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Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2019.00302

The Potential Role of Subclinical Bordetella Pertussis Infection in Epilepsy

 Steven Glazer1* and Keith Rubin1
  • 1ILiAD Biotechnologies LLC, United States

The etiology of many cases of epilepsy remains unknown (Scheffer et al., 2017). Given the increased risk for seizures and epilepsy in children after symptomatic Bordetella pertussis (BP) infection (Olsen et al., 2015), an association recognized for nearly a century (Eley, 1930), we briefly review the evidence and propose a role for subclinical BP colonizing infections (SCBPC) in epilepsy.

SCBPC is vastly more prevalent than reported pertussis (Ward, 2005). In multiple countries with high BP vaccination rates, evidence of subclinical BP infection is demonstrated in 4.8-7.1% of asymptomatic individuals by nasal swab PCR (Klement, 2003; Zhang et al., 2014; Naeini et al., 2015), and in 6.6%-14.1% by serology indicative of infection during the past year (de Melker et al., 2006; De Greeff et al., 2010; Palazzo et al., 2016). Based on serology, investigators in the United States (US) acellular BP vaccine trial estimated undocumented rates of BP infection at 1 to 10 million cases in the US annually (Ward, 2005), in years when the CDC reported approximately 7000 cases per year (

Multiple lines of evidence support the hypothesis that subclinical nasopharyngeal BP colonizing infections have unrecognized clinical consequences including epilepsy. B. pertussis secretes pertussis toxin, which compromises the blood-brain barrier in human brain endothelium models (Kugler et al., 2007), as seen in epilepsy (Oby and Janigro, 2006). In mice, respiratory BP infection induces inflammatory cytokines in the brain (Loscher et al., 2000), and intracerebroventricular pertussis toxin lowers the drug-induced seizure threshold (Durcan and Morgan, 1991). At the neuronal level, mechanistic plausibility is supported in that pertussis toxin increases excitatory neuronal glutamate release (Cullen et al., 1994) and decreases Gi/o receptor-mediated neuroinhibitory GABA activity (Padgett and Slesinger, 2010), as well as GABA receptor binding (Moss and Vaughan, 1988).

Clinical observation supports the association between BP and epilepsy. In children < 2 years of age admitted to the hospital with pertussis, new seizures were reported in 2.3%, and encephalopathy in 0.5% (Halperin et al., 1999) of patients. In BP-associated encephalopathy, elevated antibody titers to BP toxins have been demonstrated with tenfold higher concentrations in CSF compared with serum, indicating entry of BP antigens to the CNS (Grant et al., 1998). In Denmark between 1978-2011, the incidence of epilepsy at 10 years of age 10 was 1.7% for patients with a history of hospital-diagnosed pertussis, and 0.9% in a matched cohort [HR 1.7 (95% CI, 1.3-2.1)] (Olsen et al., 2015). Almost all of the increased epilepsy risk occurred in the first 1.5 years after clinical pertussis, and did not vary with age at pertussis diagnosis.

Given the totality of the data available, we believe that a causal role for SCBPC in epilepsy is plausible. Testing this hypothesis could be achieved by screening patients presenting with an initial idiopathic seizure, as well as controls, for evidence of current or recent BP infection, with nasopharyngeal swab BP PCR and BP serology.

Keywords: Bordetella pertussis, Epilepsy, Bordetella pertussis toxin, Subclinical infection, Epiliptogenesis, seizure

Received: 06 Apr 2019; Accepted: 07 Aug 2019.

Copyright: © 2019 Glazer and Rubin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Steven Glazer, ILiAD Biotechnologies LLC, New York, United States,