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AUTHOR AND EDITOR INFORMATION

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Author: Niranjan N Singh, MD, DNB, Fellow in Neurophysiology, Department of Neurology, St Louis University School of Medicine

Niranjan N Singh is a member of the following medical societies: American Academy of Neurology

Coauthor(s): Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Associate Program Director, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University

Editors: William J Nowack, MD, Associate Professor, Department of Neurology, Epilepsy Center, University of Kansas Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author and Editor Disclosure

Synonyms and related keywords: acquired immunodeficiency syndrome, AIDS, intracellular parasite, Toxoplasma gondii, T gondii, CNS disease in AIDS, HIV infection, complication of HIV, complication of AIDS, advanced HIV infection

INTRODUCTION

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Background

Toxoplasmosis is the leading cause of focal CNS disease in AIDS. Usually, it is a complication of the late phase of the disease.

Typically, lesions are found in the brain and dominate the clinical presentation. Rarely, intraspinal lesions need to be considered in the differential diagnosis of myelopathy.

Pathophysiology

CNS toxoplasmosis results from infection by the intracellular parasite Toxoplasma gondii. It is usually due to reactivation of old CNS lesions or to hematogenous spread of a previously acquired infection.

Occasionally, it results from primary infection. CNS disease occurs during advanced HIV infection when CD4+ counts are less than 200 cells/µL.

Frequency

United States

Clinical CNS toxoplasmosis occurs in 3-10% of patients with AIDS in the US. Some clinically silent lesions come to diagnosis only at autopsy.

In 5% of patients, it is the presenting opportunistic infection of AIDS.

The incidence rate has decreased due to highly active antiretroviral therapy (HAART) and prophylactic treatment of Pneumocystis carinii infections.

International

Clinical CNS toxoplasmosis occurs in as many as 50% of patients in Europe and Africa.


CLINICAL

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History

The natural history of CNS toxoplasmosis includes the following:

  • Initially, constitutional symptoms and headache
  • Later, confusion and drowsiness, seizures, focal weakness, and language disturbance
  • Without treatment, progression to coma in days to weeks

Physical

  • Personality and mental status changes are noted.
  • Seizures, hemiparesis, hemianopia, aphasia, ataxia, and cranial nerve palsies may be observed.
  • Occasionally, symptoms and signs of a radiculomyelopathy predominate.


DIFFERENTIALS

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Cardioembolic Stroke
HIV-1 Associated Opportunistic Infections: Cytomegalovirus Encephalitis
HIV-1 Associated Opportunistic Infections: PML
HIV-1 Associated Opportunistic Neoplasms: CNS Lymphoma
HIV-1 Associated Vacuolar Myelopathy

Other Problems to be Considered

Tuberculous abscesses
Tuberculomas
Nocardial abscesses
Candidal abscesses
Syphilitic gummas

Progressive multifocal leukoencephalopathy (PML) can cause mental status changes and focal signs, but headache and seizures are unusual. PML lesions themselves cause no mass effect.


WORKUP

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Lab Studies

  • Serology
    • Rising serum immunoglobulin G (IgG) titers are observed.
    • An immunoglobulin M (IgM) antibody response is seen in cases of newly acquired toxoplasmosis or Toxoplasma encephalitis.
    • Serologic testing can be falsely negative or noncontributory if levels do not rise from a baseline.
    • Antibody levels may be very low, especially in AIDS patients.
    • In one study, 16% of patients with a clinical diagnosis and 22% of patients with a histologic diagnosis of toxoplasmosis had undetectable anti-T gondii IgG levels.
    • Causes of false-negative results include recent infection and insensitive assays.
  • Lumbar puncture may be contraindicated because of increased intracranial pressure. Cerebrospinal fluid (CSF) findings may include elevated protein and variable glucose and WBC counts. The presence of Epstein-Barr virus DNA in the CSF favors the diagnosis of lymphoma.
  • Identification of T gondii nucleic acids by polymerase chain reaction (PCR) may be helpful in the diagnosis.

Imaging Studies

  • CT scan or MRI
    • Single or multiple hypodense or hypointense lesions in white matter and basal ganglia with mass effects may be observed.
    • Lesions may enhance in a homogeneous or ring pattern with contrast.
    • Imaging studies may be normal in diffuse toxoplasmosis.
    • MRI is more sensitive than CT scan in detecting multiple lesions.
    • Single lesions favor the diagnosis of lymphoma over that of toxoplasmosis. However, while multiple lesions are more common than single lesions in toxoplasmosis, in one study 27% of patients had a single lesion on CT scan. In the same study, 14% had a single lesion on MRI.
    • Thallium Th 201 brain single-photon emission computed tomography (SPECT) may be useful in distinguishing between lymphoma and toxoplasmosis. Lymphoma shows an increased uptake compared with toxoplasmosis. False-positive and false-negative results may occur if the lesion is smaller than 2 cm.

Procedures

  • Indications for brain biopsy include the following:
    • Single mass lesion and negative serologic results
    • No response to 14 days of empiric therapy
  • Diagnostic yield of stereotactic biopsies increases with the number of specimens obtained.

Histologic Findings

  • Lymphocytic meningitis, individual cyst-containing lesions
  • Astroglial and microglial nodules
  • Associated lymphocytic vasculitis
  • Diffuse encephalitis


TREATMENT

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Medical Care

Algorithms have been developed for the evaluation and treatment of adult HIV-seropositive patients with neurological symptoms and signs.

  • A brain CT scan or MRI with and without contrast is indicated for all patients presenting with altered mental status, headaches, seizures, or focal neurological signs.
    • MRI clearly is the superior technique but is not available universally.
    • If the initial imaging study is normal or shows atrophy or focal signal abnormalities (but no mass lesion), diagnostic consideration should be given to meningitides, AIDS dementia complex, or progressive multifocal leukoencephalopathy.
    • If imaging shows 1 or more focal mass lesions with impending herniation, an open biopsy with decompression is indicated. Treatment for lymphoma, toxoplasmosis, or other opportunistic infections and neoplasms is initiated, depending on biopsy results.
    • If imaging shows 1 or more focal mass lesions without impending herniation, additional studies are warranted.
  • Where available, 201Th SPECT or 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) can provide high specificity, albeit at low sensitivity, strong evidence that a mass lesion represents a lymphoma; this can be confirmed by stereotactic biopsy.
  • When 201Th SPECT or 18FDG-PET cannot be conducted, toxoplasmosis serology in conjunction with imaging results will determine how to proceed.
    • In cases of a single mass lesion and negative serologic findings or lack of response after 14 days of empiric therapy, stereotactic brain biopsy is indicated.
    • In cases of multiple lesions, whether serologic results are negative or positive, antitoxoplasmosis therapy should be initiated.

Surgical Care

In cases of impending herniation, an open biopsy with decompression is indicated.


MEDICATION

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The decision to treat a patient for CNS toxoplasmosis is usually empiric; standard therapy consists of combination pyrimethamine, sulfadiazine, and folinic acid given as primary therapy for 6 weeks, followed by long-term suppressive therapy at reduced doses, with the duration determined by response to potent HAART. The long-term suppressive therapy can be discontinued in patients with persistent elevation of CD4+ counts of greater than 200 cells/µL and resolution of lesions on MRI. TMP-SMZ can be used as an alternative regimen. A recent Cochran data base review failed to find a significant difference between standard therapy and TMP-SMZ. Clindamycin can be used in patients allergic to sulpha drugs. Last but not least, effective antiretroviral therapy is equally important.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Antibiotic combinations usually are recommended to circumvent resistance from bacterial subpopulations (which may be resistant to 1 of the antibiotic components) and to provide additive or synergistic effect.

Drug NamePyrimethamine (Daraprim)
DescriptionFolic acid antagonist that selectively inhibits dihydrofolate reductase, highly selective against Plasmodium species and T gondii. Does not destroy gametocytes but arrests sporogony in mosquito.
Adult Dose100 mg PO bid on day 1, followed by 25-100 mg PO qd for at least 6 wk
Long-term suppressive therapy: Use lower dose of pyrimethamine (50 mg PO qd) plus sulfadiazine at 1 g PO qid
Pediatric Dose1 mg/kg PO bid for 2-4 d, followed by 0.5 mg/kg PO bid; not to exceed 25 mg qd
ContraindicationsDocumented hypersensitivity, megaloblastic anemia that results from folate deficiency
InteractionsAntifolic acids (eg, methotrexate, pyrimethamine) may increase risk of bone marrow suppression; lorazepam may cause mild hepatotoxicity
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsDepending on patient response, discontinue or reduce dose if signs of folate deficiency develop; use caution in patients with hepatic or renal impairment; monitor for toxoplasmosis by performing semiweekly blood counts, including platelet counts; may precipitate hemolytic anemia in patients with G-6-PD deficiency, generally in presence of other stressful events

Drug NameSulfadiazine (Microsulfon)
DescriptionThrough competitive antagonism of PABA, interferes with microbial growth. Useful for treating toxoplasmosis.
Adult Dose1-2 g PO qid for at least 6 wk
Long-term suppressive therapy: Use lower dose of pyrimethamine (50 mg PO qd) plus sulfadiazine at 1 g PO qid
Pediatric Dose75 mg/kg PO initial loading dose, followed by 150 mg/kg/d divided q4-6h; not to exceed 6 g/dose
ContraindicationsDocumented hypersensitivity
InteractionsIncreases effects of oral anticoagulants and oral hypoglycemic agents; effects decreased by PABA or PABA metabolites of drugs (eg, proparacaine, tetracaine, sunscreens, procaine)
PregnancyD - Unsafe in pregnancy
PrecautionsUse caution in patients with impaired renal or hepatic function or G-6-PD deficiency; adjust dose in patients with renal insufficiency

Drug NameClindamycin (Cleocin)
DescriptionInhibits bacterial protein synthesis by its action at bacterial ribosome. Antibiotic binds preferentially to 50S ribosomal subunit and affects process of peptide chain initiation. As alternative to sulfonamides, may be beneficial in combination with pyrimethamine in acute treatment of CNS toxoplasmosis in AIDS.
Adult Dose1200-4800 mg/d PO/IV/IM divided q6-8h
Pediatric Dose20-40 mg/kg/d IV/IM divided tid
ContraindicationsDocumented hypersensitivity, regional enteritis, hepatic impairment, ulcerative colitis, antibiotic-associated colitis
InteractionsIncreases duration of neuromuscular blockade induced by tubocurarine or pancuronium
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsMay be necessary to adjust dose in patients with severe hepatic dysfunction; no adjustment necessary in patients with renal insufficiency; has been associated with severe and possibly fatal colitis

Drug NameClarithromycin (Biaxin)
DescriptionReversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl tRNA from ribosomes.
Adult Dose2 g PO qd or divided bid
Pediatric Dose7.5 mg/kg PO bid
ContraindicationsDocumented hypersensitivity, concurrent pimozide, astemizole (recalled from US market), cisapride, or terfenadine (recalled from US market)
InteractionsFluconazole may increase levels significantly; pimozide may result in toxic levels and possibly death; rifabutin or rifampin may decrease antimicrobial effects or increase frequency of adverse GI effects; important to monitor anticoagulant function in patients receiving anticoagulants and any macrolide antibiotic; taking with astemizole may cause adverse cardiovascular effects (eg, death, cardiac arrest, torsades de pointes, other ventricular effects); taking with cisapride may cause serious cardiac arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT interval prolongation); may increase disopyramide plasma levels, causing arrhythmias and increasing QTc intervals; may increase plasma levels of certain benzodiazepines, prolonging CNS depressant effects
May increase carbamazepine concentrations; may increase serum digoxin concentrations as a result of effects on gut flora, which metabolize digoxin in more than 10% of patients; may cause acute ergot toxicity, characterized by severe peripheral vasospasm and dysesthesia (important to monitor patients who are receiving ergot alkaloids and any macrolide antibiotic); increases risk of severe myopathy or rhabdomyolysis associated with HMG CoA inhibitors; coadministration of omeprazole and clarithromycin may increase plasma levels of both drugs; may elevate serum tacrolimus levels, increasing risk of adverse effects such as nephrotoxicity
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsConcurrent ranitidine/bismuth citrate therapy not recommended in patients with CrCl <25 mL/min; may be administered without dosage adjustment to patients with hepatic impairment and normal renal function; in severe renal impairment (CrCl <30 mL/min) with or without coexisting hepatic impairment, dosage should be halved or dosing interval doubled; like nearly all antibacterial agents, may cause mild to severe pseudomembranous colitis— consider this diagnosis in patients who present with diarrhea after receiving antibacterial agents; antibiotic use, especially prolonged or repeated, may result in bacterial or fungal overgrowth of nonsusceptible organisms, possibly leading to a secondary infection (take appropriate measures if superinfection occurs)

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and may decrease intracranial pressure. They cause profound and varied metabolic effects and modify the body's immune response to diverse stimuli. They should be used only when warranted in cases of impending brain herniation. Their use may complicate the interpretation of a response to antitoxoplasmosis therapy.

Drug NameDexamethasone (Decadron, Dexone)
DescriptionUsed in treatment of various inflammatory diseases, decreases inflammation by suppressing migration of polymorphonuclear leukocytes, inhibiting proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma), and down-regulating recruitment of inflammatory cells.
Adult Dose16 mg/d PO/IV divided q6h starting dose; continue until patient improves; taper to cessation or minimum effective dose
Much higher doses (up to 100 mg/d divided) may be indicated in treatment of intraspinal lymphoma
Pediatric Dose0.15 mg/kg/d PO/IV divided q6h
ContraindicationsInfection, peptic ulcer disease, psychosis, hypertension
InteractionsBarbiturates, phenytoin, and rifampin can decrease effects; decreases effect of salicylates and vaccines used for immunization
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsWith impending herniation that is not amenable to decompression, treat patient carefully and watch for adverse sequelae; important to monitor for adrenal insufficiency when tapering drug; commonly elevates serum glucose and blood pressure; may inhibit normal immune response, contribute to formation of peptic ulcers, and cause myopathy and behavioral changes; because of risk of adverse effects, use cautiously in elderly, in smallest possible dose and for shortest possible time; adverse effects include infections, hyperglycemia, hypokalemia, osteoporosis, aseptic hip necrosis, headaches, anxiety, psychosis, insomnia, myalgia, steroid myopathy, cataracts, glaucoma, acne, hirsutism, facial plethora

Drug Category: Folic acid derivative

These agents are used to rescue cells from the deteriorating effects of folic acid antagonists.

Drug NameFolic acid (Wellcovorin, Folinic acid)
DescriptionReduced form of folic acid, does not require reduction reaction by enzyme for activation. Allows for purine and pyrimidine synthesis, which is needed for normal erythropoiesis. It prevents bone marrow suppression.
Adult Dose10-15 mg PO qd
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity, pernicious anemia, vitamin-deficient megaloblastic anemias, intrathecal or intraventricular administration
InteractionsNone reported
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsDo not administer intrathecally or intraventricularly


FOLLOW-UP

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Further Inpatient Care

  • Seventy-four percent of patients improve by day 7 of antibiotic therapy, and 91% improve by day 14.

Further Outpatient Care

  • Treatment is continued indefinitely unless the patient's CD4+ cell count rises to more than 200 cells/µL with HAART.
  • Imaging studies are performed every 4-6 weeks until complete resolution of the lesion or stabilization after partial resolution.

Deterrence/Prevention

  • Patients should avoid eating undercooked meat and should wash their hands carefully after contact with soil or cats.

Prognosis

  • Prognosis is guarded. Patients may relapse because of noncompliance or increasing dose requirements.


MISCELLANEOUS

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Medical/Legal Pitfalls

  • Delayed diagnosis and treatment may lead to death.


MULTIMEDIA

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Media file 1:  T1-weighted MRI after gadolinium contrast shows a hyperintense lesion in the left cerebellar hemisphere.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  MRI

Media file 2:  T2-weighted MRI of the same patient as in Image 1 demonstrates intense edema surrounding the lesion.
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Media type:  MRI

Media file 3:  Toxoplasma gondii abscesses are seen on this brain slice. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo

Media file 4:  High-magnification photomicrograph shows a tissue cyst and tachyzoites in the brain parenchyma. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo


REFERENCES

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  • AAN Quality Standards Subcommittee. Evaluation and management of intracranial mass lesions in AIDS. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Jan 1998;50(1):21-6. [Medline].
  • Behbahani R, Moshfeghi M, Baxter JD. Therapeutic approaches for AIDS-related toxoplasmosis. Ann Pharmacother. Jul-Aug 1995;29(7-8):760-8. [Medline].
  • Bertschy S, Opravil M, Cavassini M, et al. Discontinuation of maintenance therapy against toxoplasma encephalitis in AIDS patients with sustained response to anti-retroviral therapy. Clin Microbiol Infect. 2006;12(7):666-71. [Medline].
  • Dedicoat M, Livesley N. Management of toxoplasmic encephalitis in HIV-infected adults (with an emphasis on resource-poor settings). Cochrane Database Syst Rev. 2006;3:CD005420. [Medline].
  • Fung HB, Kirschenbaum HL. Treatment regimens for patients with toxoplasmic encephalitis. Clin Ther. Nov-Dec 1996;18(6):1037-56; discussion 1036. [Medline].
  • Klepser ME, Klepser TB. Drug treatment of HIV-related opportunistic infections. Drugs. Jan 1997;53(1):40-73. [Medline].
  • Marra MC. Infections of the central nervous sytem in patients infected with human immunodeficiency virus. Continuum. 2006;12:111-32.
  • Offiah CE, Turnbull IW. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients. Clinical Radiology. 2006;61:393-401. [Medline].
  • Verma A. Neurological manifestations of human immunodeficiency virus infection in adults. In: Neurology in Clinical Practice. Vol 2. 2004:1581-1601.
  • Walker M, Zunt JR. Parasitic central nervous system infections in immunocompromised hosts. Clin Infect Dis. Apr 1 2005;40(7):1005-15. [Medline].
  • de Gans J, Portegies P. Neurological complications of infection with human immunodeficiency virus type 1. A review of literature and 241 cases. Clin Neurol Neurosurg. 1989;91(3):199-219. [Medline].

HIV-1 Associated Opportunistic Infections: CNS Toxoplasmosis excerpt

Article Last Updated: Feb 23, 2007