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INVITED REVIEW In the second part of our review the role of antecedent infections in the

pathogenesis of GBS is discussed. The association with Campylobacter


jejuni (C. jejuni) is highlighted and the concept of molecular mimicry,
i.e., sharing of epitopes between microbes and peripheral nerve, ex-
plained. Alternative mechanisms to relate an infection with the im-
mune-mediated neuropathy are elaborated. Current therapies of the
GBS include plasma exchange, high-dose intravenous immunoglobu-
lins, and supportive treatment directed to secondary complications.
Published therapeutic trials are reviewed and future approaches are
outlined. Principles of general care are also summarized. 0 1995 John
Wiley 8 Sons, Inc.
Key words: Guillain-Barre syndrome Campylobactef jejuni ganglio-
side antibodies molecular mimicry plasma exchange IVlG man-
agement
MUSCLE & NERVE 18:154-164 1995

IMMUNOPATHOGENESIS AND
TREATMENT OF THE
GUILLAIN-BARRE
SYNDROME-PART II
HANS-PETER HARTUNG, MD, JOHN D. POLLARD, MD,
GRAHAM K. HARVEY, PhD, and KLAUS V. TOYKA, MD

I n about two thirds of GBS patients a history of a tecedent C. jejuni infection has been documented
preceding acute infectious illness can be found. A by serological methods o r stool culturing in 12-
more than chance association of GBS with a viral 60% of GBS c a s e s ~ . 1 0 , 2 0 . 2 4 . 2 7 . 3 0 . 4 6 , 4 ~ , 5 3 , 5 4 , 6 3 , 6 4 ,
disease has been established for cytomegalovirus, 67,71,78,80,91,92.111-113,116,117,119 (,-f, Table 1). It ap-
Epstein-Barr virus, human immunodeficiency vi- pears that regional variations exist in the fre-
rus, and vaccinia virus.3'39,73*83,1
l4 quency of C. jejuni infections in the general popu-
lation as well as in GBS patients. It has been
ETIOLOGY suggested by several groups that a preceding C.
Antecedent Infections. Recently, much interest jejunilEscherichia coli infection prognosticates a
has centered around the enteropathogenic agent, more severe d i s e a ~ e . ' ~ ~ ~Th' " is~ ~has ' ~not ~ ~ ' ~ ~
Campylobacterjejuni. This gram-negative rod is the been our experience in 53 GBS patients.20 C. jejuni
most common cause of bacterial diarrhea in the strains are heterogeneous with regard to their
Western world. Sources of infection include
12763 heat-stable and heat-labile antigens whose pres-
poultry, raw milk, and contaminated water. An an- ence is used for serotyping.12 The Penner typing
method utilizes heat-stable antigens (lipopolysac-
From the Department of Neurology, Julius-Maximilians-Universitat,
charide), and the Lior method relies on thermo-
Wurzburg, Germany (Drs. Hartung and Toyka), and Institute of Clinical labile (protein) antigens.74 Certain serotypes are
Neurosciences, University of Sydney, Sydney, Australia (Drs. Pollard and
Harvey).
greatly overrepresented in GBS patients compared
to controls without neurological disease. For exam-
Acknowledgments: We are indebted to our colleagues, Drs. J. Archelos.
P. Arrnati, A. Constable, U. Enders, S. Jung, B. Schmidt, G. Stoll, and J. ple, Kuroki et al., in their study of 46 GBS cases in
Zielasek, for their contributions. Mrs. 6.Goebel provided expert secre- Japan, could isolate C . jejuni from stools in 30%.54
tarial assistance. Work cited from the authors' laboratories was supported
by Deutsche Forschungsgemeinschaft Ha 1563/4-1, BMFT (01 KD 9001/ When serotyped using the Penner scheme, 82%
8), BMFT (01 KD 89030), and Gemeinnutzige Hertiestiftung. G.K. Harvey were PEN 19 positive while the frequency of this C .
was a fellow of the Alexander von Humboldt Foundation.
jejuni strain in a control population was less than
Address reprint requests to Hans-Peter Hartung, MD, Neurologische
Klinik. Julius-Maximilians-Universitat, Josef-Schneider-Strasse 11, 97080
2%. The most common serotype associated with
Wurzburg, Germany. uncom licated enteritis is PEN 2, equivalent to
Accepted for publication June 9, 1994. Lior 4T4 In our study of GBS patients we noted
CCC 0148-639W95/020154-11
that a preceding C. jejuni infection was almost in-
0 1995 John Wiley & Sons, Inc variably caused by the Lior 11 serotype, which is

154 Guillain-Barrk Syndrome-II MUSCLE & NERVE February 1995


Table 1. Association of Guillain-Barre syndrome with Camwlobacter ieiuni infection.
Authors Reference Observations

Rhodes and Tattersfield, 1982 78 Single case; stool cultures and serology positive.
Molnar et al., 1982 64 Single case; stool culture positive for C. fetus subspec. jejuni.
Constant et al., 1983 10 Single case; stool culture positive.
Kaldor and Speed, 1984 46 Retrospective study; 21 of 56 patients had serologic evidence of preceding
C. jejuni infection (ELISA).
Speed et al., 1987 92 Twenty-two of 45 patients serologically positive by Western blot analysis; 10
of 19 C. jejuni positive patients reported preceding diarrhea.
Winer et al., 1988 114 Fourteen of 99 patients serologically positive; 11 of 99 positive for recent
CMV infection (IgM); 21 patients reported diarrhea during 14 weeks before
onset of disease.
Winer et al., 1988 113 Patients with serologic evidence of recent C. jejuni infection had decreased
CD8 T cells relative to healthy controls; patients with serologic evidence of
a recent CMV infection had decreased CD4+ T cells.
Ropper, 1988 80 Four of 106 patients stool culture positive. Nine of 106 patients reported
preceding diarrhea (5 of these were stool culture negative).
Yuki et al., 1990 119 Two patients serologically positive for C. jejuni infection had antibodies to
gangliosides GM,, GD,,, and asialo-GM, (ELISMLC overlay technique).
Walsh et al., 1991 112 Fourteen of 94 patients had antibodies to GM, . Eleven of 95 patients had
antibodies to GD,, (9 had also antibodies to GM,).
Zero of 95 patients with antibodies to GT, and GT,, predominantly IgG;
patients with ganglioside antibodies had a higher incidence of antecedent
C. jejuni injfection.
Gruenewald et all, 1991 30 Three of 17 patients stool culture and serologically positive for C. jejuni
(ELISA).
Boucquey et al., 1991 7 Six of 42 patients serologically positive (Western blot); 5 had antibodies
against 35-45-kd and 60-65-kd antigens; all 5 had diarrhea.
Nine of 41 patients serologically positive for recent (IgM) CMV infection; 2
patients had coinfection with C. jejuni and CMV.
Kuroki et al., 1991 53 Seven of 8 stool culture positive; all were PEN 19.
Yuki et al., 1991 117 Six of 6 patients HLA-B35 positive; all were serologically positive for C. jejuni.
Two of 6 patients stool: isolation of C. jejuni Lior 7.
Six of 6 patients had antibodies to gangliosides (5 to GM,, 1 to GD,,).
Yuki et al.. 1992 116 Seven of 13 patients were HLA-B35 positive; 1 of 13 HLA-B51 positive; 1 of 7
HLA-Bw52 positive (HLA-B51 and Bw52 have epitopes similar to
HLA-B35).
Fujimoto et al., 1992 24 Four C. jejuni strains isolated from GBS patients (total sample unkown), all
belonged to PEN 19/Lior 7.
van der Meche et al., 1992 105 Prospective study (Dutch IVlG trial), 129 patients: 36% serologically positive
for C. jejuni, 15% serologically positive for CMV.
Poorer outcome after C. jejuni infection.
Nobile-Orazio et al.. 1992 67 Three of 16 patients serologically positive (complement fixation), all had GM,
antibodies of the same isotype; GM, and C. jejuni antibodies could be
absorbed with C. jejuni lysate and GM,
Gregson et al., 1993 27 Fifteen of 42 patients serologically positive (ELISA); 7 of 12 patients with GM,
antibodies were serologically positive; weak/no correlation with GM,
antibody titers.
Kuroki et al.. 1993 54 Fourteen of 46 patients stool culture positive; 9 of 10 culture positive patients
had C. jejuni antibodies; 5 of 29 culture negative patients had antibodies to
C. jejuni; 14 of 39 patients serologically positive; 10 of 12 stool isolates
were PEN 19; only 2 of 8 patients with C. jejuni infection had HLA-B35
antigen; and 3 of 11 patients without C. jejuni infection had HLA-B35
antigen.
Enders et al., 1993 20 Twenty-seven of 38 patients serologically positive (26 IgG, 15 IgA, 4 IgM); 14
of 15 patients with IgA antibodies to C. jejuni had Lior type 11; no
correlation to severity or ganglioside antibodies.
Vriesendorp et al., 1993 111 Ten of 58 patients serologically positive (ELISA); 2 of 10 C. jejuni-positive
patients had antibodies to GM,; no correlation with clinical severity.
Mishu et al., 1993 63 Forty-two of 116 serologically positive (however, 38% of control subjects also
had C. jejuni antibodies).
Enders et all, 1994 19 Isolation of C. jejuni Lior type 11 from stools of 4 of 26 GBS patients.

Guillain-BarrB Syndrome-ll MUSCLE & NERVE February 1995 155


rare in enteritis not attended by neuropathy or in of developing GBS with influenza vaccine formu-
disease controls; e.g., multiple sclerosis and myas- lations used during 1979-1988.3,48,55,84,s6
thenia gravis.*' We isolated C .jejuni from the stool Cases of an acute motor neuropathy following
in 4 of 26 (15%)GBS patients. All belonged to the rabies vaccination have been reported from South
Lior type 11.'' In uncomplicated enteritis the C. America. There the vaccine is prepared from ra-
jejuni serovar belonged mostly to the Lior 4 group. bies virus-infected suckling mouse or rat
Similarly, data emanating from the Dutch multi- More recently, a report from Finland claimed an
center trial on intravenous immunoglobulin treat- increased incidence of GBS after vaccination with
ment indicate a much higher frequency of the live-attenuated poliovirus, but the numbers are too
LAU 19 and 3/25 serotypes in GBS cases versus small to draw definite conclusions.51
controls. These as well as other investigators noted
a positive correlation of serological evidence for C. Molecular Mimicry. Polyclonal activation of B or T
jejuni infection and the presence of GM, antibod- lymphocytes and molecular mimicry are possible
ies'05 (van der Mecht, personal communication). mechanisms to link a preceding microbial infection
Other workers failed to notice such a correla- with the subsequent immune-mediated nerve dam-
tion.202s82111van der Meche et al. (personal com- age in GBS.68 Microorganisms may act as poly-
munication) used an absorption ELISA to show clonal activators stimulating B-lymphocyte prolif-
that the heat-stable extract of lipopolysaccharide eration and antibody production. The presence of
from LAU 3/25+ C. jejunz inhibited binding of IgG antiglycolipid antibodies of low and medium titer
,
anti-GM antibodies indicating the possibility of may reflect polyclonal B-cell stimulation.8pg6Alter-
molecular mimicry (vide infra). Nobile-Orazio et natively, they may directly precipitate the libera-
al. detected C. jejuni antibodies in 3 of 14 patients tion of cytokines which coordinate immune re-
and were able to absorb the autoantibody activity sponses. Induction of MHC class I a n d I1
with GM,. Similarly, 3 of 14 patients had anti-GM, molecules in response to interferon y o r TNF-a
antibodies, and their activity was greatly decreased may be of particular importance, which in associ-
by preincubation with C. jejuni l y ~ a t eIn . ~contrast,
~ ation with self-antigens could prime an autoreac-
Gregson et al. examined 42 patients and were un- tive T-cell response. So-called superantigens of mi-
able to absorb with bacterial antigens GM, anti- crobial origin (e.g., enterotoxins) can trigger
body activity in those sera from 7 of 12 atients oligoclonal responses of T lymphocytes with a lim-
who concurrently had C. jejuni antibodies2' In the ited bias of their receptor usage.36 Microbes could
study of Kuroki et al.54 PEN 19 isolates from pa- directly infect and destroy immunocompetent cells
tients with GBS were also typed with lectins which resulting in an altered balance between immuno-
specifically recognize a small portion of carbohy- suppressive and immunoaugmenting mechanisms.
drates on the bacterial cell ~ u r f a c e . ~The
' PEN 19 Finally, microbial agents can contain chemical
isolates invariably were lectin type 8 positive indi- structures that mimic normal host self-protein
cating that their surface contained terminal forming the basis of molecular m i m i ~ r y . ~Un- ,~~,~~
(3-GlcNAc residues. It is of interest that the entero- der these circumstances, a B- or T-cell response
toxin elaborated by C . jejuni appears to be a 68-kd initially directed toward microbial antigens may
polypeptide that binds to g a n g l i ~ s i d e s . ' ~The cross-react with self-constituents, hence creating
enterotoxin-GM, complex could serve as a car- autoimmunity. Autoimmunity due to molecular
rier for the terminal GalPl-3GalNAc hapten. mimicry can only occur when shared epitopes are
Mechanisms by which a preceding infectious illness different enough to break B- or T-cell tolerance,
can be causally linked to the immune response provided the response is mounted against a self-
to peripheral nerve in GBS will next be dis- epitope of the host that carries significant biologi-
cussed.68 cal a ~ t i v i t yWith
. ~ regard to molecular mimicry, by
computer search, partial homology of amino acid
Vaccination. Vaccination has also been associated sequences has been discovered for cytomegalovi-
with Guillain-Barre ~ y n d r o m e . ' ~
There was a rus, varicella zoster virus, and the PO glycopro-
slightly increased risk of developing Guillain- tein.56 PO is a neuritogen in rat EAN,57,62to which
Barre syndrome during 6 weeks following ad- transient early T-cell responses have been re-
ministration of vaccines containing New Jersey corded in GBS patients as well as circulating
swine influenza virus in 1976, which was appar- antibodies in some patient^.^''^^'^^ Recently, im-
ently related to some but not all vaccine aliquots. munochemical evidence for a shared antigenic de-
Subsequent studies did not reveal an increased risk terminant between herpes simplex virus ribonu-

156 Guillain-BarrB Syndrome-I I MUSCLE & NERVE February 1995


Table 2. Treatment of Guillain-Barre svndrome: an overview of clinical trials.
Number of
Authors Ref. patientsidesign Treatment Results
Hughes et al., 1978 40 40iope1-1,randomized Oral prednisolone (n = 21) vs. Corticosteroid group slightly
conventional therapy (n = 19). worse.
Osterman et al., 1984 71 38ioper1, randomized Plasma exchange (n = 20) (6 L Improvement in PE therapy
plasma for at least five sessions) group.
vs. conventional therapy.
Greenwood et al., 26 29/open, randomized Plasma exchange (n = 14) ( 3 5 x No significant difference
1984 40-50 mUkg body weight) vs.
conventional therapy (n = 15).
GBS Study Group, 31 245/open, randomized Plasma exchange (3-5 x 40-50 Plasma exchange significantly
1985 mUkg body weight) vs. superior.
conventional therapy (n = 122).
French Cooperative 22,23 220iopen, randomized Plasma exchange of albuminifresh Plasma exchange significantly
Group 1987 and frozen plasma (4 x 100 mUkg superior, in particular with
1992 body weight) vs. conventional early institution; effect
therapy (n = 109). sustained after 1 year.
van der Meche el al., 105 147iopen, randomized Intravenous immunoglobulin (n = Immunoglobulin at least as
1992 74) (5 x 400 mglkg body efficient as PE, possibly
weight) vs. plasma exchange (n suDerior.
= 73).
Guillain-Barre 32 242idou ble-blind Methylprednisolone 5 x 500 mg IV No significant difference
Syndrome Steroid randomized (iplasma exchange) vs.
Trial Group, 1993 placebo (*plasma exchange).
Dutch GBS STudy 99 25iopen Intravenous immunoglobulin (5 x Combined treatment superior
Group, 1994 400 mgikg body weight) plus to IVlG (historical controls).
intravenous methylprednisolone
5 x 500 mg.

cleotide reductase and peripheral nerve PO with a may also indirectly influence cellular immune re-
molecular weight of 29 kd has been put forth.37 actions.
One group has identified a cross-reactive epitope Following several anectodal reports and smaller
contained in the lipopolysaccharide moiety of C. studies, two large and definitive open randomized
j,junz (PEN 19) and GM, isolated from a GBS pa-
tient with anti-GM, ganglioside antibodies.' l8 Ap-
parently, GM, and GD,, epitopes are also con- Table 3. Plasma exchange and high dose intravenous
tained in the LPS fraction of C. jejuni (PEN 1) and immunoglobulin: possible mechanisms of action.
(PEN 4).I2O T h e role of such mimicry in GBS, how- Plasma exchange:
ever, remains hypothetical at present. 0 Removal of pathogenic circulating factors (antibodies,
complement, cytokines, inflammatory mediators).
0 lmmunomodulation (favoring suppressor mechanisms).
IMMUNOTHERAPY OF CBS
High-dose intravenous immunoglobulin:
0 Antiidiotypic antibodies.
Plasma Exchange. Plasmapheresis removes po-
0 Blockade of Fc receptors on macrophagesiinterference
tentially pathogenic soluble factors from the circu- with ADCC (antibody-dependent cellular cytotoxicity).
lation'" (cf. Table 2). Circulating factors that have 0 Downregulation of B cells/antibody production.
been implicated in the pathogenesis of GBS com- Downregulation of CD5+ B cells by anti-CD5 antibodies.
prise antibodies, cytokines, complement compo- 0 Downregulation of cytokine production (IL-2, IFN-y, TNF-a,

nents, and other inflammatory mediators (Table IymphotoxinTTNF-p).


0 lnhibitioniattenuation of cytokine actions by anticytokine
3). In one recent study, comparison of serum titers antibodies (anti-IL-la, anti-TNF-a, anti-IL-6).
of peripheral myelin-directed antibodies before 0 Interference with T-cell activation by contaminating soluble
and after plasma exchange clearly demonstrated a HLA class I I gene products and soluble CD4 molecules (?).
decline following this procedure, and relapses fol- Interference with superantigen-induced T-cell activation by
lowing plasma exchange in a few patients were as- antitoxin antibodies.
Inhibitionineutralizationof complement-mediated effects.
sociated with rising titers of antimyelin antibod- 0 Induction of T-suppressor cells.
i e ~ . ~ By
~ ,removal
"~ of cytokines plasma exchange

Guillain-BarrB Syndrome-I I MUSCLE & NERVE February 1995 157


multicenter trials established the therapeutic effi- bound and, as mentioned before, in one study, re-
cacy of plasma exchange.26.3',61,70,71,90 (cf. Table currence of disease after plasma exchange was in-
2). In a North American trial published in 1985, deed associated with increased levels of peripheral
122 patients were treated with plasmapheresis myelin-directed antibodies.' l o However, this hy-
while 123 received supportive therapy. T o be in- pothesis has been challenged.'6.'0' Plasmapheresis
cluded patients had to be incapable of walking in- also appears to be feasible, efficacious, and safe in
dependently. Two hundred to 250 mL/kg body children with GBS although controlled studies are
weight of plasma were exchanged over 7-14 days. not a ~ a i l a b l e .Questions
~ ~ , ~ ~ that still remain open
Overall, patients treated with plasma exchange im- are: Do patients with less severe neuropathy, i.e.,
proved more rapidly, needed less assisted ventila- those still ambulatory, profit likewise from plasma
tion, spent less time in intensive care units, and less exchange? Are more frequent exchanges more
time in the hospital. Treatment was most effica- efficacious? What is the best time to initiate this
cious when initiated within 1 week of the onset of therapy? Would the combination of plasma ex-
neuropathic symptoms. If plasma exchange could change with high-dose intravenous immunoglo-
not be instituted before 2 weeks after onset of bulin be superior to either treatment given
symptoms, patients did not benefit. Interestingly, alone? Plasma exchange is reasonably safe, but it is
outcome at 6 months was the same in plasma- not a totally innocuous treatment. Patients with
pheresed and conventionally treated patient^.^' GBS are particularly prone to infections and auto-
These results were corroborated by the study of
the French Cooperative Group on Plasma Ex-
change in Guillain-Barre Syndrome.22Plasma ex-
change was started within 17 days of disease onset,
*
nomic disturbance, and it is under these circum-
stances that lasma exchange may be hazard-
ous.28,38,77,79, 0.95.100 These risks, availability of

apparatus and trained personnel, and efficacy in


and comprised 4 x 2 plasma volumes, a larger vol- only up to 55% of patients prompted the search
ume than was used in the North American trial. for alternative treatments.
Plasmapheresed patients had a more rapid onset
of recovery, and the time to unassisted walking was Corticosterolds. A small-sized open, randomized
shortened as was duration of mechanical ventila- trial of oral prednisolone (60 mg/d), showed no
tion.22 This trial also demonstrated equal effects of benefit.40 Recently, a doubleblind, multicenter
replacing patients with albumin or fresh frozen trial has been completed that looked at the effects
plasma. Since 5 of 52 patients that received fresh of a high-dose intravenous methylprednisolone
frozen plasma contracted hepatitis these investiga- regimen. T w o hundred forty-two patients were
tors advised against using it as replacement fluid. randomized to receive intravenous methylprednis-
This is in agreement with recommendations given olone 500 mg/d for 5 days or placebo. Patients
by a Consensus Development Conference held by were entered within 15 days of onset of neuro-
the NIH in 1986. In a follow-up the French Coop- pathic symptoms. They were unable to run. No
erative Group recently reported the 1-year assess- significant difference was noted in any outcome
ment of patients treated by either plasma exchange criterion between the 124 patients treated with
or conventional therapy. In contrast to the North high-dose corticosteroids and 118 patients who re-
American study, long-term benefit from plasma- ceived placebo. It is of note that the relapse rates
pheresis was observed as demonstrated by full were not different in the two treatment arms.32
muscular strength recovery at 1 year: 7 1% in the However, the study has been criticized and its con-
plasma exchange group vs. 52% in the control clusions questioned." Plasma exchange was al-
group. However, plasma exchange did not affect lowed and applied more often in the placebo
the percentage of patients with severe motor dis- group than in the corticosteroid group raising the
ability.23Poor outcome was associated with dimin- possibility that a salutary effect of methylprednis-
ished summed compound muscle action potentials olone may have been obscured.gg The results of
(<20% of normal) upon distal stimulation in the this study are somewhat astonishing in view of the
North American trial.61 Plasma exchange was still dramatic effects seen with corticosteroids in the an-
beneficial in this group. It has been reported that imal model of experimental autoimmune neuritis
u p to 25% of patients experienced some kind of (EAN). In EAN, inflammatory mediator produc-
relapse approximately 1-2 weeks after plasma ex- tion was diminished and cellular reactions involved
change, which usually responded to further plas- in inflammation were greatly d a m ~ e n e d .Sev-~~.~~
m a p h e r e s i ~ . ~ Relapses
~ * ~ ~ , ~after
' plasma exchange eral possible explanations have been advanced.
are generally thought to result from antibody re- They include interference by steroids with macro-

158 Guillain-BarrcS Syndrome-lI MUSCLE & NERVE February 1995


phage function in the repair phase, suppression of caution against the preferential use of IVIG be-
Schwann cell proliferation, and consequently, in- cause relapses and worsening of the disease oc-
hibition of remyelination. Steroids may also pre- curred during the treatment with reportedly high
vent the development of antiidiotypic antibody or f r e q u e n ~ y .Another
~ , ~ ~ small open trial was confir-
T-cell suppressor mechanisms that normally control matory of these results43; however, controversy
immune responses and allow recovery from GBS. continue^.^'^^"^^ Hence, there is need for further
evaluation. T o address this issue and explore the
High-Dose Intravenous Immunoglobulin (IVIG). relative value of these treatments a multicenter
High-dose intravenous immunoglobulin has trial is underway in which patients will be random-
shown therapeutic promise in a number of disor- ized to receive either plasma exchange, WIG, o r a
ders of a presumed autoimmune nature. van der combination of both therapies. Results are due in
MechC and his Dutch colleagues recently reported middle or late 1995. Another pilot trial looked at
the results of an open randomized trial in which possible synergistic activities of IVIG and high-
patients were assigned to receive either five plasma dose intravenous corticosteroids (5 x 500 mg
exchanges (200-250 mL/kg body weight) or five methylprednisolone), and found this combined
doses of intravenous immunoglobulin (0.4 g/kg treatment effective in 19 of 25 patients (76%) vs.
body weight/day). l o 5 Treatment was initiated 39 of 74 (53%)of historical controls given IVIG in
within less than 2 weeks and patients had to be the large Dutch multicenter A larger,
unable to walk independently. T h e predefined prospective randomized trial is underway.
outcome measure was improvement at 4 weeks by IVIG is not completely without risk and ad-
at least one grade on a seven-point scale of motor verse effects.663115 Back pain, meningeal reaction,
function. T h e trial was stopped when an interim fever, tachycardia, and headache during or within
analysis of 150 patients revealed that 53%of the 74 hours of completing the infusion are known side
patients who received immune globulin had im- effects of intravenous immunoglobulin (reviewed
proved by one grade or more compared with 34% in refs. 102 and 115). Anaphylactic reactions can
of those treated with plasma exchange. Median occur in patients with IgA immunodeficiency and
time to improvement by one grade was 27 days anti-IgA antibodies. It may also be hazardous to
with immunoglobulin therapy and 41 days with administer IVIG to patients with impaired renal
plasma exchange. Fewer patients in the IVIG function since a few cases of reversible renal
group required assisted ventilation. Mean duration failure using one particular IVIG preparation
of respiration was 15.2 days in the IVIG group and have been r e p ~ r t e d . ~ ~Besides,
,"~ IVIG has
22.6 days in the plasma exchange group.105This been claimed to precipitate migraine attacks and
study also looked at prognostic factors that had cerebral ischemia, probably by increasing serum
been identified in previous trials and found that, in viscosity. 1,14287 Mechanisms by which this ther-
univariate analysis, old age and low distal ampli- apy is thought to act are summarized in Table
3.1,2,5,17,18,29,58,59,89,97,107-109
tude of the compound muscle action potential was
associated with a poorer prognosis. However, A recent report is of particular interest in this
when a multivariate logistic-regression analysis was context. Lundkvist et al. advanced evidence that
performed only age remained statistically signifi- spontaneous recovery from GBS was associated
cant. Furthermore, serologically proven C. jejuni with antiidiotypic antibodies which recognized a
infection [46 of 129 (36%)patients examined] and cross-reactive idiotype on antineuroblastoma cell
the presence of antibodies to GM, (30%)predicted line a n t i b o d i e ~ . ~ ~
a poorer outcome in this trial. While these results Future immunotherapy may utilize recombi-
would suggest superiority of IVIG over plasma ex- nant immunoregulatory cytokines (e.g., IL-10,
change, one has to consider that plasma exchanged TGF-P, IFN-P), antibodies to inflammatory cyto-
patients in the Dutch trial fared significantly worse kines (e.g., TNF-a), soluble cytokine receptors, or
than in the two previously published studies. A cytokine antagonists (e.g., pentoxifylline), either
number of differences between the two treatment alone or in combination with established modalities.
areas might have biased the outcome. Plasma ex-
change was delayed by a mean of 1 day compared GENERAL MANAQEMENT OF GBS PATIENTS
with IVIG. Plasmapheresed patients were older, Ropper et al.83 give an excellent account of the
had been ill longer before commencement of ther- genera1 medical management and nursing care of
apy, and on average had lower summed distal com- patients with GBS. Immobilized patients are par-
pound muscle action potentials. Anecdotal reports ticularly prone to nosocomial infections (pneumo-

Guillain-BarrB Syndrome41 MUSCLE & NERVE February 1995 159


nia, tracheobronchitis, urinary infections, and less Nonsteroidal analgesics or carbamazepine may be
commonly sepsis). Up to 5% of bed-bound patients effective. Meticulous nursing care is required and,
had embolism as a consequence of immobiliza- above all, psychological support. Physical therapy
tion. Appropriate early antibiotic treatment and is of paramount importance. It includes facilitation
anticoagulation with heparin can prevent these of pulmonary toilet, range of motion exercises, ap-
complications.25~4*~76~94Pain may be particularly propriate limb positioning, strengthening exer-
bothersome and occurs in up to half of patients.82 cises, and assisted mobilization. Later, gait retrain-

INFECTION I

MHC II PGE, L l
L'

FIGURE 1. Overview of immune responses in GBS. An attempt has been made to incorporate evidence gathered from studies
in the animal model, experimental autoimmune neuritis and investigations in patients with GBS. The upper shaded panel
represents the systemic immune compartment (peripheral blood). Autoreactive T cells circulate with specificity for myelin
antigens. How they are triggered to become activated remains elusive. An attractive hypothesis implies sharing of antigenic
epitopes on microbes and myelin (molecular mimicry) and holds that an immune response mounted to the infectious agent is
misdirected to peripheral nerve. Through release of cytokines T cells can either instruct B cells to proliferate and secrete
myelin-directed antibodies and/or elaborate interferon-y which is known to enhance vascular permeability and activate macro-
phages. T-cell-independent antigens can directly stimulate 6-cell proliferation obviating the need for cognate T-cell help. The
systemic immune compartment is separated from nerve by the blood-nerve barrier. This is not complete and its function is
disturbed early in inflammation when T cells are instrumental in breaching it. Subsequently, antibodies and inflammatory
mediators can access the endoneurium. Further breakdown of the blood-nerve barrier also permits invasion of additional T cells,
neutrophils, monocytes, and macrophages. Upon stimulation by IFN-y or TNF-a antigen-presenting cells express MHC class II
gene products on its surface along with accessory recognition molecules (e.g., ICAM-1) plus the relevant autoantigen in suitably
processed form. Only if autoreactive T cells encounter an antigen-presenting cell in nerve (endoneurial macrophage, pericyte,
possibly Schwann cell) they can clonally proliferate and initiate a local immune response. Macrophages are further activated by
IFN-y or TNF-a to enhanced phagocytosis and release noxious mediators that act on the myelin sheath. Myelin-directed anti-
bodies can bind via the Fc receptor to macrophages and guide them to their target. Through activation of the complement
system they effect demyelination of nerve fibers. Mast cells subserve a role in providing vasoactive amines that open the
blood-nerve barrier.

160 Guillain-Bark Syndrome-I I MUSCLE 8, NERVE February 1995


ing and instruction in the use of orthotic devices is shared epitopes of nerve and microbes (molecular
provided. mimicry). Research over the past few years makes
Based on his large experience at the Massachu- it increasingly likely that multiple autoantigenic
setts General Hospital Neurology ICU, Ropper has epitopes exist both for T- and B-cell responses. T-
established criteria for admission of GBS patients and B-cell responses mounted to the same or pos-
to intensive care units and for artificial respira- sibly different epitopes may cooperate in launch-
t i ~ n Patients
. ~ ~ are intubated if the vital capacity ing an immune attack on peripheral nerve. The
goes down to 12-15 mWkg and blood gases dete- pathogenic significance of antiglycoconjugate anti-
riorate (Pao, < 80 mEq/L, Paco, < 45 mEq/L). If bodies has yet to be established. Studies on T-cell
bulbar paralysis is present, intubation is recom- sensitization to neural antigens, examination of
mended at a vital capacity of 15-18 mL/kg.83z94 nerve-specific antibody repertoire, association with
Acute autonomic dysfunction is common in infections by diverse microbes with different anti-
GBS. It can manifest itself as, e.g., cardiac arrhyth- genic make-up, different clinical courses, and dis-
mia, labile blood pressure dysregulation, or disor- tinct electrophysiolgical changes and pathological
dered gastrointestinal motility. lo' Autonomic dis- alterations raise the possibility of multiple etiolo-
turbances often resolve spontaneously. Thus, it is gies of the Guillain-Barre syndrome.
not always necessary to administer blood-pressure- Despite our advances in understanding the
lowering drugs in hypertensive episodes. Increas- contribution of various pathogenic factors that op-
ing fluid is preferred for treatment of hypotension erate in the model situation of EAN, the final ef-
whereas sympathomimetics in this situation are fector mechanisms of nerve damage in GBS re-
best avoided because blood pressure may over- main to be elucidated.
shoot due to denervation hypersensitivity. How- Concerning therapy, the past few years have
ever, episodes of second- and third-degree AV also witnessed great advances. Plasma exchange is
block and severe bradycardia should prompt one effective, obviously by removing single or multiple
to consider insertion of a (temporary) demand pathogenic circulating factors whose nature is still
pacemaker to avoid progression toward asyst01e.l~ not established (antibodies, cytokines, or other sol-
uble mediators). Most recently, therapeutic effi-
CONCLUSIONS cacy of high-dose intravenous immunoglobulin G
There is now cumulative evidence to suggest that has been documented. Mechanisms underlying
nerve dysfunction and tissue damage in GBS are this type of treatment remain hypothetical and in-
the result of an orchestrated action of immuno- clude, among others, antiidiotypic interactions,
competent and inflammatory cells, their soluble regulation of B and T cells, Fc receptor blockade,
communication signals, and their injurious biosyn- or neutralization of pathogenic cytokines. How-
thetic products (cf. Fig. 1). Definite proof that GBS ever, only around 50% of all patients benefit from
is autoimmune in nature still needs to be fur- either plasma exchange or IVIG therapy. There
nished. In general, autoimmunity culminating in are still those who develop severe axonal damage.
peripheral damage could result from a failure of We need a better understanding of the underlying
mechanisms that normally operate to maintain mechanisms of nerve injury if we are to develop
self-tolerance. Failure of self-tolerance could be better rational therapy.
due to incomplete deletion or silencing of self-
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