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Next-generation sequencing identified rare cause of hydrocephalus
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Using unbiased next-generation sequencing of cerebrospinal fluid, physicians at the University of California, San Francisco, diagnosed leptospirosis in a 14-year-old boy with fever and headache that progressed to hydrocephalus and status epilepticus, according to a report in The New England Journal of Medicine.
The boy was enrolled in a research study for pathogen detection using this sequencing after no tests, including extensive infectious disease workup and biopsies, revealed the cause for the hydrocephalus. The results of the next-generation sequencing identified the Leptospira infection within 48 hours.
“Unbiased next-generation sequencing coupled with a rapid bioinformatics pipeline provided a clinically actionable diagnosis of a specific infectious disease from an uncommon pathogen that eluded conventional testing for months after the initial presentation,” the researchers wrote. “This approach thus facilitated the use of targeted and efficacious antimicrobial therapy.”
The boy had severe combined immunodeficiency caused by adenosine deaminase deficiency. He presented to the ED in early April 2013 with headache and fever and was discharged after resolution. He was readmitted at the end of the month with fever, photophobia and daily frontotemporal headaches, as well as increasing fatigue, abdominal pain and weight loss. There were no abnormal findings on an infectious disease workup, and the boy was released. His symptoms fluctuated during the next 2 months.
He was admitted again in July with fever, headache, diffuse weakness, myalgias, nausea and vomiting. An MRI of the head showed hyperintensities in the basal ganglia and development of basilar leptomeningitis into the cerebral hemispheres. A biopsy was performed, and the examination showed inflamed leptomeninges with a granulomatous infiltrate.
Those findings, along with an elevated angiotensin-converting enzyme level in the cerebrospinal fluid (CSF) and a history of presumed autoimmune disease led to treatment for possible neurosarcoidosis, which had no effect. The patient deteriorated and developed new psychiatric symptoms and was placed in a medically induced coma.
The boy was then enrolled in the study in which the Leptospira infection was identified through gene sequencing. He began treatment with high-dose IV penicillin G. He gradually recovered after 7 days and was discharged to rehabilitation 14 days after completing the 7-day course of treatment. The infection was confirmed via PCR analysis and Sanger sequencing 5 days after the next-generation sequencing analysis. A phylogenetic analysis found that the CSF harbored L. santarosai, a species that had not yet been deposited in the National Center for Biotechnology Information nucleotide reference database.
The patient is suspected to have contracted the disease during a trip to Puerto Rico in August 2012, when he swam in freshwater and a fellow traveler developed fever and hematuria suggestive of Leptospira infection. The species also is consistent with the geographic location.
Disclosure: One researcher has received research funding from the NIH and Abbott Laboratories.
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