2026 AAN Neurology Updates: The Changing Face of Neuroinfectious Disease

The landscape of neuroinfectious diseases is shifting beneath our feet. As presented at the AAN Annual Meeting 2026 by Dr. Prashanth Ramachandran, we are witnessing the emergence of novel pathogens, a deeper understanding of genetic susceptibility in catastrophic viral outbreaks, and a complete reimagining of the standard protocols for steroids and fungal management. For the frontline neurologist, these updates represent a critical shift from “watchful waiting” to precise, biomarker-driven, and patient-centered intervention.

Neurology updates for 2026 highlight critical shifts in managing neuroinfectious diseases

• Pegivirus (PAEM): Human Pegivirus-1 (HPgV-1) is now recognized as a cause of progressive encephalomyelitis in chronically immunocompromised patients, often mimicking autoimmune conditions. MRI showing bilateral, symmetric involvement of optic and corticospinal tracts necessitates specific PCR or mNGS testing.
• Acute Necrotizing Encephalopathy (ANE): This influenza-related crisis is heavily tied to genetics, with 47% of cases carrying variants like RANBP2. Mandatory genetic testing and preventative vaccination are the primary clinical directives, given the rapid progression and high mortality.
• Steroid Nuance: The DexEnceph trial confirmed dexamethasone’s safety in HSV encephalitis, supporting empirical use alongside aciclovir. Timing is vital; a “DEX first” approach is recommended because delayed administration correlates with significant drops in verbal memory. In TBM, high-dose rifampin must be avoided as it negates steroid benefits.
• AMBITION-CM: For HIV-associated cryptococcal meningitis, a single high-dose liposomal amphotericin infusion followed by oral therapy is now the standard. This regimen reduces hospitalization from 19 to 7 days, significantly lowering toxicity and patient-directed discharge rates while maintaining efficacy.

1. The Rise of Pegivirus-Associated Encephalomyelitis (PAEM)

Why It Matters

For decades, Human Pegivirus (HPgV-1) was considered universally non-pathogenic, a “virus in search of a disease.” That has officially changed. New evidence from the Charité Berlin series (NEJM 2025) has identified HPgV-1 as a cause of progressive, devastating encephalomyelitis in the immunocompromised. This is not just a new entry in a textbook; it is a clinical mimic of autoimmune conditions that can lead to death or severe disability within two years if missed.

Who It Affects

This pathogen specifically targets the chronically immunosuppressed, with a high predilection for renal transplant recipients and patients with hematological malignancies. Much like the JC Virus adaptation leading to PML, HPgV-1 undergoes CNS-specific mutations in these patients, allowing for neuroinvasion and replication within astrocytes and microglia.

What Changes

Clinicians must now add HPgV-1 to their differential for progressive optic neuropathy and spastic paraparesis. The “MRI Signature”—bilateral, symmetric involvement of the optic tracts, corticospinal tracts, and brainstem pyramids—should prompt immediate specific PCR or metagenomic Next-Generation Sequencing (mNGS), as standard infectious panels will miss it.

2. Acute Necrotizing Encephalopathy (ANE): A Genetic Crisis

Why It Matters

The 2024-25 influenza season was the first “high-severity” designation since 2017, leading to a national CDC surveillance call for pediatric ANE. This is no longer viewed as a random complication of the flu. It is now seen as a life-threatening inflammatory surge with a GCS nadir of 6 and a high mortality rate.

Key Findings and Pathogenesis

The study highlights that IA-ANE accounts for roughly 9% of pediatric influenza deaths nationally. The disease involves a complex interaction between viral triggers, immunologic hyper-reactivity, and host genetic susceptibility.

• Genetic Susceptibility: Nearly half (47%) of the cases evaluated in recent cohorts carry relevant genetic variants, most notably in the RANBP2 gene, which is a known predictor of familial or recurrent ANE.
• Clinical Course: The progression is often catastrophic; in fatal cases, the median time from illness onset to death was just 3 days, primarily due to cerebral herniation.

Who It Affects

While often considered a pediatric disease (median age 5), it is increasingly recognized in adults. Crucially, it affects the “healthy” population: 55-76% of cases occur in previously healthy individuals. However, the true “who” is determined by genetics. In recent cohorts, 47% of patients carry relevant genetic variants, most notably in RANBP2, which predicts recurrence and dictates family management.

The Role of Prevention and Vaccination

A critical observation in this cohort was the low rate of vaccination. Only about 20% of the children affected by influenza-associated mortality had been fully vaccinated. The researchers emphasize that mass vaccination of school-aged children is associated with significantly reduced mortality from influenza-associated encephalopathy by decreasing community transmission.

What Changes

Genetic testing is now mandatory for all ANE cases. A positive result necessitates family counseling, a fever management plan, and mandatory vaccination for all household contacts. With only 16% of affected patients being vaccinated in recent outbreaks, the primary clinical directive remains clear: preventative vaccination is the only shield against this genetic vulnerability.

Management and Significance

Due to the high mortality and risk of severe disability, the study advocates for:

• Prompt Diagnosis: Intensive management is required immediately upon suspicion, including neuroprotective critical care.
• Immunotherapy: While controlled trials are still needed, current management often includes high-dose corticosteroids, plasmapheresis, tocilizumab, or intravenous immunoglobulin.
• Family Care: Identification of genetic variants like RANBP2 necessitates family counseling and specific fever management plans to prevent future episodes.

3. The Steroid Nuance: When to Pulse

Why It Matters

Steroids are the double-edged sword of neuroinfection. New Phase 3 RCT data (DexEnceph, 2026) have finally provided clarity on their role in HSV encephalitis and bacterial meningitis. In the past, clinicians were often hesitant to use steroids in Listeria or viral cases for fear of impairing clearance. We now know that the risk of withholding them often outweighs the risk of the infection itself.

The DexEnceph trial was a multicentre, phase 3, randomised controlled trial conducted in the UK to determine if adjunct dexamethasone improves outcomes in adults with herpes simplex virus (HSV) encephalitis. While aciclovir is the standard antiviral treatment, many survivors are left with significant neurocognitive disabilities, particularly impaired verbal memory due to the virus’s predilection for the temporal lobes.

Methodology and Findings

The study recruited 94 patients across 53 hospitals, randomly assigning them to receive either intravenous aciclovir alone or aciclovir plus 10 mg of dexamethasone four times daily for four days. The primary endpoint was the verbal memory score at 26 weeks, measured by the Wechsler Memory Scale-IV. The trial found no significant difference between the groups, with mean scores of 71 in the dexamethasone group and 69 in the control group. There were also no significant differences in secondary outcomes, including visual memory, brain swelling on imaging, or all-cause mortality.

Safety and Implications

Crucially, the study demonstrated that dexamethasone had a satisfactory safety profile. It did not lead to increased viral replication, as evidenced by similar rates of HSV detection in the CSF at 14 days between both groups. Post-hoc exploratory analysis suggested that earlier administration of the steroid might correlate with better outcomes, though the study was not designed to confirm this.

Conclusion

The researchers concluded that while adjunct dexamethasone does not routinely improve verbal memory in HSV encephalitis, its safety allows it to be administered empirically in suspected cases where the etiology could be HSV or autoimmune encephalitis. This prevents treatment delays for autoimmune patients while diagnostic results for HSV are pending.

Who It Affects

The data now support a full 4-day course for all community-acquired bacterial meningitis, regardless of the organism. This includes Listeria monocytogenes, where mortality is highest (32%), and the absence of dexamethasone is independently associated with worse outcomes. In HSV, while the primary memory benefit was not demonstrated, the safety was confirmed, and a significant “timing signal” was identified.

What Changes

For HSV, timing is everything. Post-hoc analysis showed that every one-day delay in starting dexamethasone correlated to a nearly 5-point drop in verbal memory. The protocol is now a “DEX first” approach: start dexamethasone with the first dose of antibiotics or acyclovir. In Tuberculous Meningitis (TBM), clinicians must avoid high-dose rifampin (35 mg/kg), as it induces CYP3A, accelerates steroid metabolism, and negates the life-saving anti-inflammatory benefit of the dexamethasone.

4. AMBITION-CM: Shifting to Outpatient-Friendly Regimens

Why It Matters

Cryptococcal Meningitis (CM) has traditionally required 14-19 days of hospitalization for amphotericin infusions, a burden that leads to high rates of patient-directed discharges. The AMBITION-CM regimen, a single high dose of liposomal amphotericin followed by oral therapy, has been proven equivalent in efficacy but significantly safer.

This pre-post cohort study, conducted at Los Angeles General Medical Center, evaluated the AMBITION protocol, a single high-dose infusion of liposomal amphotericin B followed by 14 days of oral fluconazole and flucytosine, for treating HIV-associated cryptococcal meningitis (CM) in a high-resource setting. Traditionally, CM treatment requires at least 14 days of daily intravenous amphotericin, a regimen linked to significant toxicity and prolonged hospitalization.

Methodology and Findings

The study compared 34 patients treated with the AMBITION protocol (2022–2024) against 26 patients who received standard daily lipid-based amphotericin (2020–2022).

• Primary Outcome: The AMBITION group achieved a significantly higher composite success rate (survival without recurrence or severe adverse events at 90 days) compared to the control group (76.0% vs 35.0%).
• Safety: This improved outcome was primarily driven by a marked reduction in severe adverse events (20.6% vs 61.5%), specifically fewer instances of metabolic abnormalities and cytopenia.
• Efficacy: There were no statistically significant differences in mortality or CM recurrence between the two groups at any assessed interval.

Who It Affects

Recent US-based data (2026) shows this regimen is highly effective in high-resource settings like Los Angeles General. It specifically helps patients who struggle with long hospital stays, reducing the “against medical advice” (AMA) discharge rate from 34.6% to 11.8%.

Patient-Centered Benefits

The AMBITION protocol facilitated more patient-centered care. Patients on this regimen had shorter median hospital stays (7 days vs 19 days) and significantly lower rates of patient-directed discharges against medical advice (11.8% vs 34.6%). Shorter stays improved the therapeutic alliance and allowed more patients to establish long-term care and complete consolidation therapy.

What Changes

The study concludes that the AMBITION protocol is a safe, effective, and less toxic alternative to daily amphotericin in high-resource settings, especially for patients with financial or social barriers to prolonged hospitalization.

The standard of care is shifting from a 19-day stay to a 7-day stay. This patient-centered approach results in fewer metabolic abnormalities and severe adverse events while improving the therapeutic alliance. Clinicians should now feel confident adopting the AMBITION regimen for HIV-associated CM, provided there is adequate social support and case management for the outpatient phase.

References

1. Ramachandran, P. Updates in Neuroinfectious Diseases. AAN Annual Meeting 2026.
2. Scheibe F, Melchert J, Radbruch H, et al. Pegivirus-Associated Encephalomyelitis in Immunosuppressed Patients. N Engl J Med. 2025;392(18):1864-1866. doi:10.1056/NEJMc2501512
3. Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group, Silverman A, Walsh R, et al. Influenza-Associated Acute Necrotizing Encephalopathy in US Children. JAMA. 2025;334(8):692-701. doi:10.1001/jama.2025.11534
4. Solomon T, Hooper C, Easton A, et al. Safety and efficacy of adjunct dexamethasone in adults with herpes simplex virus encephalitis in the UK (DexEnceph): a multicentre, observer-blind, randomised, phase 3, controlled trial. Lancet Neurol. 2026;25(2):136-146. doi:10.1016/S1474-4422(25)00454-5
5. Clark D, Barranco-Trabi J, Goo I, et al. Single-Dose Liposomal Amphotericin Plus Fluconazole and Flucytosine for Cryptococcal Meningitis at a US Public Hospital. JAMA Netw Open. 2026;9(1):e2553552. Published 2026 Jan 2. doi:10.1001/jamanetworkopen.2025.53552