Acta
Neuropathologica

Acta Neuropathol. (Berl.) 48, 223- 226 (1979)

~ Springer-Verlag 1979

A Neuropathologic Study of Whipple's Disease
J a m e s M. Powers 1 a n d S t e p h e n E. R a w e 2
Departments of Pathology (Neuropathology)1 and Neurosurgery 2, Medical University of South Carolina,
171 Ashley Avenue, Charleston, SC 29403, USA

S u m m a r y . A p a t i e n t w i t h W h i p p l e ' s disease d e v e l o p e d
massive a n d irreversible C N S i n v o l v e m e n t after a drugi n d u c e d intestinal remission. T h e m u l t i f o c a l b r a i n
lesions were a p p a r e n t grossly with the heaviest conc e n t r a t i o n being n o t e d in r h i n e n c e p h a l o n , diencephalon, and m e s e n c e p h a l o n . This p a t i e n t e x h i b i t e d
progressive n e u r o l o g i e d e t e r i o r a t i o n , a l t h o u g h viable
o r g a n i s m s c o u l d n o t be identified in the b r a i n at
a u t o p s y . A s t r o c y t e s , pericytes, a n d c h o r o i d plexus cells
a t t e m p t e d to dispose o f the o r g a n i s m , in a d d i t i o n to the
t r a d i t i o n a l l y i m p l i c a t e d microgliaI a n d e p e n d y m a l cell.
Key words: Pre-senile d e m e n t i a
Hydrocephalus
Ataxia

-

Infection

-

M i c r o s c o p i c i n v o l v e m e n t o f the central n e r v o u s system
( C N S ) in W h i p p l e ' s disease is well d o c u m e n t e d
(Sieracki et al., 1960; L a m p e r t et al., 1962), b u t
infection severe e n o u g h to be reflected in grossly
d e t e c t a b l e b r a i n lesions has been e n c o u n t e r e d only
rarely ( R o m a n u l et al., 1977). It has b e c o m e o b v i o u s
t h a t n e u r o l o g i c d y s f u n c t i o n in W h i p p l e ' s disease m a y
exist w i t h o u t a p p a r e n t intestinal i n v o l v e m e n t or after a
d r u g - i n d u c e d intestinal remission (Silbert et al., 1976;
K n o x et al., 1976; R o m a n u l et al., 1977; F e u r l e et al.,
1979). N e u r o p a t h o l o g i c p r o o f o f C N S infection in such
cases has been limited (Silbert et al., 1976; R o m a n u l et
al., 1977; F e u r l e et al,, 1979). W e have recently
e x a m i n e d a p a t i e n t with a l o n g h i s t o r y o f t r e a t e d
W h i p p l e ' s disease, w h o d e v e l o p e d n e u r o l o g i c disease
d u r i n g an intestinal remission. T h e gross a n d m i c r o scopic features o f the p r e s e n t case p r o v i d e conclusive
p r o o f t h a t C N S i n v o l v e m e n t in W h i p p l e ' s disease can
be diffuse, severe a n d irreversible, even when the
intestinal disease h a s been eradicated.

Materials and Methods
Case Report

A 58~-year-oldwhite male had a 20-year history of relapsing intestinal
Whipple's disease which had responded to treatment with I g of

tetracycline daily and steroids. The patient took his medications
sporadically. His intestinal symptomatology went into permanent
remission 6 years prior to his death. About 6 months after his final
intestinal remission, he presented with his first signs of nervous
system involvement in the form of "falling". Over the next 5 years he
developed a variety of clinical symptoms: frontal headache, urinary
incontinence, intermittent disorientation, loss of recent memory,
depression, and paranoia. Neurologic signs consisted of diffuse
hyperreflexia, equivocal right Babinski response, hypalgesia of V-I
on the right and a slightly ataxic gait. Several episodes of chills and
fever were recorded, but frequent blood and spinal fluid cultures
(lumbar theca and shunt) were negative. A diagnosis of communicating hydrocephalus was made during the first year of his neurologic
disease and numerous shunts and shunt revisions were performed
with a variable clinical response. A brain biopsy from the right frontal
lobe obtained during his last shunt revision was non-diagnostic.
Unfortunately, only superficial cortex was submitted. One year
before his death there was a further loss of memory and he developed
diminished hearing bilaterally, increasing spasticity and gait disturbance, and hyponatremia secondary to inappropriate secretion of
antidiuretic hormone (ADH), His terminal admission was necessary
because of fever (103.6~ loss of consciousness and shock secondary
to dehydration, Computer assisted tomographic (CT) scan and
tapping of the shunt system revealed that his shunt was working
effectively. Cultures of the CSF were negative. He subsequently had
three grand mal seizures and died.
Family history was provocative in that a brother developed
adult-onset ataxia due to an ill-defined PAS-positive neuronal
storage disease (perhaps Kufs form of ceroid-lipofuscinosis); a sister
had been diagnosed clinically as alcoholic or nutritional WernickeKorsakoffsyndrome (no autopsy); and a son is ataxic and currently is
considered to be a probable case of multiple sclerosis.
Autopsy revealed pulmonary emboli, emphysema, and a few
weakly positive, periodic acid-Schiff (PAS) macrophages in jejunal
submucosa and mesenteric lymph nodes, which were consistent with
inactive intestinal Whipple's disease.
Routine sections of formalin-fixed brain were embedded in
paraffin and stained with hematoxylin and eosin (H & E), diastaseperiodic acid-Schiff (D-PAS), Gomori's methenamine silver, and
phosphotungstic acid-hematoxylin (PTAH), Sections of frontal
cortex, amygdala, hippocampus, midbrain, and pons were also
treated with Brown-Brenn and acid-fast stains.
Selected 1 - 3 mm pieces of formalin-fixed frontal cortex, hippocampus, periaqneductal gray, and tegmentum of midbrain and
pons were postfixed in 2 ~ unbuffered osmium tetroxide and
processed routinely for electron microscopy. Finally, specific areas
were removed from the paraffin blocks, deparaffinized in xylene,
rehydrated, and then processed for electron microscopy.

0001-6322/79/0048/0223 / $1.00

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Acta Neuropathol. (Berl.) 48 (1979)

Results

The brain weighed 1,240 g prior to fixation. It was
small and demonstrated slight, diffuse gyral atrophy.
Three shunts and their tracts were noted: one right
superior-frontal, which was found to terminate in the
right fornix at the splenium; one right lateral-frontal
which drained the body of the right ventricle; and one
right parieto-occipital, which ended in the right posterior horn. There were no cingulate, uncal or tonsillar
herniations. Coronal sections of the cerebral hemispheres (especially after prolonged fixation in formalin)
revealed multifocal, granular, depressed lesions, which
were most prominent at the gray-white junction (Fig. 1)
and in periventricular tissue. The centrum semiovale
and corpus callosum were essentially unremarkable,
except for shunt tracts. The right lateral ventricle was
small with marked adhesions in the frontal horn, while
the left lateral and third ventricles were dilated. The
right foramen of Munro was almost totally occluded by
thickened ependyma. A beige ependymal membrane
covered the posterior part of the third ventricle with
complete obstruction of the anterior end of the aqueduct of Sylvius. Transverse sections of the brainstem
revealed that the aqueduct was occluded by firm white
tissue throughout its entire length. The superior and
inferior portions of the fourth ventricle were about
6 0 ~ compromised by thickened ependymal tissue
(Fig. 2), while its midportion was totally occluded. The
periaqueductal tissue was firm and white; the foramina
of Luschka were probe patent. Serial sections of spinal
cord were grossly unremarkable.
The lesions noted grossly were composed histologically of cell clusters containing weakly hematoxylinophilic macrophages, gliosis, and occasionally collagen. These clusters were often found near small blood
vessels. Both PAS and methenamine silver identified
two elements: a peripheral one, composed of intensely
positive, elongated structures measuring 5 - 1 5 gm in
length admixed with reactive astrocytes; and a central
one, composed of intensely positive (the hematoxylinophilic) macrophages. These two elements were often
haphazardly mixed. Occasionally, weakly PASpositive, foamy macrophages were also present.
Brown-Brenn and acid fast stains were consistently
negative. Inflammatory cells, usually lymphocytes,
were rarely seen, except when the lesions were near the
lateral ventricular surface. It was common to find
chronic inflammation, multinucleated giant cell reaction and ependymal granulations in the periventricular lesions. Ependymal granulations were most severe at the inferior margin of the septum pellucidum
adjacent to the right foramen of Munro and in the
inferior portion of the right anterior horn. The shunt
tracts demonstrated circumferential subacute to cystic

Fig. 1. Dark and granular depressions (arrows) are present at the
gray-whitejunction of the straight and orbital gyri. Magnification
x2
Fig.2. The inferior portion of the IV ventricle is distorted and
contracted by ependymalgranulationtissue. Rare fociof discolored
cerebellar tissue (arrows) are seen. Magnificationx 2
necrosis and gliosis, but very little PAS-positive
material.
PAS-positive cell clusters in cerebral cortex were
situated in the deeper cortical layers and impinged on
subcortical white matter. They also were observed in
the caudate nucleus, putamen, globus pallidus, hypothalamus, infundibulum, thalamus, hippocampus,
amygdala, corpus callosum, centrum semiovale, and
septum pellucidum. The cerebral areas with the greatest
concentration of PAS-positive cells (hypothalamus,
amygdala, and hippocampus) demonstrated an apparent decrease in neuronal perikarya. PAS-positive
material was found predominantly in macrophages or
microglia but was seen also within reactive astrocytes,
ependymal cells, choroid plexus epithelium, and arachnoid granulations. Conclusive demonstration of the

J. M. Powers and S. E. Rawe: Neuropathologic Study of Whipple's Disease

225

Fig. 3. The aqueduct of Sylvius (A)
shows total occlusion by a profuse
proliferation of glial tissue studded with
positive debris (arrows). Methenamine
silver. Magnification x 36. Inset: Locus
coeruleus. A multinucleated (N) giant
neuron with clumps of neuromelanin
(NM). H.-E. Magnification x 230

Fig. 4, Partially digested bacterial cell walls

(arrows) lie within astrocytes rich in
filaments (/0. Uranyl acetate-lead citrate.
Magnification x 9,600
Fig. 5. Residual bacterialcell wall (arrow)is
present in a pericyte (P). The basement
membrane (BM) and endothelial cell
nucleus (E) are labeled for orientation.
Uranyl acetate-lead citrate.
Magnification • 9.600
same type of cytoplasmic inclusions in neurons could
not be accomplished, even with the electron microscope.
Multiple sections o f midbrain and pons confirmed
the complete gliotic obstruction of the aqueduct o f
Sylvius and m i d p o r t i o n o f fourth ventricle. PAS
and methenamine silver stains demonstrated countless
positive fragments enmeshed in the obliterative glial

tissue (Fig. 3) and n u m e r o u s positive cell clusters
t h r o u g h o u t the t e g m e n t u m of midbrain and pons.
Smaller numbers o f PAS-positive cells were seen in
medullary subependymal regions, medial lemniscus,
and reticular formation. The basis pontis, inferior
medullary olives, and pyramidal tracts were conspicuously spared. One n o t e w o r t h y and unexpected histologic finding was the presence o f multinucleated neu-

226
rons in the locus coeruleus (Fig. 3, inset). The sections
of meninges and spinal roots contained a few PASpositive deposits, while optic nerves, tract and chiasm,
spinal cord, peripheral nerve, and pituitary were essentially unremarkable.
Ultrastructural examination of 20 areas of brain
failed to demonstrate morphologically intact microorganisms, but confirmed that the weakly hematoxylinophilic, intensely PAS- and methenaminesilverpositive material in macrophages was identical to
partially degraded ceil walls of Whipple's bacteria
(de Groodt-Lasseel and Martin, 1969; Kitamura,
1975). Astrocytes (Fig. 4) and pericytes (Fig. 5) displayed the same cytoplasmic debris as microglial cells,
but less frequently.

Discussion
The present case provides conclusive p r o o f that CNS
involvement in Whipple's disease can be a devastating
clinical problem even when the intestinal component is
well under control. The demonstration of gross CNS
lesions such as these is extremely rare and reflects the
severity of this patient's neurologic disease; their
distribution correlates well with the clinical symptomatology. The sites of predilection: rhinencephalon, diencephalon, and mesencephalon, recapitulate many of the
cases reported in the literature (Stoupel et al., 1969;
Pallis and Lewis, 1974; Schliep et al., 1979). Proximity
to ependyma appears to be a c o m m o n link between
these major sites of involvement. The demonstration of
PAS-positive, intracytoplasmic debris within ependymal and choroid plexus cells and of diffuse ependymal damage emphasize the importance of the ventricular system in the dissemination, and perhaps
persistence, of disease within the CNS. The severe,
obtiterative midbrain lesions in the present case probably reflect a combined effect of infection and a
complication of shunting (Foltz and Shurtleff, 1966).
This case confirms the histologic observations of
several investigators (Lampert et al., 1962; Romanul et
al., 1977), but fails to document viable or intraneuronal
organisms. Although microglial and ependymal cells
are the most frequent brain cells to contain remnants of
Whipple's bacteria, we also find them within astrocytes,
pericytes, and choroid plexus cells.
In addition to the demonstration o f gross lesions,
the most important point to be learned from the present
case is that CNS damage in treated Whipple's disease
can be irreparable, either because of neuronal loss or
because of the magnitude of the infection. This study
provides a pathologic substrate for the clinical observation that neurologic responses to therapy are slower
and less predictable than those in other organs (Bayless

Acta Neuropathol. (Berl.) 48 (1979)
and Knox, 1979). N o viable, or morphologically intact,
organisms could be found after an exhaustive search.
We assume that the severity and persistence of CNS
disease in the present case was due to delay in instituting, or failure in maintaining, appropriate therapy and
to a defect in the brain's ability to dispose of the
organisms. These two deficiencies would permit the
accumulation of insurmountable numbers of bacteria
and bacterial debris. We agree that cortical biopsy can
be a definitive diagnostic test (Finelli et al., 1977;
Romanul et al., 1977). The anatomic distribution of the
lesions, however, emphasizes that brain biopsies should
be at least full cortical thickness and should be multiple,
if false negative results are to be minimized.

Acknowledgements. We thank Ms. Patricia Cummingand Ms. Carol
Moskos for photographic assistance and Ms. Trudie Shingledecker
for preparing the manuscript.

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Received July 25, 1979/AcceptedAugust 23, 1979