KYOTO, Japan — Even after recovery from Ebola virus disease (EVD) — often a rare event — survivors are not out of the woods, a new study shows. Wide-ranging neurologic sequelae are common and may last from months to years.
Discovered in an outbreak in 1976 in Zaire (now the Democratic Republic of the Congo), EVD has shown a mortality rate of 25% to 90% over about a dozen outbreaks, with mortality varying by Ebola species and outbreak. Neurologic manifestations and sequelae were not well characterized in the outbreaks before the 2014-2015 event in West Africa.
In that event, there were more than 28,000 cases and 11,000 deaths, including more than 10,000 cases and 4000 deaths in Liberia. This formed the basis of a database that Jeanne Billioux, MD, from the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, calls a “goldmine of information about Ebola.”
As part of the NINDS Partnership for Research on Ebola Vaccines in Liberia III study (PREVAIL III), researchers are tracking the natural history of the disease, characterizing sequelae in various bodily systems, tracking relapses and viral persistence, and performing clinical studies on pharmacologic interventions and vaccines.
PREVAIL III involves 1500 survivors and uses their close contacts as controls. The study is a partnership between the National Institutes of Health and the Ministry of Health of Liberia and will follow the participants for 5 years.
Dr Billioux reported on neurologic sequelae among 153 self-identified survivors and 82 close contacts here at the XXIII World Congress of Neurology (WCN). Evaluations consisted of a questionnaire of symptoms and a neurologic examination, with follow-up every 6 months; so far, 2 follow-ups have been performed.
Both survivors and close contacts had a mean age of about 35 years and were equally divided between males and females. Most survivors (69.5%) had spent 14 or more days in an Ebola treatment unit (ETU).
At the baseline neurologic visit during or after the ETU, the most common symptoms were headaches (72.5%); depression (70.6%); muscle soreness (64.1%); difficulty walking, memory loss, limb weakness, vertigo, visual changes, and confusion (all about 50% each); abnormal sensations (41.8%); and hallucinations (26.1%). Less common were tremor or meningitis (about 22% each), hearing loss (14.4%), and seizure and stroke (1.31%, but not different from controls).
At the baseline neurologic exam, survivors had a higher sum of all neurologic abnormalities on the case report form compared with contacts (3.7 ± 3.5 vs 2.2 ± 2.9, respectively; P < .001) and a higher sum of central nervous system abnormalities (2.2 ± 2.5 vs 0.8 ± 1.3; P < .001).
On the modified Rankin Scale, only 6 of 153 patients (3.9%) were free of symptoms. The rest had a score of 1 (83.7%), 2 (9.8%), or 3 (2.6%).
The neurologic exam showed frontal release signs in 15%. Cranial nerve exams revealed abnormal pursuits (40.6%), abnormal saccades (26.1%), and nystagmus (9.8%) — all statistically greater than in close contact controls. Also different from controls was a positive Romberg test result in 19.6%, abnormal Babinski reflex in 4.6%, tremor in 20.9%, and dysmetria in 9.8%.
On follow-up, several of the symptoms present at baseline persisted: headache (64.7%); memory loss (55.6%); depression (49%); trouble concentrating (42.5%); and muscle soreness, lack of motivation, personality changes, sexual dysfunction, abnormal sensations, and trouble sleeping (26.1% to 34.6%).
Follow-up at 18 months was very good, with 142 survivors (92.8%) and 68 close contacts (82.9%) available for evaluation. At that time, EVD symptoms still lingered.
Table. Proportion of Patients With Symptoms 18 Months After EVD
| Symptom | Proportion of Patients (%) |
|---|---|
| Depression | 36.6 |
| Debilitating fatigue | 38.7 |
| Muscle soreness | 32.4 |
| Vision issues | 29.6 |
| Trouble concentrating | 28.2 |
| Limb weakness | 23.2 |
| Lack of motivation | 15.5 |
| Sexual dysfunction | 10.6 |
Diederik van de Beek, MD, PhD, professor of neurology at the Academic Medical Center in Amsterdam, the Netherlands, told Medscape Medical News that “apparently these patients who are surviving still suffer from significant impairments.” Although these findings are not surprising, he said, “It’s the first study showing this.”
He said it is important to remember that the close contact controls also “suffered from the disease” in the sense that they were in the same environment and may have been affected by stress and other psychological effects.
Some baseline neurologic abnormalities that were noted in a proportion of the survivors did not differ from those in controls: facial (4%), auditory (7.2%), and hypoglossal (3.3%) nerve findings; motor weakness (8.5%) and abnormal tone (4.6%); peripheral neuropathy (27.5%); abnormal reflexes (30.7%); and gait abnormalities (9.8%).
“That might also be the explanation that these controls had a relatively high level of abnormalities in my opinion,” Dr van de Beek said. “The contrast might even be bigger if you used population-based controls, not in the disease area.”
Then there is the question of what to do for the survivors. Dr van de Beek said one thing to investigate is whether the neurologic sequelae are an effect of the virus on the central nervous system, possibly using MRI to look for brain infarctions. He suggested that another big question is why these patients survived in the face of a very high mortality rate, so a comparison of the immune function of survivors to that in general population controls could be informative.
Dr Billioux said imaging studies and studies on cerebral spinal fluid are planned, as is longer-term follow-up with neurologic tests.
The study had no commercial funding. Dr Billioux and Dr van de Beek have disclosed no relevant financial relationships.
XXIII World Congress of Neurology (WCN). Abstract 415. Presented September 18, 2017.
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