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Cognitive dysfunction is a common presenting symptom in patients with HIV/AIDS. It is usually directly associated with HIV infection or due to opportunistic infection. Rapidly progressive dementia, however, is rarely observed in acute HIV infection or during immune reconstitution. Recently, a case of Creutzfeld-Jakob disease (CJD) has been reported in a patient with chronic HIV infection. The incidence of CJD is not known to be increased among immunocompromised patients.We here report the case of a 59-year-old male patient with a recent diagnosis of HIV/AIDS and Pneumocystis jiroveci pneumonia presenting with secondary behavioral changes and disorientation. Over the course of several weeks, progressive dementia developed characterized by apraxia, gait ataxia, and mutism.After the exclusion of common HIV-associated neurologic conditions, the clinical course as well as findings on electroencephalogram (EEG), magnetic resonance imaging (MRI), and a positive 14-3-3 assay converged into a probable diagnosis of CJD. The diagnosis was later confirmed histopathologically.Palliative care was provided, and the patient passed away within 2 months of symptom onset.HIV/AIDS is an important stratifying condition during the work-up of many clinical syndromes including encephalopathy but may prematurely exclude important differential diagnoses. Non-opportunistic etiologies have to be considered as part of a secondary workup as this case of concomitant AIDS and CJD demonstrates. Rapidly progressive dementia should be distinguished from delirium as early as possible in order to be able to choose the correct diagnostic pathway. Despite the common occurrence of neurologic syndromes in the setting of immunodeficiency, an analytical diagnostic approach is advisable to minimize diagnostic bias.