CNS Toxoplasmosis in HIV

CNS Toxoplasmosis in HIV

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Toxoplasmosis is the leading cause of focal central nervous system (CNS) disease in AIDS. CNS toxoplasmosis in HIV-infected patients is usually a complication of the late phase of the disease.

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

The decision to treat a patient for CNS toxoplasmosis is usually empiric. Primary therapy is followed by long-term suppressive therapy, which is continued until antiretroviral therapy can raise CD4+ counts above 200 cells/µL.

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

CNS toxoplasmosis results from infection by the intracellular parasite Toxoplasma gondii. It is almost always due to reactivation of old CNS lesions or to hematogenous spread of a previously acquired infection. [1] Occasionally, it results from primary infection.

CNS disease occurs during advanced HIV infection when CD4+ counts are less than 200 cells/µL. The greatest risk is in patients with CD4+ counts below 50 cells/µL. [1]

Clinical CNS toxoplasmosis occurs in 3-15% of patients with AIDS in the United States. Some clinically silent lesions come to diagnosis only at autopsy. Clinical CNS toxoplasmosis occurs in as many as 50-75% of patients in some European countries and in Africa.

The probability of developing reactivated toxoplasmosis is as high as 30% among AIDS patients with a CD4 count <100 cells/microL who are toxoplasma seropositive and are not receiving effective prophylaxis or antiretroviral therapy. The most common site of reactivation is the central nervous system (CNS). [2]

Recently in a epidemiologic study in Mexico city with 320 patients AIDS patients, the main conditions related to HIV/AIDS were brain toxoplasmosis (42%), cerebral cryptococcosis (28%), tuberculous meningitis (8.7%), lymphoma (non-Hodgkin) (3.75%), acute HIV infection (3.4%), and AIDS dementia complex (3%). [3]

The widespread use of antiretroviral treatment has decreased the incidence of toxoplasmic encephalitis. As an example, among HIV-infected patients in the United States, the annual number of toxoplasmosis-related hospitalizations peaked at more than 10,000 in 1995, dropped sharply to 3643 in 2001, and then decreased to 2985 in 2008. [4]

CNS toxoplasmosis begins with encephalitis and constitutional symptoms and headache. Fever is usually but not always present. Later, confusion and drowsiness, seizures, focal weakness, and language disturbance develop. Without treatment, patients progress to coma in days to weeks.

Extracerebral involvement can also be seen including but not limited to pneumonitis, chorioretinitis, etc. 

On physical examination, personality and mental status changes may be observed. Seizures, hemiparesis, hemianopia, aphasia, ataxia, and cranial nerve palsies may be evident. Occasionally, symptoms and signs of a radiculomyelopathy predominate.

The differential diagnosis of CNS toxoplasmosis includes the following:

CNS Lymphoma in HIV

Mycobacterial infection (eg, tuberculous abscess, tuberculoma)

Fungal infection (eg, cryptococcosis, candidiasis)

Chagas disease

Bacterial abscess (eg, Nocardia)

Neurosyphilis

Cardioembolic Stroke

Cytomegalovirus Encephalitis in HIV

Progressive Polyradiculopathy in HIV

Vacuolar Myelopathy in HIV

Progressive Multifocal Leukoencephalopathy

Like CNS toxoplasmosis, progressive multifocal leukoencephalopathy (PML) can cause mental status changes and focal signs. However, headache and seizures are unusual with PML, and PML lesions themselves cause no mass effect.

Serologic studies in patients with CNS toxoplasmosis may demonstrate rising titers of anti-toxoplasma immunoglobulin G (IgG) antibodies. An immunoglobulin M (IgM) antibody response is seen in cases of newly acquired toxoplasmosis or Toxoplasma encephalitis.

However, anti-Toxoplasmagondii IgG detection may be unreliable in immunodeficient individuals who fail to produce significant titers of specific antibodies. 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 also include recent infection and insensitive assays.

Definitive diagnosis of CNS toxoplasmosis requires the following [1] :

Compatible clinical findings

Identification of one or more mass lesions by CT, MRI, or other radiographic testing

Detection of T gondii in a clinical sample

Detection of T gondii DNA on polymerase chain reaction (PCR) testing of cerebrospinal fluid (CSF) samples may facilitate the diagnosis and follow-up of toxoplasmosis in patients with AIDS. [5] In a study using the B1 gene, rapid PCR showed a sensitivity of 83.3% and specificity of 95.7%. [6]

CSF findings may also include elevated protein and variable glucose and WBC counts. The presence of Epstein-Barr virus DNA in the CSF favors the diagnosis of lymphoma.

Lumbar puncture may be contraindicated because of increased intracranial pressure, however. For many clinicians, therefore, CNS toxoplasmosis is an empiric diagnosis that relies on clinical and radiographic improvement in response to specific anti-T gondii therapy. In patients who fail to respond to specific therapy, brain biopsy can be used to secure a clinical sample for testing. [1]

A brain CT scan or MRI with and without contrast is indicated for all patients presenting with altered mental status, headaches, seizures, or focal neurologic signs. MRI clearly is the superior technique but is not available universally.

Single or multiple hypodense or hypointense lesions in white matter and basal ganglia with mass effects may be observed on CT or MRI scans. Lesions may enhance in a homogeneous or ring pattern with contrast (see the images below). Imaging studies may be normal in diffuse toxoplasmosis.

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. MRI is more sensitive than CT scan in detecting multiple lesions.

Several MRI patterns have been described in cerebral toxoplasmosis. A concentric target sign is a recently described MRI sign on T2-weighted imaging of cerebral toxoplasmosis; it has concentric alternating zones of hypointensity and hyperintensity. [7]

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 one 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 one or more focal mass lesions without impending herniation, additional studies are warranted.

Magnetic resonance spectroscopy (MRS) was not found helpful in differentiating CNS lymphoma from nonmalignant CNS lesions in HIV-infected patients, particularly CNS toxoplasmosis. [8]

Indications for brain biopsy include either of 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 include the following (also see the images below):

Lymphocytic meningitis, individual cyst-containing lesions

Astroglial and microglial nodules

Associated lymphocytic vasculitis

Diffuse encephalitis

In patients in whom brain imaging shows multiple lesions, whether serologic results are negative or positive, antitoxoplasmosis therapy should be initiated. In cases of impending herniation, an open biopsy with decompression is indicated. Corticosteroid treatment may be warranted in cases of impending brain herniation. However, their use may complicate the interpretation of a response to antitoxoplasmosis therapy.

Recently in 100 patients treated with pyrimethamine-sulfadiazine, the use of adjunctive steroids to treat cerebral edema associated with focal lesions appeared safe but was not associated with better neurologic outcomes. [9]

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 one of the antibiotic components) and to provide additive or synergistic effect.

Standard therapy consists of pyrimethamine, sulfadiazine, and folinic acid in combination. Trimethoprim-sulfamethoxazole (TMP-SMZ) can be used as an alternative regimen. [10] A Cochrane database review found no significant differences between standard therapy and TMP-SMZ. Clindamycin can be used in patients allergic to sulfa drugs. Effective antiretroviral therapy is equally important. [11, 10, 12, 13]

Suggested dosing:

With antibiotic therapy, 74% of patients improve by day 7, and 91% improve by day 14. Imaging studies are performed every 4-6 weeks until complete resolution of the lesion or stabilization after partial resolution.

Primary therapy is given for 6 weeks, followed by long-term suppressive therapy at reduced doses, with the duration determined by response to highly active antiretroviral therapy (HAART). The long-term suppressive therapy can be discontinued in patients with persistent elevation of CD4+ counts greater than 200 cells/µL and resolution of lesions on MRI.

To prevent primary toxoplasmosis, patients should avoid eating undercooked meat and should wash their hands carefully after contact with soil or cats. Patients who are seropositive for Toxoplasma should be started on prophylaxis against CNS toxoplasmosis if their CD4+ count drops below 100 cells/μL. [1]

The preferred prophylactic regimen is one double-strength tablet of trimethoprim-sulfamethoxazole (TMP-SMZ) daily, which also provides prophylaxis against Pneumocystis jiroveci pneumonia (PCP). [1] An alternative regimen is one double-strength TMP-SMZ tablet 3 times weekly. The recommended alternative for patients who cannot tolerate TMP-SMZ is dapsone-pyrimethamine plus leucovorin, which is also effective against PCP.

 

 

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Gulshan Uppal, MD Private Practice at Freeman Hospital

Gulshan Uppal, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Florian P Thomas, MD, PhD, MA, MS Chair, Neuroscience Institute and Department of Neurology, Director, Multiple Sclerosis Center and Hereditary Neuropathy Centers, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine

Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary’s Stroke Program, SSM Neurosciences Institute, SSM Health

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society

Disclosure: Nothing to disclose.

CNS Toxoplasmosis in HIV

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