HIV Associated CNS Lesions

This entry gives a systematic clinical and radiological approach to a focal or diffuse central nervous system lesion in a patient with HIV infection. Several opportunistic and malignant processes overlap in presentation but need fundamentally different management.

The main causes are:

• Toxoplasma encephalitis, the commonest cause of a focal, ring enhancing central nervous system lesion in advanced HIV infection.
• Primary central nervous system lymphoma, the principal and critical differential diagnosis.
• Progressive multifocal leukoencephalopathy.
• Cryptococcal disease, which can also produce focal cryptococcomas.
• Further causes, including central nervous system tuberculosis and other opportunistic infections.

Diagnostic framework and the toxoplasmosis-lymphoma distinction

• The degree of immunosuppression, best reflected by the current CD4 count, guides risk stratification and differential diagnosis. Central nervous system opportunistic infections and malignancy become more likely and more diverse as the CD4 count falls, particularly below 200 and further below 100 cells per microlitre.
• Toxoplasma encephalitis and primary central nervous system lymphoma are the two principal differential diagnoses for a focal, ring enhancing lesion in advanced HIV infection. They overlap substantially in clinical presentation and, to a meaningful degree, in standard structural imaging.
• Accurate distinction carries critical management implications. Toxoplasmosis needs targeted antimicrobial treatment. Lymphoma needs consideration of radiotherapy, chemotherapy and, critically, antiretroviral therapy optimisation.
• Steroids have a lymphotoxic effect and can confound a subsequent diagnostic biopsy in suspected lymphoma.
• Given this overlap, the standard approach is a time limited empirical trial of anti-toxoplasma treatment first. It applies where toxoplasma serology is positive and the clinical and imaging picture is compatible, because toxoplasmosis is far more prevalent in this context.
• Reassess clinically and radiologically after approximately one to two weeks of treatment. If the expected improvement is absent, reconsider the diagnosis and pursue brain biopsy to evaluate for lymphoma or an alternative diagnosis.
• This approach avoids routine upfront biopsy in every case. It balances diagnostic certainty against the morbidity and resource implications of universal biopsy at initial presentation.

• Shared presentation across the possible causes includes focal neurological deficit, seizures, headache and altered mental status, in variable combination according to lesion location and extent.
• Multiple or more extensive lesions may add features of raised intracranial pressure.
• Clinical presentation alone frequently cannot reliably distinguish between the possible diagnoses without the structured diagnostic approach.
• Toxoplasma encephalitis typically presents with multiple lesions, with a predilection for the basal ganglia and grey-white matter junction. It develops over days to a few weeks. Further clinical detail is given under that condition.
• Primary central nervous system lymphoma more typically, though not invariably, presents with a solitary lesion. Toxoplasmosis more typically produces multiple lesions, but this distinction is imperfect and cannot be relied upon in isolation.
• Lymphoma has a characteristic periventricular distribution, reflecting its origin from cells in this region.
• Lymphoma onset is generally more insidious and subacute. Toxoplasma encephalitis typically evolves somewhat more rapidly. This distinction is also imperfect and should not be used as a sole discriminator.
• The clinical features of progressive multifocal leukoencephalopathy and cryptococcal disease are addressed under those conditions.

• Magnetic resonance imaging with contrast is the essential initial investigation. It characterises the number, location, enhancement and other radiological features of the lesion or lesions.
• Magnetic resonance spectroscopy can help where structural imaging remains ambiguous. Lymphoma shows an elevated choline to creatine ratio and reduced N-acetylaspartate, reflecting increased cellular turnover. Toxoplasmosis more characteristically shows a lactate and lipid peak pattern, reflecting tissue necrosis.
• Perfusion imaging is also useful where available. Lymphoma typically shows increased relative cerebral blood volume, reflecting its hypervascular nature, in contrast to toxoplasmosis.
• Check toxoplasma serology in every case. A positive result supports toxoplasma encephalitis but does not confirm it, as high background seroprevalence reflects past exposure rather than necessarily current active disease. A negative result makes the diagnosis considerably less likely.
• Assess the current CD4 count and HIV viral load. Both inform risk stratification and the relative likelihood of the possible diagnoses.
• Cerebrospinal fluid analysis adds diagnostic information where lumbar puncture is safe. Exclude significant mass effect or midline shift on prior imaging first, because of the risk of precipitating herniation.
• Epstein-Barr virus polymerase chain reaction on cerebrospinal fluid is strongly associated with HIV associated primary central nervous system lymphoma. A positive result is valuable supportive evidence.
• Send cytology, and test for other opportunistic pathogens according to the clinical context.
• Brain biopsy gives definitive histological confirmation where the diagnosis remains genuinely uncertain despite non-invasive work-up. It is generally reserved for cases with no clinical and radiological improvement on the empirical trial, or where the picture from the outset strongly suggests an alternative diagnosis.

• Start empirical treatment for toxoplasma encephalitis where the clinical and radiological picture is compatible and toxoplasma serology is positive. Toxoplasmosis is far more prevalent in this context.
• The regimen is pyrimethamine, sulfadiazine and folinic acid (or a clindamycin based alternative), detailed in full under that condition elsewhere.
• Reassess clinically and radiologically after approximately one to two weeks of empirical treatment. Clear improvement supports continuing the established toxoplasma encephalitis course.
• If the expected improvement is absent, urgently reconsider the diagnosis and pursue brain biopsy to evaluate for lymphoma or an alternative cause.
• Manage confirmed primary central nervous system lymphoma with high dose methotrexate based systemic chemotherapy, where overall clinical status and renal function permit.
• Start or optimise antiretroviral therapy promptly in lymphoma. Effective immune reconstitution alone can produce meaningful, sometimes substantial, tumour regression. Profound immunosuppression itself often contributes to the pathogenesis and progression of this malignancy.
• Consider radiotherapy as an additional or alternative treatment according to clinical circumstances and response.
• Whatever the confirmed or presumed diagnosis, prompt initiation or optimisation of effective antiretroviral therapy is central to management. Underlying immunosuppression drives susceptibility to most conditions in this differential. Principles and timing are detailed under HIV associated conditions generally.
• Manage with close multidisciplinary input from infectious disease and neurology and, for the confirmed diagnosis where relevant, oncology and radiotherapy.
• Provide supportive care for associated seizures, raised intracranial pressure and other neurological complications.