INTRODUCTION
Neurocysticercosis (NCC) is caused by Taenia solium and is the most common helminth infection of the central nervous system (CNS). Cysticercosis is endemic in most of the developing world, particularly where pigs are raised.1 Clinical manifestations of neurocysticercosis depend on the number, size, and location of CNS lesions and on the intensity of the host immune response.2,3 Infection with HIV is becoming more frequent in cysticercosis areas, and NCC has been associated with up to 27% of CNS lesions in HIV-infected individuals presenting with neurologic symptoms in South Africa.4 Despite that, there is very little literature on the presentation, treatment, and outcomes of patients with NCC and HIV infection.
The introduction of highly active antiretroviral therapy (HAART) has decreased the mortality and morbidity associated with HIV infection. However, in some patients, immune recovery leads to an inflammatory condition termed immune reconstitution inflammatory syndrome (IRIS). IRIS presents with clinical worsening of an opportunistic infection under treatment or uncovering of a sub-clinical infection.5
Several case reports have described the effects of HIV infection on the clinical course of NCC6–12; however, systematic reviews addressing this co-infection are lacking. Here we report a patient with AIDS who presented with an intense inflammatory reaction to NCC after starting HAART. We also systematically reviewed the literature to summarize all of the reported cases of NCC in HIV-infected individuals.
MATERIALS AND METHODS
For the literature review, we searched the English literature in November 2006 with PubMed using the search terms [HIV AND neurocysticercosis], [HIV AND cysticercosis], and [AIDS AND cysticercosis]. We also searched references from previous literature. Abstracts were reviewed, and papers that presented original cases of NCC and HIV were reviewed in detail.
For the immunohistochemistry, sections of brain tissue from our case were cut at 5 μm and stained using hematoxylin and eosin (H&E). Immunophenotyping was performed using commercially available antibodies (DAKO) against CD3, CD20, CD8, CD56, and CD68. Positive and negative controls were used.
RESULTS
Literature review.
We identified 27 cases, including ours, with HIV and NCC co-infection reported in the literature (Table 1). The most frequent presentation of NCC in HIV patients was with multiple parenchymal lesions (enhancing or non-enhancing cysts) seen in 61% of cases (14 of 23; data were not available in 4 cases). Other presentations included single parenchymal lesions in four patients (17%), atypical forms (giant brain cyst and spinal epidural lesion) in two (9%), and mixed forms (parenchymal, subarachnoidal, and ventricular) in three (13%). Seven patients (30%) had other concomitant CNS infections. Among those, toxoplasmosis encephalitis/abscess and tuberculous brain abscess were the most commonly described. Fifteen patients (56%) had either serum or cerebrospinal fluid (CSF) serology positive for cysticercosis. Thirteen patients received cysticercal therapy, and 85% of these patients responded to therapy. Only three patients died, for a mortality rate of 12%. All deaths were during the pre-HAART era. Because of the limited amount of available information, we were not able to assess the association between CD4 cell counts and type of NCC lesions.
Case report.
The patient was a 35-year-old Hispanic man diagnosed with HIV in 2002. His initial CD4+ T-cell count was 103/mm3, and his HIV RNA viral load was 546,000 copies/mL. Shortly after diagnosis, he began efavirenz, tenofovir, and lamivudine, which led to a marked improvement in his CD4+ T-cell count and suppression of HIV RNA viral load (Figure 1). Two months after starting HAART, his HIV viral load had fallen to < 400 copies/mL, and his CD4+ lymphocyte count had risen to 238/mm3. He presented to Ben Taub General Hospital (Houston, TX) in December 2003 with new-onset generalized tonic-clonic seizures. He also complained of headaches and right-sided hemiparesis for 16 and 2 months, respectively. Computed tomography (CT) of the head with contrast revealed an enhancing 4.5 × 3 × 2-cm cystic lesion with surrounding edema located in the left posterior frontal region. No evidence of hydrocephalus or midline shift was observed (Figure 2). Magnetic resonance imaging (MRI) of the brain with gadolinium did not disclose any further lesions. Laboratory studies revealed a normal complete blood count, CD4 count of 462/mm3, and HIV RNA viral load < 400 copies/mL. Chest x-ray and serologic tests for syphilis, cryptococcal antigen, and toxoplasma IgG were negative. A left frontal cyst aspiration was performed. The aspirate cultures did not reveal any bacteria, fungi, or mycobacteria, and cytology did not show any malignant cells. A left frontal craniotomy and resection of the lesion was performed. The procedure was uncomplicated, and histologic studies identified this lesion as NCC.
Immunohistochemistry.
Immunohistochemical analysis of brain tissue revealed large populations of CD3+ and CD8+ lymphocytes, as well as abundant numbers of CD68+ cells (macrophages and dendritic cells) (Figure 3). In contrast, there were very sparse numbers of B cells anti-CD20+, CD4+ T cells, and natural killer (NK) cells.
DISCUSSION
Despite the wide endemicity of cysticercosis and HIV infection, < 30 cases of NCC have been reported in HIV-infected patients. Clearly, given the growing problem of HIV infection in India, Sub-Saharan Africa, and other areas endemic for cysticercal disease, more research on how to treat co-infected patients is needed. Nonetheless, based on our review, some important observations are noted. Approximately one third (7 of 22) of patients with NCC and HIV presented with at least one other neurologic infection at the time of diagnosis. This high rate of co-infections suggests that in some, if not most of these cases, NCC was an incidental finding in patients undergoing imaging studies for other causes. The range of causes with similar clinical and neuroimaging manifestations also complicates the diagnosis of NCC, such that some patients, including ours, underwent neurosurgical procedures, which would not be required if the diagnosis were made preoperatively.
More than one half of our patients had a positive cysticercal serology, which underscores its importance for the non-invasive diagnosis of the infection. The response rate to cysticidal therapy in HIV patients was 85%, similar to that reported in the literature for the general population.2 This may be attributable to several factors, namely, less inflammatory response after administration of cysticidal drugs as a result of impaired cellular immunity, improved outcome of patients with parenchymal lesions (viable or enhancing) after receiving antiparasitic drugs,13 or resolution of symptoms produced by specific therapy for CNS infections other than NCC.
Compared with series of NCC in patients without HIV, we noted a high case fatality rate (12%). Other HIV-associated conditions may have also contributed to this high mortality rate. Although it is possible that patients present with more severe forms of disease as a result of the underlying HIV infection, we found no clear evidence of this. Alternatively, there may be selection bias toward disproportionate diagnosis or reporting of severe cases. No fatal cases were observed in the HAART era.
In regard to our patient, the onset of clinical symptoms and signs clearly correlated with the recovery of the immune system as documented by an undetectable HIV RNA viral load and an increase in the CD4+ T-lymphocyte count. Thus, based on this correlative evidence, this patient meets current case definitions for IRIS.14 However, it is impossible to be certain that this did not reflect the natural history of NCC, in which symptoms typically develop after a prolonged latent period. Our patient developed headaches shortly after recovery of the CD4+ cell count to > 200/mm3, but only developed hemiparesis and seizures when the CD4+ cell numbers rose to > 400/mm3.
In NCC, there is normally a chronic immune response with multiple cell types (plasma cells, B and T lymphocytes, macrophages, and mast cells) that together secrete Th1 and Th2 cytokines (inflammatory and anti-inflammatory cytokines). Viable parasites seem to induce Th2 and regulatory cytokines and suppress the host Th1 response. In contrast, death of the cysticerci is associated predominantly with Th1 cytokines.15,16 Seizures in NCC are thought to result from the inflammatory response to release of parasite antigens at the time of parasite death,17 and this response may be mediated by host molecules including substance P.18
HAART leads to a protective immune response against a wide variety of pathogens in HIV/AIDS patients. However, a profound, pathologic inflammatory reaction termed IRIS occurs in some patients in response to subclinical or previously recognized microbial infections. The spectrum of IRIS is varied and consists of clinical worsening of a treated opportunistic infection, atypical appearance of an unrecognized infection, or even autoimmune disorders.5 Low baseline CD4+ lymphocyte count, higher HIV RNA viral load, and faster and more marked elevation in CD4+ lymphocyte count coupled with a rapid fall of the HIV RNA viral load after initiation of HAART have been linked to IRIS cases.19,20 In this case, the patient had a low nadir CD4+ T-lymphocyte count (103/mm3) and a high initial viral load of 546,000 copies/mL.
Although some authors have suggested that patients with higher CD4+ T lymphocyte counts are more likely to develop symptomatic NCC needing treatment,4,9 whereas patients with advanced HIV and lower CD4+ T lymphocyte counts present with either asymptomatic or atypical lesions (giant cysts and racemose forms),6,8,10 we found no clear evidence to support these hypotheses. Theoretically, giant cysts could be caused by an uncontrolled parasitic growth as a result of the impaired cell-mediated immune response, as has been documented in echinococcal disease,21 but we could not confirm this proposed relationship.
The immunopathogenesis of IRIS is poorly understood. Initial descriptions showed that activated memory cells (CD4+CD45RO+) account for the early incremental phase of CD4+ cell recovery after effective HAART. Naïve activated CD4+ cells (CD4+CD45RA+CD62L+) do not reappear until several months of therapy.5 CD4+ T cells are required to sustain a CD8+ cytotoxic T-cell response during certain infections such as chronic viral infections. Thus, after HAART, rapid recovery of CD4+ T-cell count may induce a strong CD8+ cytotoxic T-cell response that likely initiates the immune cascade leading to IRIS. Uncontrolled studies have shown a preponderance of CD8+ T cells in cerebral biopsies from HIV patients with IRIS.22 This finding was also observed in the analysis of the immunophenotype of our case.
In brief, NCC co-infection is likely to be increasingly recognized in patients with HIV and should be included in the differential diagnosis of CNS infections in HIV patients. Epidemiologic factors should be studied, and consideration of the patient’s immune status should alert the clinician to potential atypical presentations. NCC also needs to be considered in endemic populations even when there are atypical manifestations (e.g., giant cysticerci) or lesions suggestive of other infections (e.g., enhancing lesions compatible with toxoplasmosis). Further studies are necessary to clarify the pathogenesis, diagnosis, and therapeutic response of NCC in the setting of HIV infection.
NCC cases reported in HIV-infected patients
| Case number, author (reference), year | Age/sex | CD4 count | Radiologic findings | Comorbidities | Treatment | Outcome |
|---|---|---|---|---|---|---|
| NA, not available. | ||||||
| 1 Moskowitz and others [11], 1984 | 22/F | NA | Multiple parenchymal enhancing lesions | Toxoplasma encephalitis, tuberculous abscess | None | Died |
| 2 Thornton and others [7], 1992 | 40/M | NA | Multiple parenchymal and subarachnoid lesions | Generalized lymphadenopathy | Albendazole, steroids | Improved |
| 3 Thornton and others [7], 1992 | 30/M | NA | Multiple parenchymal viable cysts | Oral candidiasis, generalized lymphadenopathy | Albendazole, steroids | No improvement |
| 4 Thornton and others [7], 1992 | 36/M | NA | Multiple parenchymal viable cysts | Generalized lymphadenopathy | Praziquantel | Recurrent seizures |
| 5 Thornton and others [7], 1992 | 25/M | NA | Multiple parenchymal viable cysts | Oral candidiasis, thrombocytopenia | None | Died |
| 6 Jessurun and others [23], 1992 | NA | NA | NA | NA | NA | Died |
| 7–9 Mason and others [12], 1992 | NA | NA | NA | NA | NA | NA |
| 10 White and others [10], 1995 | 29/M | NA | Multiple parenchymal viable cysts | Cryptococcal meningitis | None | Improved |
| 11 Soto and others [6], 1995 | 29/M | 150 | Giant parenchymal cystic lesion | None | Surgical excision, albendazole | Improved |
| 12 Soto and others [6], 1995 | 41/F | NA | Single parenchymal and subarachnoid lesions | Herpes zoster, toxoplasma encephalitis | V/P shunt | Improved |
| 13 Delobel and others [8], 2004 | 45/M | 241 | Single parenchymal and lumbar epidural cyst | Toxoplasma encephalitis | Surgical spinal cyst removal, albendazole | Improved |
| 14–19 Modi and others [4], 2004 | NA | 106–768 | Single (3), and multiple (3) parenchymal lesions | None | Albendazole | Improved |
| 20–22 Modi and others [4], 2004 | NA | 30–104 | Multiple parenchymal lesions | Tuberculosis and toxoplasma encephalitis | Albendazole | Improved |
| 23 Prasad and others [9], 2006 | 51/F | 350 | Multiple parenchymal enhancing lesions | Bacterial brain abscess | Albendazole | Improved |
| 24 Prasad and others [9], 2006 | 40/M | 32 | Multiple parenchymal enhancing lesions | Toxoplasma encephalitis | None | Improved |
| 25 Prasad and others [9], 2006 | 72/M | 105 | Multiple parenchymal enhancing and nonenhancing lesions | None | Albendazole, steroids | Improved |
| 26 Chianura and others [24], 2006 | 22/F | 473 | Multiple parenchymal, ventricular, and subarachnoidal cysts | None | Albendazole, steroids | Improved |
| 27 Current case, 2007 | 35/M | 462 | Single parenchymal enhancing lesion | None | Surgical excision | Improved |
Plot of log viral load and CD4+ T-lymphocyte count vs time. Arrows indicate relevant clinical events. This figure appears in color at www.ajtmh.org.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
Plot of log viral load and CD4+ T-lymphocyte count vs time. Arrows indicate relevant clinical events. This figure appears in color at www.ajtmh.org.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
Plot of log viral load and CD4+ T-lymphocyte count vs time. Arrows indicate relevant clinical events. This figure appears in color at www.ajtmh.org.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
Computed tomography of head with contrast revealing a 4.5 × 3 × 2-cm hypodense lesion with surrounding edema in the left posterior frontal lobe.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
Computed tomography of head with contrast revealing a 4.5 × 3 × 2-cm hypodense lesion with surrounding edema in the left posterior frontal lobe.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
Computed tomography of head with contrast revealing a 4.5 × 3 × 2-cm hypodense lesion with surrounding edema in the left posterior frontal lobe.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
A, Cysticercosis (T. solium) organism cuticle and internal structures adjacent to inflamed neuropil with predominantly lymphocytic, plasma cell, and histiocytic elements. (H&E; magnification, ×40). B, Inflamed neuropil (H&E; magnification, ×200) showing predominantly lymphocytes and plasma cells with some histiocytes and occasional eosinophils. Immunohistochemical phenotyping showing (C) abundant CD3 immunoreactive mature lymphocytes (T cells). D, CD20 immunoreactive mature lymphocytes (B cells) were seen in significantly lower numbers. E, CD8 immunoreactive lymphocytes (T cells) were even less abundant. and F, CD68 immunoreactive monocytes series cells were present in relatively small numbers. This figure appears in color at www.ajtmh.org.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
A, Cysticercosis (T. solium) organism cuticle and internal structures adjacent to inflamed neuropil with predominantly lymphocytic, plasma cell, and histiocytic elements. (H&E; magnification, ×40). B, Inflamed neuropil (H&E; magnification, ×200) showing predominantly lymphocytes and plasma cells with some histiocytes and occasional eosinophils. Immunohistochemical phenotyping showing (C) abundant CD3 immunoreactive mature lymphocytes (T cells). D, CD20 immunoreactive mature lymphocytes (B cells) were seen in significantly lower numbers. E, CD8 immunoreactive lymphocytes (T cells) were even less abundant. and F, CD68 immunoreactive monocytes series cells were present in relatively small numbers. This figure appears in color at www.ajtmh.org.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
A, Cysticercosis (T. solium) organism cuticle and internal structures adjacent to inflamed neuropil with predominantly lymphocytic, plasma cell, and histiocytic elements. (H&E; magnification, ×40). B, Inflamed neuropil (H&E; magnification, ×200) showing predominantly lymphocytes and plasma cells with some histiocytes and occasional eosinophils. Immunohistochemical phenotyping showing (C) abundant CD3 immunoreactive mature lymphocytes (T cells). D, CD20 immunoreactive mature lymphocytes (B cells) were seen in significantly lower numbers. E, CD8 immunoreactive lymphocytes (T cells) were even less abundant. and F, CD68 immunoreactive monocytes series cells were present in relatively small numbers. This figure appears in color at www.ajtmh.org.
Citation: The American Journal of Tropical Medicine and Hygiene 77, 1; 10.4269/ajtmh.2007.77.113
Address correspondence to A. Clinton White Jr., Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch at Galveston, 301 University Blvd., Route 0435, Galveston, TX 77555-0435. E-mail: acwhite@utmb.edu
Authors’ addresses: Jose A. Serpa, Department of Internal Medicine, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM286, Houston, TX 77030, Telephone: 713-798-8918, Fax: 713-798-8948, E-mail: jaserpaa@bcm.tmc.edu. Ana Moran, Department of Internal Medicine, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM286, Houston, TX 77030, Telephone: 713-798-4252, Fax: 713-798-8948, E-mail: amoran@bcm.tmc.edu. Jerry C. Goodman, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM315. Houston, TX 77030, Telephone: 713-798-7234, Fax: 713-798-5838, E-mail: jgoodman@bcm.tmc.edu. Thomas P. Giordano, Department of Internal Medicine, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, Telephone, 713-794-8682, Fax: 713-748-7359, E-mail: tpg@bcm.tmc.edu. A. Clinton White Jr., Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch at Galveston, 301 University Blvd., Route 0435, Galveston, TX 77555-0435, Telephone: 409-747-1910, Fax: 409-772-6527, E-mail: acwhite@utmb.edu.
Financial support: This work was supported in part by the facilities and resources of the Harris County Hospital District, Houston, TX.
Disclaimer: None of the authors report any conflict of interests.
REFERENCES
- 1↑
Garcia HH, Wittner M, Coyle CM, Tanowitz HB, White AC Jr, 2006. Cysticercosis. Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases: Principles, Pathogens, and Practice, Philadelphia: Churchill-Livingstone, 1289–1303.
- 2↑
Garcia HH, Del Brutto OH, 2005. Neurocysticercosis: Updated concepts about an old disease. Lancet Neurol 4 :653–661.
- 3↑
Serpa JA, Yancey LS, White AC Jr, 2006. Advances in the diagnosis and management of neurocysticercosis. Expert Rev Anti Infect Ther 4 :1051–1061.
- 4↑
Modi M, Mochan A, Modi G, 2004. Management of HIV-associated focal brain lesions in developing countries. QJM 97 :413–421.
- 5↑
Shelburne SA, Montes M, Hamill RJ, 2006. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 57 :167–170.
- 6↑
Soto Hernandez JL, Ostrosky Zeichner L, Tavera G, Gomez Avina G, 1996. Neurocysticercosis and HIV infection: report of two cases and review. Surg Neurol 45 :57–61.
- 7
Thornton CA, Houston S, Latif AS, 1992. Neurocysticercosis and human immunodeficiency virus infection. A possible association. Arch Neurol 49 :963–965.
- 8↑
Delobel P, Signate A, El Guedj M, et al., 2004. Unusual form of neurocysticercosis associated with HIV infection. Eur J Neurol 11 :55–58.
- 9↑
Prasad S, MacGregor RR, Tebas P, et al., 2006. Management of potential neurocysticercosis in patients with HIV infection. Clin Infect Dis 42 :e30–e34.
- 10↑
White AC Jr, Dakik H, Diaz P, 1995. Asymptomatic neurocysticercosis in a patient with AIDS and cryptococcal meningitis. Am J Med 99 :101–102.
- 11
Moskowitz LB, Hensley GT, Chan JC, et al., 1984. The neuropathology of acquired immune deficiency syndrome. Arch Pathol Lab Med 08 :867–872.
- 12↑
Mason P, Houston S, Gwanzura L, 1992. Neurocysticercosis: experience with diagnosis by ELISA serology and computerised tomography in Zimbabwe. Cent Afr J Med 38 :149–154.
- 13↑
Del Brutto OH, Roos KL, Coffey CS, Garcia HH, 2006. Meta-analysis: Cysticidal drugs for neurocysticercosis: albendazole and praziquantel. Ann Intern Med 145 :43–51.
- 14↑
Robertson J, Meier M, Wall J, et al., 2006. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 42 :1639–1646.
- 15↑
Restrepo BI, Alvarez JI, Castano JA, et al., 2001. Brain granulomas in neurocysticercosis patients are associated with a Th1 and Th2 profile. Infect Immun 69 :4554–4560.
- 16↑
White AC Jr, Robinson P, Kuhn R, 1997. Taenia solium cysticercosis: host-parasite interactions and the immune response. Chem Immunol 66 :209–230.
- 17↑
Stringer JL, Marks LM, White AC Jr, Robinson P, 2003. Epileptogenic activity of granulomas associated with murine cysticercosis. Exp Neurol 183 :532–536.
- 18↑
Robinson P, White AC, Lewis DE, et al., 2002. Sequential expression of the neuropeptides substance P and somatostatin in granulomas associated with murine cysticercosis. Infect Immun 70 :4534–4538.
- 19↑
Shelburne SA, Visnegarwala F, Darcourt J, et al., 2005. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 19 :399–406.
- 20↑
Lipman M, Breen R, 2006. Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis 19 :20–25.
- 21↑
Sailer M, Soelder B, Allerberger F, et al., 1997. Alveolar echinococcosis of the liver in a six-year-old girl with acquired immunodeficiency syndrome. J Pediatr 130 :320–323.
- 22↑
Venkataramana A, Pardo CA, McAuthur JC, et al., 2006. Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients. Neurology 67 :383–388.
- 23
Jessurun J, Barron-Rodriguez LP, Fernandez-Tinaco G, Hernandez-Avila M, 1992. The prevalence of invasive amebiasis is not increased in patients with AIDS. AIDS 6 :307–309.
- 24
Chianura L, Sberna M, Moioli C, et al., 2006. Neurocysticercosis and human immunodeficiency virus infection: a case report. J Travel Med 13 :376–380.