the jurnal

GBS epidemiology
GBS Pathogenesis
differential diagnosis
neurophysiological testing
GBS investigation
GBS clinical spectrum
GBS antecedent event
GBS and vaccine
GBS clinical subtype
GBS in children
Autoimmune
GBS treatment
GBS prognosis

GUILLAIN-BARRE SYNDROME
Dr. Eka Widyadharma, M.Sc, Sp.S

Guillain-barre syndrome
Clinical entity characterized by rapidly
progressing limb weakness and the loss
of tendon reflexes
Affects children and adults of all age,
sexes, men>women
Preceded by viral or bacterial ilness,
upper respiratory tract infections or
gastroenteritis in 60-70% cases
Kuwabara, 2004.

Guillain-barre syndrome
Is an autoimmune disorder
encompassing heterogenous group of
pathological and clinical entities.
Antecedent infections are thought to
trigger an immune response, which
subsequently cross-react with nerves
leading to demyelination or axonal
degeneration.
Seneviratne, 2000

 Guillain-Barr syndrome (GBS) is

described most accurately as a
collection of clinical syndromes
manifested by an acute inflammatory
polyradiculoneuropathy with resultant
weakness and reflex changes.
(Cha-Kim, 2004)

GBS Epidemiology
Annual incidence 0,4-4,0 ( median 1,3 ) cases per
population of 100.000.
1,15 cases per population 100.000 in Japan
Kuwabara, 2004

1-3/100.000 population in Europe, USA and Australia

Seneviratne, 2000

0,5-1,5 /100.000 in individual less than 18 years of age

Sladky, 2004

GBS Epidemiology
Occurs in all ages
Slight peak in late adolescence and young adulthood
CMV and C jejuni infection
Elderly susceptible for autoimmune disorders
decrease immune suppressor mechanism
Men > women ( 1,25 : 1 )
Kuwabara, 2004

Males affected more commonly

Bimodal distribution : peak in young adult and elderly
No consistent geographical variation
Lower during pregnancies, increases after deliveries
Infants : the lowest risk
Seneviratne, 2000

GBS Epidemiology
0,6-4 cases/100.000 population throughout
the world
Europe : 1,2-1,9/100.000
Fishers syndrome 0,1/100.000
Men > women (1,5:1)
Increase steadily with advancing age
China : 0,66/100.000 in all ages
Hughes & Comblath, 2005

GBS Epidemiology
the overall death rates range from 2-12% of
increase markedly with age.
In the United States, the case-fatality ratio ranges
from 0.7% less than 15 years to 8.6% more than 65
years.
In age 60 years or more, the risk of death increases
6-fold compared with persons aged 40-59 years and
increased 157-fold compared with persons aged less
than 15 years.
Males have a death rate 1.3 times greater than
females after the age of 40 years.
Cha-Kim, 2004

GBS Epidemiology
outcome of GBS more favorable in children than adults.
Deaths are rare and 75-90% achieve full recovery. The
recovery period is longer than the duration of the acute
illness, often weeks to months, with a median estimated
recovery time of 7 months. In another series, the median
time from onset of symptoms to initial recovery was 17
days; to walk unaided was 37 days; and to be symptom
free, 66 days.

The most common serious complications are weakness of the

respiratory muscles and autonomic instability. Pneumonia, adult
respiratory distress syndrome, septicemia, pressure sores, and
pulmonary embolus are also important potential complications.
During the acute progressive phase of the disease, close
attention should be paid to respiratory status. Measurements
such as vital capacity provide objective data to follow and
compare.

Recurrence of GBS occurs in approximately 5% of cases, often

many years after the initial bout. Recurrence is relatively
uncommon in children.
Some patients experience a chronic progressive course, known
as chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP).

GBS PATHOGENESIS

Klasifikasi GBS dan patologi

Ganglioside
The name ganglioside was first applied by the
German scientist Ernst Klenk in 1942 to lipids newly
isolated from ganglion cells of brain. They were shown
to be oligoglycosylceramides containing Nacetylneuraminic acid (sialic acid or 'NANA' or 'SA' or
Neu5Ac) residues (or less commonly N-glycoloylneuraminic acid, Neu5Gc), joined via glycosidic
linkages to one or more of the monosaccharide units,
i.e. via the hydroxyl group on position 2, or to another
sialic acid residue.
As a result, the polar head groups of the lipids carry a
net-negative charge at pH 7.0 and they are acidic.
These lipids can amount to 6% of the weight of lipids
from brain, but they are found at low levels in all animal
tissues where like the neutral oligoglycosphingolipids
they are concentrated in 'rafts' in the plasma
membrane. They are not found outwith the animal
kingdom. One of the common monosialo-gangliosides
(ganglioside GM1) is illustrated -

Gangliosides

Immune mechanism in GBS

Gangliosides in GBS

Mollecular mimicry

Differential diagnosis of acute flaccid

paralysis

CIDP

Diagnosis

Acute neuropathy reaching peak in under 4 wks

Weakness
Hyporeflexia or areflexia
Raised protein concentration on CSF
may be mistaken for a psychological complaint at first in
patient recovering from a febrile illness
Hughes & Cornblath, 2005

 Onset phase lasting for up to 4 weeks

Different from CIDP, which the onset phase lasts for 4-8
weeks or more than 8 weeks
Difficulties : recurrent GBS between 8%-16%
Von Koningsweld & Van Door, 2005 : patient who
deteriorated 9 wks after onset or had more than two
treatment related fluctuation more likely to develop CIDP
Hughes & Cornblath, 2005

Neurophysiological testing

Neurophysiological testing
Sufficient data required from
at least three sensory nerves
at least three motor nerves with multisite stimulation
F waves
Bilateral tibial H-reflexes
Sign of demyelination finding probability increase as more
nerves were studied, including late responses, F waves,
and H-reflexes
There is still no consensus on neurophysiological criteria
for classification
Hughes & Cornblath, 2005

Neurophysiological testing
USA, Australia, and Europe: early electrodiagnostic study
abnormality showing demyelination in 85% cases
13% remains normal
Motor conduction studies were abnormal earliest, sensory
later
Early abnormalities : prolonged distal and F-wave
latencies, reduced conduction velocities, partial motor
conduction block
Feature of axonal degeneration developed over time
including reduced evoked amplitude and abnormal
electromyography

Neurophysiological testing
Sensory conduction:
Sural Action Potential is frequently normal
Median SAP is abnormal
normal sural-abnormal median pattern
No particular best time to do nerve conduction studies
Better be done as soon as possible
Repeated after 1 or 2 weeks

Parameters in ENMG

Distal latency
Nerve conduction velocity
(NCV)
CMAP amplitude
CMAP duration
F-waves
Sensory conduction studies
H-reflex
Needle EMG

Distal Latency

DL- latency from stimulus onset to appearance of CMAP

Depends on
NCV of distal segment
Neuromuscular Jn. And muscle membrane transit time

Abnormal ?
> 125 % ULN if CMAP amplitude is normal
> 150% ULN if CMAP amplitude is < 80%

Nerve Conduction Velocity

Slowing of NCV is one of the hallmarks of demyelinating

neuropathy
Normal
UL > 50 m/s
LL > 40 m/s

Abnormal?
<80% of LLN if CMAP >80% of LLN
<70% of LLN if CMAP < 80% of LLN

CMAP Amplitude

Amplitude depends on the no. Of functioning motor

axons with secure conduction

So, Low amplitude can occur with both demyelination and

axonopathy

Amplitude < 20% of normal axonopathic if there are no

features of demyelination

CMAP Duration

Depend on the range of conduction velocities of

conducting fibers

Abnormal ?
>15% increase in the negative peak duration of the proximal
evoked CMAP compared to distal CMAP -called Temporal

Dispersion

CMAP area: Amplitude X duration

Conduction Block

Difference of CMAP
amplitude between distal
and proximal stimulation
Value ? consensus

20%, 30%, 50%

60% for Tibial

Conduction Block

Amplitude fall >30% in proximal stimulation compared to

distal irrespective of change in the duration [Temporal
dispersion]

Both TD and CB signify the same process-i.e., segmental

demyelination

F-waves

Antodromic impulse from the motor nerve proximal

nerve root AHC motor nerve elicits a delayed
small action potential called F-wave

When Distal segment study is normal, abnormal F-wave

indicate proximal dysfunction

Abnormal ? >120% of ULN if amp >20% LLN or in-excitable

Abnormal F-wave

H-reflex

Electrophysiological correlate of areflexia

Monosynaptic spinal reflex
Sensory N
Motor nerve

Dorsal Root
H Reflex

Synapse Motor root

Abnormal ?
Absence of H-reflex

Almost an universal finding in early GBS

Evolution Of ENMG Features

Most proximal and most distal segments are affected
early
NC Velocities are often normal early
Motor NCV slowest-3rd week
Sensory NCV slowest-4th week
Change in NCV - often the last to recover
When patient improves, NCV may paradoxically slow

Electrodiagnostic Criteria (AIDP)

Albers
et al

CV

Albers & Cornbla

Kelly
th (CIDP)

Ho et al

Dutchgr
oup

Italy
group

<95
(85)

<90
(80)

80%
(70%)

<90
(85)

<70

<80
(70)

DL

>110

>115

>125%

>110

>150

>125

CB

30

30

20%

30

30

30

TD

30

30

20%

30

30

F-wav

>120

>125

>120%

>120

>150

120-150

43 pts

72%

37%

21%

58%

63%

56%

(Low amp)

Criteria For Electrophysiological

Classification
Primary Demyelinating
At least 1 of the following in 2 nerves or 2 in 1 nerve if others
are of low amplitude/ in-excitable

MCV <90% LLN (85% if amp. <50% LLN)

DML >110% ULN (120% if amp. < 20%LLN)
C.Block 50% fall proximally if CMAP >20% LLN
F-latency >120% ULN

Classification contd
Primary Axonal [AMAN/AMSAN]
None of the features of demyelination in any nerve
Distal CMAP amp <80% LLN in at least 2 nerves

Inexcitable
Distal CMAP absent in all nerves
OR present in only 1 nerve with amp.<10%LLN

Classification contd
Equivocal
Does not exactly fit criteria for any group

Follow up studies will help in reclassifying the

Inexcitable and Equivocal group into
axonal/demyelinating
[GBS study Group. Ann Neurol 1998]

Early GBS ENMG Features

Early diagnosis is important

CSF is often normal in early stages
Gordon & Wilbourn, 2001

31 patients studied within 7 days

H-reflex absent 97%
Absent or Low amplitude SNAPs in UE-61%
Abnormal Median & Normal Sural SNAP 48%
Abnormal F-waves 84%

Early GBS contd

Prolonged DL 65%
Low CMAP amp 71%
Temporal dispersion 58%
Conduction Block 13%
Slowed Motor conduction velocity 52%
Definitive diagnosis in 55% usually by 5th day

[Gordon et al.Arch Neurol 2001;58:913]

AMNS Responses

Median: Wrist-finger
Sural: Calf-Lat mall

In GBS most distal and prox.

Segments are affected early
In true sense AMNS is an
artifactual finding

Isolated Absent F-waves in GBS

Kuwabara et al. studied 62 pts (Japan)

12 had Isolated F-wave absence
Follow up conduction revealed 2 patterns
Rapid restoration of normal F-waves ! Normal parameters
in other sites too [ Rapid clinical recovery ]
Evolution into AMAN!!

Pathophysiology of Isolated Absent

F-wave in GBS

1.

2.

3.

4.

Demyelinative
conduction block
in proximal
segment
Acute axonopathy
in proximal
segment
Reversible
conduction failure
at nodes of Raniver
(AMAN)
Impaired
excitability
[Kuwabara JNNP
2000;68:191]

Inexcitable?

Nerve may have

conducting axons
but inexcitable by
conventional
stimulation

EMG

Preferably done in all cases

Denervation features may
occur as early as first week of
illness
Indicate axonopathic process

Miller Fisher Syndrome

Sensory
Axonal loss
Reduced SNAPs
Can be completely normal

Motor: Usually Normal

F-waves: Prolonged; Dispersed; Absent
Serial conduction studies- more useful

Prognostic Factors

CMAP amplitude 0-20% LLN -poor outcome

Other parameters-do not predict
Recurrent GBS Vs CIDP?
No electrophysiological features
Rely more on clinical features
A documented normal study between relapses may help

Conclusion

Electro-clinical diagnosis
No universally accepted EP criteria
Majority 56-87% -AIDP
Early GBS - normal study unlikely with significant deficit
Axonal GBS diagnosed in the absence of demyelination
features
Low CMAP only prognostic indicator

Main pathologic events of primary segmental demyelination in

immune-mediated inflammatory polyneuropathies (Potts,
2001)

Normal peripheral motor nerve anatomy and

responses to injury (Quan, 1999)

ENMG demielinisasi dan aksonopati (Hughes, 2002)

Distal Latency (Moosa, 2002)

DL- latency from stimulus onset to appearance of CMAP

Depends on
NCV of distal segment
Neuromuscular Jn. And muscle membrane transit time
Nerve Conduction Velocity
Slowing of NCV is one of the hallmarks of
demyelinating neuropathy
Conduction velocity is calculated by
comparing the latency of muscle activation
after stimulation from two measured points
along the nerve.

CMAP Amplitude (Moosa, 2002)

Amplitude depends on the no. Of functioning motor

axons with secure conduction
So, Low amplitude can occur with both demyelination
and axonopathy
Amplitude < 20% of normal axonopathic if there
are no features of demyelination

Conduction Block (Mossa, 2002)

Difference of CMAP amplitude between distal

and proximal stimulation
>15% increase in the negative peak duration of
the proximal evoked CMAP compared to distal
CMAP -called Temporal Dispersion
Amplitude fall >30% in proximal stimulation
compared to distal irrespective of change in the
duration [Temporal dispersion]
Both TD and CB signify the same process-i.e.,
segmental demyelination

F-waves (Moosa, 2002)

Antodromic impulse from the motor nerve proximal nerve root
AHC motor nerve elicits a delayed small action potential called
F-wave
Delayed or absent F wave showing root demyelination

H-reflex (Moosa, 2002)

Electrophysiological correlate of areflexia

Monosynaptic spinal reflex -> Sensory N ->
Dorsal Root ->
Synapse Motor root -> Motor nerve -> H Reflex
Abnormal : Absence of H-reflex
Almost an universal finding in early GBS

Early GBS ENMG Features (Moosa, 2002)

31 GBS patients studied within 7 days

H-reflex absent 97%
Absent or Low amplitude SNAPs in UE-61%
Abnormal Median & Normal Sural SNAP 48%
Abnormal F-waves 84%
Prolonged DL 65%
Low CMAP amp 71%
Temporal dispersion 58%
Conduction Block 13%
Slowed Motor conduction velocity 52%

(Gordon et al.Arch Neurol 2001;58:913)

Aksonopathy VS Myelinopathy(Potts, 2001)

Study

Axonal
degeneration

Motor-nerve conduction studies

a
CMAP amplitude
Decreased
Distal latency
Normal
Conduction velocity
Normal
Conduction block
Absent
Temporal dispersion
Absent
F wave
Normal
H reflex
Normal
Sensory-nerve conduction studies
SNAP amplitude
Decreased
Distal latency
Normal
Conduction velocity
Normal
Needle electromyography (spontaneous activity)
Fibrillations
Present
Fasciculations
Present
Recruitment
Number of motor units
Decreased

Segmental
demyelination
b

Normal
Prolonged
Slow
Present
Present
Prolonged or absent
Prolonged or absent
Normal
Prolonged
Slow
Absent
Absent
Decreased

GBS Investigation

GBS investigation: CSF findings

Progressive motor weakness prime

protein
10 mononuclear cells/mm3
CSF protein N in first week
Pleocitosis raises doubt, associated with HIV

LCS
The
Evaluation
Pressure
Color
Blood
Cells
Culture &
Sensitivity
Protein
Glucose
Chloride
(not routinely
evaluated)

Normal Findings

What abnormal findings may indicate

Less than 200cm H2O tumors, hydrocephalus, intracranial bleeding

Clear and colorless
Cloudy-bacteria, WBCs
Red-tinged--subarachnoid bleeding
None
Cerebral hemorrhage or Traumatic tap (inadvertant rupturing a
blood vessel )
No Red blood cells,
Red blood cells-- blood within the spinal canal,
<5 lymphocytes/mm2 White blood cells--infection
No organisms present Bacterial or fungal infection
15 - 45 mg/dl
Meningitis, encephalitis, myelitis, tumors, inflammatory processes
up to 70mg/dl for
elderly and children
50 - 75 mg/dl
Meningitis, neoplasm
or 60 to 70% of blood
glucose level
700 - 750 mg/dl
Meningeal infections, tubercular meningitis

Dissosiasi sitoalbuminique

reaksi inflamasi dan edema menimbulkan kompresi.

Terjadi transudasi protein serum ke dalam ruang
subarachnoid dan css.
Hal ini menimbulkan kenaikan karakteristik kadar protein
dalam css.
Hiperemi dan dilatasi pembuluh darah yang terjadi akibat
inflamasi menyebabkan pasokan protein lebih besar ke css

CSF findings in GBS

Elevated protein (higher than 0,5 g/dl)
No pleocitosis (abnormal cell number in CSF)
CSF often normal in less than 48 hours, but by the
end of one week the protein level is elevated.
Pleocitosis (cell count 10-100/mm3) with typical GBS
symptom increase the possibility of Lyme disease,
HIV, and other disease.

Diagnosis Kriteria for typical GBS

GBS CLINICAL SPECTRUM

GBS feature
Acute/sub acute onset
Gradual recovery after plateau phase
Mean time nadir; improvement; recovery : 12;
28; 200 days
Plateau phase 4 wks from onset
Seneviratne, 2000

Clinical Features
Most patients are essentially well
Lack systemic symptoms, including fever, when PNS
symptoms begin

Initial neurological symptoms vary from patient to patient

Cardinal features of GBS include:
Paresthesias
Weakness
Diminished or absent DTRs

Paresthesias

Distal, usually symmetrical paresthesias involving the toes,

fingers, or both herald the onset of the disorder in at least 50%
of patients
Typically spreads proximally but seldom extends beyond the
ankles and wrists
Substantial sensory abnormalities are found infrequently on
exam
In contrast with the high incidence of sensory symptoms

Typically, vibration and proprioception are the most severely

affected
Sensory modalities mediated over large myelinated fibers

Weakness

Weakness is often first noted a few days after the onset of

paresthesias
Typically, it begins in the lower extremities, especially in the
proximal muscles
Patients may experience difficulty climbing stairs and rising from
chairs for a day or two before they realize that they are ill

Weakness soon spreads (ascends) to the upper extremities

Less often, weakness begins simultaneously in the upper and
lower extremities
Lower extremities usually more severely affected

Deep Tendon Reflexes

On clinical examination, one of the earliest findings
is decreased or absent DTRs
These may either precede or follow by a few days
the demonstration of weakness on physical exam
In some cases, profound proprioceptive loss results
in sensory ataxia and pseudoathetosis

Disease Progression

Progressive phase of the illness lasts from a few days to a month

~ 50% of patients reach the nadir of clinical function by 2 weeks and
80% by 3 weeks
Flaccid weakness is ultimately present and varies considerably in
severity and distribution
Often is profound, involving all four limbs, the respiratory muscles,
and the face
Facial diplegia, or bilateral facial weakness, is seen in ~ 50% of the
patients
Occasionally, fasciculations are noted

Pain

Although the prominent features are motor in nature, pain occurs in

over 75% of patients with acute GBS
Usually, it is most severe in the shoulder girdle, back, and posterior
thighs
Notoriously more severe at night

Diagnosis of pain in children is particularly difficult due to limited

history and cooperation during the neurological exam
Most often misdiagnosed and under-treated

GBS antecedent events

Two third patient of GBS

URTI or GE
Resolved at onset
Interval preceding infection : 1-3 wks (mean 11 days)
Kuwabara, 2004

C jejuni
Major cause of bacterial GE throughout the
world
Most frequent antecedent infection of GBS
Commonest pathogen identified : 20%
diarrhoea
Eur & USA 26%-30% culttured (+)
Japan 45%
Kuwabara, 2004; Seneviratne, 2000

C. Jejuni and serotype

AMAN and AMSAN
more often; AIDP
less often
Most frequent in
MFS
Associated with
slow recovery,
severe residual and
axonal degeneration

In America Risk 1:1058

After inf O:19 1:158

Serotype & susceptibility

important role
Japan: Penner serotype
O:19 ( 18% GBS)
USA and German 29%
seropositive for O:19
South Africa : O:41
MFS : O:2

Seneviratne, 2000

C jejuni pathogenesis
Mollecular mimicry
Gangliosides: important surface molecule in nervous
system
Antibodies formed against ganglioside-like epitope in
lypopolysacharida C jejuni cross react with peripheral
nerves causing damage
High titre of antibodies against : GM1, GM1b, GD1a or
Ga1NAc-GD1a.
Host susceptibility : important
GBS & enteritis similar ganglioside like epitopes
Kuwabara, 2004; Seneviratne, 2000

C jejuni

C. jejuni and GBS fact

C. jejuni and GBS fact

CMV and GBS

Second commonest infection

Japanese 5%; European: 11-13%; Belgium 13%
> ; Young age
Severe course initially + respiratory difficulties
Often with cranial nerve palsy (bilateral facial palsy) and
severe sensory loss
SNAP
NCV, conduction blocks, denervation activities ~ others
Recovery delayed
Liver function disturbance liver enzymes
Molecular mimicry : possible
Host factor important individu with antibodi anti GM2.
Seneviratne, 2000

Haemophilus Influenza
13% serological evidence in 41 cases in
Japan
Antiganglioside antibodies (+)
AMAN ~ C jejuni
Presence of ganglioside GM1-like structure
on the surface
Seneviratne, 2000

Other infection and GBS

EBV
Mycoplasma pneumonia
Parainfluenza type 1 virus
Influenza A & B virus
Adenovirus
Varicella zoster virus (VZV)
Parvovirus B19
HIV
Lyme disease
Hepatitis A,B,C, and D
Typhoid
Plasmodium falciparum
Seneviratne, 2000

GBS and Vaccine

A/New Jersey (Swine Flu) vaccination programme in USA
1976-1977 GBS
RR 4-7,8 in 6 wks
8.6 cases/million in Michigan
9.7 cases/million in Minnesota
1978-1979 RR1.4
1980-1988 RR 1.1
1992-1993 RR 1.7 ~ 1-2/million age < 45
1999 10/million
Other virus : not clear
Immunization continued risk and benefit
Seneviratne, 2000

GBS and Vaccine

Finland
GBS during Nationwide Oral Polio Vaccine
Failed to prove case-effect relationship
Latin America
No temporal association between the mass oral polio
vaccination campaign and GBS in 1989-1991
TT not significant
MMR & Measles anecdotal case records; not significant
in South America 1992-1993.
HBV immunization: 9/850.000
Seneviratne, 2000

Guillain Barre Syndrome following

Influenza Vaccination JAMA, 2004.

GBS Clinical Subtypes

American Academy of Family Physician, 2004

Acute Inflammatory Demyelinating

Polineuropathy
Most common form 85-90%
GBS ~ AIDP
Lymphocyte infiltration of peripheral nerve & macrophage
mediated segmental demyelination
Infiltration of T Cells in endoneurium
Immune target: Schwann cells surface or myelin. Molecule
target not known
Axonal loss may also occur in severe case as secondary
event
Mediated by humoral and cellular immunity
EP : segmental demyelination
Recovery : remyelination
Seneviratne, 2000; Kuwabara, 2004; Hughes & Cornblath, 2005

AIDP image

AMAN
Majority case in China 1991-1992
76% seropositive for C jejuni
Antiganglioside antibody anti GM1, GM1b, GD1a, GD1b,
Ga1NAc-GD1a
CAMP
Motor distal latencies, motor conduction velocities, SNAP,
F Wave Normal
Wallerian degeneration of motor axon
Earliest pathologic feature:
- lengthening of node of ranvier
- distortion of paranodal myelin
- dissection of axon from Schwann cell adaxonal
plasmalemma by extending macrophage processes
- may be reversible

AMAN image

AMAN
Tendon reflexes could be preserved or
exaggerate
Hyperreflexia in 1/3 cases esp early phase
occasionally acute phase anti GM1
antibody less severe case
Characterized by rapidly progressive
weakness often with respiratory failure
Usually good recovery
Seneviratne, 2000; Kuwabara, 2004; Hughes & Cornblath, 2005

AMSAN
EP inexcitable motor nerves and evidence of
sensory & motor axonal dysfunction
Axonal degeneration with no demyelination or
inflammation
Wallerian degeneration sensory and motor fibre with
little demyelination or lymphocytic infiltration
Could follow C jejuni infection
Numerous macrophage in periaxonal and intraaxonal
space epitope in such space
The course typically fulminant
Slow and incomplete recovery
The worst form of GBS
Seneviratne, 2000; Kuwabara, 2004; Hughes & Cornblath, 2005

Miller Fisher Syndrome (MFS)

Associated wit C jejuni infection

Penner Serotype 2 and Lior Serotype 4
IgG autoantibody against GQ1b
GQ1b in
- N III, IV, VI ophtalmoplegia
- dorsal root ganglia areflexia
- interfere neuromuscular transmission
weakness
Seneviratne, 2000; Kuwabara, 2004; Hughes & Cornblath, 2005

Ataxia in MFS
Peripheral mechanism
Abnormal joint position sense
Abnormal muscle spindle proprioception
Fisher : out of proportion to the degree of sensory loss
Central mechanism
Based on MRI and EP test
Stain of the cerebellar molecular layer with IgG anti
GQ1b antibodies
Seneviratne, 2000; Kuwabara, 2004; Hughes & Cornblath, 2005

MFS Neuropathological
Scanty, rare disorder
Demyelination and inflammation of N III& VI
Demyelination and inflammation of spinal
ganglia
Demyelination and inflammation peripheral
nerve
No axonal damage

Seneviratne, 2000; Kuwabara, 2004; Hughes & Cornblath, 2005

MFS Electrophysiology
or absent SNAP
Motor and sensory nerve conduction velocity
N or
Absent tibial H reflex
Absent denervation changes In limb muscle

Other variant of GBS

Pure sensory
Pure dysautonomia
Pharyngeal-brachial-cervical
Paraparetic variant

Pure sensory variant GBS

Symetri sensory loss

Areflexia
Mild or no weakness
CSF and EP ~ GBS
Necropsy : demyelination with mononuclear
cell infiltration of nerve and posterior roots

Dysautonomia variant GBS

Vary in feature
Cardiovascular involvement
plasma cathecolamine and cortisol hypertension,
tachycardia
ECG : ST depression, T inverted, tall T wave,
prolonged QTc interval in 1/3 case
Lymphocytic infiltration of autonomic ganglia and
perivascular lymphocytic infiltration in hypothalamus
and brainstem
Fatal case : wide fluctuation of BP
Vagal overactivity : arrhythmia,

GBS in children

0,5-1,5 cases/million
Most common cause of acute paralysis
Affects all ethnic group
Incidence among countries variable
Unclear genetic susceptibility
potential pathogens infections
Associated with antecedent infection
EBV, CMV, Hepatitis, VZV, HSV
M. pneumonia, Campilobacter
Role of immunization anecdotal never concincingly
establihed
Sladky, 2004

Clinical Features Children with GBS

Sladky, 2004
J Child Neurol; 116

Clinical course Childhood GBS

J Child Neurol, 2004;116

Onset and progression of symptoms

Evolves rapidly from mild to mechanical ventilators over
hours
Nadir 2 wks (small group 4 wks)
Immune mediated attack on myelin and axon
Followed by plateau phase
Plateau phase
Variable duration
Peripheral nerve damage slows
Regeneration process

Clinical course Childhood GBS

J Child Neurol, 2004;116

Recovery
Weeks or months
Severity at nadir quite variable
Mean disability grade : 3.5-4
(Hughes criteria)
45% score 2-3
40% score 4
15% score 5
Mortality is rare with high
quality supportive
management
90-95% completely recovered
within 6-12 months
Minor Residual deficit

Management childhood GBS

J Child Neurol, 2004;116
Hospitalization until maximal degree of disability
Fulminant fashion and respiratory failure can developrd
rapidly
Pain : often under-treated
Autonomic complication
Careful attention to nutrition requirement
Early introduction of physical and occupational therapy

Treatment Childhood GBS

J Child Neurol, 2004;116
Plasma Exchange
Descriptive reports
Enhances time of recovery and shortening time to discharge
from hospital
Mostly for severe case
Dose and schedule have not been determined
Generally safe in children weighing 10 Kg or more
Cumulative total 250 ml/kg exchange or roughly triple volume
exchange
IVIG
Similar with PE
Total dose 2g/kgBW (0.4kg/kgBW 5 days; 1g/kgBW 2days,
0,5g/kgBW 4 days ?? )
Steroid
No potential role

Prognosis of Childhood GBS

Rust&Flemming, 1996
Good prognosis:
Young age
No need for respiratory assistance
Slow progression of illness
Normal EP study
Treatment with PE or IVIG

Clinical Evidence Childhood GBS

Clinical Evidence Childhood GBS

Koul, et al, 2003

Clinical Evidence Childhood GBS

Graaf, et al, 1999

Clinical Evidence Childhood GBS

Shanbag, et al, 2003

Clinical Evidence Childhood GBS

Clinical Evidence Childhood GBS

Clinical Evidence Childhood GBS

Clinical Evidence Childhood GBS

Autoimmunity & Autoimmune Disease

Lancet, 2003

Autoimmunity & Autoimmune Disease

Lancet, 2003

Autoimmunity & Autoimmune Disease

lancet, 2003

Major histocompatibility complex (MHC)

Pengertian:
MHC = seperangkat gene yang menghasilkan protein yang mempunyai
peran penting dalam imunologi
MHC molecule = molekul yang dihasilkan oleh MHC
Molekul MHC :
MHC I diekspresikan oleh semua sel somatik; fungsinya
mempresentasikan antigen kpd limfosit Ts
membunuh sel
MHC II diekspresikan hanya oleh fagosit dan beberapa sel lain; fungsinya
mempresentasikan antigen kpd limfosit Th
produksi antibodi
penting pada manipulasi kekebalan spesifik

MHC

Presentasi antigen kepada sel T

Gb. atas oleh fagosit : fagosito-sis
proses penghancuran presentasi
Ag kepada sel T bersama MHC II
Gb tengah oleh sel B : internalisasi
antigen presentasi kepada sel T
bersama MHC II
Gb bawah oleh sel dendritic :
pinositosis (?) presentasi kepada
sel T bersama MHC II

GBS Treatment : supportive

Respiratory assistance significantly improve outcome
Intubation and mechanical ventilation required for 25-33%
Measurement of maximal expiratory vital capacity VC
15ml/kg intubation & mechanical ventilation
Bulbar palsy : intubation required to prevent aspiration
Continuous monitoring of BP and HR
Hypotension associated with dysautonomia in 10% severe
cases iv infusion & vasopressor agents
Hypertension short acting anti-hypertensive medication
Prevention of thromboembolic and pulmonary embolism
heparin
Respiratory infection minimal sedation in ICU
Pain analgesics and early rehabilitation

GBS treatment Immunomodulating

Plasma exchange
Improved more rapidly
Weaned from ventilators more quickly
Able to walk unaided in shorter period of time
Improve long-term outcome
Adverse events more often according to number of
session
Severe case : 4 session; mild case 2 session
Secondary worsening after PE n 10% cases
Acceptable safety profile when patient condition carefully
monitored haemodynamically unstable patients and
infection complication
Limited facilities, high cost need to discover alternative
treatment

Plasma Exchange
Requires skilled personnel and specialized
equipment
May not be available in all hospitals
May increase the risk of infection and
hemorrhage due to the removal of
immunoglobulins and clotting factors
Complications and side effects : hypotension,
septicemia, pneumonia, cardiac arrhythmias,
malaise, hypoprothrombinemia with
bleeding/abnormal clotting, and hypocalcemia

Mechanism of PE
Plasma exchange or plasmapharesis -The mechanism of plasmapheresis is
the removal of immunoglobulins and
antibodies from the serum by removing
the blood from the body, separating
cells from the plasma, and replacing the
cells in fresh frozen plasma, albumin, or
saline. Adult Dose3-5 exchanges of 50
mL/kg of plasma over 1-2 wk via central
venous catheter suggested

Corticosteroids
No benefit in GBS
124 patients treated with methyl prednisolone 500 mg for
5 days compared with 118 control (Lancet, 1993): no
significant difference
Cochrane evidence based review 2003 : corticosteroid
alone should not be used in the treatment of GBS

From Cochrane Review Abstracts

Corticosteroids for Guillain &hyphen; Barr syndrome

Posted 10/01/2005
RAC Hughes

Introduction
Date of Most Recent Substantive Amendment: 2000 02 03
Background
The cause of Guillain Barr syndrome (GBS) is inflammation of the peripheral nerves which corticosteroids would be expected to benefit.
Objectives
To examine the efficacy of corticosteroids in hastening recovery and reducing the long term morbidity from Guillain Barr syndrome (GBS).
Search strategy
Search of the Cochrane Neuromuscular Disease Group register for randomised trials and enquiry from authors of trials and other experts in the field.
Selection criteria
Types of studies: quasi randomised or randomised controlled trials Types of participants: patients with GBS of all ages and all degrees of severity Types of interventions: any
form of corticosteroid or adrenocorticotrophic hormone Types of outcome measures: Primary: improvement in disability grade on a commonly used seven point scale four weeks
after randomisation Secondary: time from randomisation until recovery of unaided walking, time from randomisation until discontinuation of ventilation (for those ventilated),
mortality, proportion of patients dead or disabled (unable to walk without aid) after 12 months, improvement in disability grade after six months, improvement in disability grade
after 12 months, proportion of patients who relapse, and proportion of patients with adverse events related to corticosteroid treatment
Data collection and analysis
We identified six randomised trials. One author extracted the data and the other checked them. We obtained some missing data from investigators.
Main results
The six eligible trials included a total of 195 corticosteroid treated patients and 187 control subjects. One trial of intravenous methylprednisolone accounted for 243 of the total
382 subjects studied (63%). This trial did not show a significant difference in any disability related outcome between the corticosteroid and placebo groups.
There was no significant difference between the corticosteroid and control groups for the primary outcome measure, improvement in disability grade four weeks after
randomisation. The weighted mean difference of the three trials for which this outcome was available showed no significant difference. The actual figure was 0.06 (95% CI
0.32 to 0.19) grade in favour of the control group.
There was also no significant difference between the groups for most of the secondary outcome measures. However in the largest trial hypertension developed less often in the
intravenous methylprednisolone group (2/124, 1.6%) than in the control group (12/118, 10.2%), a significant difference in favour of corticosteroid treatment (relative risk 0.20,
95% CI 0.04 to 0.66).
Authors' conclusions
Corticosteroids should not be used in the treatment of Guillain Barr syndrome. If a patient with Guillain Barr syndrome needs corticosteroid treatment for some other
reason its use will probably not do harm. The effect of intravenous methylprednisolone combined with intravenous immunoglobulin in Guillain Barr syndrome is being tested
with a randomised trial.

Intravenous Immunoglobulin
IVIG is an immunomodulating agent that has multiple
activities. These include modulation of complement
activation; suppression of idiotypic antibodies; saturation
of Fc receptors on macrophages; and suppression of
various inflammatory mediators, including cytokines,
chemokines, and metalloproteinases (Dalakas, 2002).
The Fc region of IgG facilitates interaction with and
signaling through Fc receptors on phagocytes, B cells,
and other cells and with Fc-binding plasma proteins (eg,
components of the complement system) (Kazatchkine,
2001).

Mechanism of action of IVIG

Mekanisme aksi Ig terapi (Kazatchkine, dkk, 2001)

Mekanisme kerja IG (Abe, 1996)

Pharmacology

Intravenous immune globulin contains a broad

spectrum of antibodies against bacterial, viral,
and parasitic antigens that are capable of
opsonization of as well as neutralization of
microbes and toxins.
Appropriate doses can restore low IgG levels to
normal range.

Pharmacokinetics
Important features are as follows:
Bioavailability is 100% after intravenous injection
A five-fold rise of serum IgG following intravenous
injection with a decline to 50% in 3 days and
return to normal in 3 to 4 weeks
A two-fold rise of CSF level of IgG following
intravenous injection and return to normal
within a week
The half-life of intravenous immune globulin varies
from 2 to 4 weeks

Kontra indikasi IVIg

Prior anaphylactic reaction with IVIG; anaphylactic reactions

may occur in patients with IgA deficiency with anti-IgA
antibodies; when present, IVIG treatments can be performed
with low-level IgA preparations; renal complications can be
minimized by diluting the IVIG preparation, slowing the rate of
infusion, and ensuring adequate hydration of the patients; in
severe congestive heart failure, complications can be reduced
by slower rates of infusion to minimize risk of rapid fluid
overload

Efek samping IVIg

Adverse reactions to IVIG

usually are minor (eg,
headache, fever, chills,
malaise, myalgia); less
common side effects may
include migraines, aseptic
meningitis, pulmonary edema,
skin reactions (eg, urticaria,
pruritus, petechia), and renal
complications; serum viscosity
increases with IVIG therapy,
which can result in rare cases
of stroke, PE, and myocardial
infarction

Fact about IVIG

Clinical and Experimental Immunology, 2005; 142.

Gamimune
Gamimune-N (Miles; Elkhart, Ind; Bayer)
Sterile solution in 5% and 10% concentrations
Sodium content in mEq/mL considered trace amount
(incompatible in saline)
Not sugar-glycine based
Advanced viral removal and inactivation technologies
used in manufacturing; solvent detergent treated
Contraindicated in patients with history of prior systemic
allergic reaction to IVIG products or a history of IgA
deficiency
pH of 4-4.5
Additives in 5% solution include 9-11% maltose; in 10%
solution, 0.16-0.24 M glycine
IgA content of 270 mcg/mL

IVIG use in GBS : expert consensus

GBS with significant or severe involvement seen within 2
weeks
Patient require aid to walk
Impaired bulbar or require ventilation
Rapidly deteriorating
Individuals in difficulties in performing ADL
Treatment should be initiated early within 2 weeks of
onset.
Mild GBS/ GBS seen more than 2 weeks after onset
Consider potential benefit versus clinical risks
Mild GBS usually recovers well without treatment
May be considered if deterioration continue

Recommended dose and duration of

infusion
Standard total dose 2 g/kgBW
Conventionally given 0,4g/kgBW for 5 consecutive days
Many centers use 1g/kgBW for 2 days for faster and more
convenient administration
Side effect ~ shorter course of infusion

Evidence of IVIG in GBS

Evidence of IVIG in GBS

Prognosis GBS

Table Summary of evidence

Condition

Evidence level

Guillain-Barre syndrome

1a

Chronic inflammatory demyelinating

polyneuropathy

1b

Multifocal motor neuropathy

1b

Other lower motor neuron syndromes

IV

Amyotropic lateral sclerosis*

III againts
current use

Neuropathy associated with paraprotein

IV

Myasthenia gravis (acute severe or deteriorating)

1b

Lambert-Eaton syndrome

1b

Inclusion body myositis

1b againts
curren use

Condition

Evidence level

Dermatomyositis

1b

Polymyositis

IV

Stiff-man syndrome

III/IV

Multiple sclerosis (Relapse rate? Disability)

1b

Kawasaki disease

1a

Sarcoid, Behcets disease

No evidence

CNS vasculitis

III/IV

CNS lupus, antiphospholipid syndromes

IV

Epilepsy

III/IV

Condition

Evidence level

Lennox Gastaut, West syndromes

III/IV

Rasmussen encephalitis

IV

Landau-Kleffner syndrome

IV

Paraneoplastic disorders of the CNS

III/IV

Adrenoleukodystrophy

III against
current use

5S Immunoglobulin

Specific IgGs dramatically inhibit the proliferation

of T cells stimulated in vitro by staphylococcal
This supressive effect persists when preparations
containing F(ab)2 are used instead of 7S IVIG,
thereby demonstrating that this inhibitory activity
is Fc-independent, and antigen-specific

 It is beilved that the F(ab)2 fragments of

superantigen-specific IgG may blockeither the
epitope of the toxin required for binding to the
MHC II peptides, or the correct presentation
of the toxin/MHC II complex to T cells or both
5S-immunoglobulin, splits off the Fc fragment
producing a smaller F(ab)2 molecule that is
more effective at penetrating tissues.
5S IgG also has a shorter half life
Those properties of 5S-immunoglobulin may
provide a particular advantage when treating
acute infections