Background:  Despite the introduction of HAART therapy, progressive multifocal leukoencephalopathy (PML) and not determined JC virus (JCV)-negative leukoencephalopathy (NDLE) remain frequent and untreatable diseases, whose progression is not predictable at the onset.

Methods:  HIV⁺ HAART-treated patients were subjected every 6 months to physical, neurological, magnetic resonance imaging (MRI) examinations, and lumbar puncture. Virological studies were carried out in cerebrospinal fluid (CSF) and, when possible, in brain stereotactic biopsy, to verify the presence of JCV and human herpesviruses; CSF HIV and JCV loads were determined by real-time polymerase chain reaction. Neurological assessment was evaluated using Scripps Neurological Rating Scale at baseline, after 6 months, and after 12 months. Statistical evaluations were done by Student’s t test and repeated 2-way analysis of variance.

Results: During 27 months, 170 eligible HIV⁺ subjects were examined and 27 (78% male, mean age 36) of these, with positive MRI and neurological symptoms, were enrolled in a prospective study of NDLE (12 subjects) and PML (15 subjects). A mean of 3 follow-up examinations per patient was performed. No virus was found in CSF of NDLE patients, both at the baseline and at follow-up. At follow-up, mean CD4⁺ cell count was higher in NDLE than in PML patients (310/mL vs 180/mL, p <0.005), whereas mean CSF HIV load was higher in PML than in NDLE patients (3.24 log copies/mL vs 2.74 log copies/mL, p <0.05). Mean Scripps Neurological Rating Scale score was significantly higher (p <0.0001, test for interaction) in NDLE (baseline 80±22.3, 6-month follow-up 87±22.9, 12-month follow-up 83.5±25.3) than in PML patients (baseline 55±12.4, 6-month follow-up 45±15.2, 12-month follow-up 45±11.4). During the follow-up, stereotactic brain biopsies collected from 2 NDLE patients revealed the presence of JCV DNA and, only after 7 months was JCV DNA also found in the CSF of both patients. Among PML patients, 8 had a poor clinical outcome and showed CSF JCV DNA levels significantly higher than 9 slow-progressing, characterized by good prognosis (5.73 log copies/mL vs 4.11 log copies/mL, p <0.005).

Conclusions:  CD4⁺ cells count, CSF HIV RNA levels, and Scripps Neurological Rating Scale scores significantly differ between NDLE and PML during the follow-up, being indicative of a better clinical outcome of NDLE than PML patients. Regarding PML, our findings suggest the brain as a possible site of latency for JCV and that in the classic form of PML, high CSF JCV viral load is predictive of poor survival.