0041-1337/01/7108-1169/0

TRANSPLANTATION
Copyright 2001 by Lippincott Williams & Wilkins, Inc.

Vol. 71, 11691183, No. 8, April 27, 2001

Printed in U.S.A.

Transplantation
BRIEF COMMUNICATIONS
GUILLAIN-BARRE SYNDROME IN ORGAN AND BONE MARROW
TRANSPLANT PATIENTS
KETAN R. BULSARA,1,4 PEDRO W. BARON,2 J. E. TUTTLE-NEWHALL,2 PIERRE-ALAIN CLAVIEN,2 AND
JOEL MORGENLANDER 3
Divisions of Neurosurgery, Transplant Surgery, and Neurology, Departments of General Surgery and Internal Medicine,
Duke University Medical Center, PO Box 3807, Durham, North Carolina 27705

Background. Guillain-Barre Syndrome (GBS) is believed to be caused by autoimmune mechanisms that

are predominantly T-cell mediated. We report GBS in
organ transplant patients and bone marrow transplant patients, both of whom have iatrogenically suppressed T-cell function.
Methods. We reviewed the Duke University Medical
Center database from 1989 1999 for all patients who
met the criteria for GBS. There were a total of 212
patients. Of these patients, two had undergone organ
transplantation and two had undergone autologous
bone marrow transplantation.
Results. Our report supports the notion that the humoral immune system is involved in the pathogenesis
of GBS. Contrary to previous reports, however, functional recovery can occur without return of T-cell
function.
Conclusions. This suggests that in organ transplant
patients, GBS may be humorally mediated and, even
more importantly, responds well to treatment.
Guillain-Barre syndrome (GBS) is the most common cause
of acute generalized paralysis (11). Yet, to date, the pathogenesis that underlies GBS has not been firmly established
(4,5). There is considerable evidence to suggest that aberrant
immunological mechanisms underlie this disorder (6 9).
This is supported by findings that almost one-third of patients with GBS have a preceding Campylobacter jejuni infection, (14) with an associated high titer of anti-GM1 antibody titers (24) and clonal expansion of mutant CD8
hypoxanthine guanine phosphoribosyltransferase T cells
(23). Furthermore, cytomegalovirus (CMV) infection results
in the production of anti-CMV IgM that can bind a surface
determinant of a Forssman-like lipid of human peripheral
nerve myelin (15) that can lead to a polyneuropathy.
There is widespread support that a primary lymphocytic
T-cell mechanism is responsible for the inflammation associated with GBS (11). Supporters of this concept cite evidence
that activation of T-lymphocytes has been shown to correlate

with disease activity (6, 7, 8, 9). Furthermore, injections of

antimyelin T-cell lines into animal models cause GBS (16).
One view of T-lymphocyte involvement suggests that T
cells have an aberrant response to a precipitating factor (11).
The immunological mechanism, however, seems more complex. Pathological studies of patients with GBS reveal that
perineural inflammation is infrequent or a late phenomenon
(12, 23). Some clinically typical cases of GBS have shown no
evidence of lymphocytic infiltration (13). Furthermore, patients with AIDS, who have known impairment of T-lymphocyte function, can develop GBS (17, 18).
We report two patients who had successful organ transplantation and subsequently developed GBS. We also report
two patients who underwent autologous bone marrow transplantation and later developed GBS. All these patients were
iatrogenically immunocompromised. We review other reports
of GBS in immunocompromised patients and discuss the
implications of these observations.

PATIENTS AND METHODS

We reviewed the Duke University Medical Center database from
1989 1999 for all patients who had met the criteria for GBS (1).
There were a total of 212 patients. Of these patients, two had undergone organ transplantation and two had undergone autologous
bone marrow transplantation. None of these patients had evidence of
CMV infection. The organ transplant patients had good outcomes in
regard to their transplants with none of them experiencing organ
rejection.
Patients

Patient 1. P.R. was a 40-year-old patient who was status postorthotopic liver transplantation in June 1997. In October 1997, she
developed ascending muscular weakness and paresthesias. Physical
examination revealed 4/5 muscle strength in all tested groups. Her
reflexes were absent. Her albumin level was 3.8 g/dL. Cerebrospinal
fluid examination revealed protein of 78 mg/dL, glucose of 76 mg/dL,
and no cells. Her nerve conduction and EMG studies showed evidence of an acute proximal demyelinating neuropathy. She was
1
Division of Neurosurgery.
treated with a five-day course of intravenous immunoglobulins
2
Division of Transplant Surgery.
(IVIG) (0.4 g/kg/day; total 140 g) with near complete resolution of her
3
Division of Neurology.
symptoms. She had a relapse of her symptoms in December 1997.
4
Address correspondence to: Ketan R. Bulsara, MD, Duke Uni- She once again responded well to a three-day course of IVIG (0.4
versity Medical Center, Division of Neurosurgery, PO Box 3807, g/kg/day; total 84 g). Her neoral level was well within therapeutic
Durham, North Carolina 27705.
levels. She was also taking prednisone. At her two-year follow-up,
1169

GBS 1 yr

GBS 2 wk

AIDS

AIDS

cardiac
liver

cadaveric
renal
bone marrow
bone marrow

30-year-old male (Qureshi et al.)

33-year-old male (Qureshi et al.)

66-year-old male (Qureshi et al.)

40-year-old female

53-year-old male

7-year-old male

7-year-old female

GBS 1 mo

GBS 4 mo

GBS 3 yr

unknown date
of diagnosis

unknown date
of diagnosis

GBS 3 mo

cardiac

62-year-old male (Baldwin et al.)

rejection 1 mo
GBS 3 mo
GBS 3 mo

Clinical Course

61-year-old male (Baldwin et al.)

Transplant

cadaveric
renal
cardiac

40-year-old male (Bale et al.)

Age

not reported

not reported

not reported

patient ()

donor ()
patient ()
donor ()
not reported

patient ()

patient ()

not reported

patient ()

not reported

patient ()

donor ()
patient ()

donor ()
patient ()

patient ()

positive

Posttransplant

patient ()

patient ()

Pretransplant

CMV

IVIG

IVIG

IVIG

IVIG

plasmapheresis

IVIG

plasmapheresis

IVIG and
plasmapheresis
and ganciclovir

IVIG and
plasmapheresis

not reported

Treatment

TABLE 1. Reported cases of GBS in organ and bone marrow transplant patients

full functional recovery

by 4 yr
full functional recovery
by 9 yr

almost full functional

recovery by 2 yr

improvement but
persistent
neurological deficits
1 yr
improvement but
persistent difficulty
ambulating
improvement but
difficulty ambulating
full functional recovery
by 2 yr

almost complete
functional recovery
by 4 mo

full functional recovery

within 4 mo

not reported

Outcome

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BRIEF COMMUNICATIONS

she had full strength in all of her extremities with trace reflexes. She
has continued on neoral and prednisone.
Patient 2. W.R. was a 53-year-old patient who underwent a cadaveric renal transplant in 1997. He was readmitted because of a
perforated diverticulum one year later. He was having an uneventful
recovery when he began to develop extremity weakness. Physical
examination revealed 3/5 muscle strength in all tested groups. His
reflexes were absent. EMG and nerve conduction studies showed
evidence of an acute proximal demyelinating neuropathy. His albumin level was 3.0 g/dL and total protein was 7.0 g/dL. Cerebrospinal
fluid examination revealed protein of 117 mg/dL, glucose of 55 mg/
dL, 4 nucleated cells, and 1 red blood cell. He had a therapeutic
neoral level. Patient was also taking prednisone. He was treated
with a five-day course of IVIG (0.4 gm/kg/day; total 140 g). He has
had gradual improvement of his symptoms to the point that he is
currently self-ambulatory.
Patient 3. B.C. was a 7-year-old patient who was diagnosed with
acute myelogenous leukemia. In January 1995, he was treated with
busulfan and melphalan. He was readmitted to the hospital for
treatment of Gram-negative sepsis when five days later, he developed ascending muscle weakness (4/5 diffusely). He was areflexic.
EMG and nerve conduction studies showed evidence of an acute
proximal demyelinating neuropathy. He was treated with two fiveday courses of IVIG (0.2 gm/kg/day; total 16 g each total therapy) and
was discharged home with home physical therapy and occupational
therapy. At his four-year follow-up visit, he had made excellent
functional recovery.
Patient 4. L.J. was a 7-year-old patient who was diagnosed with
PreB-cell acute lymphocytic leukemia in December 1990. She was
treated with methotrexate, Cytabarine, prednisone, vincristine, and
L-asparagine. She underwent autologous bone marrow transplantation. Approximately one month later, she developed lower extremity
weakness that subsequently involved her upper extremities (4/5
diffusely). She was areflexic. Her nerve conduction study and EMG
disclosed severe sensorimotor neuropathy with demyelinating features. She was treated with a five-day course of IVIG (0.4 gm/kg/day;
total 17.5 g). She had made an excellent functional recovery at her
nine-year follow-up visit.
DISCUSSION

At the onset, it is important to emphasize that GBS is a

complex autoimmune disease with many unanswered questions at both the clinical and laboratory levels. The possibility that the pathogenesis of this disorder is variable depending on the clinical situation cannot be excluded (21). All of the
patients in this study were iatrogenically immunosuppressed. When their immunosuppression regimen is considered, however, it is readily apparent that, though not absolute, the cell-mediated branch of the immune system was
most suppressed. A similar trend is noted when reviewing
previously reported cases of GBS in transplant patients (2, 3,
18) (Table 1). In reviewing the literature, it seems that male
patients are predominantly affected and that the onset of
GBS occurs within 3 months of transplant in the majority of
patients. Although previous reports have suggested a causal
role for CMV infection in the occurrence of GBS, we did not
find this to be the case in our patients. Furthermore, although both high-dose gamma globulin treatment and plasmapheresis have been used successfully to treat these patients, it appears that plasmapheresis is emerging as the
preferred treatment modality (20). Thus, it is clear from the
limited population of transplant patients that it is difficult to
establish a definitive mechanism for the pathology.
When our case series is coupled with previously reported
series, it questions the widely held notion that the resolution

of GBS correlates with the return of T-suppressor cell function (2, 3, 18). Patients with AIDS and documented absence
of T-cell function recover from GBS in a time course similar
to that of transplant patients with partially suppressed T-cell
function (Table 1). Thus, it appears that the return of Tsuppressor cell activity is not primarily responsible for the
resolution of GBS.
Mounting evidence suggests that humoral autoimmune
mechanisms are also involved in the pathogenesis of GBS (2,
8). The animal models support this notion. Experimental
allergic neuritis, a close animal model of GBS, can be elicited
by sensitizing animals to the P-2 myelin antigen or its fragments (19). The experimental disease appears to be predominantly cell-mediated; it can be transferred by lymphocytes
from sensitized animals but not by serum (11). On the other
hand, a purely humoral noninflammatory demyelination is
produced by the intraneural injection of galactocerebroside or
directly by anticerebroside antibody (19).
Clinical data are consistent with findings in animal models
that a purely humoral-mediated demyelination can occur
(23). For example, patients with Hodgkins disease who lack
lymphocyte proliferation to standard antigens in in vitro
testing develop GBS (15). Furthermore, only three cases of
GBS after cardiac transplantation and only one case after
renal transplantation have been reported (2, 3, 18). Orthotopic liver transplantation has also been associated with a
3% incidence of acute polyneuropathies (10).
As has previously been reported, our bone marrow transplant patients made excellent functional recovery (22). Although it is tempting to interpret their neurological recovery
as secondary to return of T-cell function, our organ transplant patients reveal an interesting finding. Even though
these patients continued to have cell-mediated immunosuppression, they did make functional recovery. This is in contrast to the belief that T-lymphocytes are always needed for
the down-regulation of the autoimmune process (18). What it
does suggest is that GBS in transplant patients may be
humorally mediated and, more importantly, responds well to
treatment.
Acknowledgment. The authors thank Nita K. Bulsara for her assistance in the preparation of this manuscript.
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Received 14 March 2000.

Accepted 15 August 2000.

HELICOBACTER PYLORIASSOCIATED GASTRIC MALT

LYMPHOMA IN LIVER TRANSPLANT RECIPIENTS
THOMAS M. SHEHAB,1 ERIC D HSI,2 JOHN J. POTERUCHA,3 NARESH T. GUNARATNAM,1 AND
ROBERT J. FONTANA1,4
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0362; Department
of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio 44195; and Division of Gastroenterology and
Hepatology, Mayo Clinic, Rochester, Minnesota 55905

Background. Immunosuppressed transplant recipients are at increased risk of developing several forms
of malignancy. The aim of this study is to report the
clinical presentation, treatment, and outcome of four
liver transplant recipients with Helicobacter pylori
associated gastric mucosae-associated lymphoid tissue (MALT) lymphoma.
Methods. The medical records of four liver transplant recipients with gastric MALT lymphoma were
reviewed. In situ hybridization for Epstein-Barr encoded ribonucleic acid was performed on formalinfixed tissues.
Results. All four subjects presented with abdominal
symptoms at a mean of 6.1 years posttransplant. Ulcerative lesions biopsied at endoscopy demonstrated earlystage gastric MALT lymphoma with associated Helicobacter pylori gastritis. In situ hybridization revealed no
evidence of Epstein-Barr virus infection in examined
tissues. Antibiotic eradication of Helicobacter pylori
1
Department of Internal Medicine, University of Michigan Medical School, 3912 Taubman Center, Ann Arbor, MI 48109-0362.
2
Department of Clinical Pathology, L-11, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.
3
Division of Gastroenterology and Hepatology, Mayo Clinic, 200
First Street SW, Rochester, MN 55905.
4
Address correspondence to: Robert J. Fontana, MD, Assistant
Professor of Medicine, 3912 Taubman Center, Ann Arbor, MI
48109-0362.

lead to disease remission in three subjects with a mean

follow-up of 21 months, and one subject failed to respond
to antibiotics and radiation therapy and died from metastatic gastric adenocarcinoma.
Conclusions. Early-stage, low-grade gastric MALT
lymphoma that was associated with Helicobacter pylori gastritis responded to antibiotic therapy with a
sustained clinical remission in three of four treated
subjects. If other studies confirm a higher than expected incidence of gastric MALT lymphoma in immunosuppressed transplant recipients with Helicobacter
pylori infection, screening and treating Helicobacter
pylori infection in selected transplant patients may
prove beneficial.
Liver transplant and other solid organ transplant recipients are at increased risk of developing several malignancies
due to reduced immune surveillance (1). In addition, infection with oncogenic viruses is associated with the development of several of these posttransplant malignancies such as
Epstein-Barr virus (EBV) infection and posttransplant lymphoproliferative disorders (PTLD) and human papilloma virus infection and cervical cancer (13). Helicobacter pylori
(HP) infection of the gastric mucosae is present in 30% to 50%
of the general population and a comparable proportion of
patients with cirrhosis (4). In addition to its recognized importance in the development of peptic ulcer disease, a minor-