01Approach to the Critical Patient/attcp48

Immediate priorities

›Airway and hemodynamic threats

›Depressed consciousness with inability to protect airway

›GCS < 8 or rapidly declining

›Prepare for rapid sequence intubation

›Signs of herniation

›Unilateral fixed dilated pupil

›Cushing triad: hypertension, bradycardia, irregular respirations

›Decerebrate or decorticate posturing

›Status epilepticus

›Benzodiazepine as first-line: lorazepam 0.1 mg/kg IV

›Levetiracetam 60 mg/kg IV (max 4500 mg) as second-line

›Respiratory failure from disseminated toxoplasmosis

›ARDS-like presentation with pulmonary involvement

›Supplemental oxygen with SpO2 target >94%

Stabilization and initial management

›Immediate actions

›CT head without contrast before lumbar puncture to evaluate mass effect

›Multiple ring-enhancing lesions favour TE over CNS lymphoma

›Do not delay empiric therapy for biopsy results

›Initiate empiric anti-Toxoplasma therapy if clinical suspicion is high

›Do not await biopsy confirmation before starting treatment

›Class I recommendation: IDSA/OI guidelines 2025

›Neuroimaging priority: CT head immediately, MRI brain within 24 hours

›Large bore IV access, continuous cardiac monitor, pulse oximetry

Key decision points

›Clinical suspicion triggers

›HIV-positive patient with CD4 <100 cells/mm3 and focal neurologic deficits

02History/hx70

Presentation pattern

›Core neurologic syndrome

›Headache (most common presenting symptom)

›Subacute onset over days to weeks

›Progressive worsening

›Focal neurologic deficits

›Hemiparesis or hemisensory loss

›Aphasia or dysarthria

›Visual field cuts

›Cranial nerve palsies

›Cognitive and behavioral changes

›Confusion and disorientation

›Personality changes

›Memory impairment

›Seizures

›Focal or generalized

›New onset in immunocompromised host

Alarm features

›High-risk presentations requiring immediate escalation

›Rapidly progressive altered mental status or coma

›Suggests diffuse encephalitis, rapidly fatal without treatment

›Signs of cerebral herniation

›Unilateral pupil dilation

›Cushing triad

›Status epilepticus in immunocompromised host

›Respiratory distress

›May indicate disseminated toxoplasmosis with pulmonary involvement

›No improvement within 10-14 days of empiric therapy

03Physical Exam/exam47

Neurologic assessment

›Mental status

›Level of consciousness (GCS)

›Confusion, lethargy, disorientation

›Personality and behavioral changes

›Orientation and cognitive function

›Focal deficits

›Motor examination

›Hemiparesis or hemiplegia

›Drift on pronator drift test

›Sensory examination

›Hemisensory loss

›Language and speech

›Aphasia (expressive or receptive)

›Dysarthria

›Cranial nerves

›Cranial nerve palsies (III, VI, VII most common)

›Visual field deficits on confrontation

›Cerebellar function

›Gait ataxia

›Dysmetria on finger-nose and heel-shin testing

›Intention tremor

›Movement disorders

›Tremor

›Chorea or hemiballismus (basal ganglia involvement)

Fundoscopy

›Retinal examination

›Retinochoroiditis

04Differential Diagnosis/ddx49

Life-threatening mimics

›Primary CNS lymphoma (PCNSL)

›Most important mimic of toxoplasmic encephalitis

›EBV PCR in CSF >10,000 copies/mL raises concern for lymphoma

›Often single lesion vs multiple lesions in TE

›Hyperdense on non-contrast CT (vs hypodense in TE)

›Thallium-201 SPECT or FDG-PET: increased uptake in lymphoma

›ICD-10: C85.20

›Distinguishing feature: no response to empiric anti-Toxoplasma therapy at 10-14 days

›Pyogenic brain abscess

›Peripheral source of infection (endocarditis, IVDU, dental)

›Streptococcus, Staphylococcus, anaerobes most common

›Usually single or few lesions

›DWI restriction on MRI (helpful feature)

›ICD-10: G06.0

›CNS tuberculosis (tuberculoma)

›Ring-enhancing lesions with meningeal enhancement

›Basilar meningitis pattern more common than in TE

›AFB culture and PCR on CSF

›ICD-10: A17.82

Viral and fungal CNS infections

›Progressive multifocal leukoencephalopathy (PML)

›White matter lesions, non-enhancing, no mass effect

›JCV PCR positive in CSF (sensitivity ~76%, specificity ~96%)

›Subcortical U-fibers involved

›ICD-10: A81.2

›Cryptococcal meningitis

›Typically meningeal rather than parenchymal

05Laboratory Tests/lt49

Serology

›Toxoplasma IgG serology

›Positive in ~97% of confirmed TE cases

›Negative IgG makes TE diagnosis unlikely but does not exclude it

›Very high negative predictive value in immunocompetent patients

›IgM is usually negative (reactivation not primary infection)

›Do not routinely order IgM unless primary infection is suspected

›Class I recommendation: IDSA OI guidelines 2025

HIV-specific labs

›CD4 count and HIV viral load

›CD4 <100 cells/mm3 is primary risk threshold

›Greatest risk at CD4 <50 cells/mm3

›Viral load guides ART management and IRIS risk

›HIV genotype if virologic failure suspected

Hematology

›Complete blood count with differential

›Baseline before starting pyrimethamine

›Leukopenia and thrombocytopenia from myelosuppression

›Repeat weekly during pyrimethamine therapy (IDSA 2025)

›Anemia from bone marrow suppression

Metabolic panel

›Basic metabolic panel

›Hyponatremia from SIADH (common in CNS infection)

›Renal function for drug dosing adjustments

›Electrolyte management in setting of seizures

›Liver function tests

›Baseline prior to drug initiation

›Pyrimethamine and sulfadiazine hepatotoxicity monitoring

06Diagnostic Tests/dt62

Scoring Systems

›Response-to-therapy diagnostic strategy

›Clinical improvement expected within 5-7 days of empiric treatment

›74% of patients improve by 7 days of appropriate therapy

›91% improve within 14 days (Porter and Sande, NEJM 1992)

›10-14 day clinical and radiographic reassessment

›Failure to improve by day 10-14 mandates diagnosis reassessment

›Brain biopsy indicated if no response or atypical features

›Thallium-201 SPECT scan

›Increased uptake favours PCNSL over TE

›Low specificity limits routine use

›FDG-PET

›Hypermetabolic lesions suggest lymphoma over TE

›Useful when biopsy carries high risk

MRI

›MRI brain with and without gadolinium contrast

›Preferred modality for TE (superior to CT)

›Sensitivity superior to CT for detecting early or small lesions

›Multiple bilateral ring-enhancing lesions in 70-80% of cases

›Classic features

›Predilection for basal ganglia, thalamus, grey-white junction

›Ring-enhancing lesions with surrounding vasogenic edema

›Concentric target sign (alternating rings of enhancement): pathognomonic when present

›Corresponds to alternating zones of necrosis, inflammation, and gliosis

›Susceptibility-weighted imaging (SWI)

›Hypointense rim around lesions (iron deposition, hemorrhage)

›Helps differentiate TE from CNS lymphoma

›SWI hypointense rim more common in TE

07Disposition/dispo32

Admission criteria

›All patients with suspected or confirmed TE require inpatient admission

›Initiation of IV or oral anti-Toxoplasma therapy under observation

›Monitoring for medication toxicity (myelosuppression, crystalluria)

›Seizure precautions and neurologic monitoring

›Diagnostic workup coordination (MRI, LP, serology, ID consult)

›IDSA OI Guidelines 2025: observation alone is not appropriate

ICU admission indications

›High-acuity requirements

›Altered consciousness or coma (GCS <13)

›Continuous neurologic monitoring required

›Status epilepticus not controlled with first-line agents

›Signs of cerebral herniation or imminent herniation

›Respiratory failure requiring mechanical ventilation

›Disseminated toxoplasmosis with multi-organ dysfunction

Specialist consultation triggers

›Infectious disease

›All cases: therapy guidance, ART timing, IRIS management

›Neurosurgery

›Brain biopsy consideration at 10-14 days if no response

›Stereotactic biopsy preferred over open biopsy

›Neurology

›Seizure management and antiepileptic selection

›Ophthalmology

›Visual symptoms or fundoscopic evidence of retinochoroiditis

Transfer criteria

›Transfer to higher level of care

›Neurosurgical capability required for brain biopsy

08Treatment/t84

Empiric therapy initiation

›Start empiric therapy when clinical suspicion high

›Do not await biopsy confirmation

›IDSA OI Guidelines 2025: Class I recommendation

›Response to therapy is both diagnostic and therapeutic

›Preferred regimen: pyrimethamine + sulfadiazine + leucovorin

First-line treatment (acute induction, minimum 6 weeks)

›Pyrimethamine + sulfadiazine + leucovorin (gold standard)

›Pyrimethamine dosing

›Loading dose: 200 mg PO once

›Maintenance: 50 mg/day PO if <60 kg

›Maintenance: 75 mg/day PO if >=60 kg

›Sulfadiazine dosing

›1000 mg PO q6h if <60 kg

›1500 mg PO q6h if >=60 kg

›Leucovorin (folinic acid, NOT folic acid)

›10-25 mg PO daily (concurrent with pyrimethamine)

›Prevents pyrimethamine-induced myelosuppression

›Do not substitute folic acid (does not protect against toxicity)

›Duration: minimum 6 weeks of induction

›IDSA OI Guidelines 2025: Class I recommendation

Alternative regimens

›TMP-SMX (trimethoprim-sulfamethoxazole)

›TMP 5 mg/kg + SMX 25 mg/kg IV or PO q12h

›Only IV option available for patients unable to take PO

›Similar efficacy to pyrimethamine + sulfadiazine

›Better tolerability profile

›IDSA OI Guidelines 2025: Class I recommendation for IV use

›Pyrimethamine + clindamycin + leucovorin (sulfa-intolerant)

›Pyrimethamine: same loading and maintenance doses as above

›Clindamycin 600 mg IV or PO q6h

›Leucovorin 10-25 mg daily

›Requires separate PCP prophylaxis (does not cover Pneumocystis)

›IDSA OI Guidelines 2025: Class I recommendation

›Atovaquone-based regimens

›Atovaquone 750-1500 mg PO BID with fatty meals

›Must be taken with fatty meal to enhance absorption

›May be combined with pyrimethamine or sulfadiazine

›Less evidence than first-line regimens

›Option for patients intolerant of both sulfa and clindamycin

Adjunctive therapy

›Corticosteroids

›Dexamethasone: only for significant mass effect or elevated ICP

›Standard dosing: 10 mg IV loading dose, then 4 mg q6h

›Taper and discontinue as soon as clinically feasible

›Can confound clinical response assessment

›IDSA OI Guidelines 2025: do not use routinely

›Anticonvulsants

›Indicated only for documented seizures

›Not used prophylactically

›Levetiracetam preferred: 500-1500 mg PO/IV BID

›Valproate: avoid with pyrimethamine (increased myelosuppression)

›Phenytoin: drug interactions with ART agents

›Duration: reassess after immune reconstitution

Monitoring during treatment

›CBC weekly during pyrimethamine therapy

›Monitor for leukopenia and thrombocytopenia

›Hold pyrimethamine for ANC <0.5 x 10^9/L or platelets <50 x 10^9/L

›Increase leucovorin dose for significant cytopenia

›Renal function and urinalysis

›Sulfadiazine crystalluria risk

›Ensure urine output >1.5 L/day

›Alkalinize urine if crystalluria detected

›Hold sulfadiazine if creatinine rising significantly

›LFTs at baseline and as clinically indicated

Chronic maintenance therapy (secondary prophylaxis)

›After completing 6-week induction

›Pyrimethamine 25-50 mg PO daily

›Plus sulfadiazine 2000-4000 mg PO daily in divided doses

›Plus leucovorin 10-25 mg PO daily

›Half-dose of acute regimen

›Continue until CD4 >200 cells/mm3 for >6 months on ART

›IDSA OI Guidelines 2025: Class I recommendation

›Restart if CD4 drops below 200 cells/mm3

›Alternative: pyrimethamine + clindamycin + leucovorin for sulfa-intolerant

ART initiation timing

›For ART-naive patients

›Start ART within 2-3 weeks of TE diagnosis

›Balance benefit of immune reconstitution vs IRIS risk

›IDSA OI Guidelines 2025 recommend deferring 2-3 weeks not longer

›Immune reconstitution inflammatory syndrome (IRIS)

›Can occur 1-4 weeks after ART initiation

›Paradoxical worsening of CNS lesions on imaging

›Treat with corticosteroids if severe IRIS

Primary prophylaxis

›TMP-SMX DS 1 tablet PO daily

›For Toxoplasma-seropositive HIV patients with CD4 <100 cells/mm3

›IDSA OI Guidelines 2025: Class I recommendation

›Also provides PCP prophylaxis

›Alternative if sulfa-intolerant

›Dapsone 50 mg PO daily + pyrimethamine 50 mg PO weekly + leucovorin 25 mg PO weekly

›Aerosolized pentamidine does NOT protect against TE

09Special Populations/sp62

Pregnancy

›Maternal considerations

›Pregnancy increases risk of primary Toxoplasma transmission to fetus

›Vertical transmission rate increases with gestational age (10% T1 to 60% T3)

›Severity of fetal disease inversely proportional to gestational age

›Pyrimethamine is teratogenic

›Avoid in first trimester (folate antagonist effect on organogenesis)

›Leucovorin supplementation essential if used after T1

›First-line regimen for maternal TE in T2 and T3

›Pyrimethamine + sulfadiazine + leucovorin with close monitoring

›TMP-SMX acceptable alternative after first trimester

›Spiramycin used for fetal prophylaxis (not treatment of maternal CNS disease)

›3g PO daily in divided doses if seroconversion detected

›Does not cross blood-brain barrier; insufficient for TE treatment

›Fetal and neonatal considerations

›Congenital toxoplasmosis manifestations

›Chorioretinitis (most common; 75-90% of untreated cases)

›Hydrocephalus and intracranial calcifications

›Hepatosplenomegaly

›Fetal monitoring

›Serial ultrasound for intracranial abnormalities

›Amniocentesis for fetal PCR if maternal seroconversion documented

›Neonatal treatment

›Pyrimethamine + sulfadiazine + leucovorin for 12 months

Geriatric

›Age-related considerations

›HIV-positive older adults

›Age >45 years associated with worse prognosis for TE

10Background/b74

Epidemiology

›Global burden

›Toxoplasma gondii infects approximately one-third of the global population

›Seroprevalence varies widely: 10-80% depending on geography

›France, Latin America, sub-Saharan Africa: highest seroprevalence (40-80%)

›North America and Northern Europe: lower seroprevalence (10-40%)

›TE in HIV/AIDS

›Most common CNS opportunistic infection in HIV/AIDS globally

›Occurs in 10-40% of Toxoplasma-seropositive HIV patients without prophylaxis

›Typically occurs at CD4 <100 cells/mm3 (greatest risk <50)

›Incidence has declined markedly with combination ART and TMP-SMX prophylaxis

›Mortality

›1-year mortality remains 20-60% despite cART (Lancet Neurology 2012)

›Poor prognostic factors

›CD4 <50 cells/mm3 at diagnosis

›Prior AIDS-defining illness

›Age >45 years

›Encephalopathy at presentation

›Non-HIV populations

›Allogeneic HSCT: median onset ~62 days post-transplant

›Solid organ transplant: donor/recipient serostatus mismatch highest risk

›Hematologic malignancies: case fatality rate >50%

Pathophysiology

›Life cycle and infection mechanism

›Toxoplasma gondii: obligate intracellular parasite

›Definitive host: felids (domestic and wild cats)

›Intermediate hosts: warm-blooded animals including humans

›Three infectious forms: oocysts (cat feces), tissue cysts (undercooked meat), tachyzoites (acute infection/dissemination)

›Human acquisition

›Ingestion of oocysts from contaminated soil, water, unwashed produce

›Ingestion of tissue cysts in undercooked or raw meat

›Vertical transmission (transplacental)

›Rarely: blood transfusion, organ transplantation

›Latency and reactivation

›Primary infection: tachyzoites disseminate hematogenously

›Immune pressure converts tachyzoites to bradyzoites within tissue cysts

›Cysts persist for life, predominantly in CNS and skeletal muscle

›Immunosuppression (CD4 <100) allows bradyzoite reactivation to tachyzoites

›Tachyzoites cross the blood-brain barrier causing focal necrotizing encephalitis

›Neuropathology

›Focal necrotizing encephalitis

›Central necrotic core surrounded by inflammatory infiltrate

›Predilection for basal ganglia, thalamus, grey-white junction

›Vasogenic edema from disruption of blood-brain barrier

›Concentric target sign

›Pathologic correlate: alternating zones of necrosis, inflammation, hemorrhage, and gliosis

›Central zone: coagulative necrosis with free tachyzoites

›Intermediate zone: organizing inflammation and macrophages

›Peripheral zone: reactive astrogliosis

Therapeutic Considerations

›Mechanism of drug action

›Pyrimethamine

›Inhibits dihydrofolate reductase (DHFR) blocking folate synthesis in parasite

›Active against tachyzoites only; not bradyzoites (cysts persist)

›Dose-dependent myelosuppression via host DHFR inhibition

›Leucovorin (reduced folate) bypasses blockade in host cells but not parasite

›Sulfadiazine

›Inhibits dihydropteroate synthase: synergistic with pyrimethamine

›Sequential folate pathway blockade with pyrimethamine

›TMP-SMX

›Same dual pathway blockade mechanism

›TMP (DHFR inhibitor) + SMX (dihydropteroate synthase inhibitor)

›Clindamycin

›Inhibits protein synthesis in apicoplast of Toxoplasma

›Active against tachyzoites; used as sulfadiazine substitute

›Atovaquone

›Inhibits mitochondrial electron transport chain

›Active against both tachyzoites and bradyzoites in vitro

›Evidence base

›Randomized controlled trial evidence limited

›Pyrimethamine + sulfadiazine established as standard of care by NEJM 1992 (Porter and Sande)

›Clinical response to therapy used as diagnostic and therapeutic standard

›IDSA OI Guidelines 2025 provide Class I recommendations for preferred regimen

›Duration and de-escalation

›Minimum 6-week induction phase established by clinical studies

›Maintenance therapy until CD4 >200 cells/mm3 for >6 months on ART

›Discontinuation safe once immune reconstitution achieved

11Patient Discharge Instructions/pdi35

copy discharge instructions

›Diagnosis and medications

›You have been treated for toxoplasmic encephalitis, a brain infection caused by the parasite Toxoplasma gondii

›This infection occurred because your immune system is weakened (HIV/AIDS or other immunosuppression)

›You must take your medications exactly as prescribed for at least 6 weeks to treat the active infection

›Your medications may include pyrimethamine, sulfadiazine, and leucovorin

›Leucovorin (folinic acid) must be taken to protect your blood cells - do not skip it

›If you take atovaquone, take it with a fatty meal to ensure it works properly

›Continue your HIV medications (ART) without interruption

›ART adherence is critical to prevent recurrence of this infection

›Return to the emergency department immediately if you experience

›Worsening headache, new weakness, numbness, or difficulty speaking

›These may indicate the infection is not responding to treatment

›Seek care within hours, not days

›Seizure or loss of consciousness

›New or worsening vision changes

›Fever that is not improving after 1 week of treatment

›No improvement in your symptoms after 7-10 days of treatment

›Requires urgent reassessment and possible repeat brain imaging

›Signs of medication side effects

›Rash, mouth sores, or easy bruising/bleeding (myelosuppression from pyrimethamine)

›Decreased urine output or blood in urine (crystalluria from sulfadiazine)

›Follow-up appointments

›Infectious disease follow-up within 1-2 weeks of discharge

›Weekly blood tests (CBC) required while on pyrimethamine

›Repeat brain MRI at 6 weeks to confirm treatment response

›HIV care provider for ART optimization and CD4 monitoring

›Prevention instructions

12References/r28

Guidelines and key sources

›IDSA/OI Guidelines 2025 (primary reference)

›Benson C, Brooks J, Dhanireddy S, et al. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. IDSA; Office of AIDS Research Advisory Council. 2025

›https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-oi/guidelines-adult-adolescent-oi.pdf

›Class I recommendations for pyrimethamine + sulfadiazine + leucovorin as preferred regimen

›Kapogiannis BG, Yates F, Li W, et al. Guidelines for the Prevention and Treatment of Opportunistic Infections in Children With and Exposed to HIV. OARAC. 2025

›https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/pediatric-oi/guidelines-pediatric-oi.pdf

›Key review articles

›Tan IL, Smith BR, von Geldern G, Mateen FJ, McArthur JC. HIV-associated Opportunistic Infections of the CNS. Lancet Neurol. 2012

›https://pubmed.ncbi.nlm.nih.gov/22710754

›1-year mortality 20-60% despite cART; prognostic factors defined

›Elsheikha HM, Marra CM, Zhu XQ. Epidemiology, Pathophysiology, Diagnosis, and Management of Cerebral Toxoplasmosis. Clin Microbiol Rev. 2021

›https://pubmed.ncbi.nlm.nih.gov/33239310

›Comprehensive review including global epidemiology and pathophysiology

›Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004

›https://pubmed.ncbi.nlm.nih.gov/15194258

›Landmark trials and original studies

›Porter SB, Sande MA. Toxoplasmosis of the Central Nervous System in the Acquired Immunodeficiency Syndrome. N Engl J Med. 1992

›https://www.nejm.org/doi/full/10.1056/NEJM199212033272306

›74% clinical improvement by 7 days, 91% by 14 days with pyrimethamine + sulfadiazine

›Li J, Xue M, Lv Z, et al. Differentiation of AIDS-Related PCNSL from Cerebral Toxoplasmosis with SWI and Contrast-Enhanced 3D-T1WI. Int J Infect Dis. 2021

›https://pubmed.ncbi.nlm.nih.gov/34670145

›Mahadevan A, Ramalingaiah AH, Parthasarathy S, et al. Neuropathological Correlate of the Concentric Target Sign in MRI of HIV-associated Cerebral Toxoplasmosis. J Magn Reson Imaging. 2013

›https://pubmed.ncbi.nlm.nih.gov/23440973

›Transplant and non-HIV immunosuppressed guidelines

›Aerts R, Mehra V, Groll AH, et al. Guidelines for the Management of Toxoplasma Gondii Infection in Haematological Malignancies and After HSCT. Lancet Infect Dis. 2024

›https://pubmed.ncbi.nlm.nih.gov/38134949

›La Hoz RM, Morris MI, AST Infectious Diseases Community of Practice. Tissue and blood protozoa including toxoplasmosis in solid organ transplant recipients. Clin Transplant. 2019

Evidence & Review

Evidence & Review