Acta Neuropathologica Acta Neuropathol (Berl) (1983) 60:305- 308 9 Springer-Verlag 1983 Acute Fulminant Toxoplasma Meningoencephalitis in a Homosexual Man T. W o n g m o n g k o l r i t ~, S.-L. M c P h e r s o n a, A. E 1 - N a g g a r 1, R. H a f n e r 3, V. C o d i s p o t i 4, A. S c h n a l l 3, D. L. J a c k s o n 3, a n d C. B o n s t e l l e 5 1 Division of Neuropathology, Institute of Pathology, 2 Dept. of Neurology, 3 Division of Critical Care Medicine, Dept. of Medicine, Dept. of Psychiatry, and 5 Division of Neuroradiology, Dept. of Radiology, Case Western Reserve, University and University Hospitals of Cleveland, Cleveland, OH 44106, USA Summary. A h o m o s e x u a l m a n w i t h a h i s t o r y o f sexually t r a n s m i t t e d i n f e c t i o n s i n c l u d i n g r e c e n t giardiasis a n d high c y t o m e g a l o v i r u s ( C M V ) titer was a d m i t t e d w i t h generalized weakness, headache, and depression. He r a p i d l y b e c a m e c o m a t o s e a n d d e v e l o p e d signs o f increased i n t r a c r a n i a l pressure. C T scan revealed a right cerebral lesion. P a t h o l o g i c e x a m i n a t i o n disclosed a n acute n e c r o t i z i n g g r a n u l o m a t o u s t o x o p l a s m o s i s inv o l v i n g the c e r e b r u m . T h i s case r e p r e s e n t s a n e x a m p l e of a n o p p o r t u n i s t i c i n f e c t i o n i n a m a l e h o m o s e x u a l a s s o c i a t e d w i t h f u l m i n a n t clinical course, p r o b a b l y o n the basis o f i m m u n e deficiency. K e y words: C e r e b r a l t o x o p l a s m o s i s - Homosexual Introduction Toxoplasma gondii i n v a d e s all cells except n o n nucleated erythrocytes. T o x o p l a s m a encephalitis m a y be c o n g e n i t a l or a c q u i r e d . T h e a c q u i r e d typical f o r m is m o r e c o m m o n i n a d u l t s a n d is c h a r a c t e r i z e d b y r a n d o m foci o f n e c r o s i s w i t h n u m e r o u s i n t r a c e r e b r a l o r g a n i s m s . A n a t y p i c a l f o r m is less c o m m o n a n d r e s e m b l e s c o n g e n i t a l t o x o p l a s m o s i s [1]. A c q u i r e d t o x o p l a s m o s i s is a n o p p o r t u n i s t i c inf e c t i o n i n p a t i e n t s w h o are i m m u n o c o m p r o m i s e d for a v a r i e t y o f r e a s o n s i n c l u d i n g m a l i g n a n t n e o p l a s m [27], o r g a n t r a n s p l a n t a t i o n [24, 27], a n d c o l l a g e n v a s c u l a r diseases [27, 28]. R e c e n t l y , t w o r e p o r t s b y H a u s e r et al. [14] a n d Vilaseca et al. [31] o n the o c c u r r e n c e o f a c q u i r e d fatal c e r e b r a l t o x o p l a s m o s i s i n m a l e h o m o sexuals h a v e b e e n p u b l i s h e d . W e are p r e s e n t i n g a clinical, radiologic, a n d n e u r o p a t h o l o g i c s t u d y o f a case Offprint requests to. Dr. Wongmongkolrit, Division of Neuropathology, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Rd., Cleveland, OH 44106, U S A o f a c u t e f u l m i n a n t cerebral t o x o p l a s m o s i s in a h o m o sexual m a n . Case Report A 35-year-old white man from New York City was admitted to hospital on August 8, 1982, complaining of generalized weakness and depression. Seventeen days prior to admission, he was seen by a physician because of anorexia, fatigue, and 4.6 kg weight loss ( 2 - 3month period). He had three brief (1/z-day) episodes of diarrhea over the past 2months; the last episode was associated with a fever of 38.9~C for 24 h. Physical examination was normal except for enlarged axillary, submental, and inguinal lymph nodes. Laboratory investigations revealed eosinophilia, sedimentation rate of 43 ram/rain, CMV titer of 1 : 1,024, negative hepatitis B surface antigen, and febrile agglutinins. Stool examination revealed Giardia lamblia. Chest X-ray showed a right hilar calcific lesion. A PPD skin test was negative. He was treated with Metronidazole. Four days prior to admission, he developed nausea, vomiting, increasing diarrhea, headaches, and generalized weakness. Metronidazole was discontinued, but the symptoms persisted. On admission he was depressed and had suicidal ideations. His past history was significant for gonorrhea, syphilis and frequent homosexual activities. On examination his temperature was 36.5~C, blood pressure 138/80 mm Hg, pulse rate 78/min. General physical examination was unchanged. Neurologically, he was oriented but drowsy. He moved all extremities equally, but quantitative assessment was impossible because of lack of cooperation. He refused to have his fundi examined. Laboratory data: Hct 42%, corrected sedimentation rate 37, WBC 5,400/gt (neutrophils 69 %, bands 5 %, lymphocytes 11%, atypical lymphocytes 1%, monocytes 9 %, eosinophils 1%). Serum titer for CMV in a single specimen by enzymelinked immunosorbent assay (ELISA) screen was 2+ (low titer). (Retrospectively, toxopIasma titer in the same serum by indirect fluorescent-antibody test was 1 : 128 with less than 1:10 IgM and CMV titer was 1:256 with less than 1 : 10 IgM.) He became agitated and confused that evening and was given a total of 4rag Haloperidol over an 8-h period. At 7:45 a.m. the next morning he was found comatose. His pupils were equal and reactive to light. He had bilateral papilledema, left greater than right. The examination was otherwise nonfocal. Decadron and Mannitol were administered i.v. At 9:00 a.m. his respiration remained spontaneous but became irregular. The pupils were fixed and dilated (6 ram), and oculovestibular reflexes were absent. At 9:30 a.m. he was intubated, hyperventflated, and had an emergency CT scan, which revealed a large isodense lesion in the right hemisphere (Fig. 1). There is no 306 T. Wongmongkolrit et al. : Toxoplasma Meningoencephalitis Fig. 2. Coronal section of the brain showing lesion in the right basal ganglia and multiple irregular lesions in the cortex (arrows) Fig. 1. Isodense lesion surrounded by edema in right basal ganglia compressing the lateral ventricle and shifting the midline. There is another lesion in right occipital lobe (arrow) enhancement in post-contrast study. His neurologic condition deteriorated. He died 28 h after admission. Postmortem Examination Gross. Autopsy was limited to the brain. The brain weighed 1,620 g. The dura and dural sinuses were unremarkable, while the leptomeninges were slightly thickened and opaque at the vault over the right cerebral hemisphere. Both hemispheres were edematous and swollen. The surface of the right temporo-parietal region near the operculum was softened. There was evidence of herniation of the right cingulate gyrus, unci, and cerebellar tonsils. The superficial veins were congested. Coronal sections of the cerebral hemispheres revealed an edematous cortical and white matter, particularly on the right side. The anterior portion of the right lateral ventricle was reduced in size because of the edematous frontal white matter and bulging right basal ganglia. There were multiple circular hemorrhagic yellow-tan necrotic lesions (up to 3 cm in diameter) involving cerebral cortex and adjacent white matter of frontal, parietal, and occipital lobes. The largest lesion (approximately 5 era) involved the entire right lenticular nucleus and extended to the internal capsule and lateral portion of the anterior thalamus; had a central brown induration surrounded by narrow irregular space containing necrotic material. The ependymal surface had a focal cloudy and yellowish-tan appearance in both lateral ventricles greatest near the third ventricle. The midbrain and pons showed edema and secondary hemorrhages near the midline. The cerebellum and medulla were mildly edematous. Microscopic. Tissue fixed in 1 0 ~ buffered formaldehyde were processed for histology and stained with HE, Cresyl violet, triOarome, and reticulin stains. Large numbers of toxoplasma cysts but few tachyzoites were present throughout the older lesion in the right basal ganglia. Fewer cysts but relatively more tachyzoites were found in other younger lesions located mostly at the bottom of the sulei with extension to both gray and white matter. There was a microscopic lesion with numerous cysts in the right hippocampus between the fascia dentata and entorrhinal cortex. The toxoplasma organisms were closely packed in cysts with argyrophilic walls inside neurons, Fig. 3. Basal ganglia lesion reveals widespread necrosis with hemorrhagic infiltration and cysts of Toxoplasma gondii. HE, x 235 Fig. 4. Cerebral meninges demonstrating infiltration with inflammatory cells (HE, • 185) and toxoplasma cysts T. Wongmongkolrit et al.: Toxoplasma Meningoencephalitis macrophages, and glial perikarya or loosely in neuropile. The older lesions at the center were extensively necrotic with inflammatory infiltrate and capillary thrombosis. The central zone was surrounded by larger vessels with pronounced edema and transmural mononuclear cell infiltration. There was also parenchymal necrosis with retention of large vessels and collagen. The organisms were most frequently found in this necrotic zone. The outermost zone exhibited extensive capillary proliferation, gliosis, and edema. The lesions had atypical morphologic features, as described by previous authors [1, 8, 16]. Judging by glial reaction and histological pattern, none of these lesions were older than 2 - 3 weeks. The periventricular area revealed focal rarefaction of subependymal tissue with macrophagic activity and reactive astrocytes. The overlying ependymal lining was focalIy duplicated. Diffuse anoxic neuronal changes were noted in the remaining sections. Sections from the midbrain and pons revealed secondary hemorrhages near the midline, surrounded by eosinophilic neurons. Discussion Several diseases have been reported recently to occur with higher frequency among male homosexuals. These include Kaposi's sarcoma [3, 9 - 1 1 , 29, 31], Burkitt'slike lymphoma [33], squamous carcinoma of the oral cavity [19], cloacogenic carcinoma of the rectum [2, 4], autoimmune thrombocytopenic purpura [22], cytomegalovirus [5, 7, 26]. Pneumocystis carinii [7, 10, 12], Cryptococcus neoformans [6], Candida albicans [6, 12], Herpes simplex [7, 15], Mycobacterium tuberculosis [6], meningococcal urethritis/proctitis, enteric protozoas [32] - bacteria-parasites (e.g., campylobacter enteritis, giardiasis, typhoid, amebiasis, enterobias, and strongyloidiasis), hepatitis A and B viruses [15] and the more common sexually transmitted diseases, such as gonorrhea, syphilis, and condyloma accuminatum [7, 15]. A recent paper by Vilaseca et al. [31] reported CMV inclusions in adrenal, liver, and lungs of a Spanish homosexual with Kaposi's sarcoma and fatal Toxoplasma gondii brain abscess. However, necropsy was limited to the thorax and abdomen. Histological examination was done in a brain biopsy material (3 cm mass). Another brief report by Hauser et al. [14] documented two homosexual males with high toxoplasma titers and cerebral involvement. The relatively high incidence of these diseases in male homosexuals may be related to an immunocompromised status associated with the use of drugs [11, 13], recurrent infections, or idiosyncrasy. Repeated CMV infection, acquired from contaminated semen, urine, or saliva [5, 17, 18] has been proposed as the primary causative agent. Recurrent CMV infection may cause reversal of the ratio of inducer/helper T-cells subset to suppressor/cytotoxic T-cell subsets [6, 12, 21, 29]. No remarkable change has been noted in humoral immunity [6, 12, 21, 29]. In our case, the marked decrease in CMV titer and low toxoplasma titers, in spite of a fulminant infection, could be due to malnutrition, chronic diarrhea, and infections rather than 307 impairment of B-cell functions. The coexistence of DNA viral infection (e.g., CMV infection) and toxoplasmosis is not uncommon and usually has a more serious outcome [27, 30]. In a VD clinic, CMV titers were found in 94% of homosexual patients when compared to 54% of heterosexual patients [5]. In addition, it is known that CMV impairs macrophagic phagocytosis which plays a role in toxoplasma eradication. CMV also causes transient immunosuppression in apparently normal hosts [25]. This all supports the contention that toxoplasmosis is secondary to CMV infection. Alternatively, toxoplasma may be the result, rather than the cause, of immunosuppression. The association of enteric infestation acquired from orofecal infection may serve as a secondary contributor to the immunocompromised state. The acquired opportunistic infection primarily affects the brain from toxoplasma parasitemia or rupture of latent cysts. The liberated, actively motile tachyzoites penetrate and destroy the nerve tissue [23] with granuloma formation. The rapid demise of these patients is secondary to tissue destruction and cerebral herniation. Because pathologically, cysts are usually associated with immunity, and proliferating taehyzoites with lack of immunity. This case might be interpreted as a condition with immunosuppression of relatively sudden onset, permitting organisms escaping cysts to multiply. Cerebral toxoplasmosis or other opportunistic infections should be suspected in homosexuals who have high CMV titers presenting with vague neurologic symptoms. CT scan and serologic (Sabin-Feldman dye, indirect fluorescence antibody and direct agglutination) tests should be obtained early. Biopsy or aspiration of the lesions can be performed for histological or cytologic studies [20]. Biopsies of other tissues, such as lymph nodes may facilitate the diagnosis if the infection is generalized. Prompt, aggressive therapy may help to improve the morbidity and mortality. Acknowledgment. The authors are grateful to Drs. P. Gambetti, R. B. Daroff, and Y. Guti6rrez for their assistance and suggestions. References 1. 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Am J M ed 5 2 : I 4 8 - 1 5 9 29. StahI RE, Friedman-Kien A, Dubin R, Marmor M, Zolla-Pazner S (1982) Immunologic abnormalities in homosexual men. Relationship to Kaposi's sarcoma. Am J Med 73 : 171 -- 178 30. Vietzke WM, Gelderman AH,Grimley PM,Valsamis MP(1968) Toxoplasmosis complicating malignancy. Cancer 21 : 8 1 6 - 827 31. Vilaseca J, Arnau JM, Bacardi R, Mieras C, Serrano A, Navarro C (1982) Kaposi's sarcoma and Toxoplasmagondiibrain abscess in a Spanish homosexual. Lancet 1:572 32. William DC, Shookhoff HB, Felman YM, DeRamos SW (1978) High rates of enteric protozoa1 infections in selected homosexual men attending a venereal disease clinic. Sex Transm Dis 5 : 1 5 5 - 157 33. Ziegler JL, Drew WL, Miner RC, Mintz L, Rosenbaum E, Gershow J, Lennette ET, Greenspan J, Shitlitoe E, Beckstead ~, Casavai~t C, Yamamoto K (1982) Outbreak of Burkitt's-like lymphoma in homosexual men. Lancet 2: 631 - 633 Received February 28, 1983/Accepted March 18, 1983