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Neurological manifestations involving cognition, mood, sensory function, and motor systems persisted for years, despite partial improvement in a subset of adult survivors of Ebola.

Results from a long-term prospective cohort study from Liberia showed that Ebola survivors had significantly higher rates of headaches, memory impairment, depression, fatigue, sleep disturbance, and sexual dysfunction compared with close contacts. 

On structured neurological examination, survivors demonstrated more abnormalities than control individuals, with higher mean general neurological examination scores (3.7 vs 2.1) and central nervous system scores (2.2 vs 0.7), suggesting lasting effects on both the central and peripheral nervous systems.

The findings show that Ebola "should be recognized as a potentially neurotropic disease with long-lasting outcomes, highlighting critical need for therapeutic interventions protecting the nervous system," lead investigator Bridgette Jeanne Billioux, MD, staff clinician, National Institute of Neurological Disorders and Stroke, National Institutes of Health, in Bethesda, Maryland, and colleagues, wrote. 

They added that neurological care "should be a focus for clinicians seeing EVD [Ebola virus disease] survivors."

The study was published online on June 10 in JAMA Neurology.

Ebola's Neurological Impact

The long-term neurological consequences of Ebola remain incompletely defined. Earlier outbreak reports described acute neurological symptoms such as headache and altered mental status, while post-acute sequelae — including memory impairment, insomnia, and sensory disturbances — have varied across small cohorts.

Prior studies suggested that survivors may experience persistent cognitive and neuropsychiatric symptoms, but most lacked structured neurological examinations performed longitudinally by trained neurologists. 

The 2014 West African Ebola epidemic, which resulted in more than 28,000 Ebola cases and more than 11,000 deaths, raised concerns about long-term morbidity, along with uncertainty regarding the duration, course, and neurological manifestations of post-Ebola symptoms.

To assess what neurological symptoms occur in adult survivors of Ebola and how long these symptoms persist following infection, investigators conducted a prospective longitudinal cohort study within the Ebola Natural History Study (PREVAIL III) Neurology sub-study in Monrovia, Liberia, using standardized neurological assessments over more than 7 years in 148 Ebola antibody-positive survivors (mean age, 34.8 years; 50% female) and 81 antibody-negative close contacts (mean age, 35.8 years; 51% female).

Participants were enrolled and followed from September 2015 through March 2023, with data analysis conducted from April 2023 to September 2025.

Biannual neurological evaluations were performed by trained neurologists, including structured symptom questionnaires and standardized neurological examinations.

Neurological findings were summarized using two composite scores developed for the study: a general neurological examination (GNE) score (range, 0-83) and a central nervous system (CNS) score (range, 0-51). Higher scores reflected greater neurological abnormality. Sleep quality was assessed using the Neuro-QoL Sleep Disturbance scale.

Long-Term Neurological Course 

At baseline, survivors reported higher rates of neurological symptoms compared with control individuals, including headaches (66.2% vs 46.9%), memory loss (56.1% vs 17.3%), depressive symptoms (49.3% vs 16.0%), and trouble concentrating (43.2% vs 8.6%).

Neurological examination scores were also higher in survivors with average GNE scores of 3.7 vs 2.1 in control individuals, and CNS scores of 2.2 vs 0.7. This indicated a greater overall neurological burden across multiple domains early after infection.

At the final follow-up, memory loss remained more common in survivors (57.4% vs 26.2%), along with irritability (36.5% vs 14.8%) and trouble concentrating (29.6% vs 9.8%). Other symptoms such as headaches, fatigue, and depression were no longer significantly different from those of control individuals at the end of the study.

Objective neurological examination findings improved substantially over time, and by the final visit, neither GNE nor CNS differed significantly between groups. However, residual cognitive symptoms persisted in a subset of survivors.

Severe neurological disease during acute infection was similarly associated with worse long-term outcomes, including higher GNE (4.4 vs 2.9) and CNS scores (2.7 vs 1.7), as well as more ongoing symptoms (7.2 vs 4.8).

Key study limitations include the lack of blinding of neurologists to survivor status, which may have introduced assessment bias, and loss to follow-up over time, particularly among control individuals. Other limitations included relying on self-reported symptoms with possible recall bias, limited data from acute illness, and the lack of standardized psychiatric assessment, which may have underestimated mental health outcomes.

Why Do Neurological Outcomes Differ?

Neurological manifestations among Ebola survivors are unlikely to reflect a single mechanism, the investigators noted. 

"Post-Ebola syndrome may have disease clusters with different underlying biological mechanisms," they wrote, which is likely to contribute to its varied clinical presentation over time.

This variability was seen with severe neurological disease during acute infection, which was associated with poorer long-term neurological outcomes, with ongoing effects persisting in a subset of survivors.

Taken together, these findings highlight the importance of "systematic long-term neurological care and monitoring of survivors to fully understand the socioeconomic and health care burden of pandemic infections," along with the need for neurological training and specialist support to address these issues.

Overall, the investigators stressed that further research is needed to better define therapeutic strategies and clarify the long-term trajectory of neurological recovery in survivors.

The study was funded by the National Institute of Allergy and Infectious Diseases, the National Institute of Neurological Disorders and Stroke, and the National Cancer Institute. Disclosure information for study authors is available in the original study publication.