CSF Testing May Rapidly Identify Cause of Neurologic Symptoms

George W. Citroner

November 01, 2018

Testing cytokine levels in cerebrospinal fluid (CSF) may rapidly differentiate brain infections from other central nervous system (CNS) diseases, new research suggests.

"We have many tests for making diagnoses, but the ones that conclusively indicate infection can often take more time than we'd like, especially in cases of childhood meningitis or encephalitis," study investigator Mark Curtis, MD, PhD, Jefferson University, Philadelphia, Pennsylvania, said in a release.

"Once confirmed with additional research, our test could provide a first, rapid, and less invasive way to look at what's happening in the brain and guide treatment or further testing," added Curtis, associate professor of pathology, anatomy, and cell biology, who also works as a hospital pathologist.

Such a test, investigators note, may prove especially useful in the diagnosis of meningitis and encephalitis and related, often serious, sequelae.

The study was published online October 31 in the journal PLOS One.

Early Sign of Infection

"Rapidly distinguishing CNS infections from other brain and spinal cord disorders that share similar clinical presentation is critical," the authors write.

"Most of the aseptic cases of meningitis are viral infections, with the majority being caused by nonpolio enteroviruses [EVs] and human parechoviruses [HPeVs], said Curtis.

"Our previous research showed that by comparing the profiles of CSF cytokines in HPeV with EV central nervous system infections and controls, we could identify EV and HPeV as marker profiles useful in identifying HPeV CNS infections in newborns," he said.

"Once we'd finished that study, we were surprised to see that bacteria, viruses, and fungi all showed a different profile. That's when we knew this was something we had to pursue," he added.

In the current proof-of-concept study, the investigators examined cytokine levels in CSF in various CNS disorders, including infections, autoimmune/demyelinating diseases, lymphomas, and gliomas, to "determine the potential utility of cytokine patterns in differentiating CNS infections from other CNS diseases."

"Infectious agents activate an inflammatory response; a component of this is the release of different combinations of cytokines. Changes in cytokine levels of CSF fluid offer a very early sign of infection," Curtis told Medscape Medical News.

Rapid Triage

The retrospective analysis used deidentified CSF samples that were no longer needed for clinical analysis.

The researchers analyzed CSF samples from 43 patients aged 2 to 80 years who had CNS disease. The patients' clinical evaluations included a white blood cell count and measurements of glucose concentration and protein levels.

Cytokine analysis included samples from seven control persons who tested negative for neuroinflammatory processes; 15 patients who had CNS infections; three patients with malignant glial (astrocytic) neoplasms; 11 patients with autoimmune and demyelinating disease; and six patients with B-cell lymphoma that involved the CNS.

The investigators found that of those identified with CNS infections, the CSF cytokine fingerprint was different in cases of viral infection compared to those with nonviral pathogens, such as bacteria or fungi.

"With only a small amount of spinal fluid needed, CSF cytokine analysis could be used as one of the first diagnostic tests to rapidly triage serious central nervous system disorders and guide immediate intervention," first author Danielle Fortuna, MD, assistant professor, Department of Pathology and Laboratory Medicine, the Hospital of the University of Pennsylvania, said in a release.

Curtis said that an initial assessment of the entire data set, including heat map and dendrogram, "definitely supports further investigation of whether CNS diseases can be separated based on a composite cytokine innate immune profile."

Curtis added that he would like to formally validate the findings with a larger sample size for future use in the clinical arena.

Time Is Brain

Commenting on the findings for Medscape Medical News, Cedric Spak, MD, infectious disease specialist, Baylor Scott and White Health All Saints Medical Center, Fort Worth, Texas, said it's too soon to determine the clinical implications of the research.

However, he noted that "about half of encephalitis cases are due to unknown causes, so there is a need for new testing to help doctors establish causality."

Every minute lost diagnosing and not treating a neurologic event can mean the death of millions of neurons.

Curtis emphasized that conventional testing can take a long time to show results.

"Sure, simple tests could be ready that same day. When we're looking for bacteria, we'll know the results within 72 hours. However, more demanding tests could take days or even weeks, and tests looking for certain antibodies could take between 1 and 2 months to come back," said Curtis.

For the future, Curtis envisions something similar to the HIV test.

"You could get a positive/negative test for viral vs nonviral and things like that. I think this test could really improve the odds, especially for pediatric patients," he said.

Especially Helpful in Kids

He believes it could be especially helpful to diagnose infants and young children, who are at greater risk for meningitis than other age groups.

"When babies come into the emergency room very sick and febrile, the differentials would include a CNS infection in these kids, and they can't tell you how they feel, so the threshold for doing a lumbar puncture is much lower in this population," said Curtis.

"Biopsy and other diagnostic methods have shortcomings that must be addressed if we're going to give patients the best odds. Once larger studies validate our results, we could have a test that will not only distinguish between whether infection is present and what type but eventually even other diseases, like B-cell lymphomas," said Curtis.

Spak agrees. "With better testing, we can move forward with better therapies and understanding of these conditions," he said.

Curtis said it could be some time before the test becomes available. "Optimistically," he said, "it could be 2 years away, maybe longer."

The authors have disclosed no relevant financial relationships.

PLoS One. Published online October 31, 2018. Full text

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