Atypical Lyme Disease Symptoms That Complicate Diagnosis

Atypical Lyme disease symptoms can make diagnosing the infection difficult. While many clinicians recognize the classic erythema migrans “bull’s-eye” rash, some patients develop unusual rashes or other atypical findings that delay recognition of Lyme disease.

Lyme disease can present with a broad range of symptoms. Many are familiar to clinicians. But in some cases, patients develop atypical Lyme disease symptoms—including rashes that do not resemble the classic target lesion. These unusual presentations may lead physicians to suspect other infections before considering Lyme disease.

These atypical presentations are discussed further in our overview of Lyme disease symptoms.

Lyme Disease Rash That Is Not a Bull’s-Eye

Not all Lyme disease rashes have the classic bull’s-eye appearance. In some cases, the rash may resemble cellulitis, appear as multiple lesions, or lack central clearing. Patients often assume Lyme disease must produce a target-shaped rash, but atypical Lyme disease symptoms frequently include skin lesions that do not resemble the classic bull’s-eye pattern.

For example, Sharma describes a patient whose rash did not resemble the classic target lesion. Instead, the patient developed a “large erythematous, warm rash without central clearing over the left lower quadrant, with similar but smaller rashes on the abdomen and back and scattered white patches on the surface and side of the tongue.”

Three weeks earlier, the man had returned from a camping trip. Soon afterward he developed headaches, fever, malaise, fatigue, generalized weakness, and diffuse joint, muscle, and back pain, writes Sharma in BMJ Case Reports. Ibuprofen provided only temporary relief.

Over time, additional symptoms appeared including chills, shaking episodes alternating with warmth, profuse sweating, retching, blurry vision, abdominal pain, leg cramps, and chest pressure. His headache was generalized without neck stiffness or photophobia.

When Lyme Disease Mimics Other Conditions

Because of the unusual findings, doctors initially suspected other illnesses. The oral pseudomembrane raised concern for HIV or infectious mononucleosis. The atypical skin lesions were thought to represent methicillin-resistant Staphylococcus aureus (MRSA) infection, and the patient was treated with vancomycin.

Testing revealed evidence of Epstein-Barr virus (mononucleosis). Meanwhile, the initial ELISA test for Lyme disease was negative.

However, laboratory tests alone may not reliably confirm early Lyme disease. Clinicians often must rely on clinical judgment when symptoms and exposure history raise suspicion for tick-borne infection.

Examples of Atypical Lyme Disease Symptoms

• Rashes without the classic bull’s-eye appearance
• Multiple cellulitis-like skin lesions
• Oral pseudomembranes
• Lymphadenopathy mimicking viral infections
• Systemic symptoms such as fever, chills, and muscle pain

Atypical Lyme disease symptoms may occur during early disseminated infection, when the bacteria have spread through the bloodstream and produce multiple or unusual skin lesions.

Empiric Treatment Leads to Rapid Improvement

Because the patient had a history of outdoor exposure and symptoms consistent with tick-borne illness, physicians started empiric doxycycline therapy.

His symptoms improved quickly.

Subsequent Western blot testing returned positive, confirming the diagnosis of early disseminated Lyme disease.

At a four-week follow-up visit, the patient’s rash and symptoms had completely resolved.

Why Recognizing Atypical Lyme Disease Symptoms Matters

This case highlights an important clinical point: Lyme disease does not always follow a textbook presentation. Atypical Lyme disease symptoms—including unusual rashes or unrelated findings—can lead clinicians to suspect alternative diagnoses.

As Sharma notes, “Lyme disease can have unrelated findings like oral pseudomembrane and lymphadenopathy that may lead one to suspect alternative diagnoses such as acute HIV or infectious mononucleosis.”

Recognizing atypical Lyme disease symptoms is important because delayed diagnosis can allow infection to progress to neurologic or cardiac Lyme disease.

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Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.

Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention