Rapid-progressing progressive multifocal leukoencephalopathy in two patients newly diagnosed with HIV: case series and review of literature

The study addresses rapidly progressing progressive multifocal leukoencephalopathy (PML) in individuals newly diagnosed with HIV who present late in the AIDS stage. The context includes the global burden of HIV, with a high proportion of late presenters (CD4 <350 cells/μL or AIDS-defining event). Late presentation is associated with adverse outcomes, including increased risk of opportunistic infections such as PML caused by JC polyomavirus (JCPyV). PML pathogenesis involves JCPyV reactivation in immunocompromised states leading to demyelination and varied neurological deficits. Diagnostic pathways endorsed by the American Academy of Neurology include either histopathology with evidence of JCPyV or compatible clinical and radiological features plus JCPyV DNA in CSF. There is no specific antiviral treatment for PML; immune reconstitution (e.g., via ARV in HIV) is the mainstay, with investigational approaches such as PD-1 checkpoint inhibitors. Mortality in HIV-associated PML remains high (30% at 1 year, 50–60% at 2 years), though rare cases progress within weeks. The paper presents two such rapidly progressing HIV-associated PML cases to highlight clinical course and challenges.

Background literature outlines: (1) Late HIV presentation remains common globally and in Europe, linked to poorer outcomes and higher risk of opportunistic CNS infections; barriers to HIV testing include risk perception and stigma. (2) PML diagnosis relies on AAN criteria via histopathology or clinical/MRI features with JCPyV DNA in CSF. (3) Historically, HIV-associated PML had very poor survival (death within months pre-ARV; ~10% alive at 1 year). With ARV, median survival improved (e.g., from 0.4 to 1.8 years), and some long-term survivors exist. (4) Reports describe atypical courses: rapid fatal PML despite ARV, PML in immunocompetent hosts, and prolonged remission following ARV. (5) Experimental therapies include PD-1 inhibitors; mirtazapine has been used in isolated immunocompetent cases. (6) Higher JCPyV CSF load at diagnosis may predict worse prognosis, though findings are inconsistent.

Design: Descriptive case series of two adults newly diagnosed with HIV at AIDS stage who developed rapidly progressive PML. Setting: Department of Infectious and Tropical Diseases and Hepatology, with initial neurology evaluations. Case identification and diagnostics: Both patients presented with subacute neurological symptoms (dizziness, visual disturbances, limb weakness, ataxia, cranial nerve deficits). HIV infection was confirmed by screening tests followed by Western blot and plasma HIV-1 RNA viral load. Immunologic assessment included CD4, CD8 counts and CD4/CD8 ratio at baseline and follow-up. Neuroimaging included MRI brain (T2-weighted sequences; assessment of contrast enhancement; DWI), with SPECT MRI considered in one case. CSF analysis included PCR for JCPyV DNA; CSF cultures for bacteria, fungi, and Mycobacterium tuberculosis were performed. Differential diagnoses considered included CNS lymphoma and toxoplasmosis; serologies for Toxoplasma gondii and CMV were assessed. Therapeutics: Immediate antiretroviral therapy (Patient A: bictegravir/emtricitabine/tenofovir alafenamide; Patient B: tenofovir alafenamide/emtricitabine/darunavir/cobicistat). Adjunctive therapies included dexamethasone; mannitol (Patient A); anti-toxoplasmosis therapy (pyrimethamine/sulfadiazine) initiated then discontinued in Patient B upon exclusion; antiepileptics for seizures (sodium valproate, diazepam; Patient A); antibiotics for secondary infections (ceftriaxone then meropenem; Patient A); oxygen therapy; consideration of PEG feeding (inserted in Patient A; declined by Patient B); parenteral nutrition (Patient B). No brain biopsy was performed due to anticipated lack of benefit and patient condition. Outcomes were monitored clinically, via repeat MRI, and laboratory follow-up at ~4–6 weeks.

• Both patients were late presenters with AIDS and developed rapidly progressive PML confirmed by JCPyV DNA in CSF and compatible clinical/MRI findings.
• Patient A (27-year-old male): Initial symptoms included dizziness, left-sided ptosis, visual field loss, nystagmus, spastic paresis, positive Babinski on left. MRI: subcortical white matter swelling in right occipital, temporal, parietal lobes; later progression to both hemispheres and cerebellum without contrast enhancement. Baseline labs: CD4 7 cells/μL; CD8 238 cells/μL; CD4/CD8 0.03; HIV-1 VL 50,324 copies/mL; JCPyV in CSF 113,000,000 copies/mL. After 4 weeks: VL undetectable; CD4 6 cells/μL; CD8 154 cells/μL; CD4/CD8 0.04. Clinical course: Seizures, pneumonia with respiratory failure; blood cultures positive for Candida albicans and Acinetobacter baumannii; died ~11 weeks after neurological symptom onset.
• Patient B (38-year-old female): Initial symptoms included dizziness, blurred vision, diplopia, left-sided weakness; later dysphagia, headaches, nausea, vomiting, central left facial paresis, ataxia of right limbs. MRI: lesions in left cerebellar peduncle and left pons; no contrast enhancement; DWI hyperintensity; progression without hydrocephalus. Baseline labs: CD4 40 cells/μL; CD8 602 cells/μL; CD4/CD8 0.07; HIV-1 VL 78,334 copies/mL; JCPyV in CSF 396 copies/mL. After 6 weeks: VL 205 copies/mL; CD4 98 cells/μL; CD8 1,191 cells/μL; CD4/CD8 0.08. Clinical course: Worsening neurologic deficits, severe dysphagia, mucus retention causing dyspnea; oxygen therapy; decision for comfort care; died ~10 weeks after neurological symptom onset.
• Despite ARV initiation and viral load suppression (complete in Patient A; near-complete in Patient B), both patients deteriorated neurologically without meaningful immune restoration (no CD4 rise in Patient A; modest increase in Patient B).
• The markedly higher CSF JCPyV load in Patient A did not translate into a substantially different time to death compared with Patient B, questioning prognostic utility in these cases.

The cases illustrate that, even in the modern ARV era, HIV-associated PML can follow an accelerated, fatal course within weeks. Both patients presented late with profound immunosuppression (very low CD4 counts and low CD4/CD8 ratios), consistent with known risk factors for PML reactivation. Diagnosis adhered to AAN criteria using clinical/MRI features with CSF JCPyV PCR, avoiding invasive biopsy given limited benefit and poor condition. Despite prompt ARV initiation and declines in HIV viremia, neurological decline continued, emphasizing that viral suppression may not promptly restore protective CNS immunity. Patient A exhibited no CD4 recovery, raising the possibility of being an immunologic non-responder, a phenotype associated with worse outcomes. Comparison with literature underscores variability: survival has generally improved with ARV, and long-term survivors exist, yet rapidly fatal courses remain reported, including in non-HIV or immunocompetent hosts. The anticipated prognostic value of higher JCPyV CSF load was not supported here (very high vs. low copies with similar clinical timelines). These findings reinforce the importance of earlier HIV detection to prevent profound immunosuppression, and the need for therapies that directly target JCPyV or augment antiviral CNS immunity beyond ARV alone.

This case series documents two newly diagnosed HIV patients at the AIDS stage who developed rapidly progressive PML and died within approximately 10–11 weeks despite timely ARV and supportive care. The main contributions are highlighting the potential for fulminant progression in the ARV era, the limited predictive value of CSF JCPyV load in these cases, and the clinical challenge posed by inadequate immune reconstitution. Clinically, any new neurological symptoms should prompt immediate HIV testing and early MRI with CSF evaluation. Future research should focus on developing effective JCPyV-directed treatments and immunotherapeutic strategies (e.g., checkpoint inhibitors or other modalities) and on optimizing approaches for patients with incomplete immune reconstitution.

• Very small sample size (two cases) limits generalizability.
• No brain biopsy was performed; diagnoses relied on clinical/MRI features plus CSF JCPyV PCR (per AAN criteria), but histopathologic confirmation was not obtained.
• Limited longitudinal sampling: repeat CSF JCPyV quantification was not performed; follow-up immune parameters were short-term.
• Clinical management constraints (e.g., patient B's refusals, rapid deterioration) may have influenced outcomes.
• No autopsy data to further characterize neuropathology.