Acta neuropath. (Berl.) 33, 275--278 (1975) 9 by Springer-Verlag 1975
Brain Involvement in Whipple's Disease A Case R e p o r t Tadahisa K i t a m u r a :Neurological Institute of Vienna University, Vienna, Austria Received June 27, 1975; Accepted August 25, 1975
Summary. A man of 22 with Whipple's disease suffered from an acute febrile state and unconsciousness. Focal inflammatory lesions accompanied by large numbers of peculiar macrophages occurred in thalamus and basal ganglia. The electron microscopic findings conform to previous reports on brain involvement in Whipple's disease. Key words: Whipple's disease -- Macrophage -- Electron microscopy -- Brain involvement.
Introduction The changes i n W h i p p l e ' s disease are n o t restricted to the i n t e s t i n a l canal, b u t occur also in joints, serosal m e m b r a n e s , l y m p h nodes a n d b r a i n (Sieracki et al.). Schoehet a n d L a m p e r t observed b r a i n lesions i n 4 of 21 cases, a n d Maizel et al. r e p o r t e d neurological signs in 8 of 18 p a t i e n t s . G r a n u l o m a t o u s encephalitis with a c c u m u l a t i o n s of macrophages c o n t a i n i n g PAS positive phagosomes is c o m m o n l y observed (Smith et al.; M i n a u f et al.): These phagosomes consist of m e m b r a n o u s a n d rod-shaped, bacteria-like s t r u c t u r e s (Stoupel et al. ; Schoehet et al. ; T h e m a n n et al.). The disease is considered to be a n infectious disease with a p r o b a b l e i m m u n o l o g i c a l defect, especially with i m p a i r e d cell-mediated i m m u n i t y (Maxwell et al., Groll et al. ; M a r t i n et al.). The findings i n a case of W h i p p l e ' s disease with i n v o l v e m e n t of the b r a i n are reported.
Case Report A man of 22 showed 14 days after returning from Australia to Austria sudden motor excitation and marked thirst. The next day he was febrile and was treated with antibiotics. He became somnolent. On admission, 17 days after the first symptoms the patient reacted faintly to pain; neck stiffness was absent. The CSF contained 92 lymphocytes/mm3, glucose was normal, and the protein moderately elevated. Blood examinations showed following pathological data: haematoerit 330/o, metabolic acidosis (BE-13), BUN 150 mg~ creatine 4.9 mg~ LDH 376 mU, GOT 42 mU. X-rays showed signs of subileus with still detectable peristaltic movements. Subsequently, hyperglycemia developed up to 427 rag~ and oliguria progressed to anuria on the 19th day of the illness, He died from cardiovascular insufficiency. Necropsy revealed fibrinous pericarditis, an enlarged, hypertrophied heart with marked edema between muscle fibres, a fatty liver with eeroid pigments in the hepatecytes and necrosis of the parenchyma probably due to ischemia. A duodenal ulcer was also found. :No changes were observed in the intestinal canal. Bacterial examination showed Pseudomonas aeruginosa and Enterobaeter in t~heintestines and Escherichia coli in spleen and gall bladder. The brain (N.I. 517-74) (1340 g) was slightly swollen and tonsils were herniated. Basal gangli~ of both sides showed a weak reddish discolouration; ventricular walls showed slightly granular surface. Large confluent lesions
276
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Fig. 1 a--d. Photomicrographs from the thalamic lesion. (a) Hypertrophied, reactive astrocytes, macrophages with PAS positive granules (arrows) and marked perivascular cuffing are seen. (b) A macrophage having many phagosomes containing membranous structures. (e) Content of a phagosorae. Membranous, laminated and circle-shaped structures are observed. (d) Content of a phagosome. Four rod-shaped, bacteria-like structures are seen
Brain Involvement in Whipple's Disease
277
were located mainly in the gray matter of the anterior portion of the thalamus and hypothalamus, extended into the caudate nucleus, pallidum and putamen. The lesions showed proliferation and hypertrophy of astrocytes and numerous newly formed small blood vessels with many maerophages around them and also in the parenchyma (Fig. 1 a). Inclusions in the macrophages was stained pMe-gray with hematoxylin-eosin and bright red with PAS. Cells around large vessels consisted largely of lymphoeytes and small numbers of plasma cells. In the subependyma of the third and lateral ventricles no accumulations of macrophages were found. Cerebral cortex, cerebellum, midbrain and medulla oblongata showed no pathological signs.
Electron Microscopy. Small pieces of thalamus after osmification were embedded in epoxy resin; sections were examined in a Zeiss EM-9 electron microscope. The maerophages contained inclusion bodies which were surrounded by a single membrane and usually filled by irregularly shaped, parallel-arranged, membranous structure of 30 A membrane width (Fig. 1 b). Some inclusions showed homogenous changes. No distinctive connections between these membranous structures and the surrounding Iysosomal membrane were observed. Thin laminar structures were also found in the inclusion bodies; these laminar structures were 150 A to 250 ]k in width and had 3 or 4 parallel, electron-dense zones separated by relatively light zones (Fig. 1 e). Occasionally electron-dense, round or rod-shaped structures were also seen in the inclusion bodies, measuring 120 mtz wide and 400--600 m~z long. They consisted of an electron-dense core surrounded by a less dense zone covered by an electrondense membrane (Fig. l e and d). Transitions between these three inclusion structures, i.e. between membranous, laminar and rod-shaped structures, were occasionally suggested.
Comments Focal i n f l a m m a t o r y lesions i n the t h a l a m u s , h y p o t h a l a m u s a n d p u t a m e n were associated with large n u m b e r of macrophages c o n t a i n i n g PAS-positive inclusion bodies. E l e c t r o n microscopy revealed phagosomes with m e m b r a n o u s or rodshaped, bacterium-like structures. These findings conform to b r a i n i n v o l v e m e n t in Whipple's disease. Eseheriehia eoli, isolated from spleen i n this ease m a y p l a y a n i m p o r t a n t role i n CNS i n v o l v e m e n t . Three s t r u c t u r e s were distinguished i n the phagosomes : m e m b r a n o u s , l a m i n a r a n d rod-shaped; the l a m i n a r s t r u c t u r e has n o t been reported p r e v i o u s l y i n this disease. A l t h o u g h the tissue is poorly preserved, t r a n s i t i o n s b e t w e e n the b a c t e r i u m - l i k e s t r u c t u r e to the l a m i n a r s t r u c t u r e or to the m e m b r a n o u s s t r u c t u r e could be observed. I t seems therefore t h a t both l a m i n a r a n d m e m b r a n o u s s t r u c t u r e s are derived from bacteria. The suggestion of L a m b e r t y et al. t h a t p a r t of the m e m b r a n o u s s t r u c t u r e o r g i n a t e d from the s u r r o u n d i n g lysosomal m e m b r a n e is n o t s u p p o r t e d b y our findings.
Acknowledgements. I would like to thank Prof. K. Jellinger for his advice and Dr. H. Budka and Dr. E. Sluga for their helpful criticism. Dr. F. Pantucek kindly provided the general autopsy data.
References Groll, A., Valberg, L. S., Simon, J. B., Eidinger, D., Wilson, B., Forsdyke, D. R.: Immunological defect in Whipple's disease. Gastroenterology 611, 943--950 (1972) Lamberty, J., Varela, Y., Font, g. G., Jarvis, B. W., Coover, J. : Whipple disease. Light and electron microscopy study. Arch. Path. 98, 325--330 (1974) Maizel, H., Ruffin, J. M., Dobbins, W. O.: Whipple's disease: A review of 19 patients from one hospital and a review of the literature since 1950. Medicine (Baltimore) 49, 175--205 (1970) Martin, F. F., Vilseck, J., Dobbins, III, W. 0., Buekley, III, C. E., Tyor, M. P. : Immunological alterations in patients with treated Whippie's disease. Gastroenterology 63, 6--18 (1972)
278
T. Kitamura
Maxwell, J. D., Ferguson, A., Mckay, A. M., Imrie, R. C., Watson, W. C. : Lymphocytes in Whipple's disease. Lancet (1968) 1, 887--889 Minauf, M., Stochdorph, O. : Das ZNS bei morbus Whipple. Arch. Psychiat. Nervenkr. 212, 180-- 199 (1969) Sehochet, S. S., Lampert, P.W.: Granulomatous encephalitis in Whipple's disease. Acta neuropath. (Berl.) 18, 1 - 1 1 (1969) Sieracki, J.C., Fine, G.: Whipple's disease--Observation on systemic involvement. II. Gross and histologic observations. Arch. Path. 67, 81--93 (1959) Smith, W.T., French, J.M., Gottsman, M., Smith, A.J., Wakes-Miller, J.A.: Cerebral complications of Whipple's disease. Brain 88, 137--150 (1965) Stoupel, N., Monseu, G., Pardoe, A., Heimann, R., Martin, J . J . : Encephalitis with myoclonus in Whipple's disease. J. :Neurol Neurosurg. Psychiat. 82, 338--343 (1969) Themann, H., Roberts, D. M., Knust, F.-J., Schmidt, E. : Eleetronenmikroskopischer Beitrag zum morbus Whipple. Beitr. path. Anat. 189, 12--36 (1969) T. Kitamura, M.D. Dept. of Pathology Kyoto Prefectural University of Mediein Kawaramaehi, Hirokoji Kamikyoku Kyoto Japan
Brain Involvement in Whipple's Disease A Case R e p o r t Tadahisa K i t a m u r a :Neurological Institute of Vienna University, Vienna, Austria Received June 27, 1975; Accepted August 25, 1975
Summary. A man of 22 with Whipple's disease suffered from an acute febrile state and unconsciousness. Focal inflammatory lesions accompanied by large numbers of peculiar macrophages occurred in thalamus and basal ganglia. The electron microscopic findings conform to previous reports on brain involvement in Whipple's disease. Key words: Whipple's disease -- Macrophage -- Electron microscopy -- Brain involvement.
Introduction The changes i n W h i p p l e ' s disease are n o t restricted to the i n t e s t i n a l canal, b u t occur also in joints, serosal m e m b r a n e s , l y m p h nodes a n d b r a i n (Sieracki et al.). Schoehet a n d L a m p e r t observed b r a i n lesions i n 4 of 21 cases, a n d Maizel et al. r e p o r t e d neurological signs in 8 of 18 p a t i e n t s . G r a n u l o m a t o u s encephalitis with a c c u m u l a t i o n s of macrophages c o n t a i n i n g PAS positive phagosomes is c o m m o n l y observed (Smith et al.; M i n a u f et al.): These phagosomes consist of m e m b r a n o u s a n d rod-shaped, bacteria-like s t r u c t u r e s (Stoupel et al. ; Schoehet et al. ; T h e m a n n et al.). The disease is considered to be a n infectious disease with a p r o b a b l e i m m u n o l o g i c a l defect, especially with i m p a i r e d cell-mediated i m m u n i t y (Maxwell et al., Groll et al. ; M a r t i n et al.). The findings i n a case of W h i p p l e ' s disease with i n v o l v e m e n t of the b r a i n are reported.
Case Report A man of 22 showed 14 days after returning from Australia to Austria sudden motor excitation and marked thirst. The next day he was febrile and was treated with antibiotics. He became somnolent. On admission, 17 days after the first symptoms the patient reacted faintly to pain; neck stiffness was absent. The CSF contained 92 lymphocytes/mm3, glucose was normal, and the protein moderately elevated. Blood examinations showed following pathological data: haematoerit 330/o, metabolic acidosis (BE-13), BUN 150 mg~ creatine 4.9 mg~ LDH 376 mU, GOT 42 mU. X-rays showed signs of subileus with still detectable peristaltic movements. Subsequently, hyperglycemia developed up to 427 rag~ and oliguria progressed to anuria on the 19th day of the illness, He died from cardiovascular insufficiency. Necropsy revealed fibrinous pericarditis, an enlarged, hypertrophied heart with marked edema between muscle fibres, a fatty liver with eeroid pigments in the hepatecytes and necrosis of the parenchyma probably due to ischemia. A duodenal ulcer was also found. :No changes were observed in the intestinal canal. Bacterial examination showed Pseudomonas aeruginosa and Enterobaeter in t~heintestines and Escherichia coli in spleen and gall bladder. The brain (N.I. 517-74) (1340 g) was slightly swollen and tonsils were herniated. Basal gangli~ of both sides showed a weak reddish discolouration; ventricular walls showed slightly granular surface. Large confluent lesions
276
T. Kitamura
Fig. 1 a--d. Photomicrographs from the thalamic lesion. (a) Hypertrophied, reactive astrocytes, macrophages with PAS positive granules (arrows) and marked perivascular cuffing are seen. (b) A macrophage having many phagosomes containing membranous structures. (e) Content of a phagosorae. Membranous, laminated and circle-shaped structures are observed. (d) Content of a phagosome. Four rod-shaped, bacteria-like structures are seen
Brain Involvement in Whipple's Disease
277
were located mainly in the gray matter of the anterior portion of the thalamus and hypothalamus, extended into the caudate nucleus, pallidum and putamen. The lesions showed proliferation and hypertrophy of astrocytes and numerous newly formed small blood vessels with many maerophages around them and also in the parenchyma (Fig. 1 a). Inclusions in the macrophages was stained pMe-gray with hematoxylin-eosin and bright red with PAS. Cells around large vessels consisted largely of lymphoeytes and small numbers of plasma cells. In the subependyma of the third and lateral ventricles no accumulations of macrophages were found. Cerebral cortex, cerebellum, midbrain and medulla oblongata showed no pathological signs.
Electron Microscopy. Small pieces of thalamus after osmification were embedded in epoxy resin; sections were examined in a Zeiss EM-9 electron microscope. The maerophages contained inclusion bodies which were surrounded by a single membrane and usually filled by irregularly shaped, parallel-arranged, membranous structure of 30 A membrane width (Fig. 1 b). Some inclusions showed homogenous changes. No distinctive connections between these membranous structures and the surrounding Iysosomal membrane were observed. Thin laminar structures were also found in the inclusion bodies; these laminar structures were 150 A to 250 ]k in width and had 3 or 4 parallel, electron-dense zones separated by relatively light zones (Fig. 1 e). Occasionally electron-dense, round or rod-shaped structures were also seen in the inclusion bodies, measuring 120 mtz wide and 400--600 m~z long. They consisted of an electron-dense core surrounded by a less dense zone covered by an electrondense membrane (Fig. l e and d). Transitions between these three inclusion structures, i.e. between membranous, laminar and rod-shaped structures, were occasionally suggested.
Comments Focal i n f l a m m a t o r y lesions i n the t h a l a m u s , h y p o t h a l a m u s a n d p u t a m e n were associated with large n u m b e r of macrophages c o n t a i n i n g PAS-positive inclusion bodies. E l e c t r o n microscopy revealed phagosomes with m e m b r a n o u s or rodshaped, bacterium-like structures. These findings conform to b r a i n i n v o l v e m e n t in Whipple's disease. Eseheriehia eoli, isolated from spleen i n this ease m a y p l a y a n i m p o r t a n t role i n CNS i n v o l v e m e n t . Three s t r u c t u r e s were distinguished i n the phagosomes : m e m b r a n o u s , l a m i n a r a n d rod-shaped; the l a m i n a r s t r u c t u r e has n o t been reported p r e v i o u s l y i n this disease. A l t h o u g h the tissue is poorly preserved, t r a n s i t i o n s b e t w e e n the b a c t e r i u m - l i k e s t r u c t u r e to the l a m i n a r s t r u c t u r e or to the m e m b r a n o u s s t r u c t u r e could be observed. I t seems therefore t h a t both l a m i n a r a n d m e m b r a n o u s s t r u c t u r e s are derived from bacteria. The suggestion of L a m b e r t y et al. t h a t p a r t of the m e m b r a n o u s s t r u c t u r e o r g i n a t e d from the s u r r o u n d i n g lysosomal m e m b r a n e is n o t s u p p o r t e d b y our findings.
Acknowledgements. I would like to thank Prof. K. Jellinger for his advice and Dr. H. Budka and Dr. E. Sluga for their helpful criticism. Dr. F. Pantucek kindly provided the general autopsy data.
References Groll, A., Valberg, L. S., Simon, J. B., Eidinger, D., Wilson, B., Forsdyke, D. R.: Immunological defect in Whipple's disease. Gastroenterology 611, 943--950 (1972) Lamberty, J., Varela, Y., Font, g. G., Jarvis, B. W., Coover, J. : Whipple disease. Light and electron microscopy study. Arch. Path. 98, 325--330 (1974) Maizel, H., Ruffin, J. M., Dobbins, W. O.: Whipple's disease: A review of 19 patients from one hospital and a review of the literature since 1950. Medicine (Baltimore) 49, 175--205 (1970) Martin, F. F., Vilseck, J., Dobbins, III, W. 0., Buekley, III, C. E., Tyor, M. P. : Immunological alterations in patients with treated Whippie's disease. Gastroenterology 63, 6--18 (1972)
278
T. Kitamura
Maxwell, J. D., Ferguson, A., Mckay, A. M., Imrie, R. C., Watson, W. C. : Lymphocytes in Whipple's disease. Lancet (1968) 1, 887--889 Minauf, M., Stochdorph, O. : Das ZNS bei morbus Whipple. Arch. Psychiat. Nervenkr. 212, 180-- 199 (1969) Sehochet, S. S., Lampert, P.W.: Granulomatous encephalitis in Whipple's disease. Acta neuropath. (Berl.) 18, 1 - 1 1 (1969) Sieracki, J.C., Fine, G.: Whipple's disease--Observation on systemic involvement. II. Gross and histologic observations. Arch. Path. 67, 81--93 (1959) Smith, W.T., French, J.M., Gottsman, M., Smith, A.J., Wakes-Miller, J.A.: Cerebral complications of Whipple's disease. Brain 88, 137--150 (1965) Stoupel, N., Monseu, G., Pardoe, A., Heimann, R., Martin, J . J . : Encephalitis with myoclonus in Whipple's disease. J. :Neurol Neurosurg. Psychiat. 82, 338--343 (1969) Themann, H., Roberts, D. M., Knust, F.-J., Schmidt, E. : Eleetronenmikroskopischer Beitrag zum morbus Whipple. Beitr. path. Anat. 189, 12--36 (1969) T. Kitamura, M.D. Dept. of Pathology Kyoto Prefectural University of Mediein Kawaramaehi, Hirokoji Kamikyoku Kyoto Japan
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