Lyme Neuroborreliosis: Known Knowns, Known Unknowns

John J. Halperin; Randi Eikeland; John A. Branda; Rick Dersch


Brain. 2022;145(8):2635-2647. 

In This Article

Abstract and Introduction


Lyme borreliosis affects the nervous system in three principal ways—mononuclear cell meningitis, cranial neuropathies and radiculoneuropathies—the last a broad term encompassing painful radiculopathy, unifocal and multifocal peripheral nerve involvement. Diagnostic tools have been significantly refined—including improved peripheral blood and CSF serodiagnostics—and much has been learned about the interactions between the causative pathogen and the nervous system. Despite these advances in our understanding of this disease, a broad range of other disorders continue to be misattributed to nervous system Lyme borreliosis, supported by, at best, limited evidence. These misattributions often reflect limited understanding not only of Lyme neuroborreliosis but also of what constitutes nervous system disease generally. Fortunately, a large body of evidence now exists to clarify many of these issues, establishing a clear basis for diagnosing nervous system involvement in this infection and, based on well performed studies, clarifying which clinical disorders are associated with Lyme neuroborreliosis, which with non-neurologic Lyme borreliosis, and which with neither.


It has been 100 years since the first report describing what is now known as Lyme neuroborreliosis (LNB)—nervous system infection with Borrelia burgdorferi sensu lato (Bbsl). That century-old report described a French sheep farmer who, 3 weeks after a tick bite, developed an enlarging erythematous rash, then months of severe, multifocal radicular pain with deltoid atrophy. With a CSF pleocytosis and weakly positive Wasserman it was concluded this was 'undoubtedly due to a spirochete'. Treatment with neoarsphenamine, the standard of care for neurosyphilis at the time, was followed by rapid symptom improvement.[1]

The clinical triad—various combinations of painful radiculoneuritis, meningitis and cranial neuropathy, occurring following Ixodes species tick bites and typically preceded by the unusual rash, erythema migrans (EM), became well known.[2–5] By the 1950s penicillin was shown effective.[6] In the 1970s the triad was recognized in the USA in association with newly described Lyme arthritis.[7] Following identification of the responsible tick-borne spirochetes, collectively Bbsl, in the 1980s, the term Lyme borreliosis came into use.

Despite advances in diagnostic tools and therapeutics, LNB remains the subject of considerable debate. Building on current understanding of LNB's pathophysiology, this review's goal will be to provide a rational approach to patients with neurological disorders in whom a diagnosis of LNB is being considered.