THE AMERICAN JOURNAL OF GASTROENTEROLOGY
1, 2000
© 2000 by Am. Coll. of Gastroenterology
Published by Elsevier Science Inc.
Intestinal Pseudo-Obstruction
and Acute Pandysautonomia
Associated With Epstein-Barr Virus Infection
M. Besnard, M.D., C. Faure, M.D., G. Fromont-Hankard, M.D.,
H. Ansart-Pirenne, M.D., M. Peuchmaur, M.D., J. P. Cezard, M.D., and J. Navarro, M.D.
Departments of Pediatric Gastroenterology and Pathology and Immunology Unit, Hôpital Robert Debré,
Paris, France
ABSTRACT
We report the association of neurological and intestinal
disorders with the reactivation of Epstein-Barr virus (EBV)
in a child. This previously healthy 13-yr-old boy presented
with pharyngitis and acute abdominal ileus. Laparotomy
excluded a mechanical obstruction. Postoperatively, he suf-
fered from prolonged intestinal obstruction, pandysautono-
mia, and encephalomyelitis. Histological examination of the
appendix and a rectal biopsy taken 3 months after the onset
showed an absence of ganglion cells (appendix) and hy-
poganglionosis (rectum), with a mononucleate inflamma-
tory infiltrate in close contact with the myenteric neural
plexuses. EBV-PCR was positive in the blood and cerebro-
spinal fluid, and in situ hybridization with the Epstein-Barr
virus encoded RNA probe showed positive cells throughout
the appendix wall including the myenteric area, in a mes-
enteric lymph node, and in the gastric biopsies. EBV spon-
taneous lymphocytic proliferation was noted in the blood.
The serology for EBV showed previous infection but anti-
early antigen antibodies were present. No immunodefi-
ciency was found. Neurological and GI recovery occurred
after 6 months of parenteral nutrition and bethanechol. The
omnipresence of EBV associated with the neurointestinal
symptoms suggest that the virus was the causal agent. This
is the first documented case of acquired hypoganglionnosis
due to EBV reactivation. (Am J Gastroenterol 2000;95:
280 –284. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION
Epstein-Barr virus (EBV) can be responsible for a wide
range of disorders including hepatitis, pancreatitis, and se-
vere neurological impairments due to encephalomyelitis, or
polyneuropathies. However, there have been few reports of
the autonomic nervous system involvement in association
with infectious mononucleosis (1). Dysautonomia can be
associated with metabolic disorders (diabetes, amyloidosis,
etc.), viral infections, or toxic disease; or it can be idio-
pathic. Autonomic dysfunction can involve both the cholin-
ergic (parasympathetic and sudoromotor sympathetic) and
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ISSN 0002-9270/00/$20.00
PII S0002-9270(99)00768-6
adrenergic systems, or can be selective for only one. Gut
motility depends on the electrical and contractile property of
the smooth muscle, with intrinsic control by the enteric
nervous system and extrinsic control by the autonomic system.
Pandysautonomia could therefore lead to intestinal paresia.
One case of intestinal pseudo-obstruction due to autonomic
dysfunction in association with EBV infection (2) has been
reported, but no association between EBV infection and lesions
of the intrinsic nervous system has yet been described except in
a retrospective study in one patient with chronic symptoms (3).
This report describes the case of a young patient who presented
with acute pandysautonomia, intestinal pseudo-obstruction
syndrome, histopathological lesions of acquired hypoganglion-
nosis, and inflammatory infiltration of the enteric nervous sys-
tem, together with EBV reactivation.
CASE REPORT
A 13-yr-old boy, born on the island of La Réunion, from
unrelated parents, was referred to the gastroenterology unit
of our institution for subacute persistent intestinal obstruc-
tion. He had no familial or personal medical history, and his
growth was developing on ⫹ 2.5 SD. In August 1996, he
suddenly presented with pharyngitis and with fever that was
refractory to antibiotics. Ten days later, he was admitted in
emergency for an acute abdominal syndrome, including
vomiting, abdominal pain, weight loss (2 kg), poor general
condition, and fever. His abdomen was tender and an ex-
ploratory laparotomy was performed; no visceral injury was
found (the small bowel was not dilated), and the peritoneal
fluid was sterile. The appendix and a mesenteric lymph node
were resected. Postoperative outcome was marked by sub-
obstruction that needed prolonged gastric aspiration, paro-
tiditis, pancreatitis (lipasemia 1200 U/L (normal ⬍ 40U/L)),
hepatitis (transaminases 300 U/L (normal ⬍ 45 U/L), or-
thostatic malaise, altered consciousness, and seizures. Sub-
obstruction and a loss of 9 kg indicated prolonged total
parenteral nutrition, for which he was transferred. A pyra-
midal syndrome of the lower limbs and signs of encepha-
lomyelitis were also noted. Lumbar puncture showed nor-
AJG – January, 2000 Intestinal Pseudo-Obstruction, Dysautonomia, and EBV Infection 281

mal cerebrospinal fluid protein, cytology, and sterile culture.

Cerebral CT was unremarkable. Local infectious agents
were eliminated and his serology was ancient for EBV (IgG
VCA 1/160) and for cytomegalovirus.
When he was admitted to our unit, he still had signs of
pandysautonomia with a persistant fever (38.5°), vesical
retention, orthostatic hypotension, and unvariable pulse (60/
min). Clinical examination revealed intestinal subobstruc-
tion, bilateral pyramidal syndrome, and decreased muscular
strength and peripheral sensitivity to a pin prick on the feet.
His counsciousness was fluctuant. The right pupil was di-
lated and unreactive to light. He also had a sicca syndrome
with asialia, alacrymia, severe keratitis, and anhydrosis. A
second lumbar puncture was normal (cerebrospinal fluid
protein and lactic acid), as was the protein electrophoresis
pattern, but the EBV-PCR was positive. Cerebral MRI
showed a T2 hypersignal in the white matter. The electro-
encephalogram showed slow posterior waves and mild, non-
specific anomalies. The electromyogram was moderately
perturbed, with signs of peripheral neuropathy. Pandysau-
tonomia was documented with anhydrosis on the sweat
tests, abnormal ocular response to pilocarpine and atropine
showing abnormal parasympathetic reflex of the pupils,
abnormal heart rate recording and head-up tilting test to 30°
(systolic tension fell to 35 mm Hg). Polysomnography
showed no decrease of sensitivity of the respiratory center to
CO2 or defective ventilatory adaptation suggesting the ab-
sence of involvement of the respiratory center in the dys-
autonomia. The upper GI tests revealed a stenotic ileum
alternating with dilated loops and a normal jejunum (Fig. 1) Figure 1. Initial upper digestive tract opacification. Note the ste-
and diverticula all along the colon on the late x-rays. The notic ileum alternating with dilated loops with normal jejunum.
barium enema was normal. GI manometry was performed,
but the proximal jejunal record failed and esophageal record tive for HIV, HTLV1, hepatitis, and trypanosomiases, and
showed low amplitudes of the waves with abnormal prop- were ancient for cytomegalovirus, measles, rubella, and
agation of the distal two-thirds of the esophagus; rectal arboviruses. Immunological tests excluded classical immu-
manometry was normal. Urinary ultrasound examination nodeficiency and autoimmunity (absence of enteric neuronal
showed an initial megacystis with a sediment from poor autoantibody).
emptying and candidal urinary infection. A full-thickness Outcome
rectal biopsy specimen was taken 5 cm above the anal verge The patient was treated with polyvalent immunoglobulin
3 months after the onset of pandysautonomia. Biopsies were (0.5 g/kg/day for 5 days), but this treatment was ineffective.
also taken of the sural nerve, muscle, salivary gland, and Parenteral nutrition and bethanechol (0.5 mg/kg/day) al-
liver 6 months after the onset of the disease. lowed gradual GI remission and improvement of the neu-
rovegetative and counsciousness disturbances. Bladder
Laboratory Tests catheterization was necessary for 3 wk, after which the
Complete blood cell count was normal, but the erythrocyte patient began to void spontaneously. Gastric aspirate de-
sedimentation rate was elevated (100 mm at h 1). EBV creased and bowel movements appeared. Oral feeding re-
serologies showed ancient infection (positive IgG VCA placed parenteral nutrition 3 months after its beginning. The
1/160 and IgG EBNA 1/20). Four months after the onset, barium x-rays improved in April 1997. Only mild pupil
antiearly antigen antibodies were positive (1/80) and there dilation, occasional vomiting and constipation persisted. He
was a positive EBV-PCR both in serum (30 –300 copies/ was discharged and returned to the island of La Réunion in
1.5.105 mononucleated cells) and in the cerebrospinal fluid, May 1997, with a low-fiber diet and bethanechol. He re-
suggesting reactivation of the infection. Repeated blood mains well 12 months later.
tests showed persistent spontaneous proliferation of EBV
and a persistent inflammatory syndrome. Lactic acid was Pathology Methods
normal. Mitochondrial enzyme analysis on fresh-frozen The surgical specimens (appendix and mesenteric lymph
skeletal muscle was normal. Exhaustive checks were nega- node) were fixed in 10% formalin, embedded in paraffin, cut
282 Besnard et al.
Figure 2. Muscular layers of the appendix: immunostaining with
anti-CD68 antibody shows numerous inflammatory cells com-
posed mainly of macrophages, grouped in clusters in the myenteric
area (X 250).
5 ␮m, and stained with hematoxylin and eosin. The biopsy
specimens were fixed in 10% formalin, and fresh samples
from the same sites were frozen in liquid nitrogen. Immu-
nohistochemical staining was performed on formalin-fixed
tissues using a streptavidin-biotin immunoperoxidase
method, with antibodies directed against: neuron-specific
enolase (NSE, Dakopatts, Glostrup, Denmark), T cells
(CD45RO, Dakopatts), and macrophages (CD68, Dako-
patts). Immunohistochemistry was done on frozen tissue
sections using an indirect immunoperoxidase technique with
antibodies directed against: T cells (CD3, CD2, CD5, and
CD7, Becton Dickenson, Mountainview, CA), B cells (CD22,
Dakopatts), macrophages (CD68, Dakopatts), and HLA DR
(Becton Dickenson). In situ hybridization was performed on
formalin-fixed tissues with the Epstein-Barr virus encoded
RNA (EBER) probe (Dakopatts) according to the manufac-
turer’s recommendations.
Results
Histological examination of the appendix showed the ab-
sence of ganglion cells in both the submucosal and myen-
teric areas. This feature was associated with an inflamma-
tory infiltrate composed of mononuclear cells, mainly
located in the intestinal muscle. The inflammatory cells
were grouped in small clusters in the myenteric area (Fig. 2).
No acute appendicitis was found. Immunohistochemical
staining with NSE confirmed the absence of ganglion cells
from the appendix wall. The inflammatory infiltrate was
mainly of CD68-positive macrophages, and CD45RO-
positive T cells. Staining with the EBER probe showed
EBER-positive cells scattered throughout the appendix wall,
including the myenteric area (Fig. 3). Numerous EBER-
positive cells were also found within the mesenteric lymph
node.
The full thickness rectal biopsy revealed a markedly
reduced number of ganglion cells (maximum, 2 per section),
with large hyperplastic nerve trunks in the submucosal and
the myenteric areas (Fig. 4). These features were associated
AJG – Vol. 95, No. 1, 2000
Figure 3. Staining with the EBER probe in the appendix evidences
EBER-positive cells in both the mucosa and the myenteric area
(insert) (⫻400, ⫻600).
with a mild inflammatory infiltrate, containing mainly T-
cells, in the lamina propria and inside the nervous structures
(Fig. 5). No EBER-positive cell was found.
The gastric biopsies revealed lesions of nonatrophic
chronic gastritis, with a diffuse mononuclear infiltrate in the
lamina propria. The inflammatory cells were mainly T-cells
with a few plasma cells. HLA DR was overabundant on
epithelial cells. EBER-positive cells were found scattered
within the infiltrate. No Helicobacter pylori was found.
A biopsy of the sural nerve showed an axonal neuropathy
and a mild mononuclear cell infiltrate. The muscular biopsy
excluded mitochondrial cytopathy and showed nonspecific
denervation. The salivary gland and liver biopsies showed
nonspecific, mild inflammatory infiltrate of T cells, within
the portal areas. No EBER- positive cells were noted.
DISCUSSION
Our patient suffered from severe acute pandysautonomia
and intestinal pseudo-obstruction resulting from EBV reac-
tivation. The symptoms of autonomic dysfunction included
Figure 4. Full-thickness rectal biopsy. Large hyperplastic nerve
trunk in the myenteric area with rare ganglion cells (arrow) (he-
matoxylin and eosin, ⫻250).
AJG – January, 2000
Figure 5. Full thickness rectal biopsy. Immunostaining with anti-
CD45RO antibody shows a mild mononuclear inflammatory infil-
trate within the nerve trunks (⫻400).
parasympathetic signs such as a lack of sweat, saliva, and
tears; difficulties with micturition; pupil abnormalities; and
sympathetic signs such as orthostatic hypotension, unvary-
ing pulse rate, and motor and sensory deficits. The first case
of acute acquired pandysautonomia was reported in 1969 by
Young et al. (4); it particularly affected young people and
resulted in prolonged, incomplete recovery. Pandysautono-
mia has also been reported in cases of autoimmune disorders
(lupus), porphyria, botulism, posttraumatic, and hypotha-
lamic dysfunction (5–7). Only 20% of the reported cases of
pandysautonomia had been temporally associated with viral
infections, such as EBV (8 –12). In the present case, all
known causes of pandysautonomia were excluded, except
EBV infection. Our patient displayed signs of EBV reacti-
vation, including circulating antiearly antigen antibodies,
and a positive PCR-EBV in the serum and in the cerebro-
spinal fluid. The ubiquitous presence of EBV was also
indicated by spontaneous lineage, activated circulating T-
cells, and EBER-positive cells in the mesenteric lymph node
and appendix, and in the gastric biopsies. The temporal
association between the widespread presence of EBV and
signs of dysautonomia suggests that EBV was responsible
for the neurological and GI disorders of our patient. The
most striking finding in the present case was the association
of pandysautonomia with intestinal pseudo-obstruction. Gut
dysfunction was most likely acquired, inamuch as the onset
was late in life, and because he has no past medical history
or growth failure. Gut dysfunction appeared quite acutely,
probably aggravated by the surgery and the neurological
impairment. GI x-rays excluded obstruction or structural
disease, and manometry showed esophageal dysmotility,
suggesting a neuropathic pseudo-obstruction. The colonic
diverticula were probably related to the motility distur-
bances of the GI tract, as noted in patients with intestinal
pseudoobstruction in POLIP syndrome (13).
Only two cases of pseudo-obstruction associated with
EBV infection have been reported (2, 3). In the first case,
histological examination of a resected colon specimen
Intestinal Pseudo-Obstruction, Dysautonomia, and EBV Infection 283
showed normal submucosal and myenteric ganglions with
no evidence of inflammation, so that the bowel dysmotility
was due to the dysfunction of the autonomic nervous sys-
tem, as in other reported cases of dysautonomia (4, 8, 14).
In the other case, there was evidence of chronic inflamma-
tory infiltrate involving the myenteric plexus with presence
of EBV in the Schwann cells demonstrated by in situ hy-
bridization (EBER probe). In our patient, the gut dysmotility
might have resulted from the abdominal vagal dysfunction
due to the dysautonomia, and from the destruction of the
enteric neurons by the postviral immune infiltrate. The in-
volvement of the enteric nervous system might result from
a direct viral injury or an abnormal T-cell immune response.
Direct viral injury was reported in a case of intestinal
pseudo-obstruction related to cytomegalovirus infection
(15), with evidence of cytomegalovirus inclusions in the
enteric neurones. No EBER-positive enteric neuron was
found in our patient but, conversely, an immune-mediated
damage is supported by the presence of an inflammatory
infiltrate, in close contact with the enteric plexuses, in both
the appendix, and the rectum.
Acquired aganglionosis due to an immune process has
been described, and it seems to be mainly of paraneoplastic
or autoimmune origin (16 –19). The main evidence for im-
mune destruction of the enteric nervous system was the
favorable response to steroid therapy. Our patient was given
an immunomodulatory treatment with intravenous IgG in
case it was an immunoallergic reaction (1, 20). No immu-
nosuppressor or antiinflammatory drug was given because
of the spontaneous proliferation of EBV lymphocytes.
The digestive symptoms associated with encephalomy-
elitis may suggest a mitochondrial neurogastrointestinal en-
cephalomyopathy (MNGIE) (21). In our patient, the clinical
presentation was atypical for such a diagnosis (absence of
ptosis, spontaneous clinical remission), metabolic investi-
gations were negative (lactic acid in blood and in cerebro-
spinal fluid, absence of mitochondrial respiratory chain de-
fect on fresh-frozen skeletal muscle analysis), and no lactic
acidosis episode occurred. The skeletal muscle biopsy was
normal and the pathological findings were not suggestive of
MNGIE as no atrophy of the muscularis propria was noted.
The bilateral pyramidal syndrome was considered as related
to the involvement of the central nervous system by the
EBV infection.
In conclusion, this is, to our knowledge, the first docu-
mented case of acquired hypoganglionnosis related to EBV
reactivation. The spontaneous favorable outcome for both
neurological and GI disorders might have depended on the
patient’s immunological ability to control virus reactivation.
Reprint requests and correspondence: Christophe Faure, M.D.,
Service de Gastro-entérologie et nutrition pédiatriques, Hôpital
Robert Debré, 48, boulevard Sérurier, 75019 Paris, France.
Received June 26, 1998; accepted Dec. 11, 1998.
284 Besnard et al.
REFERENCES
1. Benneth JL, Mahalingam R, Wellish MC, et al. Epstein-Barr.
Virus associated acute autonomic neuropathy. Ann Neurol
1996;40:453–5.
2. Vassallo M, Camilleri M, Caron BL, et al. Gastrointestinal
motor dysfunction in acquired selective cholinergic dysauto-
nomia associated with infectious mononucleosis. Gastroenter-
ology 1991;100:252– 8.
3. Debinski HS, Kamm MA, Talbot IC, et al.. DNA viruses in the
pathogenesis of sporadic chronic idiopathic intestinal pseudo-
obstruction. Gut 1997;41:100 – 6
4. Young RR, Asbury AK, Corbett JL, et al. Pure pandysauto-
nomia with recovery. Brain 1975;98:613–36.
5. Takayama H, Kazahaya Y, Kashihara N, et al.. A case of
panganglionic cholinergic dysautonomia. J Neurol Neurosurg
Psychiatry 1987;50:915– 8.
6. Edelman J, Gubbay SS, Zilko PJ. Acute pandysautonomia due
to mixed connective tissue disease. Aust New Zealand J Med
1981;11:68 –70.
7. Arruda WO, Teive HG, Ramina R, et al. Autonomic neurop-
athy in systemic lupus erythematous. J Neurol Neurosurg
Psychiatry 1989;52:539 – 47.
8. Yahr MD, Frontera AT. Acute autonomic neuropathy. Its
occurrence in infectious mononucleosis. Arch Neurol 1975;
32:132–3.
9. Thomashefsky AJ, Horwitz SJ, Feingold MH. Acute auto-
nomic neuropathy. Neurology 1972;22:251–5.
10. Low PA, Dyck PJ, Lambert EH, et al. Acute panautonomic
neuropathy. Ann Neurol 1983;13:412–7.
11. Neville BGR, Sladen GE. Acute autonomic neuropathy fol-
lowing primary herpes simplex infection. J Neurol Neurosurg
Psychiatry 1984;47:648 –50.
AJG – Vol. 95, No. 1, 2000
12. Fujii N, Tabira T, Shibasaki H, et al. Acute autonomic and
sensory neuropathy associated with elevated Epstein-Barr vi-
rus antibody titre. J Neurol Neurosurg Psychiatry 1982;45:
656 – 61.
13. Simon LT, Houroupian DS, Dorfman LJ, et al. Polyneurop-
athy, opthalmoplegia, leukoencephalopathy, and intestinal
pseudo-obstruction. POLIP syndrome. Ann Neurol 1990;28:
349 –360
14. Camilleri M, Malagelada JR, Stanghellini V, et al. Gastroin-
testinal motility disturbances in patients with orthostatic hy-
potension. Gastroenterology 1985;88:1852–9.
15. Sonsino E, Mouy R, Foucaud P, et al. Intestinal pseudo-
obstruction related to cytomegalovirus infection of myenteric
plexus. N Engl J Med 1984;311:196 –7
16. Lennon VA, Sas DF, Busk MF, et al. Enteric neural autoan-
tibodies in pseudo-obstruction with small-cell lung carcinoma.
Gastroenterology 1991;100:137– 42.
17. Gerl A, Storck M, Schalhorn A, et al. Paraneoplastic chronic
intestinal pseudo-obstruction as a rare complication of bron-
chial carcinoid. Gut 1992;33:1000 –3.
18. Horoupian DS, Kim Y. Encephalomyeloneuropathy with gan-
glionitis of the myenteric plexus in the absence of cancer. Ann
Neurol 1982;6:628 –32.
19. Smith VV, Gregson N, Foggensteiner L, et al. Acquired in-
testinal aganglionosis and circulating autoantibodies without
neoplasia or other neural involvement. Gastroenterology 1997;
112:1366 –71.
20. Heafield MTE, Gammage MD, Nightingale S, et al. Idiopathic
dysautonomia treated with intravenous immunoglobulin. Lan-
cet 1996;347:28 –9.
21. Perez-Atayde AR, Fox V, Teitelbaum JE, et al. Mitochondrial
neurogastrointestinal encephalomyopathy: Diagnosis by rectal
biopsy. Am J Surg Pathol 1998;22:1141–7.