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AIDS COMMENTARY

Toxoplasmic Encephalitis in AIDS Benjamin J. Luft and Jack S. Remington

From the Division of Infectious Diseases. SUNY at Stony Brook. Stony Brook. New York; and the Department of Immunology and Infectious Diseases. Research Institute. Palo Alto Medical Foundation. Palo Alto. and the Division of Infectious Diseases. Stanford University Medical Center. Stanford. California

-Merle A. Sande Among patients with AIDS, >95% of toxoplasmic encephalitis (TE) is due to recrudescence ofa chronic (latent) infection as a result of the progressive loss of cellular immune surveillance [1]. In most instances, TE develops when the CD4 cell count falls below 100/mm 3 [2]. The incidence of TE is therefore directly proportional to the prevalence of antibodies to Toxoplasma in any given population. In the United States, where from 10%to 40% ofadults with AIDS are latently infected, one-third of these patients will develop TE [ 1]. In Africa, Haiti, Europe, and Latin America, where the incidence of latent infection is much higher, the number of individuals with AIDS who develop TE will be three to four times greater than that in the United States [3-5]. It is not clear, however, whether a greater proportion (i.e., greater than one-third) of seropositive patients from these regions will develop TE. For instance, in a recent study from Austria, 47.4% of patients with AIDS who had antibod-

Received 17 April 1992. Reprints or correspondence: Dr. Benjamin J. Luft, Division of Infectious Diseases, HSC T-15, Room 080, SUNY at Stony Brook, Stony Brook, New York 11794-8153.

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ies to Toxoplasma gondii developed TE [3]. In Europe and Africa, it is estimated that 25%-50% of patients with AIDS will ultimately, develop TE [4, 5]. In these areas, there may be epidemiological factors that result in an increased propensity to develop TE; this propensity is perhaps related to the large burden of T. gondii in latent form that results from recurrent reinfections with T. gondii in these populations. It is not clear why only 30%-50% of human immunodeficiency virus (HIV)-positive patients who are latently infected with T. gondii develop TE when their immune system becomes severely compromised. Host factors (such as genetic predisposition) or variation in virulence among different strains of this parasite may playa role in predisposing these patients to recrudescence of active infections. For instance, it has been recently found that susceptibility to formation of Toxoplasma cysts [6] and encephalitis [7] is genetically determined in mice. In addition, virulent strains of T. gondii can be differentiated from nonvirulent strains by restriction fragment length polymorphism analysis (L. D. Sibley and J. C. Boothroyd, personal communication). Seronegative patients also are at risk of developing acute toxoplasmosis. In a prospective study performed in France, Partisani et al. [8] reported a seroconversion rate of 5.5% during a median period of observation of 28 months. Thus, in countries in which the rate of acquisition of toxoplasmic

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Involvement of the central nervous system (CNS) is common in patients with advanced disease due to human immunodeficiency virus (HIV). Symptoms range from lethargy and apathy to coma, incoordination and ataxia to hemiparesis, loss of memory to severe dementia, and focal to major motor seizures. Involvement may be closely associated with HIV infection per se, as in the AIDS dementia complex, but is frequently caused by opportunistic pathogens such as Toxoplasmagondii and Cryptococcus neoformans or malignancies such as primary lymphoma of the CNS. The clinical presentations of attendant and direct CNS involvement are remarkably nonspecific and overlapping, yet a correct diagnosis is critical to successful intervention. Toxoplasmic encephalitis is one of the most common and most treatable causes of AIDS-associated pathology of the CNS. A great deal has been learned in the last 10 years about its unique presentation in the HIV-infected patient with advanced disease. Drs. Benjamin J. Luft of the State University of New York at Stony Brook and Jack S. Remington of the Stanford University School of Medicine and Palo Alto Medical Foundation's Research Institute have studied T. gondiifor many years and are two of the leading experts in the field. This commentary comprises an update of their initial review (J Infect Dis 1988;157:1-6) and a presentation of the current approaches to diagnosing and managing toxoplasmic encephalitis in HIV-infected patients.

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infection is high (e.g., France, Germany, Central Africa, and Haiti), patients with AIDS and other HIV-positive patients with CD4 cell counts of 80% ofpatients will have multiple lesions [9]. Even with use of MRI, the percentages are probably an underestimation ofthe multifocal pathological process that may be occurring below the resolution of the MRI. The spontaneous and simultaneous development of multifocal brain lesions strongly suggests that although TE arises because of reactivation of a latent infection, the multiple areas ofthe brain that are involved are likely a result of hematogenous spread of the parasite, and involvement of the brain is due to the particular proclivity of T. gondii for causing disease in the CNS. The latter is likely due to the fact that the brain is an immunologically pristine site rather than an actual site oftropism ofthe organism. This supposition is further supported by the observation that patients who relapse after receiving an adequate course of'therapy often develop new lesions in areas of the brain previously free of infection [10]. If this pathogenic mechanism is correct, it will have important implications for the design of prophylactic regimens and in determining the level of drug needed to prevent development of TE.

Clinical Presentation The clinical picture of TE at the time of presentation can vary between focal and nonfocal signs and symptoms ofCNS dysfunction (II, 12]. In one autopsy study, diffuse TE without focal lesions was observed in 10% of patients [13]. Constitutional signs and symptoms of infection such as fever and malaise are variable, and infrequently patients have a diffuse encephalitic process without focal abnormalities that can be rapidly fatal [13]. Generally, patients who present with signs and symptoms of diffuse cortical dysfunction develop signs of focal neurological disease as the infection progresses. The focal neurological abnormalities that develop reflect the multifocal nature of this necrotizing encephalitis as well as the associated edema, vasculitis, and hemorrhage [14-16] that occur as a result of active infection. The clinical presentation of TE varies from an insidious process evolving over weeks to an acute confusional state with or without focal neurological deficits. Focal abnormali-

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ties include hemiparesis, hemiplegia, hemisensory loss, cerebellar tremor, visual field defects, cranial nerve palsies, aphasia, severe localized headache, and focal seizures. The focal neurological problems may be subtle and transient initially and with time evolve to persistent focal neurological deficits or may result in a rapidly fatal disease [17]. Nonfocal symptoms and signs of neurological dysfunction can predominate and include weakness, disorientation, frank psychosis, lethargy, confusion, or coma. There may be difficulty in differentiating cerebral toxoplasmosis from a number ofother opportunistic infections or tumors including herpes simplex encephalitis [18], cryptococcal meningitis, progressive multifocal leukoencephalopathy, and CNS lymphoma. Panhypopituitarism [19] and hyponatremia resulting from inappropriate antidiuretic hormone secretion [1, 19] can complicate the neurological picture, and the latter may be a poor prognostic indicator [2]. It may be difficult to differentiate AIDS-related dementia from TE in patients who present with global cognitive impairment associated with attention deficits, impaired recent memory, and slowness of global and motor responses [20]. After successful treatment oftoxoplasmosis, patients may continue to have generalized impairment of cognitive function that progressively deteriorates, and repeated brain biopsy often fails to identify Toxoplasma. Myelitis is more frequent than previously reported and often presents in association with monoparesis and/or numbness. Connus medullaris syndrome has also been described [21, 22]. Although Toxoplasma can infect any cell in the brain, there is a tendency for the parasite to cause localized disease in the brain stem, basal ganglia, pituitary gland, and corticomedullary junction [14, 23, 24]. With brain stem involvement, neurological symptoms such as ataxia, cranial nerve palsies [25], and dysmetria commonly occur [26, 27]. Acquired hydrocephalus, choreiform movements, and choreoathetosis have been described in patients with basal ganglia involvement [28]. Because toxoplasmic infection causes predominantly encephalitis with little or no meningeal involvement, meningismus is rare; the CSF may be normal or may have a greater than normal number of cells and an elevated protein level, usually without depression of the glucose concentration. Autopsy studies of patients infected with Toxoplasma have demonstrated involvement of multiple organ systems [29]. Clinical manifestations ofsevere organ involvement, particularly the gastrointestinal tract, have infrequently been mentioned in case reports or series of cases. It is important to be aware that infection in these organs, including the skin, lung, heart, eye, and liver, can occur independently of CNS involvement. Severe infection of the entire gastrointestinal tract and pancreas may also occur [23, 29-32]. Toxoplasmic pneumonia has more frequently been described in patients with AIDS in France than in those in the United States. Whether this occurrence represents a lack of

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Toxoplasmic Encephalitis in AIDS

vigilance for this manifestation of toxoplasmosis in the United States or reflects differences in the strains of Toxoplasma is not known [33-38]. The clinical manifestations are nonspecific and are similar to those seen with Pneumocystis carinii pneumonia. Patients usually present with dyspnea, fever, and a nonproductive cough that may rapidly progress to acute respiratory failure in a setting similar to that of septic shock with hypotension, metabolic acidosis, and disseminated intravascular coagulation [33, 38]. Hemoptysis has occasionally been described [38]. Chest roentgenograms usually show bilateral interstitial infiltrates with or without nodules and hilar adenopathy [33-38]. Histopathologic examination reveals T. gondii in the lung tissue that is associated with necrosis and a mixed cellular infiltrate. Intracellular and free tachyzoites and cysts can be found in healthy tissue [33, 39-41]. Clinical and pathological diagnoses require a high index of suspicion. Giemsa or eosin-methylene blue stains of fluid obtained by bronchoalveolar lavage or of lung biopsy specimens may be helpful in identifying the pathogen. False-negative results of biopsy have been reported and can be overcome by using immunohistologic staining techniques [33]. T. gondii pneumonia often occurs independently of encephalitis and usually represents reactivation of latent infection. Primary toxoplasmic myocarditis manifested by cardiac tamponade or biventricular failure has been reported [42, 43], but cardiac infection is usually asymptomatic and is seen in the setting of disseminated disease in which the infection in the CNS predominates [44]. Definitive diagnosis requires an endomyocardial biopsy [45]. The small amounts of tissue obtained along with the patchy tissue involvement decrease the sensitivity of this procedure. Retinochoroiditis can occur with or without concomitant encephalitis. It is important to differentiate toxoplasmic retinochoroiditis from chorioretinitis caused by cytomegalovirus. Chorioretinitis due to cytomegalovirus is more hemorrhagic than that due to Toxoplasma, which is often associated with a heavy vitriol haze and severe involvement ofthe vitreous and anterior uvea. At times, the development of toxoplasmic retinochoroiditis is a harbinger of toxoplasmic encephalitis [46-48]. Orchitis and peritonitis due to T. gondii have occasionally been described in patients with AIDS

[49-51]. Diagnosis At present, treatment ofTE is usually initiated upon presumptive diagnosis, and the clinical diagnosis is made as a result of clinical and radiographic response to specific therapy. This clinical practice has evolved with the advent of AIDS because of the morbidity associated with brain biopsy, the inability to biopsy all the numerous and often inaccessible lesions, and the fact that more than one infectious and/or noninfectious process may occur concurrently. Since Toxo-

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plasma is the most common opportunistic pathogen of the brain in patients with AIDS, the practice ofpresumptive therapy for patients with a characteristic finding on computerized axial tomography (CAT) scan or MRI [I5, 23, 52-55] and a positive serology for Toxoplasma is widely accepted (see figure I for algorithm). With use of these criteria, the predictive value in one study was estimated to be as great as 80% [56]. However, for patient populations such as intravenous drug abusers in whom otherCNS processes are more prevalent, the predictive value ofa positive serology for Toxoplasma may be diminished [57]. In addition, it has been demonstrated that patients with AIDS who have CNS lymphoma are four times more likely to have solitary lesions on MRI than patients with TE [9]. This suggests that for patients with a single lesion, a positive serology for Toxoplasma may not have the same high predictive value. In patients who are treated empirically, a clear clinical response should be evident within 14 days, and there should be a clear radiographic response ofall lesions within 3 weeks [32]. In a recent study from the AIDS Clinical Trials Group in which the efficacy of pyrimethamine/clindamycin was assessed, > 50%of patients who ultimately responded to therapy showed a quantifiable clinical improvement by day 3 oftherapy and >90% showed clinical improvement by day 7. Furthermore, for >90% of patients, more than one-half of their abnormal baseline signs and symptoms abated by day 14 of therapy (B. J. Luft et aI., unpublished data). In contrast, for patients who ultimately failed to respond to therapy or who had lymphoma, baseline signs and symptoms worsened and new abnormalities appeared by day 7 of therapy. Therefore, for patients who fail to respond to therapy, brain biopsy should be seriously considered relatively early in the course of treatment, with or without change in therapy. The definitive diagnosis of toxoplasmosis is made by the demonstration ofthe tachyzoite form of Toxoplasma in clinical specimens. For patients with TE and pneumonitis, detection of the pathogen in CSF [58] and fluid obtained by bronchoalveolar lavage [33, 52] has been found to be useful in the diagnosis of CNS and pulmonary involvement, respectively. Previously, isolation of T. gondii from clinical specimens required inoculation of the specimen into a laboratory animal, most commonly a mouse [59]. With use ofthis technique, as long as 6 weeks may be necessary to demonstrate the organism by direct observation of the tissue cyst in the brain of these animals or by seroconversion. Recently, tissue culture systems, commonly used for viral isolation, have been useful for the isolation of T. gondii from clinical specimens obtained from patients with AIDS [59]. These systems may offer a more practical and expedient method for the microbiological demonstration of this pathogen, although it is not as sensitive as the method of mouse inoculation. Other possible diagnostic methods might utilize antigens in blood or urine or nucleic acid sequences specific for T. gondii [60]. One such technique is the selective amplification of DNA

em

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HIV Positive; Signs Referable to CNS

Toxo Serology Unknown? Draw & proceed ; Patients with single or multiple lesions receive empiric therapy until status determined

Lesions

Sing~ sion

~;tR~esion

/'

Or Repeat ~CT Scans

MRI

/

Available;

Single Lesion

Possible

Multip e Evaluate for other etiology in addition to T.E . for clinical illness

24-48 Hours No Treatment T.E.

' - Lesions

I No 810 sy

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No

Multiple

Negative: Rules out : Conside r other Causes

Negative : Does not rule out Isolation Studies

Positive

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Definiti ve Diagnosis Toxop lasmic Encephalitis Continue Therapy for AcuteT.E.

Figure 1. An algorithm for diagnosis and management of suspected toxoplasmic encephalitis in patients with AIDS.

sequences specific to T. gondii by the polymerase chain reaction [61] . Th is technique holds great promise as a sensitive and specific assay for the direct identification of T. gondii; however, its efficacy for detection of specific nucleic acid sequences in CSF from patients with focal encephalitis remains to be determined.

Brain biopsy is generally reserved for those patients who present with a diagno stic dilemma or do not fulfill the crite ria for presumptive treatment and for those patients who have not responded to appropriate antitoxoplasmic chemotherapy. For patients with a single lesion on MRI, there has to be a high index of suspicion of lymphoma, and strong

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Toxoplasmic Encephalitis in AIDS

consideration should be given to early biopsy. Although other infectious and noninfectious processes can cause focal abnormalities indistinguishable on CAT scan or MRI from those caused by T. gondii, the predictive value of a positive test for antibodies to Toxoplasma in most patient populations with multiple characteristic contrast-enhancing lesions on CAT scan appears to be good [62, 63]. In contrast, biopsy has proved diagnostic by histopathological examination in only 50% of patients for whom toxoplasmic encephalitis was clinically diagnosed [56]. Intraoperative sonography and needle biopsy with a stereotactic device have proved useful for the diagnosis ofdeep intracerebral lesions; however, morbidity continues to be associated with brain biopsy. Given the fact that the histological changes associated with TE may closely resemble those of viral encephalitis and that tachyzoites may be difficult to distinguish from nuclear debris, the histological diagnosis of infection caused by Toxoplasma may be difficult [64]. Specialized immunohistochemical techniques are frequently necessary to detect the organism or its antigens [65]. The reactive round-cell infiltrates found in patients with TE may be difficult to differentiate from an intracerebral lymphoma [32]. In these cases, immunohistological stains of the atypical cells found in toxoplasmic lesions consist predominantly ofT cells and histocytes [32]. Thus, it is recommended that if a diagnosis of T. gondii infection or lymphoma is not made definitively on needle biopsy, immunohistological studies with pathogen- and cell-specific antibodies be performed. Characteristically, patients with TE will have focal or multifocal abnormalities demonstrable on MRI or CAT scan. These focal areas of encephalitis may be single or multiple, bilateral, isodense or hypodense, diffuse, or ring enhancing. These findings are not pathognomonic of TE. In a recent review, 40% ofCNS lymphomas were multifocal and --50% were ring enhancing [66]. In 70%-80% of patients with TE, the lesions on CAT scans are multiple, and the contrast-enhancing lesions are located in both cerebral hemispheres [ 14, 23, 55, 63, 66, 67]. The basal ganglia and corticomedullary junction are most commonly involved. The lesions are frequently associated with edema. It has been suggested that a study with delayed double-dose contrast CAT scan may be a more sensitive means of diagnosis ofTE [23, 63]. Although the CAT scan seems to be a sensitive diagnostic modality for patients with focal neurological symptoms, it may underestimate the minimal inflammatory response seen during early disease [32, 53, 54, 68]; for both CAT and MRI, false-negative response rates of --10% have been reported [9]. It is believed that, given the increased sensitivity ofMRI [53], the demonstration of a single lesion with this diagnostic modality suggests lymphoma [54, 68] and that the index of suspicion for performing a brain biopsy should be heightened. It is recommended that an MRI be performed for patients with neurological symptoms and antibody to Toxoplasma whose CAT scans show no or only a single abnormality, and it is

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also recommended that for patients with persistent or worsening focal neurological signs and symptoms of disease a repeated MRI be performed if results of the initial procedure were negative. MRI or CAT scan is useful for assessment of response to empirical therapy. The radiographic response to therapy may lag behind the clinical response. Complete resolution of abnormalities on CAT scan may vary between 3 weeks and 6 months, although patients who respond to therapy will usually have radiographic evidence ofimprovement within 3 weeks of initiation of therapy. Before 3 weeks there may be radiographic evidence ofworsening in patients whose conditions are clearly improving clinically. The time to resolution of the lesions may depend on the area of the brain involved. Superficial lesions appear to respond more quickly than do deeper lesions. As a rule, patients with encephalitis should have evidence ofeither clinical or radiographic improvement within 3 weeks of initiation of empirical therapy. Serological evidence of toxoplasmic infection, independent of the level of antibody, is seen in virtually all patients before the development of encephalitis [69]. It is therefore important to determine the status ofantibody to Toxoplasma in all HIV-positive patients to define the population at risk for development ofTE. With the onset ofencephalitis, significant rises in antibody titers are found in only a minority of patients with AIDS who have TE [69, 70]. However, there has been some suggestion that increases in antibody titer may occur before the onset of encephalitis. Thus, whether rises in antibody titer may be a harbinger for the development ofTE remains to be determined. The level of antibody titer does not seem to be predictive ofthe presence ofTE [64, 70]. The titer (IgG antibody) measured by the Sabin-Feldman dye test varies from negative to I: 1,024 in patients with AIDS and TE [64]. Approximately one-fifth of patients have antibody titers of I: 1,024 or greater, and 80% of patients who could tolerate therapy (B. J. Luft, unpublished data). The toxic effects ofclindamycin are well known and include nausea, vomiting, diarrhea, neutropenia, rash, and pseudomembranous colitis [122]. Myopathy with typical electromyographic findings and elevated levels of creatine phosphokinase that reversed upon discontinuation ofclindamycin have also been reported [123]. Although these trials have established pyrimethamine/clindamycin to be comparable with pyrimethamine/sulfadiazine, these studies did not compare the alleviation of morbidity and neurological dysfunction. Further comparative trials are needed to compare not only ultimate mortality and residual morbidity but also the speed ofresolution ofdisease as well as neurological dysfunction in a clinically and scientifically objective manner. Recently, roxithromycin, clarithromycin, and azithromycin, three new macrolide/azalide antibiotics, have been found to be highly active in treating murine toxoplasmosis [124-126]. These agents possess improved pharmacokinetic properties, including greater bioavailability, and higher and more persistent serum and/or intracellular levels [126]. When compared with each other, azithromycin appears to be considerably more active on a weight basis than other macrolides both in vitro and in animal models. In addition, azithro-

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mycin possesses activity against the cyst form of Toxoplasma [127]. For human TE the combination of pyrimethamine and clarithromycin seemed to be effective in a prospective pilot study of 13 patients with AIDS [128]. Hearing loss and increased transaminase levels were noted. Further studies are necessary to determine the role that these agents may have in the treatment of acute TE and in primary and secondary (maintenance) prophylaxis for TE. At the present time, there is no evidence that either the lincosamides or macro lides when used alone are efficacious as therapy for TE. Although chlortetracycline, doxycycline, and minocycline had antitoxoplasma activity in a murine model of infection [76-78], doxycycline (100 mg twice a day) was ineffective in preventing the recurrence of TE in patients who were intolerant of pyrimethamine/sulfadiazine [129]. BW566C80 may prove to be useful for the treatment of TE [84]. BW566C80 was shown to be effective in both systemic and encephalitic models of infection. It also possesses activity against the tissue cyst of Toxoplasma [84]. This drug was also shown to be effective in a rat model of P. carinii pneumonia [130]. Recent unpublished studies demonstrated that this agent is unique in its ability to sustain prolonged remission of disease when used alone. The anticyst activities of BW566C80, arprinocid N-oxide, and azithromycin suggest the potential for a chemotherapeutic regimen that will radically cure TE and thereby circumvent the need for chronic suppressive (maintenance) therapy. Pyrimethamine/sulfadiazine and pyrimethamine/clindamycin are active only against the tachyzoite form and not the cyst form of T. gondii. Since both forms are present in patients with active TE, discontinuation of specific chemotherapy almost invariably results in recrudescence ofencephalitis [56]. Thus, after the initial 6 weeks oftreatment ofTE, maintenance therapy for patients includes 25-50 mg of'pyrimethamine with 2-4 g of sulfadiazine daily. In instances when sulfonamides cannot be continued, pyrimethamine (75 mg/ d) in combination with clindamycin (450 mg three times a day) can be used. Data from a retrospective study [131] have provided evidence that indicates that pyrimethamine, when given at a sufficient dose (50-75 mg/d), may be adequate as chronic suppressive therapy. The efficacy of a biweekly oral regimen with pyrimethamine (25 mg/d) in combination with either sulfadiazine (4 g/d) or clindamycin was recently reported by Pedrol et aI. [132]. The efficacy of pyrimethamine and clindamycin for chronic maintenance therapy has been reported by other investigators [133, 134], although relapse ofTE in patients receiving this regimen has also been noted [132, 135]. Primary prophylactic therapy is particularly appealing given the ease with which patients at risk of developing TE (those who are seropositive for T. gondii) can be identified. Small studies have reported that pyrimethamine alone or in combination with dapsone or co-trimoxazole was not always effective [136, 137]. In studies ofprimary and secondary pro-

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Toxoplasmic Encephalitis in AIDS

phylaxis for P. cannu pneumonia in patients with AIDS, there was a low incidence of TE in those patients receiving either trimethoprim-sulfamethoxazole or pyrimethamine/ sulfadoxine [138]. Unfortunately, these studies were not prospective for Toxoplasma and often not controlled. Large comparative trials of various agents, doses, and drug combinations will be needed to determine optimal regimens for primary and secondary prophylaxis.

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17. Engstrom JW. Lowenstein DH. Bredesen DE. Cerebral infarctions and transient neurologic deficits associated with acquired immunodeficiency syndrome. Am J Med 1989;86:528-32. 18. Carrazana EJ. Rossitch E. Schachter S. Cerebral toxoplasmosis masquerading as herpes encephalitis in a patient with the acquired immunodeficiency syndrome. Am J Med 1989;86:730-2. 19. Milligan SA. Katz MS. Craven PC. Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome. Am J Med 1984;77:760-4. 20. Navia BA. Petito CK. Gold JW. Cho E-S. Jordan BD. Price RW. Cerebral toxoplasmosis complicating the acquired immune deficiency syndrome: clinical and neuropathological findings in 27 patients. Ann Neurol 1986; 19:224-38. 21. Mehren M. Burn DO. Maurauir CS. Toxoplasmic myelitis mimicking intramedullary spinal cord tumor. Neurology 1988;38: 1648-50. 22. Overhage JM. Griest A. Brown D. Connus medullaris syndrome resulting from Toxoplasma gondii infection in a patient with the acquired immunodeficiency syndrome. Am J Med 1990;89:814-5. 23. Whelan MA. Kricheff II. Handler M. et al. AIDS: cerebral computed tomographic manifestations. Radiology 1983; 149:477 -84. 24. Farkash AE. Maccabbee PJ. Sher JH. CNS toxoplasmosis in acquired immune deficiency syndrome: a clinical-pathological-radiological review of 12 cases. J Neurol Neurosurg Psychiatry 1986;49:744-8. 25. Hamed LM. Schatz NJ. Galetta SL. Brainstem ocular motility defects and AIDS. Am J Ophthalmol 1988; 106:437-42. 26. Sanchez-Ramos JR. Factor SA. Weiner WJ. Marquez J. Hemichoreahemiballismus associated with acquired immune deficiency syndrome and cerebral toxoplasmosis. Mov Disord 1989;4:266-73. 27. Helweg-Larsen S. Jakobsen J. Boeser F. et al. Neurological complications and concomitants ofAIDS. Acta Neurol Scand 1986;74:46774. 28. Nolla-Sallas J. Ricart C. D'Ohlaberringue L. Gali F. Lamorca J. Hydrocephalus: an unusual CT presentation of cerebral toxoplasmosis in a patient with acquired immunodeficiency syndrome. Eur Neurol 1987;27: 130. 29. Tschirhart D. Klatt EC. Disseminated toxoplasmosis in the acquired immunodeficiency syndrome. Arch Pathol Lab Med 1988; I 12: 1237-41. 30. Haverkos HW. Assessment of therapy of Toxoplasma encephalitis. The TE study group. Am J Med 1987;82:907. 31. Leport C. Raffi F. Matheron S. et al. Treatment of central nervous system toxoplasmosis with pyrimethamine-sulfadiazine combination in 35 AIDS patients: efficacy of long term continuous therapy. Am J Med 1988;84:94-100. 32. Luft BJ. Toxoplasma gondii. In: Walzer PD. Gertz RM. eds. Parasitic infection in the compromised host. New York: Marcel Dekker, 1989: 179-279. 33. Catterall JR. Hofflin JM. Remington JS. Pulmonary toxoplasmosis. Am Rev Respir Dis 1986; 133:704-11. 34. Couvreur J. Toxoplasmosis. Rev Mal Respir 1975;3:525-32. 35. Tourani JM. Israe-Biet D. Veret A. et al. Unusual pulmonary infection in a puzzling presentation of AIDS. Lancet 1985; I:989. 36. Mendelson MH. Finkel LJ. Meyers BR. Lieberman J. Hirschman S. Pulmonary toxoplasmosis in AIDS. Scand J Infect Dis 1987; 19:703-6. 37. Tawney S. Masci J. Berger HW. Subietas A. Pulmonary toxoplasmosis: an unusual nodular radiographic pattern in a patient with AIDS. Mt Sinai J Med 1986;53:683-5. 38. Oksenhendler E. Cadranel J. Sarfati C. et al. Toxoplasma gondii pneumonia in patients with the acquired immunodeficiency syndrome. Am J Med 1990;88(5N):18-21. 39. Maguire GP, Tatz J. Giose R. Ahmed T. Diagnosis of pulmonary toxoplasmosis by bronchoalveolar lavage. NY State J Med 1986;78:204-50.

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