Herbert B. Newton, MD, FAAN
DESCRIPTION
Central nervous system complications are frequent in patients with HIV infection and often manifest as enhancing or nonenhancing focal lesions of the brain. The most common focal brain lesions in HIV-infected patients are cerebral toxoplasmosis, primary CNS lymphoma (PCNSL), and progressive multifocal leukoencephalopathy (PML). If patients do not respond to an empiric trial of anti-toxoplasmosis therapy, surgical biopsy is required for a definitive histological diagnosis.
EPIDEMIOLOGY
Incidence/Prevalence
- Recent estimates suggest an overall incidence of intracranial mass lesions in roughly 10% of HIV-infected individuals. Cerebral toxoplasmosis occurs in approximately 5–12% of all AIDS patients. PCNSL is noted in 3–5% of all AIDS patients; incidence may be increasing. PML occurs in 2–4% of all AIDS patients. Incidence of focal brain lesions may be decreasing due to widespread use of highly active antiretroviral therapy (HAART). All races affected; most common in Caucasians and blacks. Any age affected; commonest between 20 and 40 years of age. Both sexes can be affected; most often diagnosed in males.
- Neuroimaging and autopsy studies demonstrate that cerebral toxoplasmosis accounts for 50–60% of all intracranial mass lesions, while another 20–30% are caused by PCNSL and 10–20% arise from PML.
RISK FACTORS
No specific risk factors have been identified other than diagnosis of HIV infection, low CD4 counts (i.e., less than 200/µL) and advanced stage of disease, and lack of antiretroviral therapy.
Genetics
Genetic factors have not been identified.
GENERAL PREVENTION
Other than the use of HAART therapy, no other preventive measures have been identified.
PATHOPHYSIOLOGY/ETIOLOGY
- Intracranial mass lesions usually develop in end-stage AIDS patients with CD4 counts below 200/µL. In rare patients, mass lesions can be the presenting manifestation of HIV infection. Cerebral toxoplasmosis is caused by reactivation of an endogenous infection by Toxoplasma gondii. Pathologically, the abscesses demonstrate regions of necrosis with mild inflammation and Toxoplasma cysts, endarteritis, lipid-laden macrophages, extracellular tachyzoites, and encysted bradyzoites.
- PCNSL develops from neoplastic lymphocytes (usually B cells). Epstein–Barr virus DNA is present in many of the tumors. Pathologically, the tumors show densely packed neoplastic lymphocytes with diffuse infiltration into surrounding brain, regions of necrosis, and a tendency to spread along perivascular spaces.
- PML is caused by reactivation of the JC papovavirus. Once reactivated, the JC virus infects oligodendrocytes, causing progressive demyelination. Histologically, swelling and degeneration of oligodendrocytes are noted, with minimal inflammation. Viral inclusion bodies may be present within infected cells.
- Less common causes of intracranial mass lesions include abscesses from other parasites (Cysticercosis), fungi (Cryptococcus neoformans), and bacteria (Mycobacterium tuberculosis); focal viral infections (e.g., cytomegalovirus, herpes simplex virus); gliomas; metastatic brain tumors (e.g., Kaposi's sarcoma, systemic lymphoma); and cerebrovascular disease.
HISTORY
- Cerebral toxoplasmosis is more acute than either PCNSL or PML; symptoms develop over several days. Initial symptoms are typically headache and confusion (>50% of patients). Other frequent symptoms include lethargy, low-grade fever, seizures, and focal neurological deficits (e.g., hemiparesis, dysphasia, ataxic gait, hemianopsia, sensory loss).
- With PCNSL symptoms evolve over a week to several weeks. Common symptoms are headache, confusion, lethargy, personality changes, seizures, and memory loss. Focal neurological signs and symptoms are frequent and similar to that noted above. Fever and other constitutional symptoms are generally absent.
- PML evolves over several weeks or more. Signs and symptoms of elevated intracranial pressure, fever, and constitutional symptoms are absent. Deterioration of memory and higher cognitive functions, focal signs.
- HIV dementia causes progressive impairment of short-term memory, cognition, concentration, and motivation. Associated motor abnormalities include unsteady gait, leg weakness, tremor, and incoordination.
- Less common causes of focal intracranial mass lesions present in a similar fashion.
PHYSICAL EXAM
Will be variable depending on the process involved and the region of brain affected, as outlined above.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
The most important tests consist of blood counts (including CD4 counts, to determine stage of HIV infection), toxoplasmosis serology, and serum antibody titers of other infectious agents.
Imaging
Initial Approach
- MRI, with contrast, is the most sensitive technique to evaluate for a focal intracranial mass lesion. Cerebral toxoplasmosis: Multiple ring-enhancing lesions, surrounding edema, in the gray matter of the diencephalon and cortex. PCNSL: Solitary or multifocal lesions, deep periventricular white matter, diffuse enhancement. Mild edema and/or mass effect may be noted. PML presents with patchy, nonenhancing, white-matter lesions that slowly enlarge and coalesce. HIV dementia may demonstrate atrophy or scattered, nonenhancing, white-matter lesions that usually spare the subcortical fibers. Focal viral encephalitis: Mass lesions with minimal enhancement.
- For patients without access to an MRI facility, cerebral CT is still an excellent alternative, especially with double-dose iodinated contrast.
- Consider thallium-201 single photon emission computed tomography (SPECT) or fluorodeoxyglucose positron emission tomography (PET). A positive result is suspicious for PCNSL.
Diagnostic Procedures/Other
Lumbar puncture is selected to differentiate the etiology of focal brain lesions and should include routine CSF studies, bacterial/fungal antigens, cytology, CSF bacterial/viral/fungal cultures, smear and culture for acid-fast bacilli, and Venereal Disease Research Laboratory test.
Pathological Findings
The pathological findings will vary depending on the specific focal process involved, as outlined above.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis is extensive and includes any non-HIV-related diseases that can present as a focal lesion within the brain.
MEDICATION
First Line
All patients should be evaluated for HAART, since this may prevent or reduce the risk of opportunistic infections and neoplastic complications. All other drug decisions have to be individualized to the neurological complications of each specific focal mass lesion.
ADDITIONAL TREATMENT
General Measures
Antiretroviral therapy should be maximized, if possible (i.e., HAART). Corticosteroids should be avoided unless brain herniation is suspected.
Additional Therapies
All patients, require an empiric trial of anti-toxoplasmosis therapy: Pyrimethamine (loading dose of 100–200 mg, then 25–50 mg/day), sulfadiazine (6–8 g/day in divided doses), and leucovorin (5–10 mg/day). Clinical and radiological improvement in 10–14 days confirms the diagnosis. PCNSL: Whole brain irradiation (4,000–5,000 cGy) and chemotherapy (e.g., methotrexate, temozolomide, or PCV [procarbazine, CCNU (Lomustine), vincristine]) are beneficial in selected patients with good performance status. Dexamethasone has cytotoxic effects against PCNSL and often reduces tumor size and edema. Although there are no proven beneficial therapies for PML, occasional patients may stabilize or improve with HAART or IV cytarabine therapy. HIV dementia may also stabilize or improve slightly on antiretroviral therapy (zidovudine or HAART).
SURGERY/OTHER PROCEDURES
All large lesions with mass effect and impending herniation require biopsy with decompression. Biopsy is also warranted for patients with positive SPECT or PET studies, those with a single lesion and negative toxoplasma serology, and all patients that have failed an empiric trial of anti-toxoplasmosis therapy. Biopsy is accurate for diagnosis in 85–90% of cases.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
Rx raised intracranial pressure, seizures, focal signs.
Admission Criteria
Patients are admitted for acute neurological changes related to the focal brain lesion, such as altered level of consciousness, confusion, seizure activity, headache, and focal neurological deficits. Rehab for persistent deficits.
Discharge Criteria
Variable
FOLLOW-UP RECOMMENDATIONS
Variable
Patient Monitoring
Follow-up of neurological status will be required, particularly for focal lesions that need long-term therapy and serial MRI scans (e.g., PCNSL, toxoplasmosis). Patients with cerebral toxoplasmosis require life-long maintenance therapy with pyrimethamine (25–50 mg/day) and sulfadiazine (2 g/day) to prevent relapses.
PATIENT EDUCATION
PROGNOSIS
The course and prognosis for HIV patients with focal intracranial mass lesions is poor. Survival may be improving for this group because of HAART. 6-month cumulative mortality rate for cerebral toxoplasmosis is 51%, although many patients do respond to treatment with improvement of neurological symptoms and MRI scans. PCNSL: median survival; PML: median survival.
COMPLICATIONS
The complications will vary depending on the specific process involved, but may result in permanent focal deficits.
