Cytoplasmic Tubular Aggregates and Nuclear Filamentous Bodies in Two Suspected Cases of Viral Encephalitis

THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES %

DIKRAN S. HOROUPIAN, R. T. ROSS, MARK J. GURWITH, JAN HOOGSTRATEN

SUMMARY Two suspected cases of INTRODUCTION On admission, she was alert but had viral encephalitis are presented. Viral difficulty understanding commands. Her Cytoplasmic paramyxovirus-like nucleocapsids were not seen, but cytop optic fundi, visual fields and cranial lasmic paramyxovirus-like aggregates aggregates (Baringer and Swoveland, nerves were normal. She had bilateral and nuclear filamentous bodies were fre 1972) and whorled filamentous nuc flexor plantar responses. Her tempera quently encountered. Both structures lear bodies (Zu Rhein and Chou, ture was normal. Her chest, skull films, a were seen in the same cell. Contrary to 1968) have been frequently described left common carotid angiogram, and a other reports, the cytoplasmic aggre in association with virus induced in brain scan were all normal. gates were mostly observed in fectious and neoplastic conditions. Other investigations revealed a hemo hematogenous mononuclear cells, less To our knowledge, these two struc globin of 13.0 gms. %, WBC 8900/cmm. frequently in neuronal cell elements and tures have not been described in the with a normal differential and an erythro rarely in endothelial cells. The non same patient, and the appearance of cyte sedimentation rate of 38 mm. in one specific nature of these structures is em hour. Serum bilirubin, S.G.O.T., C.P.K. phasized. the former, at least in humans, has been usually confined to endothelial and alkaline phosphatase were all nor mal. Urinalysis, a Monospot test and in cells and less frequently to mononuc direct fluorescent antibody titers for tox lear cells (Baringer, 1971). This paper oplasmosis were all negative. E.E.G. RESUME: Deux cas presumes d'ence- deals with two instances of suspected phalite virale furent etudies; aucune showed evidence of a severe disturbance viral encephalitis in which these of the left temporal lobe. Spinal fluid ex nucleocapside virale ne fut decelee, structures were present in the same mais on denombra beaucoup d'aggre- amination showed a glucose of 55 mgs. %, biopsy material and the cytoplasmic gats cytoplasmiques, semblables a des protein 17 mgs. %, 19 lymphocytes and 1 paramixovirus, ainsi que des corps aggregates were found in neuronal redcell/cmm. Cultures of C.S.F. for bac nucleaires filamenteux. Ceux-ci coex- cell elements. teria, fungi and mycobacteria were all istaient dans la meme cellule. Contraire- negative. ment a d'autres rapports, la plupart des On her third hospital day she under aggregats cytoplasmiques furent decou- CASE REPORT 1 went a left temporal lobe brain biopsy. On verts dans des cellules mononucleates Miss M.A., a 16-year-old high school the basis of the pathology report it was hematogenes, certains dans des elements student, was admitted to hospital on Sep decided to treat her as a suspect herpes neuronaux, et tres peu dans des cellules tember 17, 1972. Her family said that she simplex encephalitis with idoxuridine endotheliales. Le caractere non specifi- had been unwell for one week and com (IUDR) which was administered for five que de ces structures est souligne. plained of paraesthesiae in her mouth, days, four grams per day. By the last day gums and teeth. of therapy, her S.G.O.T. was 235, L.D.H. 220, and alkaline phosphatase 62 Two days before admission she com I.U. Her S.G.O.T. remained elevated for plained of anorexia, vomited once and 50 days, although by the date of discharge stopped eating entirely. She developed it was normal. Her bilirubin rose to 1.8 intermittent paraesthesiae of the right foot and arm which lasted for several mi mgs. %. nutes at a time and disappeared for sev On the ninth hospital day her level of eral hours. She gradually became dys- consciousness was further depressed and phasic, apprehensive and began to ex lumbar puncture was repeated. Clear perience violent mood changes. Thirty- fluid under elevated pressure was re From the Department of Pathology and Medicine six hours prior to admission she had a moved containing 16 mgs. % of protein Health Sciences Centre and Faculty of Medicine, nocturnal, generalized epileptic seizure. and 20 lymphocytes per cmm. All other University of Manitoba, Winnipeg, Canada. The next day her dysphasia was much constituents were normal. Reprint address: Dr. D. S. Horoupian, worse, but she managed to make it known Her subsequent hospital course was Neuropathology Unit, Department of Pathology, that she was experiencing constant right Health Sciences Centre, 700 William Avenue, Win characterized by severe aspiration nipeg, Manitoba R3E 0Z3 Canada. face, arm and leg paraesthesiae. pneumonia, transient renal failure and a

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bleeding diathesis due to throm bar puncture revealed clear colorless 5% glutaraldehyde in phosphate buf bocytopenia. fluid with one white blood cell and 53 red fer at pH 7.3 and post fixed in buf By October 24th, her mental status had cells. All cultures were negative. Protein fered osmic acid for one hour. The improved. She could not speak or feed was 25 mg. % and sugar was 112 mg. %. tissues were washed with distilled Subsequent spinal taps were essentially herself and was doubly incontinent. At water and put in 2% aqueous solution times she had spontaneous violent rages. not altered. An echoencephalogram was normal. An E.E.G. was very abnormal, of uranyl acetate for 25 minutes. These were thought to be epileptic and After dehydration in ethanol, the tis were controlled with diphenylhydantoin but with non-specific findings. A brain and primidone therapy. scan suggested increased activity in the sues were embedded in SPURR plas right posterior fossa, but a right brachial tic and the thin sections were stained After two months stay in hospital she angiogram showed no abnormalities. with lead citrate. was discharged to a chronic disease hos Chest X-ray and E.K.G. were normal. pital, completely aphasic and needing in Virus isolation from all specimens, tensive nursing care. She returned home On the 5th hospital day the patient including the brain biopsy, was at on the 30th of January, 1973, at which underwent a right temporal lobe brain tempted in primary human amnion, biopsy and was immediately started on time she was capable of dressing and WI-38, and African Green Monkey feeding herself and fully ambulatory. She IUDR. The IUDR was discontinued after two days when the pathological report on tissue cultures. All serological tests was able to spell and write letters, read were done by the microtitre comple the newspaper, add, subtract, multiply the brain biopsy was reported to be non ment fixation method using two units and divide. Physical examination showed diagnostic. Routine cultures of the brain no abnormalities except for a speech biopsy for fungi, mycobacteriae and vir of complement and two units of an stammer. uses were negative. tigen. Immunofluorescence for The patient's subsequent hospital Herpes virus hominis on the brain course was complicated by a left lower specimen was also attempted. CASE REPORT 2 - (C.W.) lobe pneumonia and a urinary tract in This 12-year-old Jamaican boy was fection and he remained febrile approx admitted on the 14th of February, 1973 imately 30 days. because of fever and a convulsion. The patient had lived in Canada for the last On the 13th hospital day he began to four years, but on the 23rd of December, respond to verbal commands and after 1972 he went to Jamaica for a vacation. one month he responded fully, and was n^, While in Jamaica he had fever lasting able to repeat commands and walk. His for one day on the 5th and the 12th of neurological examination continued to January, 1973. He returned to Winnipeg show no focal abnormalities. L.D.H. and on January 13th, 1973 and was treated S.G.O.T. remained elevated throughout with Synalar cream and clindamycin for his stay in hospital. The last L.D.H. was "infected mosquito bites". On the 10th of 260, but S.G.O.T. had fallen to 60 I.U. February, 1973, he developed fever, His alkaline phosphatase rose to 215 chills, headache, vomiting and diarrhea while in hospital and when last measured and on the day of admission he was found was 175 I.U. Because of the persistent 4 . on the floor unconscious. abnormal liver function, a liver biopsy was done which was considered to be v His past history was unremarkable. normal. ry-' - There was no history of convulsive dis Nine months later, the patient still suf order, drug abuse or head injury. fers from local seizures and manifests . • ,* * *-* * At admission the patient responded serious behavioral difficulties. only to pain and developed a generalized seizure while in the emergency room. There were no localizing neurological MATERIALS AND METHODS signs, although bilateral Babinski signs The brain biopsy was obtained were present. from the left temporal lobe in case While in the hospital, the patient con No. 1 and from the right side in tinued to have seizures, both generalized case No. 2. The specimen was and focal, involving the right side. He remained febrile and finally required a divided into four parts for: light • «? tracheostomy. Laboratory findings in microscopy, histochemistry, electron cluded a hemoglobin of 11.2 gms. %, a microscopy and virus studies. fSS&V .V white cell count of 9,000/cmm. with 67% For light microscopy, the forma granulocytes, 2% bands, 25% lympho lin-fixed and paraffin-embedded cytes, 2% monocytes and 4% atypical tissue was stained with hematoxylin lymphocytes. Platelets were normal. r V ' *- • ••• *"o . * Urinalysis was normal. Chemical screen and eosin, luxol fast blue, phos- photungstic acid hematoxylin, • J:. • t • . -.- ing battery was normal with the exception 4». . * * of the C.P. K. of 4,790, L.D.H. of 285, and and by the Bodian and Heiden- iw* *r-j8..-'-!-iL-\.:' S.G.O.T. of 148 I.U. Alkaline phos hain techniques. For electron Figure 1 Brain biopsy from patient No. phatase and serum bilirubin were normal. microscopy, 1 mm. thick slices of 1 displaying lymphocytic infiltration Serum sodium was 141 mEq./L. A lum grey and white matter were fixed in of the leptomeninges (H & E, X 250).

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TABLE I RESULTS Viral Antibody Titres, Patient No. I (M.A.) Viral Studies Reciprocal of Complement Virus Fixation Titre The serological studies are sum 19/9/72 24/10/72 2/11/72 15/1/73 marized in Tables I and II. There Herpes virus hominis 32 8 8 were no significant serological titre rises except for the four-fold rise in Rubeola (CSF) <8 the complement fixation (CF) titre to Rubeola 8 16 16 16 mycoplasma in patient No. 1 (M. A.). Mumps 8 <8 <8 She also had a four-fold fall in the CF titre to Herpes virus hominis, and in Western Equine Encephalitis 8 <8 <8 the Parainfluenza I and II titres. Viral St. Louis Encephalitis <8 <8 <8 cultures of her pharynx, urine, stool, California Encephalitis <8 8 8 brain biopsy and CSF were negative. Mycoplasma pneumoniae <8 8 16 Immunofluorescence for Herpes virus hominis antigen in the brain Parainfluenza I 16 8 <8 biopsy was negative. Parainfluenza II 16 8 <8 In patient No. 2 (C.W.), viral Parainfluenza HI 16 8 8 cultures of stool, tracheal secretion, and brain biopsy were all negative. TABLE II Viral Antibody Titres, Patient No. 2 (C.W.) Light Microscopy Reciprocal of Complement InpatientNo. 1(M. A.), small num Fixation Titre bers of mononuclear cells were pres 19/2/73 5/3/73 ent in the leptomeninges with focal Herpes virus hominis 8 8 accentuations around venules (fig. Rubeola 8 4 1). Perivascular collections of lym Mumps 32 32 phocytes and occasional histiocytes were seen predominatnly in the cor Western Equine Encephalitis <4 <4 tex. Mild microglial proliferation Mycoplasma pneumoniae <8 <8 with early attempts to form 'glial Parainfluenza I <8 <8 nodules' was more pronounced at the junction of cortex with the white mat Parainfluenza II <8 <8 ter. The cortical cytoarchitecture Parainfluenza III <8 <8 was preserved, but a few neurons were shrunken and displayed nuclear and cytoplasmic hyperchromasia. Early astrocytic proliferation was seen in the deeper layers of the cortex and around the perivascular spaces. No intranuclear or intracytoplasmic inclusions were present. A narrow L • r- » if ,» •- •» •flET - . "V. strip of subcortical white matter was unsatisfactory for proper histological evaluation. In patient No. 2 (C.W.), the brain biopsy showed minimal satellitosis, but there were no perivascular or lep- i>; • ;^ste,i5.-5;* * 'V.- $ tomeningeal inflammatory infiltrates nor was there a significant prolifera tion of microglia.

Electron Microscopy No intranuclear or intracytoplas mic viral nucleocapsid was found in either patient. However, intertwin .-.•,-• f\ . "••• ••/ '.•' -•: % ing tubular arrays were present in hematogenous mononuclear cells Figure 2: A capillary with paramyxovirus-like aggregates in its endothelial lining (X and neuronal cell elements. Only oc 24.100). casionally were they seen in the en-

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'C troglia since fixation of the tissue was not too satisfactory. However, some of the profiles in which these aggre gates were present were definitely glial in origin. Others seemed to be long to satellite oligodendroglia or to microglia (fig. 3). In the perikarya, the tubular aggregates were often re -*-. lated to the rough endoplasmic re ! (fig. 8). Many endothelial cells were swollen and a few lymphocytes, along with phagocytes, were seen in the perivascular zones in patient No. 1 (M.A.). Several "dark" cells (Cohen and Pappas, 1969) were present in both patients.

DISCUSSION In patient No. 1 (M. A.), the history, s f^-, :ff clinical course and brain biopsy were !>L V'T'' ••"•if- "VUV compatible with the diagnosis of viral encephalitis, although a causative Figure 4: The aggregates are closely related to the rough endoplasmic reticulum (X virus was neither isolated or iden 18.500). Insert shows a trilaminar unit membrane derived from the rough E.R. surrounding the aggregate (X 127.800). tified by serologic tests. She had a low but significant serological rise to mycoplasma pneumoniae. This agent dothelium of capillaries. The indi other cells they were loosely ar has been incriminated in en vidual tubules measured approxi ranged and their tubular nature was cephalitis, however, this association mately 24 nm. in outside diameter. more apparent as their central elec- is based only on a few case reports When present in endothelial cells, tronlucent core was clearly outlined and is still tenuous (Hodges et al, they were tightly packed and in some planes of section. It was dif 1972). The four-fold drop in titre to homogenously electron dense (fig. ficult to decide whether the neuronal Herpes virus hominis is sometimes 2). When seen in the perikarya of cell elements were nerve cells or as thought to represent a late serologic

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In both patients, the pertinent ultrastructural finding was the pres ence of cytoplasmic paramyxovirus- like aggregates and whorled filamentous nuclear bodies. These two structures were rarely seen to gether in the same cell (fig. 9). The paramyxovirus-like aggregates were similar to the virus-like particles first observed by Gyorkey et al (1969) in the glomerular endothelial cells of lupus nephritis. Similar profiles were later described in different tissues under a variety of conditions (Mur phy et al, 1968; Anzil and Blinzinger, 1972; Blinzinger et al, 1969; and Landry and Winkelmann, 1972). In the human CNS, they have been most commonly described in associa tion with viral encephalitides. Baringer (1971) noted their presence Figure 5: The continuity of the tubular arrays with the nuclear membrane is illustrated in a cerebral biopsy from a patient (X 88.540). with herpes encephalitis as well as in

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Figure 6: Two nuclear filamentous bodies: a clear halo sur Figure 7: A nucleus containing four nuclear filamentous bodies rounds one of them and the other shows entrapped electron (X 13.620). dense material (X 23.100).

change in the course of Herpes en encephalitis, but the brain biopsy experimental herpes simplex en cephalitis. However, the first failed to display an inflammatory re cephalitis of rabbits and their ab serological specimens were obtained sponse and viral cultures, as well as sence in the control animal (Baringer within four days of the onset of ill the serologic tests, were negative. and Griffith, 1970). However, they ness, so it is unlikely that we can However, these negative findings did were also seen in non-viral condi ascribe any significance to this small not totally preclude the clinical im tions such as Krabbe's disease (Haas pression of encephalitis as the small drop in titre. Although SSPE was and Yunis, 1970). In all these reports, amount of tissue obtained at biopsy the aggregates were almost exclu considered, despite an atypical clin may not have been representative. sively present within endothelial ical presentation, the low CSF and Also a large proportion of presumed cells and less frequently in mononuc serum titres for rubeola make this viral encephalitis in North America lear cells. Rarely were they reported diagnosis unlikely. lack specific viral diagnosis (Center in perikarya of neuronal cell elements In patient No. 2 (C. W.), the history for Disease Control - "Annual En (Uzman et al, 1971). In the present and the clinical findings suggested an cephalitis Summary - 1970", 1972). study, on the contrary, the aggregates

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Figure 8: A longitudinal section of a filamentous nuclear body of a neuron. Its intimate relation to the nuclear envelope is apparent. The arrow points to a profile, possibly a satellite oligodendroglion, which contains the paramyxovirus-like aggregates (X 26.400).

were mostly seen in mononuclear Similarly, the whorled filamentous most frequently encountered abnor cells and in cells of the nervous sys nuclear bodies have been reported in mality reported in SSPE (Zu Rhein tem. They were conspicuously rare several pathological conditions and Choi', 1968); and a possible rela in endothelial cells. Their signifi (Tommasi et al, 1970, and tionship to the tubular nucleocapsids cance in viral diseases or other condi Masurovsky et al, 1967) as well as in of measles virus has been postulated tions in which a viral etiology is sus normal tissues (Peters et al, 1970). In (Herndon and Rubinstein, 1968; pected has not been settled. They do the CNS, they have been observed in Oyanagi et al, 1970). However, Zu not represent viral nucleocapsids, neoplastic conditions including Rhein and Chou (1968) have expres but are considered most likely to be a meningioma (Robertson, 1964) and sed some reservations. Moreover, peculiar response on the part of the glioblastoma (Robertson and Mac- these bodies seem to be more com endoplasmic reticulum to a poorly Lean, 1965), storage diseases, such mon in non-pathological tissues than understood stimulus. These aggre as metachromatic leukodystrophy was generally appreciated in the past gates have been described in normal (Perier and Vanderhaeghen, 1966) (Dupuy-Coin and Bouteille, 1972). human leucocytes, but only in in- and in a case of myoclonic epilepsy Recently, Feldman and Peters (1972) vitro studies (Chandra, 1968). (Brown et al, 1968). They are the have noted an increase in their fre-

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1972. DHEW Publication No. (HSM) 72- 8093. CHANDRA, S. (1968) Undulating tubules as sociated with endoplasmic reticulum in pathologic tissues. Laboratory Investiga tion 18, 422-8. COHEN, E. B. and PAPPAS, G. D. (1969) Dark profiles in the apparently normal cen tral nervous system: a problem in the elec tron microscopic identification of early an terograde axonal degeneration. Journal of Comparative Neurology 136, 375-96. DUPUY-COIN, A. M. and BOUTEILLE, M. (1972) Developmental pathway of granular and beaded nuclear bodies from nucleoli. Journal of Ultrastructural Research 40, 55-67. FELDMAN, M. L. and PETERS, A. (1972) Intranuclear rods and sheets in rat cochlear nucleus. Journal of Neurocytology 1, 109-27. GYORKEY, F., MIN, K. W., SINKOVICS, J. G. and GYORKEY, P. (1969) Systemic lupus erythematous and myxovirus. New England Journal of Medicine 280, 333. Figure 9 A hematogenous mononuclear cell containing both cytoplasmic aggregates HAAS, J. E. and YUNIS, E. J. (1970) Tubular and nuclear filamentous bodies (X 19.550). inclusions of systemic lupus erythematosus. Ultrastructural observations regarding their possible viral nature. Experimental and quency in normal ageing rats and as patient, to Mr. W. Stackiw from the Pro Molecular Pathology 12, 257-63. sociated them with heightened cellu vincial Laboratories for his laboratory assist HADFIELD, M. G., DAVID, R. B. and lar activity. ance and Dr. G. Hogg for reviewing the ROSENBLUM, W. I. (1972) Coiled nu- manuscript. cleocapsid configuration in subacute scler In the cases we presented these osing panencephalitis (SSPE). Acta nuclear bodies were abundant de Neuropathologica (Berl.) 21, 263-71. spite the fact that SSPE was dis- REFERENCES HERNDON, R. M. and RUBINSTEIN, L. J. proven serologically, viral nuc ANZIL, A. P. and BLINZINGER, K. (1972) (1968) Light and electron microscopy obser leocapsids were not seen and, in case Electron microscopic studies of rabbit cen vations on the development of viral particles No. 2, the diagnosis of viral encep tral and peripheral nervous system in ex in the inclusions of Dawson's encephalitis perimental Borna disease. Acta (subacute sclerosing panencephalitis). halitis was presumptive. The mere Neuropathologica (Berl.) 22, 305-18. Neurology 18, Part 2, 8-20. superimposition of a viral nucleocap- BARINGER, J. R. (1971) Tubular aggregates HODGES, G. R., FASS, R. I. and SASLAW, sid on such frequently occuring nuc in endoplasmic reticulum in herpes simplex S. (1972) Central nervous system disease lear bodies does not necessarily encephalitis. New England Journal of associated with mycoplasma pneumoniae imply that the fibrillar material of the Medicine 285, 943-5. infections. Archives of Internal Medicine nuclear bodies are converted or BARINGER, J. R. and GRIFFITH, J. F. 130, 277-82. synthesized into nucleocapsids as (1970) Experimental herpes simplex en LANDRY, M. and WINKELMANN, R. K. has been suggested by Hadfield et al, cephalitis: early neuropathologic changes. (1972) Tubular cytoplasmic inclusion in (1972). Journal of Neuropathology and Experimen dermatomyositis. Mayo Clinic Proceedings tal Neurology 29, 89-104. 47, 479-92. It is therefore apparent from this BARINGER, J. R. and SWOVELAND, P. MASUROVSKY, E. B., BUNGE, M. B. and study and previous other studies that (1972) Tubular aggregates in endoplasmic BUNGE, R. P. (1967) Cytological studies of there is no direct proof to indicate reticulum. Evidence against their viral organotypic cultures of rat dorsal root gang that these two structures, namely, nature. Journal of Ultrastructural Research lia following X-irradiation in-vitro, I. the cytoplasmic paramyxovirus-like 41, 270-6. Changes in neurons and satellite cells. Jour particles and the nuclear filamentous BLINZINGER, K., SIMON J., MAGRATH, nal of Cell Biology 32, 467-96. bodies, are viral nucleocapsids or a D. and BOULGER, L. (1969) Poliovirus MURPHY, F. A., HARRISON, A. K., crystals within the endoplasmic reticulum GARY, G. W. Jr., WHITFIELD, S. G. stage thereof. of endothelial and mononuclear cells in and FORRESTER, F. T. (1968) St. Louis the monkey spinal cord. Science 163, encephalitis virus infection of mice: elec ACKNOWLEDGEMENTS 1336-7. tron microscopic studies of central nervous Part of this work is supported by grant BROWN, J. W., KOTORII, K. andRIEHL, J. system. Laboratory Investigation 19, No. MA-4958 from the Medical Research L. (1968) Ultrastructural studies in myoc 652-62. Council of Canada. lonus epilepsy (Clinical Unverricht- OYANAGI, S., MULLER, D., TER Lafora's disease). Neurology 18, 427-38. We are indebted to Dr. F. S. Dominique MEULEN, V., KATZ, M. and KOPROW- from the Department of Neurology at St. CENTER FOR DISEASE CONTROL "An SKI, H. (1970) Electron microscopic Boniface Hospital for referring the second nual Encephalitis Summary - 1970", Jan. observations in subacute sclerosing pan-

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