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Purpose of review Although rare, central nervous system (CNS) infections are increasingly being recognized in immunocompromised patients. The goal of the present review is to provide a practical diagnostic approach for the intensivist, and to briefly discuss some of the most prevalent conditions Recent findings Immunocompromised patients presenting with new neurological symptoms should always be suspected of a CNS infection. These infections carry a poor prognosis, especially if intracranial hypertension, severely altered mental status or seizures are present. Clinical examination and serum blood tests should be followed by brain imaging, and when no contra-indications are present, a lumbar puncture including cerebrospinal fluid PCR to identify causative organisms. Empirical therapy depends on the type of immunodeficiency. In HIV-infected patients, the most common CNS infection is cerebral toxoplasmosis, whereas in other immunocompromised patients, aspergillosis, cryptococcal meningitis and tuberculous meningitis are more prevalent. Multiple pathogens can be detected in up to 15% of patients. The diagnostic value of fast multiplex PCR has yet to be evaluated in this setting. Summary CNS infections represent a rare but severe complication in immunocompromised patients. A systematic approach including early diagnosis, appropriate antimicrobial treatment, early ICU admission and aggressive measures to reduce intracranial pressure may improve outcome.