Exploring the neurological impact of pandemics, from Spanish flu to COVID-19, and the science behind encephalitis complications
In the winter of 1916, a mysterious sleeping sickness began spreading across the world. Patients would fall into a deep slumber, some never to wake again, while others awakened decades later, frozen in their own bodies. This strange illness, known as encephalitis lethargica, would become one of the greatest medical mysteries of the 20th century, affecting approximately one million people during the Spanish flu pandemic and killing an estimated 500,000.
Nearly a century later, as COVID-19 swept across the globe, neurologists began noticing concerning patterns of brain inflammation appearing in patients, suggesting that history might be repeating itself.
Encephalitis, or inflammation of the brain, represents one of the most devastating neurological complications that can emerge during viral pandemics. While respiratory symptoms typically dominate pandemic landscapes, the neurological impact—particularly encephalitis—often leaves behind lasting damage that challenges healthcare systems long after the initial outbreak subsides.
Encephalitis lethargica had a mortality rate of about 40% during the Spanish flu pandemic, with many survivors developing post-encephalitic parkinsonism1 .
The 1918 influenza pandemic, often called the Spanish flu, infected an estimated 500 million people worldwide and killed between 20-50 million1 . But behind these staggering numbers lurked another mystery: between 1917 and 1920, approximately 1 million people developed a strange neurological condition characterized by extreme sleepiness that either progressed to coma or gradually receded1 .
First described by neurologist Constantin von Economo in 1917, encephalitis lethargica presented with a bizarre constellation of symptoms: high fever, sore throat, headache, lethargy, double vision, delayed responses, sleep inversion, catatonia, and abnormal eye movements called oculogyric crises.
A century later, as the COVID-19 pandemic emerged, neurologists immediately noted parallels with the past. SARS-CoV-2, the virus behind COVID-19, demonstrated neurotropic capabilities—the ability to invade nervous tissue and cause neurological complications4 .
A systematic review of COVID-19 patients published in 2022 identified 91 cases of encephalitis among COVID-19 patients. The most common neurological manifestations included seizures (29.5%), confusion (23.2%), headache (20.5%), disorientation (15.2%), and altered mental status (11.6%)4 .
Direct viral invasion of brain tissue causing inflammation and neurological symptoms.
The COVID-19 pandemic has provided compelling evidence for the autoimmune mechanism of pandemic-related encephalitis. Several studies have reported cases of anti-NMDA receptor encephalitis following COVID-19 infection4 8 . This specific form of autoimmune encephalitis occurs when antibodies attack NMDA receptors in the brain, leading to psychiatric symptoms, seizures, and movement disorders.
A 2025 study from China compared autoimmune encephalitis cases before and after COVID-19 infection rates surged following the adjustment of prevention strategies in December 2022. The research found that AE patients in the post-COVID-19 group had higher rates of abnormal movements (54.95% vs. 35.90%), autonomic dysfunction (41.76% vs. 20.51%), and more severe symptoms overall9 .
Bickerstaff brainstem encephalitis (BBE) has been reported after COVID-19 infection, developing CNS symptoms within a week of COVID-19 onset5 .
One of the most exciting recent developments in encephalitis research comes from a 2025 study published in Nature Communications that introduced ART5803, a humanized monovalent antibody designed specifically to treat anti-NMDAR encephalitis8 .
BALB/cAJcl mice were immunized with human GluN1-NTD recombinant protein to generate prototype antibodies.
Fluorescence-activated cell sorting (FACS) was used to isolate plasma/plasmablast cells specifically binding to human GluN1-NTD.
Using knobs-into-hole technology, the researchers created a monovalent antibody that would not cause receptor internalization.
The antibody was tested in competitive ELISA assays, cellular models, and ultimately in a marmoset animal model.
The results were impressive: ART5803 showed stronger affinity (KD = 6.92 × 10â»Â¹â°M) for the GluN1-NTD than pathogenic antibodies from patients (KD = 2.85 × 10â»â·M)8 .
In competitive ELISA assays, ART5803 effectively blocked the binding of pathogenic autoantibodies with an EC50 of 0.30 μg/mL, much more potent than the pathogenic antibody itself (EC50 = 6.2 μg/mL)8 .
Most importantly, in marmoset models that received intracerebroventricular administration of a human pathogenic autoantibody, ART5803 administration—either ICV infusion or peripheral injections—rapidly reversed behavioral and motor abnormalities8 .
| Antibody | KD Value | EC50 Value |
|---|---|---|
| ART5803 | 6.92 × 10â»Â¹â°M | 0.30 μg/mL |
| Pathogenic #003-102 Ab | 2.85 × 10â»â·M | 6.2 μg/mL |
| Outcome | Percentage of Patients |
|---|---|
| Discharged (fully recovered) | 28.9% |
| Discharged (improved) | 37.8% |
| Mortality | 20.0% |
ART5803 represents a specifically targeted treatment for anti-NMDAR encephalitis, unlike current broad immunosuppressive therapies.
The therapy was designed based on a clear understanding of the disease mechanism.
Unlike current immunotherapies that can take weeks to months to show effects, ART5803 demonstrated rapid reversal of symptoms.
Studying encephalitis in pandemic settings requires specialized reagents and tools. Here are some of the key research solutions mentioned in the search results:
| Reagent/Tool | Function | Example Use Cases |
|---|---|---|
| RT-PCR | Detects viral RNA in patient samples | Confirming SARS-CoV-2 infection in encephalitis patients4 |
| Cell-based assays (CBA) | Detects neural autoantibodies in serum and CSF | Diagnosing autoimmune encephalitis types9 |
| Magnetic Resonance Imaging (MRI) | Visualizes brain inflammation and damage | Identifying abnormal patterns in encephalitis patients (64.1% abnormal in COVID-19 cases)4 |
| Electroencephalogram (EEG) | Measures electrical activity in the brain | Detecting seizure activity in encephalitis (75.5% abnormal in COVID-19 cases)4 |
| Monoclonal antibodies | Target specific antigens for therapy | ART5803 for anti-NMDAR encephalitis8 |
| Intravenous Immunoglobulin (IVIG) | Modulates immune response | Treatment for autoimmune encephalitis5 9 |
Understanding how pandemic viruses cause encephalitis involves exploring several pathological mechanisms:
Some viruses, including certain influenza strains and coronaviruses, can directly invade the central nervous system through the olfactory nerve, compromised blood-brain barrier, or retrograde axonal transport5 .
This mechanism occurs when viral proteins share structural similarities with human brain proteins. The immune system creates antibodies to fight the virus, but these antibodies then mistakenly attack brain tissue5 .
Severe viral infections can trigger an overwhelming immune response called a cytokine storm. The resulting inflammation can compromise the blood-brain barrier, allowing immune cells to enter the brain.
Systemic infection can lead to oxygen deprivation, coagulation disorders, and metabolic disturbances that indirectly damage the brain. This might explain why many COVID-19 patients with encephalitis had severe respiratory symptoms4 .
The history of pandemic-associated encephalitis offers important lessons for future preparedness:
The WHO Technical Brief on encephalitis emphasizes the importance of global surveillance systems to detect and monitor encephalitis cases during pandemics3 .
Vaccination plays a dual role—protecting against the primary viral infection and potentially reducing neurological complications.
Research into targeted therapies like ART5803 for anti-NMDAR encephalitis represents a promising direction8 .
More research is needed to determine optimal combinations of interventions for preventing not just respiratory transmission but neurological complications as well1 .
The history of encephalitis in pandemics reveals a troubling pattern: viruses that initially appear as primarily respiratory threats often reveal significant neurological complications as pandemics evolve. From the encephalitis lethargica of the Spanish flu era to the diverse encephalitis manifestations of COVID-19, these neurological sequelae often leave lasting damage that challenges healthcare systems long after the initial outbreak subsides.
Modern research has made significant strides in understanding the mechanisms behind pandemic-related encephalitis. We've progressed from merely describing symptoms to understanding molecular mechanisms, developing targeted therapies, and identifying risk factors. The development of ART5803 as a potential treatment for anti-NMDAR encephalitis represents exactly the kind of innovative approach needed to address these neurological complications8 .
As we prepare for future pandemics, we must remember to look beyond respiratory symptoms and consider the potential impact on the brain. By investing in surveillance, developing targeted therapies, and understanding the mechanisms that drive viral-related neurological damage, we can hopefully mitigate this silent aspect of future pandemics.
The lesson from a century of pandemic neurology is clear: viruses that can steal our breath may also sometimes steal our selves, but with knowledge, preparation, and scientific innovation, we can fight back on all fronts.