Lyme disease, caused by the spirochete Borrelia burgdorferi and transmitted through Ixodes tick bites, is the most prevalent vector-borne illness in North America and Europe. Early manifestations include erythema migrans and flu-like symptoms, which typically respond well to antibiotics.1 However, non-specific symptoms such as fatigue and musculoskeletal pain often create diagnostic uncertainty and contribute to overdiagnosis.2 Many patients referred for Lyme disease evaluation do not meet established diagnostic criteria and are ultimately found to have other medical or psychiatric conditions.3 Overreliance on serologic testing, particularly in low-prevalence settings, may yield false positives and lead to inappropriate treatment.4 In addition, some clinicians overdiagnose Lyme disease, occasionally bordering on quackery or fraud. Such practices result in unsupported diagnoses, further fueling overdiagnosis5 and posing significant diagnostic and therapeutic challenges.6 To illustrate this issue, we present a series of striking misdiagnosed cases from our clinical practice.
Between 2021 and 2024, we evaluated 37 patients who had been diagnosed with or suspected of having Lyme disease and were admitted to our two hospitals. Most were ultimately found to have alternative conditions-including infective endocarditis, Behçet’s disease, and psoriatic arthritis-diagnoses made possible through systematic multidisciplinary evaluation.
Of the 37 patients, 32 carried a confirmed Lyme disease diagnosis from external centers, while 5 were suspected cases without diagnostic testing. The cohort consisted of 19 males and 18 females, ranging in age from 7 to 71 years. Only one patient recalled a tick bite, and two others reported travel abroad without known exposure.
Serologic testing yielded variable results. Three patients met the two-tier IgM-positive criteria via ELISA and Western blot. Five were IgM-positive on ELISA only, with negative Western blots. Two were IgG-positive on ELISA without Western blot confirmation. Seven tested negative for both IgM and IgG on ELISA. In some cases, the initial Lyme disease diagnosis was based on spirochete-like structures observed under dark-field microscopy. Twenty-two patients had received antimicrobial therapy for durations ranging from 3 weeks to 5 years, with some treated simultaneously with up to five antibiotic agents. Most had also been prescribed various supplemental therapies. Despite these extensive regimens, the majority experienced little or no clinical improvement.
Upon admission to our department, each case was re-evaluated through review of the patient’s medical history, comprehensive physical examination, and targeted laboratory testing when indicated. This reassessment confirmed Lyme disease in only one patient. Twenty-two patients were determined not to be infected with Borrelia and were reassured without need for further investigation. The remaining 14 were referred to appropriate specialties based on their clinical history and findings; 10 of these patients accepted and completed specialist evaluations within our hospitals.
Specialist consultations established alternative diagnoses for all 10 patients, enabling revised treatment plans that resulted in symptom resolution or marked improvement. Most were diagnosed by rheumatologists with conditions such as fibromyalgia or inflammatory arthritis, including psoriatic arthritis and spondyloarthritis. One patient was diagnosed with Behçet’s disease and another with familial Mediterranean fever, both representing autoinflammatory disorders.
Neurological evaluation led to a diagnosis of multiple sclerosis (MS) in one patient, necessitating initiation of disease-modifying therapy. Another patient was diagnosed with subacute infective endocarditis by the infectious diseases team- a life-threatening condition requiring urgent antimicrobial and supportive management.
Due to severe valvular damage at the time of diagnosis, this patient subsequently underwent heart valve replacement surgery. Clinical characteristics and final diagnoses of patients initially misdiagnosed with Lyme disease are summarized in Table 1.
The diagnosis of Lyme disease remains challenging due to variations in clinical presentation and differences in diagnostic criteria. A recent meta-analysis highlighted discrepancies between American and European guidelines, particularly in non-endemic regions such as Türkiye.7 These inconsistencies, combined with physician misdiagnosis, contribute to inappropriate treatment, as illustrated by our case series.
A critical epidemiologic factor in diagnosing Lyme disease is a history of tick exposure, given that Borrelia burgdorferi is transmitted through Ixodes tick bites. In our series, however, only one patient reported a prior tick bite, and only two had traveled abroad. Although some individuals may not recall a tick bite because of the small size of nymphal Ixodes ticks, epidemiologic risk assessment remains an essential element of diagnosis.
Serologic testing was frequently positive but did not correlate with clinical improvement after antimicrobial therapy. False-positive serologic results may arise from cross-reactivity with other pathogens or non-specific antibody responses.8,9 This highlights the importance of integrating clinical findings with laboratory results rather than relying solely on serology for diagnosis.
Dark-field microscopy was also used in some patients to identify structures resembling spirochetes. However, this method is not recommended for Lyme disease due to its low sensitivity and high false-positive rates. Artifacts and other microorganisms can easily be mistaken for Borrelia species, leading to misdiagnosis and unnecessary treatment. A narrative review concluded that dark-field microscopy has significant limitations and should not be employed as a diagnostic tool for Lyme disease.10
The misdiagnosis of Lyme disease in our patients resulted in prolonged and unnecessary antimicrobial treatments, lasting from 3 weeks to 5 years, without clinical improvement. Incorrect diagnoses also delayed identification and management of the true underlying conditions. In some cases, the consequences were severe-for example, the patient with subacute infective endocarditis, where timely recognition and treatment were critical to prevent life-threatening complications. Similarly, delays in diagnosing conditions such as MS and inflammatory arthritis led to extended symptom burden and potential disease progression. These findings underscore the importance of reconsidering a Lyme disease diagnosis in patients with persistent symptoms unresponsive to standard antimicrobial therapy. A multidisciplinary approach facilitated accurate diagnoses and effective treatment, as summarized in Table 1. Misdiagnosis not only prolonged inappropriate antimicrobial use but also allowed underlying conditions to progress unchecked. The most severe case involved a patient with undiagnosed infective endocarditis who required urgent antimicrobial therapy. By the time the correct diagnosis was established, irreversible cardiac damage had occurred, necessitating heart valve replacement surgery.
In conclusion, diagnosing Lyme disease requires caution, particularly in non-endemic regions. Overreliance on serologic testing-especially misinterpretation of Western blot results-and nonspecific methods such as dark-field microscopy can lead to misdiagnosis and inappropriate treatment. A multidisciplinary approach, strict adherence to established guidelines, and thorough clinical evaluation are essential for ensuring diagnostic accuracy and optimizing patient management.
Informed Consent: Informed consent was obtained from the patient.
Authorship Contributions: Concept- E.E.G., O.U., D.G., Ş.K., Ö.E.; Design- E.E.G., O.U., D.G., Ş.K., Ö.E.; Supervision- E.E.G., O.U., D.G., Ş.K., Ö.E.; Fundings- E.E.G., O.U., D.G., Ş.K., Ö.E.; Materials- E.E.G., O.U., D.G., Ş.K., Ö.E.; Data Collection or Processing- E.E.G., O.U., D.G., Ş.K., Ö.E.; Analysis and/or Interpretation- E.E.G., O.U., D.G., Ş.K., Ö.E.; Literature Review- E.E.G., O.U., D.G., Ş.K., Ö.E.; Writing- E.E.G., O.U., D.G., Ş.K., Ö.E.; Critical Review- E.E.G., O.U., D.G., Ş.K., Ö.E.
Conflict of Interest: No conflict of interest was declared by the authors.
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