Journal of
Neura y
J. Neurol. 221, 113--125 (1979)
© by Springer-Verlag 1979
Hyperacute Experimental Allergic Encephalomyelitis in Rhesus Monkeys as a Model of Acute Necrotizing Hemorrhagic Encephalomyelitis L. Ravkina*, I. Harib, Z. Manovitch, E. Deconenko, E. Letchinskaja, and E. Papilova Institute of Poliomyelitis and Viral Encephalomyelitis, Academy of Medical Science, Moscow, USSR
Summary. A comparative study of clinical and morphological findings in three fatal cases of acute necrotizing hemorrhagic encephalomyelitis (ANHE) and hyperacute experimental allergic encephalomyelitis (HEAE) in rhesus monkeys is reported. In all cases A N H E was characterized clinically by definite prodromal respiratory infection. The course was rapidly progressive with fatal termination. The salient histopathological changes were necrosis of blood vessels with plasma exudation and fibrin impregnation, hemorrhages and inflammatory reaction in the damaged cerebral tissue. Perivascular lymphoid histiocytic infiltration with glial proliferation was also noted in all cases. Numerous compound granular cells were found in one case. H E A E was detected in five rhesus monkeys immunized with homological spinal cord emulsion with complete Freund adjuvant. The illness was acute or subacute and the course was rapidly progressive with a fatal end. There was multiple necrosis of small blood vessels with plasma exudation, fibrin impregnation and massive neutrophile infiltration of the damaged brain tissue in all rhesus monkeys with HEAE. There was also widespread glial proliferation and numerous compound granular cells alongside with necrosis of blood vessels in the brain. These findings suggest that H E A E in rhesus monkeys can be viewed as an adequate model of ANHE. Key words: Encephalomyelitis, acute necrotizing hemorrhagic (ANHE) Encephalomyelitis, hyperacute experimental allergic (HEAE) - Rhesus monkeys.
Zusammenfassung. Es werden vergleichende klinisch-morphologische Untersuchungen von 3 t6dlichen FS_llen der akuten nekrotisierenden h~imorrhagischen Encephalomyelitis (ANHE) und der hyperakuten experimentellen allergischen Encephalomyelitis (HEAE) beim Rhesusaffen beschrieben. Alle F~ille waren durch akuten Beginn, hohes Fieber, rasch progredienten Verlauf und * Corresponding author
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letalen Ausgang charakterisiert. Immer lag ein respiratorischer Infekt vor. Die charakteristischen histopathologischen Befunde bei allen Erkrankungen waren zahlreiche Nekrosen der Blutgef'~il3emit Diffusion von Plasma, Blutungen und einer Entztindungsreaktion im perivaskul~iren Gewebe. Im Gehirn werden auch lympho-histiocyt~ire Infiltrate gefunden. In einem Fall wurden granul~ire Zellen nachgewiesen. Die HEAE wurde bei 5 Rhesusaffen hervorgerufen, die mit homologer Emulsion von Riickenmark und mit komplettem Freundschem Adjuvans behandelt wurden. Die Erkrankung war akut mit einem raschen Verlauf und t6dlichem Ausgang. Im Affengehirn fand man zahlreiche Nekrosen der Blutgef~il3e mit Durchtr~inkung des perivaskul~iren Gehirngewebes durch Plasma, Blut und massiven Leukozyteninfiltraten. Neben den nekrotischen Veranderungen fand man auch Mikrogliaproliferation und granul~ire Zellen. Unsere Ergebnisse lassen die HEAE beim Rhesusaffen als ein Modell der ANHE erscheinen.
Introduction
Acute necrotizing hemorrhagic encephalomyelitis (ANHE) is a rare fatal disease (Csermely and Haberland, 1954; Crawford, 1954; Crome, 1954; Costriony, 1973; Vanderfield et al., 1960), whose nature is not quite settled. The most important communication on the subject was made by Hurst in 1940 in which he presented, under the title of ANHE, the clinical and pathological findings in two cases. Nowadays some workers regard ANHE as a hyperacute form of demyelinating diseases (Adams, 1959; Miller and Shapira, 1959). An autoimmune reaction is known to play an important role in the pathogenesis of the demyelinating diseases (Ferraro, 1944; Ferraro and Roizin, 1957; Finley, 1950; Field and Miller, 1960). Most workers have found a connection between ANHE and respiratory infections (Henson and Russel, 1942; Adams, 1949; Crome, 1954; Russel, 1955). The salient histopathological changes in ANHE are: necrosis of small blood vessels with plasma exudation and inflammatory reaction in the perivascular damaged tissue, with predominance of neutrophile leucocytes (Adams et al., 1949, 1959; Jacob, 1950; Harad, 1966; Hurst, 1940; Vanderfield et al., 1960; Costriony, 1973). Levine and Wenk (1964, 1974), Lennon et al. (1976)produced hyperacute experimental allergic encephalitis (HEAE) in rats by immunization with brain antigen and pertussis vaccine. Necrosis of small blood vessels with plasma exudation and fibrin impregnation and massive neutrophile leucocytes infiltration were found in rats with HEAE. Levine and Wenk (1964) believe that HEAE can be considerated as a model of ANHE. Kabat et al. (1947) noted neutrophile leucocytes in a few rhesus monkeys immunized with brain antigen and Freund adjuvant (Field, 1966, 1975). An investigation of HEAE in rhesus monkeys is of special interest for the evaluation of HEAE as a model of ANHE. This article deals with clinical and pathological findings in three cases of ANHE and in five rhesus monkeys with HEAE.
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Materials and Methods Monkeys. Young rhesus monkeys from India, of both sexes, weighing 1.7 to 2.3 kg were used. Encephalitogenic Mixtures. 1. Mixture I contained 50% emulsion of homological spinal cord emulsion (300 m g / m l wet weight), vaseline oil (400 mg/ml) and 10 mg/ml killed BCG mycobacteria. Mixture H contained 50% spinal cord emulsion (300 mg/ml wet weight), vaseline oil (400 mg/ml) and 0.2 m g / m l killed BCG mycobacteria. Mixture 111 contained 50% spinal cord emulsion (500mg/ml wet weight) and vaseline oil (400mg/ml). Immunization. Twenty rhesus monkeys were immunized with a single dose of Mixture I subcutaneously into four sites on the chest and belly in an amount of 0.5 to 0.55 ml at each site, the total dose per monkey being 2.0 to 2.20 ml. Twenty-four rhesus monkeys were immunized with a single dose of Mixture II subcutaneously in four sites on the chest and belly in an amount of 0.25 to 0.30 ml at each site, the total dose per monkey being 1.0 to 1.2 ml. After a month the monkeys were treated with the Mixture III subcutaneously on the chest and belly in the quantity of 0.5ml to 0.55 ml at each site, the total dose per monkey being 2.50 to 6.50ml. Maintenance. All animals were fed on vegetables, boiled rice and oatmeal porridge with butter, eggs, white bread, tea with sugar and vitamin ABCD complex. Histological Examination. The sections were stained with hematoxylin and eosin, for myelin by the Spielmeyer method, for glia by the Cajal method, for nerve cells by the Nissl method, and for axis cylinders by the Bielschowsky method. Material was fixed in 10% formalin.
L Human Cases Case 1. A girl, aged 14 years, who had frequently suffered from acute respiratory infections and tonsillitis, complained 10 days prior to admission to hospital in May 1974 that she felt generally unwell. Her temperature rose to 39°C, she developed a cough and sneezing. About 4 days prior to admission severe headache, vomitus and nausea appeared and a diagnosis of meningitis brought her to hospital. There the temperature was 38°C, pulse 86, and showed extremely ill retained counsciousness. She bad mild meningeal signs; the tendon reflexes were present. The next day she suddenly became comatose and died approximately 48 h after admission or 6 days after the onset of neurological signs. Laboratory Data. The cerebrospinal fluid (CSF) contained 1312 cells per mm 3, in which 82% were neutrophile leucocytes and total protein 3.3 mg%. No bacteria were found in a smear. Pandy and Nonne-Appelt reaction 5 were positive. The hemoglobin was 66%, the white blood count was 12,000 with 84% neutrophile leucocytes. Anatomical Diagnosis. ANHE, tracheobronchitis, tonsillitis, pulmonary edema, accidental involution of thymus. Brain and Spinal Cord. There was a small amount of subarachnoid exudate near the brain stem. Coronal sections of the formalin fixed brain and spinal cord exhibited many small hemorrhages. Microscopic Observation. Multiple necrosis of small blood vessels with plasma exudation and fibrin impregnation, necrosis in perivascular brain and spinal cord tissue were found in the brain stem and spinal cord (Fig. la, b, c). There were numerous neutrophile leucocytes in the damaged tissue around the affected vessels in the brain stem and spinal cord (Fig. la, b). Perivascular hemorrhages were also seen (Fig. ld). Along with these changes a few lymphoid histiocytic perivascular infiltrations with glial proliferation (Fig. 2a, b) and myelin destruction around them were observed in the brain and the spinal cord. In the necrotic perivascular tissue most of the axis cylinders had disappeared. Focal inflammatory reactions were observed in the leptomeninges of the brain stem.
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Fig. 1 a--d. Case 1. a Necrosis of vein with heavy neutrophile infiltration in medulla oblongata. H.-E., × 100. b Necrosis of small blood vessels with plasma exudation and numerous neutrophile infiltrations in damaged spinal cord tissue. H.-E.,× 200. c Heavy fibrin impregnation in damaged spinal cord tissue. Spielmeyer, x 2000. d Perivascular hemorrhages and small lymphoid histiocytic perivascular infiltrations in spinal cord. H.-E.,× 200
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b
Fig. 2a and b. Case 1. a Perivenous lymphoid histiocytic infiltration with glial proliferation in cerebral white matter. Nissl, × 100. b Perivascular lymphoid histiocytic infiltrations in spinal cord. H.-E., × 400
Case 2. A male, aged 24 years. About 1 month prior to admission to hospital he had tonsillitis with high temperature. A week later he returned to work but was very weak and complained of headache. About 4 days before entering hospital he developed severe headache, weakness of the right extremities and aphasia. The diagnosis of encephalitis was made and he was brought to hospital. Temperature was 38°C; blood pressure was 160/60, pulse 160 and the plantar reflexes were extensor bilaterally. There was also weakness of the right extremities and sensory aphasia. In the period of 8 days after admission his general condition became worse; he became stuporose and died 12 days after the onset of the neurological symptoms. Laboratory Data. The white blood count was 16,000 with 93% lymphocytes. The CSF contained 25 cells/mm 3. There were not bacteria in a smear. Anatomical Diagnosis. ANHE, pulmonary congestion, mucosal petechial hemorrhages in the stomach. Brain. The brain was swollen. The convolutions were flattened. Coronal sections of formalin fixed brain exhibited numerous petechial hemorrhages diffusely scattered in the cerebral matter, thalamus, midbrain and medulla oblongata. Large foci (1.5 cm) of dark red and yellow color were found in the left temporal lobe. Microscopic Observation. Large and small hemorrhages were found (Fig. 3a) both in cerebral white and gray matter. Necrosis of blood vessels with plasma exudation (Fig. 3b) and heavy fibrin impregnation (Fig. 3c) was noted. Neutrophile leucocytes, lymphocytes and compound granular cells (Fig. 3d) were observed in damaged brain tissue around the necrotic vessels. There was also widespread glial proliferation around the veins (Fig. 3e) and capillaries with numerous compound granular cells (Fig. 3f) and diffusely scattered lymphocytes. Myelinated fibers were destroyed or pale around these vessels. The neurons and glial nuclei were pyknotic in the damaged tissue. There were no definite thrombi in the vessels. There was a lymphoid histiocytic perivascular infiltration of the meninges.
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Fig. 3 a i f . Case 2. a Hemorrhages in cerebral white matter. H.-E., x 400. b Lymphoid histiocytic perivenous infiltration and plasma exudation in cerebral white matter. H.-E., x 200. e Heavy fibrin impregnation and plasma exudation in temporal lobe. Spielmeyer, x 40. d Neutrophile leucocytes and compound granular cells around necrotic small blood vessels in temporal lobe. Nissl, x 400. e Widespread glial proliferation around vein in temporal lobe. Nissl, x 100. f Compound granular cells in temporal lobe. H.-E.,x 400
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Case 3. A male, aged 60 years. About 25 days prior to the admission to the hospital he had respiratory infection with a high temperature which lasted 10 or more days and then changed into a subfebrile condition. About 18 days after the onset of the respiratory infection he developed ataxia, dizziness and vomiting. The diagnosis of brain neoplasm was made and he was admitted to hospital in December 1977 where he was found to have paresis of the facial, abducens and oculomotor nerves and nystagmus. The temperature was 37.5°C. During the following days the paresis of the cranial nerves advanced to paralysis and the patient died 24 days after the onset of the neurological symptoms. Laboratory Data. The white blood count was 9000 with 63% neutrophile leucocytes and 24% lymphocytes. The CSF contained 15 cells/mm 3, all lymphocytes and total protein amounted to O.8%. Anatomical Diagnosis. ANHE, aspirational pneumonia, cholecystitis, pyelonephritis, general atherosclerosis. Brain. Coronal sections of formalin fixed brain exhibited many petechial hemorrhages scattered mainly in the midbrain and brain stem. Microscopic Observations. Congestion of small blood vessels and small hemorrhages were found in the central white matter and brain stem. The walls of most blood vessels in the central white matter were well preserved. Complete or partial necrosis of small blood vessels with plasma exudation and fibrin impregnation were found in the midbrain, pons and medulla oblongata, mainly in the nuclei of the cranial nerves. There was necrotic tissue around the affected vessels and some glial and lymphocytic cells in the form of a ring around these zones. Ivlost of the myelin stained fibers in the damaged tissue were absent, pale or unevenly stained. In the necrotic brain tissue most of axis cylinders were damaged or had disappeared. The neurons and glial cells in the perivascular regions were pyknotic and resembled ischemic cell change. There was also some lymphoid histiocytic perivascular infiltration around small veins and capillaries. I1. HEAE in Rhesus Monkeys Among the 44 rhesus monkeys immunized with the homological spinal cord emulsion and the Freund adjuvant only five animals were found to have HEAE: three of the 20 rhesus monkeys immunized with encephalitogenic Mixture I (the rest had acute E A E ) and two of the 24 Table 1. Clinical observation of HEAE in rhesus monkeys immunized with homological spinal cord emulsion and Freund adjuvant Order of Encephalitogenic monkeys mixtures 1
D u r a t i o n o f Clinical signs clinical signs (days)
Outcome of the disease
10
1
Adinamia, anorexia
Death
2
11
1
Adinamia, anorexia
Death
3
13
2
Adinamia, anorexia
Death
25
12
Death
27
14
Ataxia, tremor, paresis of the extremities, adinamia, anorexia Ataxia, tremor, paresis of the extremities, adinamia, anorexia
4
5
Mixture I
Incubation period (days)
Mixture II and Mixture III
Death
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e
d
Fig. 4a--d. Rhesus monkeys No. 1 with HEAE. a Gross lesions in thalamus and temporal lobe. b Perivascular hemorrhages in cerebral white matter. H.-E.,x 100. e,d Perivascular lymphoid histiocytic infiltration. Nissl, x 200
monkeys immunized with encephalitogenic Mixture II (the rest had acute or chronic EAE). The clinical and morphological findings in rhesus monkeys with acute and chronic EAE were published earlier (Ravkina, 1964; Ravkina et al., 1978). The clinical findings of the five rhesus monkeys with HEAE are listed in the Table 1. Animals 1, 2 and 3 had a short incubation period and the course was rapidly progressive to a fatal termination in 1 to 2 days. In the brain of these rhesus monkeys many small hemorrhages were found. The thalamus, white matter of the temporal lobe and medulla oblongata presented large lesions of dark red color (Fig. 4a). Microscopic examination revealed perivascular hemorrhages along with perivascular lymphoid histiocytic infiltration (Fig. 4b, c, d). The gross abnormal tissue had large necrotic hemorrhagic foci that contained many necrotic blood vessels with plasma exudation and heavy fibrin impregnation (Fig. 5a). There were numerous neutrophile leucocytes in the form of a ring in the necrotic perivascular brain tissue (Fig. 5b, c), and many red corpuscules and some mononuclear cells in the area of fibrin deposition. The nerve cells and glial nuclei were pyknotic or had disappeared (Fig. 5d); most of the axis cylinders and myelin fibers in the necrotic brain tissue were absent (Fig. 5a). There were focal lymphoid histiocytic infiltrations in the leptomeninges. Duration of the illness in rhesus monkeys 3, 4 and 5 was 12 to 14 days. The coronal sections of formalin fixed brain exhibited many small hemorrhages and large foci of yellow color in the thalamus and medulla oblongata. Microscopic examination revealed that multiple large lymphoid histiocytic infiltrations around the blood vessels (Fig. 6a) were diffusely scattered in the cerebral white matter, thalamus, brainstem, medulla oblongata and cerebellum. The glial proliferation and large foci of demyelination were found around these vessels (Fig. 6b). There were also many compound granular cells (Fig. 7a) and necrosis of small blood vessels with plasma exudation and heavy fibrin impregnation were noted (Fig. 7b). Numerous neutrophile leucocytes were observed in the necrotic perivascular brain tissue. Necrotic vessels and neutrophile infiltration were often detected near the vessels with lymphoid infiltration and compound granular cells (Fig. 7a).
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Fig. 5 a--d. Rhesus monkey No. 1 with HEAE. a Multiple necrosis of blood vessels with fibrin impregnation in damaged medulla oblongata. Spielmeyer, x 40. b Multiple necrosis of small blood vessels with massive neutrophile infiltration around damaged brain tissuein the thalamus. Nissle stain, × 40. e Same place, x 100. d Degenerative glia cells in damaged medulla oblongata. Cajal, x 400
a
b
Fig. 6a and b. Rhesus monkey No.4 with HEAE. a Perivascular lymphoid histiocytic infiltration with glial proliferation in cerebellum. Nissl, x 100. b Perivascular demyelination in cerebellar white matter. Spielmeyer, x 100
a
b
Fig. 7a and b. Rhesus monkey No.4 with HEAE. a Compound granular cells and massive neutrophile infiltration in thalamus. H.-E. b Necrosis of blood vessels with heavy fibrin impregnation and massive neutrophile infiltration in thalamus, Spielmeyer, x 100
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Discussion All three patients described had respiratory infections about 4 to 24 days prior to the onset of the neurological symptoms which varied with the location of the disease process. The course was rapidly progressive to a fatal termination in 6, 12 or 24 days after the onset of the neurological signs, with high temperature and cells in the CSF. These clinical findings confirm the opinion of Russel (1955) and Gostriony (1973) that A N H E can be considered as a hyperacute stage of post infectious encephalitis (PIE). In all the cases examined the salient histopathological features were necrosis of small blood vessels with plasma exudation and fibrin impregnation and necrosis of perivascular brain tissue. The most severe destruction of brain tissue was around vessels and corresponded to the area of fibrin deposition and leucocytic infiltration. In the necrotic brain tissue most axis cylinders and myelin fibers had disappeared and the nerve and glial nuclei were pyknotic or absent. The inflammatory reaction was found in all cases, but its extent depended on the duration of the illness. Massive neutrophile infiltration was observed when the illness lasted about 6 days (Case 1). If the illness lasted about 12 days (Case 2) lymphocytes and compound granular cells were more predominant. However in Case 3 the illness lasted about 24 days but only a few lymphocytes and some glia cells were found in the necrotic brain tissue. Lymphoid histiocytic infiltration with glial proliferation was found in all cases but it was more pronounced in Case 2. Crome (1954), Jacob (1950), Henson (1942), Gostriony (1973), Lander (1955), Russel (1955) observed such infiltration in A N H E when the illness lasted 4 or more days. Since lymphoid histiocytic perivascular infiltration with glial proliferation is the salient feature of PIE (Finley, 1950), it might be proposed that A N H E is an hyperacute stage of PIE (Russel, 1955) or that PIE can be complicated by A N H E (Berry and Alpers, 1962). The clinical observation of the five rhesus monkeys with H E A E showed that the illness was acute or subacute and the course was rapidly progressive to a fatal end in 1 or 2 days in three monkeys and 12 or 14 days in two monkeys. The morphological observation of the affected monkeys revealed necrosis of small blood vessels with plasma exudation and fibrin impregnation, massive neutrophile infiltration in the damaged brain tissue, hemorrhages and lymphoid histiocytic perivascular infiltration in all animals. These morphological findings are similar to those of ANHE (Field, 1966,1975). It is very interesting to note that there were large foci of perivascular glial proliferation and demyelination with numerous compound granular cells along with necrotic changes in two monkeys. These findings are similar to those of our Case 2 and recurrent A N H E described by Lamarage (1972). The following microscopic pathological features were common both for A N H E and H E A E in rhesus monkeys: 1) necrosis of small blood vessels, 2) plasma exudation and fibrin impregnation, 3) inflammatory reaction of the damaged brain tissue, 4) hemorrhages, 5) perivascular lymphoid histiocytic infiltration and glial proliferation with or without compound granular cells, 6) perivascular demyelination, 7) focal inflammatory reaction in the leptomeninges, 8) relatively normal neurones outside of the damaged brain tissue.
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It might be c o n c l u d e d that H E A E in rhesus m o n k e y s can be viewed as an a d e q u a t e m o d e l o f A N H E . O u r findings suggest that the a u t o i m m u n e reaction plays an i m p o r t a n t role in the p a t h o g e n e s i s o f A N H E .
References Adams, R., Camniermeyer, S., Denny-Brown, D.: Acute necrotizing hemorrhagic encephalopathy. J. Neuropath. exp. Neurol. 8, 1--27 (1949) Adams, R. D.: A comparison of the morphology of the human demyelinative disease and EAE. In: Allergic encephalomyelitis (M. Kies, E. Alvord, eds.), pp. 111--189. Springfield: Thomas 1959 Berry, R. G., Alpers, B. S.: Perivenous encephalitis complicated by acute hemorrhagic leucoencephalitis. J. Neuropath. exp. Neurol. 21, 325 (1962) Crawford, T.: Acute haemorrhagic leucoencephalitis. J. Clin. Path. 7, 1--9 (1954) Crome, L.: Encephalitis during an epidemic of influenza. Mschr. Psychiat. Neurol. 128, 159-- 179 (1954) Csermely, H., Haberland, K.: Brain purpura and hemorrhagic leucoencephalitis. Acta morph. Acad. Sci. Hung. 4, 217--226 (1954) Ferraro, A.: Pathology of demyelinating disease as an allergic reaction of the brain. Arch. Neurol. Psych. 52, 443---483 (1944) Ferraro, A., Roizin, L.: Hyperergic encephalomyelitisfollowing exanthematic diseases, infectious diseases and vaccination. J. Neuropath. exp. Neurol. 16, 423--445 (1957) Field, E., Miller, H.: Current research in multiple sclerosis. Postgrad. Med. J. 36, 236--241 (1960) Field, E.: Experimental allergic demyelination. J. Roy. Coll. Phys. 56--57 (1966) Field, E.: In: Clinical aspect of immunology (Pahgne, R. R. A. Coombs, J. P. T. Lachman (eds.), pp. 1525--1586 (1975) Finley, K. H.: The pathology and pathogenesis of encephalomyelitis associated with vaccination and the exanthemas. A. Piss. Nerv. e. Nieut. 28, 341--356 (1950) Gostriony, G.: Acute hemorrhagic leucoencephalitis. Report of three Cases. Z. Neurol. 204, 43--66 (1973) Harald, K.: Zur morphologischen Differenzierung h~imorrhagischer Encephalitiden. Dtsch. Z. Nervenheilk. 188, 142--186 (1966) Henson, R. A., Russel, D. S.: Acute hemorrhagic leucoencephalitis: report of a case. J. Path. Bact. 54, 222--234 (1942) Hurst, E. W.: Acute hemorrhagic leucoencephalitis previously underined entity. Med. J. Aust. 28, 1--6 (1940) Jacob, H.: Klinik und Pathologic der ,,prim/iren" akuten hamorrhagischen Encephalitis. Arch. Psychiat. Nervenkr. 184, 522--544 (1950) Kabat, E. A., Wolf, A., Bezer, A. E.: Experimental allergic encephalomyelitis in rhesus monkeys. J. Exp. Med. 85, 118--130 (1947) Lamarche, J. B., Behan, P. O., Seejarra, J. M., Feldman, R. G.: Recurrent acute necrotizing hemorrhagic encephalopathy. Acta Neuropath. (Berlin) 22, 79--87 (.1972) Lander, H.: A case of acute hemorrhagic leucoencephalitis (Hurst) complicating varicella. J. Bath. Bact. 70, 157--165 (1955) Lennon, V., Nestall, F. C., Thourspson, M., Ward, E.: Antigen, host and adjuvant requirements for induction of hyperacute experimental autoimmune encephalomyelitis. Eur. J. Immunol. 6, 805--810 (1976) Levine, S.: Wenk, E.: Allergic encephalomyelitis. A hyperacute form. Science 146, 61--62 (1964) Levins, S.: Hyperacute, neutrophilic and localized forms of experimental allergic encephalomyelitis, a review. Acta neuropath. 28, 179--189 (1974) Miller, H., Schapira, K.: Etiological aspects of multiple sclerosis. Brit. Med. J. 19591, 737--740
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Ravkina, L.: Experimental allergic encephalomyelitis. Vestnic Acad. Med. Sci. USSR 11, 57--60 (1963) (Russian) Ravkina, L., Rogova, V., Lasarenko, L.: Chronic experimental allergic encephalomyelitis in rhesus monkeys. J. Neurol. Sci. 38 (3), 281--293 (1978) Russel, D. S.: The nosological unity of acute hemorrhagic leucoencephalitis and acute disseminated encephalomyelitis. Brain 78, 369--376 (1955) Vanderfield, G., Tompkins, Jelihovsky, T.: Clinico-pathological features of acute hemorrhagic leucoencephalitis. Aust. Amer. Med. 9, 29--33 (1960) Received September 21, 1978
Neura y
J. Neurol. 221, 113--125 (1979)
© by Springer-Verlag 1979
Hyperacute Experimental Allergic Encephalomyelitis in Rhesus Monkeys as a Model of Acute Necrotizing Hemorrhagic Encephalomyelitis L. Ravkina*, I. Harib, Z. Manovitch, E. Deconenko, E. Letchinskaja, and E. Papilova Institute of Poliomyelitis and Viral Encephalomyelitis, Academy of Medical Science, Moscow, USSR
Summary. A comparative study of clinical and morphological findings in three fatal cases of acute necrotizing hemorrhagic encephalomyelitis (ANHE) and hyperacute experimental allergic encephalomyelitis (HEAE) in rhesus monkeys is reported. In all cases A N H E was characterized clinically by definite prodromal respiratory infection. The course was rapidly progressive with fatal termination. The salient histopathological changes were necrosis of blood vessels with plasma exudation and fibrin impregnation, hemorrhages and inflammatory reaction in the damaged cerebral tissue. Perivascular lymphoid histiocytic infiltration with glial proliferation was also noted in all cases. Numerous compound granular cells were found in one case. H E A E was detected in five rhesus monkeys immunized with homological spinal cord emulsion with complete Freund adjuvant. The illness was acute or subacute and the course was rapidly progressive with a fatal end. There was multiple necrosis of small blood vessels with plasma exudation, fibrin impregnation and massive neutrophile infiltration of the damaged brain tissue in all rhesus monkeys with HEAE. There was also widespread glial proliferation and numerous compound granular cells alongside with necrosis of blood vessels in the brain. These findings suggest that H E A E in rhesus monkeys can be viewed as an adequate model of ANHE. Key words: Encephalomyelitis, acute necrotizing hemorrhagic (ANHE) Encephalomyelitis, hyperacute experimental allergic (HEAE) - Rhesus monkeys.
Zusammenfassung. Es werden vergleichende klinisch-morphologische Untersuchungen von 3 t6dlichen FS_llen der akuten nekrotisierenden h~imorrhagischen Encephalomyelitis (ANHE) und der hyperakuten experimentellen allergischen Encephalomyelitis (HEAE) beim Rhesusaffen beschrieben. Alle F~ille waren durch akuten Beginn, hohes Fieber, rasch progredienten Verlauf und * Corresponding author
0340-5354/79/0221/0113/$ 02.60
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letalen Ausgang charakterisiert. Immer lag ein respiratorischer Infekt vor. Die charakteristischen histopathologischen Befunde bei allen Erkrankungen waren zahlreiche Nekrosen der Blutgef'~il3emit Diffusion von Plasma, Blutungen und einer Entztindungsreaktion im perivaskul~iren Gewebe. Im Gehirn werden auch lympho-histiocyt~ire Infiltrate gefunden. In einem Fall wurden granul~ire Zellen nachgewiesen. Die HEAE wurde bei 5 Rhesusaffen hervorgerufen, die mit homologer Emulsion von Riickenmark und mit komplettem Freundschem Adjuvans behandelt wurden. Die Erkrankung war akut mit einem raschen Verlauf und t6dlichem Ausgang. Im Affengehirn fand man zahlreiche Nekrosen der Blutgef~il3e mit Durchtr~inkung des perivaskul~iren Gehirngewebes durch Plasma, Blut und massiven Leukozyteninfiltraten. Neben den nekrotischen Veranderungen fand man auch Mikrogliaproliferation und granul~ire Zellen. Unsere Ergebnisse lassen die HEAE beim Rhesusaffen als ein Modell der ANHE erscheinen.
Introduction
Acute necrotizing hemorrhagic encephalomyelitis (ANHE) is a rare fatal disease (Csermely and Haberland, 1954; Crawford, 1954; Crome, 1954; Costriony, 1973; Vanderfield et al., 1960), whose nature is not quite settled. The most important communication on the subject was made by Hurst in 1940 in which he presented, under the title of ANHE, the clinical and pathological findings in two cases. Nowadays some workers regard ANHE as a hyperacute form of demyelinating diseases (Adams, 1959; Miller and Shapira, 1959). An autoimmune reaction is known to play an important role in the pathogenesis of the demyelinating diseases (Ferraro, 1944; Ferraro and Roizin, 1957; Finley, 1950; Field and Miller, 1960). Most workers have found a connection between ANHE and respiratory infections (Henson and Russel, 1942; Adams, 1949; Crome, 1954; Russel, 1955). The salient histopathological changes in ANHE are: necrosis of small blood vessels with plasma exudation and inflammatory reaction in the perivascular damaged tissue, with predominance of neutrophile leucocytes (Adams et al., 1949, 1959; Jacob, 1950; Harad, 1966; Hurst, 1940; Vanderfield et al., 1960; Costriony, 1973). Levine and Wenk (1964, 1974), Lennon et al. (1976)produced hyperacute experimental allergic encephalitis (HEAE) in rats by immunization with brain antigen and pertussis vaccine. Necrosis of small blood vessels with plasma exudation and fibrin impregnation and massive neutrophile leucocytes infiltration were found in rats with HEAE. Levine and Wenk (1964) believe that HEAE can be considerated as a model of ANHE. Kabat et al. (1947) noted neutrophile leucocytes in a few rhesus monkeys immunized with brain antigen and Freund adjuvant (Field, 1966, 1975). An investigation of HEAE in rhesus monkeys is of special interest for the evaluation of HEAE as a model of ANHE. This article deals with clinical and pathological findings in three cases of ANHE and in five rhesus monkeys with HEAE.
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Materials and Methods Monkeys. Young rhesus monkeys from India, of both sexes, weighing 1.7 to 2.3 kg were used. Encephalitogenic Mixtures. 1. Mixture I contained 50% emulsion of homological spinal cord emulsion (300 m g / m l wet weight), vaseline oil (400 mg/ml) and 10 mg/ml killed BCG mycobacteria. Mixture H contained 50% spinal cord emulsion (300 mg/ml wet weight), vaseline oil (400 mg/ml) and 0.2 m g / m l killed BCG mycobacteria. Mixture 111 contained 50% spinal cord emulsion (500mg/ml wet weight) and vaseline oil (400mg/ml). Immunization. Twenty rhesus monkeys were immunized with a single dose of Mixture I subcutaneously into four sites on the chest and belly in an amount of 0.5 to 0.55 ml at each site, the total dose per monkey being 2.0 to 2.20 ml. Twenty-four rhesus monkeys were immunized with a single dose of Mixture II subcutaneously in four sites on the chest and belly in an amount of 0.25 to 0.30 ml at each site, the total dose per monkey being 1.0 to 1.2 ml. After a month the monkeys were treated with the Mixture III subcutaneously on the chest and belly in the quantity of 0.5ml to 0.55 ml at each site, the total dose per monkey being 2.50 to 6.50ml. Maintenance. All animals were fed on vegetables, boiled rice and oatmeal porridge with butter, eggs, white bread, tea with sugar and vitamin ABCD complex. Histological Examination. The sections were stained with hematoxylin and eosin, for myelin by the Spielmeyer method, for glia by the Cajal method, for nerve cells by the Nissl method, and for axis cylinders by the Bielschowsky method. Material was fixed in 10% formalin.
L Human Cases Case 1. A girl, aged 14 years, who had frequently suffered from acute respiratory infections and tonsillitis, complained 10 days prior to admission to hospital in May 1974 that she felt generally unwell. Her temperature rose to 39°C, she developed a cough and sneezing. About 4 days prior to admission severe headache, vomitus and nausea appeared and a diagnosis of meningitis brought her to hospital. There the temperature was 38°C, pulse 86, and showed extremely ill retained counsciousness. She bad mild meningeal signs; the tendon reflexes were present. The next day she suddenly became comatose and died approximately 48 h after admission or 6 days after the onset of neurological signs. Laboratory Data. The cerebrospinal fluid (CSF) contained 1312 cells per mm 3, in which 82% were neutrophile leucocytes and total protein 3.3 mg%. No bacteria were found in a smear. Pandy and Nonne-Appelt reaction 5 were positive. The hemoglobin was 66%, the white blood count was 12,000 with 84% neutrophile leucocytes. Anatomical Diagnosis. ANHE, tracheobronchitis, tonsillitis, pulmonary edema, accidental involution of thymus. Brain and Spinal Cord. There was a small amount of subarachnoid exudate near the brain stem. Coronal sections of the formalin fixed brain and spinal cord exhibited many small hemorrhages. Microscopic Observation. Multiple necrosis of small blood vessels with plasma exudation and fibrin impregnation, necrosis in perivascular brain and spinal cord tissue were found in the brain stem and spinal cord (Fig. la, b, c). There were numerous neutrophile leucocytes in the damaged tissue around the affected vessels in the brain stem and spinal cord (Fig. la, b). Perivascular hemorrhages were also seen (Fig. ld). Along with these changes a few lymphoid histiocytic perivascular infiltrations with glial proliferation (Fig. 2a, b) and myelin destruction around them were observed in the brain and the spinal cord. In the necrotic perivascular tissue most of the axis cylinders had disappeared. Focal inflammatory reactions were observed in the leptomeninges of the brain stem.
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Fig. 1 a--d. Case 1. a Necrosis of vein with heavy neutrophile infiltration in medulla oblongata. H.-E., × 100. b Necrosis of small blood vessels with plasma exudation and numerous neutrophile infiltrations in damaged spinal cord tissue. H.-E.,× 200. c Heavy fibrin impregnation in damaged spinal cord tissue. Spielmeyer, x 2000. d Perivascular hemorrhages and small lymphoid histiocytic perivascular infiltrations in spinal cord. H.-E.,× 200
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b
Fig. 2a and b. Case 1. a Perivenous lymphoid histiocytic infiltration with glial proliferation in cerebral white matter. Nissl, × 100. b Perivascular lymphoid histiocytic infiltrations in spinal cord. H.-E., × 400
Case 2. A male, aged 24 years. About 1 month prior to admission to hospital he had tonsillitis with high temperature. A week later he returned to work but was very weak and complained of headache. About 4 days before entering hospital he developed severe headache, weakness of the right extremities and aphasia. The diagnosis of encephalitis was made and he was brought to hospital. Temperature was 38°C; blood pressure was 160/60, pulse 160 and the plantar reflexes were extensor bilaterally. There was also weakness of the right extremities and sensory aphasia. In the period of 8 days after admission his general condition became worse; he became stuporose and died 12 days after the onset of the neurological symptoms. Laboratory Data. The white blood count was 16,000 with 93% lymphocytes. The CSF contained 25 cells/mm 3. There were not bacteria in a smear. Anatomical Diagnosis. ANHE, pulmonary congestion, mucosal petechial hemorrhages in the stomach. Brain. The brain was swollen. The convolutions were flattened. Coronal sections of formalin fixed brain exhibited numerous petechial hemorrhages diffusely scattered in the cerebral matter, thalamus, midbrain and medulla oblongata. Large foci (1.5 cm) of dark red and yellow color were found in the left temporal lobe. Microscopic Observation. Large and small hemorrhages were found (Fig. 3a) both in cerebral white and gray matter. Necrosis of blood vessels with plasma exudation (Fig. 3b) and heavy fibrin impregnation (Fig. 3c) was noted. Neutrophile leucocytes, lymphocytes and compound granular cells (Fig. 3d) were observed in damaged brain tissue around the necrotic vessels. There was also widespread glial proliferation around the veins (Fig. 3e) and capillaries with numerous compound granular cells (Fig. 3f) and diffusely scattered lymphocytes. Myelinated fibers were destroyed or pale around these vessels. The neurons and glial nuclei were pyknotic in the damaged tissue. There were no definite thrombi in the vessels. There was a lymphoid histiocytic perivascular infiltration of the meninges.
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Fig. 3 a i f . Case 2. a Hemorrhages in cerebral white matter. H.-E., x 400. b Lymphoid histiocytic perivenous infiltration and plasma exudation in cerebral white matter. H.-E., x 200. e Heavy fibrin impregnation and plasma exudation in temporal lobe. Spielmeyer, x 40. d Neutrophile leucocytes and compound granular cells around necrotic small blood vessels in temporal lobe. Nissl, x 400. e Widespread glial proliferation around vein in temporal lobe. Nissl, x 100. f Compound granular cells in temporal lobe. H.-E.,x 400
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Case 3. A male, aged 60 years. About 25 days prior to the admission to the hospital he had respiratory infection with a high temperature which lasted 10 or more days and then changed into a subfebrile condition. About 18 days after the onset of the respiratory infection he developed ataxia, dizziness and vomiting. The diagnosis of brain neoplasm was made and he was admitted to hospital in December 1977 where he was found to have paresis of the facial, abducens and oculomotor nerves and nystagmus. The temperature was 37.5°C. During the following days the paresis of the cranial nerves advanced to paralysis and the patient died 24 days after the onset of the neurological symptoms. Laboratory Data. The white blood count was 9000 with 63% neutrophile leucocytes and 24% lymphocytes. The CSF contained 15 cells/mm 3, all lymphocytes and total protein amounted to O.8%. Anatomical Diagnosis. ANHE, aspirational pneumonia, cholecystitis, pyelonephritis, general atherosclerosis. Brain. Coronal sections of formalin fixed brain exhibited many petechial hemorrhages scattered mainly in the midbrain and brain stem. Microscopic Observations. Congestion of small blood vessels and small hemorrhages were found in the central white matter and brain stem. The walls of most blood vessels in the central white matter were well preserved. Complete or partial necrosis of small blood vessels with plasma exudation and fibrin impregnation were found in the midbrain, pons and medulla oblongata, mainly in the nuclei of the cranial nerves. There was necrotic tissue around the affected vessels and some glial and lymphocytic cells in the form of a ring around these zones. Ivlost of the myelin stained fibers in the damaged tissue were absent, pale or unevenly stained. In the necrotic brain tissue most of axis cylinders were damaged or had disappeared. The neurons and glial cells in the perivascular regions were pyknotic and resembled ischemic cell change. There was also some lymphoid histiocytic perivascular infiltration around small veins and capillaries. I1. HEAE in Rhesus Monkeys Among the 44 rhesus monkeys immunized with the homological spinal cord emulsion and the Freund adjuvant only five animals were found to have HEAE: three of the 20 rhesus monkeys immunized with encephalitogenic Mixture I (the rest had acute E A E ) and two of the 24 Table 1. Clinical observation of HEAE in rhesus monkeys immunized with homological spinal cord emulsion and Freund adjuvant Order of Encephalitogenic monkeys mixtures 1
D u r a t i o n o f Clinical signs clinical signs (days)
Outcome of the disease
10
1
Adinamia, anorexia
Death
2
11
1
Adinamia, anorexia
Death
3
13
2
Adinamia, anorexia
Death
25
12
Death
27
14
Ataxia, tremor, paresis of the extremities, adinamia, anorexia Ataxia, tremor, paresis of the extremities, adinamia, anorexia
4
5
Mixture I
Incubation period (days)
Mixture II and Mixture III
Death
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e
d
Fig. 4a--d. Rhesus monkeys No. 1 with HEAE. a Gross lesions in thalamus and temporal lobe. b Perivascular hemorrhages in cerebral white matter. H.-E.,x 100. e,d Perivascular lymphoid histiocytic infiltration. Nissl, x 200
monkeys immunized with encephalitogenic Mixture II (the rest had acute or chronic EAE). The clinical and morphological findings in rhesus monkeys with acute and chronic EAE were published earlier (Ravkina, 1964; Ravkina et al., 1978). The clinical findings of the five rhesus monkeys with HEAE are listed in the Table 1. Animals 1, 2 and 3 had a short incubation period and the course was rapidly progressive to a fatal termination in 1 to 2 days. In the brain of these rhesus monkeys many small hemorrhages were found. The thalamus, white matter of the temporal lobe and medulla oblongata presented large lesions of dark red color (Fig. 4a). Microscopic examination revealed perivascular hemorrhages along with perivascular lymphoid histiocytic infiltration (Fig. 4b, c, d). The gross abnormal tissue had large necrotic hemorrhagic foci that contained many necrotic blood vessels with plasma exudation and heavy fibrin impregnation (Fig. 5a). There were numerous neutrophile leucocytes in the form of a ring in the necrotic perivascular brain tissue (Fig. 5b, c), and many red corpuscules and some mononuclear cells in the area of fibrin deposition. The nerve cells and glial nuclei were pyknotic or had disappeared (Fig. 5d); most of the axis cylinders and myelin fibers in the necrotic brain tissue were absent (Fig. 5a). There were focal lymphoid histiocytic infiltrations in the leptomeninges. Duration of the illness in rhesus monkeys 3, 4 and 5 was 12 to 14 days. The coronal sections of formalin fixed brain exhibited many small hemorrhages and large foci of yellow color in the thalamus and medulla oblongata. Microscopic examination revealed that multiple large lymphoid histiocytic infiltrations around the blood vessels (Fig. 6a) were diffusely scattered in the cerebral white matter, thalamus, brainstem, medulla oblongata and cerebellum. The glial proliferation and large foci of demyelination were found around these vessels (Fig. 6b). There were also many compound granular cells (Fig. 7a) and necrosis of small blood vessels with plasma exudation and heavy fibrin impregnation were noted (Fig. 7b). Numerous neutrophile leucocytes were observed in the necrotic perivascular brain tissue. Necrotic vessels and neutrophile infiltration were often detected near the vessels with lymphoid infiltration and compound granular cells (Fig. 7a).
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Fig. 5 a--d. Rhesus monkey No. 1 with HEAE. a Multiple necrosis of blood vessels with fibrin impregnation in damaged medulla oblongata. Spielmeyer, x 40. b Multiple necrosis of small blood vessels with massive neutrophile infiltration around damaged brain tissuein the thalamus. Nissle stain, × 40. e Same place, x 100. d Degenerative glia cells in damaged medulla oblongata. Cajal, x 400
a
b
Fig. 6a and b. Rhesus monkey No.4 with HEAE. a Perivascular lymphoid histiocytic infiltration with glial proliferation in cerebellum. Nissl, x 100. b Perivascular demyelination in cerebellar white matter. Spielmeyer, x 100
a
b
Fig. 7a and b. Rhesus monkey No.4 with HEAE. a Compound granular cells and massive neutrophile infiltration in thalamus. H.-E. b Necrosis of blood vessels with heavy fibrin impregnation and massive neutrophile infiltration in thalamus, Spielmeyer, x 100
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Discussion All three patients described had respiratory infections about 4 to 24 days prior to the onset of the neurological symptoms which varied with the location of the disease process. The course was rapidly progressive to a fatal termination in 6, 12 or 24 days after the onset of the neurological signs, with high temperature and cells in the CSF. These clinical findings confirm the opinion of Russel (1955) and Gostriony (1973) that A N H E can be considered as a hyperacute stage of post infectious encephalitis (PIE). In all the cases examined the salient histopathological features were necrosis of small blood vessels with plasma exudation and fibrin impregnation and necrosis of perivascular brain tissue. The most severe destruction of brain tissue was around vessels and corresponded to the area of fibrin deposition and leucocytic infiltration. In the necrotic brain tissue most axis cylinders and myelin fibers had disappeared and the nerve and glial nuclei were pyknotic or absent. The inflammatory reaction was found in all cases, but its extent depended on the duration of the illness. Massive neutrophile infiltration was observed when the illness lasted about 6 days (Case 1). If the illness lasted about 12 days (Case 2) lymphocytes and compound granular cells were more predominant. However in Case 3 the illness lasted about 24 days but only a few lymphocytes and some glia cells were found in the necrotic brain tissue. Lymphoid histiocytic infiltration with glial proliferation was found in all cases but it was more pronounced in Case 2. Crome (1954), Jacob (1950), Henson (1942), Gostriony (1973), Lander (1955), Russel (1955) observed such infiltration in A N H E when the illness lasted 4 or more days. Since lymphoid histiocytic perivascular infiltration with glial proliferation is the salient feature of PIE (Finley, 1950), it might be proposed that A N H E is an hyperacute stage of PIE (Russel, 1955) or that PIE can be complicated by A N H E (Berry and Alpers, 1962). The clinical observation of the five rhesus monkeys with H E A E showed that the illness was acute or subacute and the course was rapidly progressive to a fatal end in 1 or 2 days in three monkeys and 12 or 14 days in two monkeys. The morphological observation of the affected monkeys revealed necrosis of small blood vessels with plasma exudation and fibrin impregnation, massive neutrophile infiltration in the damaged brain tissue, hemorrhages and lymphoid histiocytic perivascular infiltration in all animals. These morphological findings are similar to those of ANHE (Field, 1966,1975). It is very interesting to note that there were large foci of perivascular glial proliferation and demyelination with numerous compound granular cells along with necrotic changes in two monkeys. These findings are similar to those of our Case 2 and recurrent A N H E described by Lamarage (1972). The following microscopic pathological features were common both for A N H E and H E A E in rhesus monkeys: 1) necrosis of small blood vessels, 2) plasma exudation and fibrin impregnation, 3) inflammatory reaction of the damaged brain tissue, 4) hemorrhages, 5) perivascular lymphoid histiocytic infiltration and glial proliferation with or without compound granular cells, 6) perivascular demyelination, 7) focal inflammatory reaction in the leptomeninges, 8) relatively normal neurones outside of the damaged brain tissue.
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It might be c o n c l u d e d that H E A E in rhesus m o n k e y s can be viewed as an a d e q u a t e m o d e l o f A N H E . O u r findings suggest that the a u t o i m m u n e reaction plays an i m p o r t a n t role in the p a t h o g e n e s i s o f A N H E .
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