OBJECTIVES:Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the CNS caused by reactivation of the JC polyomavirus (JCV), typically in immunocompromised individuals. As no specific therapy against JCV exists, current management focuses on immune reconstitution. Recently, a potential therapeutic effect of tenofovir was reported. METHODS:We report 2 patients with PML who received tenofovir under a compassionate use protocol. Treatment was accompanied by MRI, clinical, and virologic monitoring. RESULTS:In both patients (serum and CSF), viral load was markedly reduced. In 1 patient, this was accompanied by temporary clinical stabilization and reduction in MRI lesion burden. The other patient further declined clinically, accompanied by progression of MRI lesion size and contrast enhancement. Dense lymphocytic infiltration on biopsy suggested predominant effects of alleviated immunosuppression rather than the direct antiviral drug effect. Both patients ultimately died of the disease. DISCUSSION:Despite virus reduction in both cases, sustained clinical improvement was not achieved. This suggests that viral load reduction alone is insufficient, and pathogenesis may be largely driven by the immune response to the infection. A combination of tenofovir with low-dose anti-inflammatory drugs may be a useful addition to PML therapy.
BACKGROUND AND OBJECTIVES:Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a potentially reversible inflammatory syndrome for which corticosteroid administration constitutes the cornerstone of management. However, evidence that early steroid treatment improves clinical and radiologic outcomes remains limited. This study aimed to determine whether early steroid initiation is associated with improved clinical and radiologic outcomes compared with delayed treatment in CAA-ri and to further investigate 12-month all-cause mortality and CAA-ri recurrence. METHODS:This retrospective cohort study included patients admitted up to May 31, 2025, from 3 Italian academic referral centers, with a maximum follow-up of 12 months. Eligible patients had probable CAA-ri per diagnostic criteria, comparable baseline, and follow-up MRI studies and underwent modified Rankin Scale (mRS) evaluations within 12 months. Early steroid therapy was defined as initiation within 6 weeks of CAA-ri symptom onset. Patients were compared with those who initiated steroids beyond 6 weeks. The primary outcomes were functional status and vasogenic edema severity at follow-up, assessed with the mRS and the 3-point Amyloid-related Imaging Abnormalities-Edema scale, respectively; secondary outcomes were 12-month all-cause mortality and CAA-ri recurrence. Inverse-probability weighting from a propensity-score model was used. Primary outcomes were analyzed with weighted ordinal logistic regression, and secondary outcomes with weighted Cox proportional hazards models with robust variance. RESULTS:Of 70 screened patients, 48 were eligible. Of them, 30 received early steroids (mean age, 71.3 ± 7.8 years; 50% women) and 18 were treated late (mean age, 68.6 ± 9 years; 38.9% women). Early steroid treatment was associated with greater functional status at follow-up (odds ratio [OR], 0.14; 95% CI 0.03-0.58; p = 0.007) and reduced vasogenic edema (OR, 0.13; 95% CI 0.04-0.45; p = 0.001). No differences were found for 12-month recurrence (hazard ratio [HR], 1.25; 95% CI 0.31-5.07). Regarding mortality, a higher risk was suggested in the ES group (HR, 4.10; 95% CI 1.10-15.32), although not supported by complementary survival analyses. DISCUSSION:Early steroid therapy was associated with more favorable functional and radiologic outcomes. Findings on mortality and recurrence were inconclusive, reflecting limited statistical power. These results suggest an association between early steroid initiation and short-term outcomes, while longer-term trajectories warrant further investigation.
OBJECTIVES:To describe clinical outcomes following daratumumab therapy in severe anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, including a literature review. METHODS:We report 2 patients with severe anti-NMDAR encephalitis treated with anti-CD38 daratumumab after failure of multiple immunotherapies. Clinical data, treatments, and outcomes were analyzed retrospectively. A PubMed literature review identified 4 additional cases. RESULTS:Both patients (21 and 19 years) presented with severe anti-NMDAR encephalitis characterized by neuropsychiatric symptoms, seizures, abnormal movements, and dysautonomia. Modified Rankin Scale (mRS) reached rapidly 5 in both cases and required ICU transfer within the first 2 weeks of hospitalization. Despite high-dose methylprednisolone, IV immunoglobulin, plasma exchange, rituximab, and cyclophosphamide, neither patient showed improvement. Daratumumab (1800 mg s/c) was initiated 40 and 14 weeks after onset, respectively. Clinical improvement occurred within weeks after treatment initiation, with gradual recovery of cognitive and functional abilities and ultimately regained functional independence (mRS 0). Literature review identified 4 additional cases of anti-NMDAR encephalitis treated with daratumumab; most patients showed substantial neurologic improvement. DISCUSSION:These observations suggest that specific plasma cell-targeted therapy may be beneficial in severe anti-NMDAR encephalitis, potentially through reduction of pathogenic autoantibody production. However, current evidence is limited to uncontrolled reports, and further studies are needed to clarify optimal timing, efficacy, and safety.
BACKGROUND AND OBJECTIVES:It is currently difficult to accurately predict who, after the index event of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), will develop relapsing disease (R-MOGAD). Several clinical features have been reported as possibly predictive, but none have been validated in clinical practice. We used a prospectively designed analysis to assess a combined model of reported clinical prognosticators for developing R-MOGAD in 101 patients with MOGAD (86% with onset in adulthood) from 3 UK specialist centers. METHODS:A multivariable binary logistic regression model using variables identified from a scoping literature review was fitted in a retrospective clinical data set of patients with MOGAD (Nottingham MS & Neuroinflammation Centre [NUH]), with validation analysis in 2 independent data sets (Walton NMOSD Specialist Centre [WSC]; Imperial College London [ICL]). Secondary analysis investigated time to first relapse using Cox proportional hazards on the combined cohort. Results from the significant variables from the initial analysis were further examined in a meta-analysis of relevant literature studies. RESULTS:In the Neuroinflammation - Nottingham University Hospitals NHS Trust data set (n = 33), treatment with steroids ≥10 mg for ≥ 3 months after the index event was significantly associated with a lower likelihood of developing R-MOGAD (p = 0.006) with sensitivity 83% (95% CI 59-96) and specificity 73% (95% CI 45-92). A persistently positive MOG-IgG status, age at onset, optic neuritis at onset, and sex were not significant predictors of developing R-MOGAD. To assess generalizability, this predictor was tested in 2 independent data sets. In Walton Centre Liverpool (n = 39), not receiving prednisolone ≥10 mg ≥ 3 months was associated with R-MOGAD (OR = 9.7; 95% CI 2.1-45.4; sensitivity 63%; 95% CI 38-84; specificity 85%; 95% CI 62-97). In ICL (n = 29), the association was directionally consistent but inconclusive, with wide confidence intervals crossing unity (OR = 2.7; 95% CI 0.5-13.4; sensitivity 73%; 95% CI 39-94; specificity 50%; 95% CI 26-74). For the combined cohort (n = 101), not receiving prednisolone ≥ 10 mg for ≥3 months was associated with increased odds of developing R-MOGAD (OR = 6.2; 95% CI 2.6-14.8; p < 0.0001). Conversely, prednisolone ≥10 mg ≥ 3 months was associated with a lower hazard of relapse (HR = 0.47; 95% CI 0.24-0.91; p = 0.024). Median follow-up for monophasic patients was 42 months (IQR: 17.5-64.5). DISCUSSION:Prednisolone ≥10 mg for ≥ 3 months after the index event was associated with a lower likelihood of relapsing MOGAD. This association was supported in first external cohort and directionally consistent but inconclusive in a second, smaller cohort. Further prospective multicenter studies are required to assess the reproducibility and clinical utility of this association.
