The following summarizes some of the highlights from Day 1 of the American Academy of Neurology annual meeting (AAN), San Diego, CA, April 5-9, 2025.

Spinal cord lesion count not correlated with disability in SPMS
Effect of DMTs on EBV response
Frexalimab 96-week data
Worrisome side effect of CAR-T therapy
Managing pseudobulbar affect (PBA) in MS
Clinical tip of the day

CONGRESS HIGHLIGHTS – MONDAY EDITION

Spinal cord lesion count not correlated with disability in SPMS
A study in 137 SPMS patients with cervical spinal cord lesions found no correlation with lesion count and disability outcomes (Gratch et al. AAN 2025;P3.011). Motor testing included T25FW, 9HPT, and the 12-item MS Walking Scale (MSWS); the cognitive test used was the SDMT. The median spinal lesion count was 4. The median percentage of segments with lesions was 71%. While lesion count was not correlated with any disability measure, the percentage of segments with lesions was correlated with T25FW and the MSWS-12. In an analysis of individual segments, only lesions at C1-2 were significantly associated with worse motor outcomes. Spinal cord lesion burden was not correlated with SDMT.

Effect of DMTs on EBV response
A cross-sectional study in 60 RRMS patients found that treatment-naïve patients had a heightened CD4+ T cell response to EBV lytic antigens (Drosu et al. AAN 2025;P5.014). The CD4 response to lytic antigens was 10-fold greater than to latent antigens. Treatment with anti-CD20 agents significantly reduced the response to lytic antigens; response to latent antigens was unchanged. Other DMTs had a lesser effect on the EBV antigen response. The sole exception was natalizumab, which had no effect on response to lytic or latent antigens. The authors speculated that a reduction in the EBV-driven T cell response could reduce CD8+ targeting of myelin. They further suggested that the reduction in CD4+ T cell response to EBV lytic antigens may account for some of the therapeutic efficacy of DMTs, most notably anti-CD20 agents.

Frexalimab 96-week data
Frexalimab is an anti-CD40L MAb that blocks the CD40/CD40L pathway that is involved in regulating adaptive and innate immunity. A 12-week phase II study evaluated placebo vs. two frexalimab doses: 1200 mg IV q4 weeks after an 1800 mg loading dose; and 300 mg SC q2weeks after a 600 mg loading dose (Vermersch et al. N Engl J Med 2024;390:589-600). The mean number of Gd+ lesions at 12 weeks was 0.2 for the 1200-mg group, 0.3 for the 300-mg group and 1.4 with placebo. For the long-term extension, the placebo group was randomized to one of the active treatment groups; the dose was increased to 1800 mg q4weeks. Results at 18 months were presented at ECTRIMS (Giovannoni et al. ECTRIMS 2024;O066). (See NeuroSens, ECTRIMS 2024 HIGHLIGHTS – FRIDAY, SEPTEMBER 20, 2024.)

At week 96, the number of Gd+ lesions remained low in patients receiving IV frexalimab (0.1) and SC frexalimab (<0.4) (Vermersch et al. AAN 2025;S3.006). The annualized relapse rate in the IV group was 0.08. The most common adverse events were nasopharyngitis, headache, and COVID-19.

Worrisome side effect of CAR-T therapy
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 B cells has been used successfully in B cell malignancies, rheumatic diseases and myasthenia gravis. Safety concerns include a cytokine release syndrome, which occurred in 93% of patients in a trial of refractory large B cell lymphoma, as well as neurologic complications such as encephalopathy (21%) (Neelapu et al. N Engl J Med 2017;377:2531-2544). A new study examined serum NfL levels in patients on CAR-T therapy for B cell lymphoma who developed Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) (Vilaseca-Jolonch et al. AAN 2025;P1.001). Overall, 34% of patients developed ICANS. NfL levels were significantly higher at Day 7 in patients with >grade 2 ICANS (mean Z-score 2.19). The group proposed an NfL Z-score >2.144 to identify patients with more severe ICANS.

Managing pseudobulbar affect (PBA) in MS
A pooled analysis of two studies (n=476) examined the optimal dosing of dextromethorphan and quinidine (DM/Q) for the treatment of PBA (Tariq et al. AAN 2025;P1.005). One study involved MS patients, the other was a mixed population of MS and amyotrophic lateral sclerosis. The two DM/Q regimens with the greatest impact were 20/10 mg and 30/10 mg. A 30/30 mg regimen was associated with lower efficacy and a greater side-effect burden, notably nausea and fatigue.

Clinical tip of the day
Baseline sNfL levels are prognostic of new/enlarging T2 lesions in DMT-treated and -untreated patients alike. The prognostic value of higher vs. lower sNfL (cut point 9.3 pg/mL) was examined for patients enrolled in the ASCLEPIOS trials of ofatumumab (Bittner et al. AAN 2025;P5.009). The prognostic value was based on the last DMT prior to study entry. The annualized rate of new T2 lesions with higher vs. lower baseline sNfL was comparable in treatment-naïve (RR 2.16) and previously-treated patients (RR 2.25). The relative risk was higher in patients receiving natalizumab (RR 3.41) and DMF (RR 4.41).