Epidemiology, Pathophysiology, Diagnosis, and Management of Cerebral Toxoplasmosis

Abstract

Toxoplasma gondii is known to infect a considerable number of mammalian and avian species and a substantial proportion of the world's human population. The parasite has an impressive ability to disseminate within the host's body and employs various tactics to overcome the highly regulatory blood-brain barrier and reside in the brain. In healthy individuals, T. gondii infection is largely tolerated without any obvious ill effects. However, primary infection in immunosuppressed patients can result in acute cerebral or systemic disease, and reactivation of latent tissue cysts can lead to a deadly outcome. It is imperative that treatment of life-threatening toxoplasmic encephalitis is timely and effective. Several therapeutic and prophylactic regimens have been used in clinical practice. Current approaches can control infection caused by the invasive and highly proliferative tachyzoites but cannot eliminate the dormant tissue cysts. Adverse events and other limitations are associated with the standard pyrimethamine-based therapy, and effective vaccines are unavailable. In this review, the epidemiology, economic impact, pathophysiology, diagnosis, and management of cerebral toxoplasmosis are discussed, and critical areas for future research are highlighted.

Keywords: Toxoplasma gondii; cerebral toxoplasmosis; diagnosis; immunocompromised patients; pathophysiology; toxoplasmic encephalitis; treatment.

FIG 1

Schematic illustration of T. gondii traversal across the blood-brain barrier (BBB) and the mechanisms that underlie the disruption of BBB permeability and brain dysfunction. (A) Different routes of T. gondii entry into the brain and associated alterations in the tight junction (TJ) proteins and adhesion molecules of the cerebrovascular endothelium. The extracellular tachyzoites can directly enter the brain by paracellular or transcellular route or via a “Trojan horse” mechanism in which tachyzoites cross the BBB within infected leukocytes. (B) Due to their unique metabolic and immunological attributes, neurons are often vulnerable to the parasite’s attack; the parasite replicates within neurons, causing neuronal injury with production of cytokines and chemokines and resulting in more impairment of the neurological function and disturbance of brain metabolism. Neurons also provide a permissive niche to the development of cysts, which persist in dormancy for a long time within the brain. (C) Following entry to the brain, the tachyzoites activate resident microglia and astrocytes and elicit immune responses to limit the parasite proliferation. The M1 phenotype of activated microglia produces proinflammatory cytokines, which exacerbate BBB dysfunction by altering the architecture of the TJ proteins ZO-1, claudin-5, and occludin. The effects of M1 microglia are counterbalanced by alternatively activated M2 microglia, which produce anti-inflammatory cytokines. Maintaining this immune-inflammatory equilibrium is key to the establishment of latent infection. Infection of astrocytes and microglia also leads to the disruption of neuroreceptors, such as the alpha-7 nicotinic acetylcholine receptor (α7 nAChR) and N-methyl-d-aspartate receptor (NMDAR), which may lead to cognitive dysfunction and neurodegeneration. Activated microglia and astrocytes secrete chemokines (e.g., CXCL9 and CXCL10) which function as ligands for CXCR3 to promote the influx of T cells and myeloid cells (granulocytes and monocytes) into the brain. (D) Matrix metalloproteinases (e.g., MMP-8 and MMP-10) and TIMP-1 also contribute to the regulation of the perivascular accumulation and influx of lymphocytes into the brain to prevent the reactivation of dormant cysts. (E) Reactivation from latency can occur due to various mechanisms, such as reduced expression of VCAM-1/α4β1 integrin, CD3δ, CD4, CD8β, interferon gamma (IFN-γ), and inducible nitric oxide synthase (iNOS). Reduced levels of CXCL9, CXCL10, MyD88, interleukin 12 (IL-12), MMP-8, or MMP-10 during reactivated toxoplasmosis decrease the influx of T cells into the brain.

FIG 2

Representative magnetic resonance images from a 68-year-old man living with HIV with toxoplasmic encephalitis. (A and C) T1 FLAIR post contrast. (B and D) Corresponding FLAIR. Note contrast enhancement of both lesions (A and C, bright white rim around the lesion), the “target sign” of the left temporal lobe lesion (white arrow), and significant mass effect (dark [low] signal on panels A and C; white [high] signal on panels B and D).