

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of

pain

is

important

because

specific

treatments

can

be

offered

[11,46].

Autonomic

failure

Autonomic

dysfunction,

like

labile

blood

pressure,

tachycardia

or

heart

rate

disturbances,

often

occurs

in

GBS

patients.

Reco-

gnition

of

autonomic

dysfunction

is

important,

because

it

may

be

an

important

cause

of

death

in

GBS.

Three

to

10%

of

patients

die,

presumable

partly

due

to

(sudden)

autonomic

failure.

It

is

yet

not

well

possible

to

predict

which

patients

will

develop

serious

autonomic

failure

and

therefore

need

continue

moni-

toring

[47].

From

observational

studies,

it

seems

that

patients

not

only

die

while

being

admitted

on

an

ICU

due

to

serious

autonomic

failure

or

pulmonary

problems,

but

also

the

first

period

after

discharge

from

an

ICU

can

be

a

high-risk

period

especially

when

a

patient

has

a

tracheostoma

and

stasis

of

sputum.

The

presence

and

treatment

of

severe

fatigue

after

Guillain-Barré

syndrome

(GBS)

Fatigue

after

GBS

is

an

important

problem.

It

was

found

that

severe

fatigue

was

even

present

in

60–80%

of

patients.

Eighty

percent

of

patients

reported

fatigue

as

being

among

their

three

most

disabling

symptoms

[48].

A

12-week

bicycle

exercise

training

however

was

likely

to

be

effective

in

16

severely

fatigued

but

neurologically

well-recovered

GBS

and

four

stable

CIDP

patients

[49].

The

rather

intensive,

three

times

weekly

training

program

we

used

was

well

tolerated

in

patients

who

were

neurologically

rather

well

recovered

from

GBS,

and

self-

reported

fatigue

scores

decreased

significantly.

Physical

fitness,

functional

outcome,

and

quality

of

life

were

also

improved.

A

RCT

however

still

needs

to

be

done.

Although

the

effect

of

the

physical

training

program

cannot

fully

be

explained

yet,

it

seems

to

help,

possible

also

by

ensuring

and

changing

life

style.

Prognosis

of

Guillain-Barré

syndrome

(GBS)

Several

studies

have

been

published

on

the

prognosis

in

GBS.

Some

of

these

found

a

relationship

between

electromyographic

(EMG)

features

and

an

increased

chance

to

need

artificial

ventilation

or

to

have

a

poorer

outcome.

One

large

study

showed

that

demyelinating

features

when

assessing

the

per-

onal

nerve

was

a

high

chance

needing

artificial

ventilation

[50].

We

recently

constructed

and

validated

a

pro-

gnostic

model,

Erasmus

GBS

Respiratory

Insufficiency

Scale

(EGRIS)

that

can

be

used

already

at

the

day

of

admission

to

determine

the

change

for

artificial

ventilation

[23].

Days

bet-

ween

onset

of

weakness

and

admission,

Medical

Research

Council

sum

score,

and

presence

of

facial

and/or

bulbar

weak-

ness

were

the

main

predictors

of

mechanical

ventilation.

This

simple

model

only

requiring

clinical

features

potentially

can

be

of

great

help

to

make

decisions

where

to

admit

patients:

at

a

general

neurology

ward

or

at

the

intensive

care

unit.

Regarding

the

prognosis

of

outcome

after

one

to

6

months

from

onset,

age

is

generally

considered

to

be

a

poor

prognostic

factor.

Another

prognostic

model

(Erasmus

GBS

Outcome

Scale)

has

been

constructed

and

validated

to

determine

outcome

after

6

months

[51].

A

modification

of

this

model

(mEGOS)

showed

that

it

is

already

possible

to

determine

outcome

1

week

after

hospital

admission.

When

using

three

simple

clinical

factors:

high

age,

preceding

diarrhea,

and

low

Medical

Research

Council

sum

score

both

at

hospital

admission

and

at

1

week

were

independently

associated

with

being

unable

to

walk

at

4

weeks,

3

months,

and

6

months

(all

P

0.05–0.001).

This

model

offers

the

possibility

to

select

patients

with

a

poor

prognosis

already

within

the

first

week

after

admission.

This

is

important,

not

only

for

counseling,

but

also

when

considering

more

intensified

treatment

for

GBS

already

early

in

the

course

of

disease.

In

this

early

phase

of

disease,

it

is

more

likely

that

intensified

treatment

is

still

effective

because

irreversible

nerve

damage

has

not

yet

been

occurred.

We

now

use

this

mEGOS

to

select

patients

to

study

the

effect

of

a

second-dose

immuno-

globulin

(SID-GBS

trial).

Prognosis

of

GBS

is

an

important

issue

because

treatment

really

needs

to

be

improved.

In

light

of

this,

it

is

of

extreme

importance

that

the

Inflammatory

Neuropathy

Consortium

(INC)

has

recently

started

a

large

international

collaborative

study.

This

International

GBS

outcome

study

(IGOS)

is

conducted

by

a

worldwide

consortium

of

neurologists,

it

investigates

outcome

especially

in

relation

to

clinical,

immu-

nological,

microbiological,

and

genetic

factors.

Future

directions

New

treatment

options

in

GBS

are

absolutely

necessary

because

the

prognosis

in

a

large

group

of

GBS

patients

is

e199

Box

5

Differences

between

GBS-TRF

and

acute

onset

CIDP

(A-CIDP)

[45]

GBS-TRF

patients:

more

frequent

cranial

nerve

dysfunction;

more

rapid

onset

of

weakness;

more

severe

weakness;

only

one

or

two

TRF’s;

first

TRF

sooner

compared

to

deterioration

in

A-CIDP;

TRF(’s)

occur(s)

<

2

months

from

onset.

A-CIDP

patients:

no

ventilatory

support;

more

demyelinating

features

on

EMG;

when

three

or

more

exacerbations;

when

deterioration

occurs

>

2

months

from

onset.

Diagnosis,

treatment

and

prognosis

of

Guillain-Barré

syndrome

(GBS) IMMUNE-MEDIATED

NEUROPATHIES

tome

42

>

n86

>

juin

2013

still

far

from

good.

One

option

in

the

acute

phase

could

be

a

second

IVIg

treatment

in

patients

with

a

poor

prognosis.

The

SID-GBS

RCT

is

going

on

in

The

Netherlands,

and

the

interna-

tional

second-dose

IVIg

study

(I-SID-GBS)

has

been

started.

Recent

experiments

indicate

that

agents

that

interfere

with

complement

activation

are

potentially

attractive

candidates

to

be

tested

in

a

very

early

phase

of

GBS

[52].

Since

it

is

now

possible

to

predict

outcome

in

individual

patients

more

accura-

tely,

new

drugs

like

eculizumab

or

other

regimens

could

be

tested

especially

in

a

restricted

GBS

population

with

a

poor

prognosis.

Focus

also

on

the

pathophysiological

effect

of

treat-

ment,

such

as

studying

the

mechanism

of

action

of

IVIg,

poten-

tially

could

also

lead

to

more

personalized

treatment

once

it

is

shown

that

some

patients

require

other

IVIg

dosages

or

treat-

ment

regimens.

Treatment

trials,

especially

in

rare

diseases,

usually

require

a

long

period

of

time

to

include

sufficient

patients.

A

new

trial

design

in

a

selected

population

(like

is

being

done

in

the

SID-GBS

RCT)

uses

covariate

adjustment

which

reduces

the

sample

size

required

to

reach

sufficient

power

[53].

Using

the

most

appropriate

outcome

measurements

to

evaluate

the

effect

of

treatment

is

essential.

This

is

currently

under

investigation

in

the

Peripheral

Neuropathy

Outcome

Study

(Perinoms)

[54].

New

trials

investigating

less

aggressive

treatments

are

also

indicated

in

mildly

affected

patients,

and

possibly

also

in

patients

with

MFS.

More

attention

should

be

paid

to

pain,

autonomic

dysfunction,

and

severe

fatigue,

all

yet

often

under-recognised

conditions.

The

Inflammatory

Neuropathy

Consortium

(INC)

is

an

excellent

platform

to

conduct

these

studies.

Disclosure

of

interest:

the

author

initiated

the

ongoing

randomized

controlled

second-dose

IVIg

trial

in

GBS

patients

with

a

poor

prognosis

(SID-

GBS),

Guillain-Barr?? syndrome: Pathogenesis, diagnosis, treatment and prognosis

Abstract