What is the management of Central Nervous System (CNS) toxoplasmosis?

CNS Toxoplasmosis and Its Management

CNS toxoplasmosis is an opportunistic infection caused by Toxoplasma gondii that primarily affects immunocompromised patients, particularly those with HIV/AIDS, and requires prompt treatment with pyrimethamine plus sulfadiazine with leucovorin supplementation as first-line therapy.

Definition and Epidemiology

Toxoplasma gondii is an intracellular coccidian protozoan that causes toxoplasmosis. CNS toxoplasmosis is:

• Most commonly seen in immunocompromised patients, particularly those with HIV/AIDS
• Reported as an AIDS-defining condition in <1% of pediatric AIDS cases 1
• Usually a result of reactivation of latent infection in immunocompromised hosts
• Estimated to develop in 24-28% of HIV-infected patients with positive Toxoplasma antibodies 2

Clinical Manifestations

In Immunocompromised Patients

• Neurological symptoms: focal neurological deficits, seizures, altered mental status
• Fever and reduced alertness
• Headache often associated with focal neurological symptoms such as hemiplegia or hemiparesis 3
• Multiple ring-enhancing lesions on brain imaging, especially in the basal ganglia and cerebral corticomedullary junction 1

In Congenital Toxoplasmosis

• 70-90% of infants are asymptomatic at birth but may develop late sequelae 1
• Symptomatic newborns may present with:
  • Generalized disease: maculopapular rash, lymphadenopathy, hepatosplenomegaly, jaundice
  • Neurological disease: hydrocephalus, intracerebral calcification, microcephaly, chorioretinitis, seizures 1

Diagnosis

Diagnostic Approach

1. Serologic Testing:

   • Toxoplasma-specific IgG antibodies to detect latent infection
   • Toxoplasma-specific IgM, IgA, or IgE in neonatal serum for congenital toxoplasmosis 1

2. Neuroimaging:

   • CT or MRI showing multiple, bilateral, ring-enhancing lesions
   • MRI is more sensitive and will confirm basal ganglia lesions in most patients 1

3. Definitive Diagnosis:

   • Brain biopsy showing leptomeningeal inflammation, microglial nodules, gliosis, and Toxoplasma cysts 1
   • Biopsy should be considered when:
     • Early neurological deterioration despite empiric treatment
     • Failure to respond to anti-Toxoplasma therapy after 10-14 days
     • Solitary lesions or patients without AIDS 4

Treatment

First-Line Therapy

Pyrimethamine plus sulfadiazine with leucovorin supplementation is the preferred treatment regimen for CNS toxoplasmosis 1, 5:

• Pyrimethamine:

  • Loading dose: 2 mg/kg/day orally divided twice daily for first 2 days
  • Maintenance: 1 mg/kg/day daily for 2-6 months, then 1 mg/kg/day three times weekly 5
  • Monitor for bone marrow suppression; weekly blood counts recommended 6

• Sulfadiazine:

  • 100 mg/kg/day orally divided twice daily 5

• Leucovorin (folinic acid):

  • 10 mg three times weekly to prevent pyrimethamine-induced bone marrow suppression 5, 6
  • Should be administered until normal hematopoiesis is restored 6

Alternative Regimens

For patients who cannot tolerate first-line therapy:

• Pyrimethamine plus clindamycin 3
• Trimethoprim-sulfamethoxazole (TMP-SMX) 5
• Atovaquone with or without pyrimethamine 5

Duration of Therapy

• Acute therapy: At least 6 weeks with clinical and radiological response assessment 5
• For congenital toxoplasmosis: 12 months of treatment recommended 1

Maintenance Therapy

• All patients who have had toxoplasmosis should receive lifelong suppressive therapy to prevent recurrences 5
• For HIV patients: Continue maintenance therapy until immune reconstitution with CD4+ count >100 cells/μL 5

Prophylaxis

Primary Prophylaxis

For HIV-infected patients with CD4+ counts <100 cells/μL:

• First choice: TMP-SMX 5
• Alternatives:
  • Dapsone-pyrimethamine plus leucovorin
  • Atovaquone with or without pyrimethamine 5

Prevention Measures

• Avoid raw or undercooked meat, particularly pork, lamb, or venison
• Cook meat to an internal temperature of 165°F (73.8°C)
• Wash hands after handling raw meat, gardening, or contact with soil
• Wash fruits and vegetables thoroughly before eating raw
• Change cat litter box daily, preferably by an HIV-negative, non-pregnant person 5

Monitoring and Follow-up

• Regular neuroimaging to assess treatment response (2 weeks after initiating therapy) 4
• Weekly complete blood count while on daily pyrimethamine 6
• Regular ophthalmologic examinations to monitor for chorioretinitis 5

Special Considerations

Pregnancy

• Avoid pyrimethamine-containing regimens due to teratogenicity concerns 5, 6
• Spiramycin achieves high concentrations in the placenta and is useful for treatment during pregnancy 4, 7
• TMP-SMX can be used for prophylaxis during pregnancy 5

Pediatric Patients

• Pyrimethamine should be kept out of reach of children due to extreme susceptibility to adverse effects 6
• Deaths in pediatric patients have been reported after accidental ingestion 6

CNS toxoplasmosis remains a significant cause of morbidity and mortality in immunocompromised patients, but prompt diagnosis and appropriate treatment can improve outcomes.