Opinion VIEWPOINT Lyme Disease Authentic Imitator or Wishful Imitation? Michael T.Melia, MD The spirochete Borrelia burgdorferi may afflict skin, ease; this optimism is bolstered by Internet resources Division of Infectious heart, joints, and the central or peripheral nervous sys- supporting such notions. A critical point, however, is the Diseases, Department tem. This agent of Lyme disease, perhaps because of its highly focal geographic distribution of Lyme disease— of Medicine, Johns varied presentations, is often raised as the cause of head- none of the aforementioned neurologic diseases are Hopkins University School of Medicine, ache, fatigue, and subjective neurocognitive dysfunc- uniquetoareaswithhighLymediseasetransmission.Fur- Baltimore, Maryland. tion. For clinicians who trained in the 20th century when thermore, Lyme disease is readily distinguished from the spirochete Treponema pallidum was invoked as the these conditions on clinical grounds. Patients with Lyme Paul M. Lantos, MD “Great Imitator,”testing for Lyme disease now seems as disease do not exhibit the white matter plaques seen on Department of Internal or more common than it had been for syphilis. With a nar- imaging of patients with multiple sclerosis, for ex- Medicine, Duke University School of rower disease spectrum than syphilis, is such frequent ample, and when patients with Lyme disease have oli- Medicine, Durham, testing for Lyme disease justified, and how should re- goclonal bands in their cerebrospinal fluid, they are ac- North Carolina; and sults be interpreted? tually reactive against B burgdorferi. Lyme disease does Department of Pediatrics, Duke If contemplating Lyme neuroborreliosis, under- not produce the upper motor neuron signs seen in amyo- 4 University School of standing the epidemiologic likelihood of acquiring this trophic lateral sclerosis. Medicine, Durham, tick-borne infection, its potential manifestations, and While sometimes considered as an explanation for North Carolina. proper interpretation of serologic testing are all essen- objective neuropathology, more often asked is if Lyme tial. For patients from Lyme-endemic areas, Lyme dis- disease explains subjective neurocognitive dysfunc- Paul G. Auwaerter, MD Division of Infectious ease is among the most common causes of facial nerve tion. Such inquiries likely stem from early reports of neu- Diseases, Department palsy,asepticmeningitis,andneuroradiculitis.Whilesuch rocognitive symptoms accompanying objective, inflam- of Medicine, Johns manifestations of early disseminated Lyme disease arise matory manifestations of Lyme disease, including Lyme Hopkins University in up to 10% to 15% of patients not treated at an earlier arthritis.1 While such symptoms can be seen with Lyme School of Medicine, Baltimore, Maryland. stage, late neurologic complications such as encephali- disease,thisassociationshouldnotbetakentomeanthat tisanddiffusepolyneuropathyareexceptionallyrare.De- all patients with subjective neurocognitive dysfunction spite the rarity of late Lyme neuroborreliosis, many phy- have Lyme disease; such symptoms can also be found siciansincludeLymediseaseintheirdifferentialdiagnosis not only among patients with other infectious and non- for a variety of chronic neurologic syndromes. This ap- infectious inflammatory conditions, but also among oth- proach may be partly because of brain imaging reports erwise healthy persons.1 Even among patients with Lyme that commonly reference Lyme disease among the pos- disease, the presence of subjective neurocognitive sible explanations for nonspecific white matter changes, symptoms is more likely to reflect systemic inflamma- despite the fact that B burgdorferi infection essentially tion than genuine central nervous system infection. This never causes such findings.1 point was highlighted in a study of patients with ery- B burgdorferi infection is well known to affect the thema migrans, among whom the presence of symp- seventh and less commonly sixth cranial nerves. An of- toms such as headache, vertigo, paresthesias, and ten-posed question, therefore, is whether B burgdor- memory,concentration,orsleepdisturbancedidnotpre- feri infection can produce other isolated cranial neu- dict the presence of cerebrospinal fluid (CSF) pleocyto- ropathies, such as sensorineural hearing loss and optic sis indicative of authentic central nervous system neuritis.Arecentreviewadvocatedagainstscreeningpa- infection.5 tients with sudden-onset sensorineural hearing loss for If after careful consideration, neuroborreliosis is en- Lyme disease because of an unproven causative tertained as a diagnostic possibility,can laboratory test- relationship.2 While children with Lyme meningitis can ing help confirm or exclude the diagnosis? For patients have papilledema, and adults with B burgdorferi– with syndromes compatible with Lyme neuroborrelio- driven optic neuritis manifesting as papillitis have been sis, such as seventh nerve palsy or aseptic meningitis, the described, this latter phenomenon appears uncom- positive predictive value of serologic testing is high, as mon. A case series of 440 patients with optic neuritis is the negative predictive value of acute followed by con- from a Lyme-endemic region found 25 seropositive but valescent testing. IgG immunoblots are particularly im- only 1 with evidence of active B burgdorferi infection.3 portant, especially when considering the high preva- Corresponding The rarity of this association was reinforced in the ac- lence of false-positive IgM immunoblots—perhaps the Author: Michael T. Melia, MD, Johns companying literature review. most common pitfall of Lyme diagnostics. In one repre- Hopkins University Lyme disease is often investigated during the ini- sentative series, more than 50% of patients with head- School of Medicine, tial evaluation of conditions such as multiple sclerosis, aches and nearly 25% with neurocognitive symptoms 1830 E Monument St, amyotrophic lateral sclerosis, dementia, or parkinson- thought potentially attributable to Lyme disease were Ste 448, Baltimore, MD 21287 (mmelia4@jhmi ism. Many patients facing these devastating diseases due to something else, as a false-positive IgM immuno- .edu). maintain hope for a curable diagnosis, such as Lyme dis- blot was the only test result suggesting B burgdorferi jamaneurology.com JAMA Neurology Published online August 4, 2014 E1 Copyright 2014 American Medical Association. All rights reserved. Downloaded From: http://archneur.jamanetwork.com/ by a Duke Medical Center Library User on 08/12/2014 Opinion Viewpoint infection.6 The high (27.5%) prevalence of false-positive IgM immu- tive, but as with all antibody-based Lyme diagnostics, considering noblots in this series is one of the primary reasons screening for Lyme the clinical context is essential. Furthermore, elevated CSF anti- disease is discouraged when the diagnosis is improbable. The IgM body levels can persist even after adequate antibiotic therapy. immunoblot is only useful for patients with illnesses of less than 4 Patients with persistently positive serologic test results and on- weeks’ duration that are compatible with early Lyme disease. After going symptoms can present a challenge, especially when a com- 4 weeks of illness, Lyme IgM immunoblots should be disregarded pelling alternative diagnosis has not been discovered. Unlike syphi- irrespective of their reported result. lis, where the rapid plasma reagin titer declines with adequate The attribution of IgG immunoblot seropositivity to a patient’s treatment, there is no test of cure for Lyme disease. Patients with- illness still requires clinical judgment; a positive IgG immunoblot is out new symptoms or findings should not be retested or retreated nondiagnostic without a compatible clinical syndrome. Low prob- because seropositivity, including IgM, can persist for decades. For ability testing often lands patients in consultants’ offices, creating patients with a history of Lyme disease and persistent symptoms, challenges explaining results and countermanding the often patient- theineffectivenessofadditionalcoursesofantibiotictherapyinthose driven inclination to “just try antibiotics” that may lead to harmful previously treated should stay further antibiotics.7 drug adverse effects without chance of benefit. This approach may While B burgdorferi infection can cause neurologic disease, fa- also delay arrival at the correct diagnosis and treatment. miliar presentations far outnumber atypical manifestations. Con- In the event that the diagnosis of neuroborreliosis remains plau- sultants should base neuroborreliosis diagnoses on epidemiology, sible but uncertainty remains, assessing the ratio of B burgdorferi an- objective findings, and sound laboratory testing. When Lyme dis- tibodies between CSF and blood can be useful. Isolated CSF anti- ease is deemed unlikely, educating patients and referring physi- body testing is discouraged, as correcting for blood antibody levels cians alike will help avoid unnecessary antibiotic therapy and direct is essential to distinguish intrathecal antibody production from spill- consideration of alternative diagnoses. While Lyme disease is no im- age into the CSF. A ratio of 1.3 or more is usually considered posi- poster, syphilis’ title as the Great Imitator remains secure for now. ARTICLE INFORMATION Disclaimer: The content is solely the responsibility 4. Galbussera A, Tremolizzo L, Isella V, et al. Lack of Published Online: August 4, 2014. of the authors and does not necessarily represent evidence for Borrelia