Lyme Disease Differential Diagnoses

  • Author: John O Meyerhoff, MD; Chief Editor: Burke A Cunha, MD   more...
 
Updated: Sep 27, 2011
 
 

Diagnostic Considerations

In most patients with erythema migrans, a carefully elicited history (including definitions of epidemiologic context) and a physical examination are all that is required to establish the diagnosis. However, although many patients with Lyme disease present with erythema migrans, others first present with extracutaneous symptoms, possibly due to erythema migrans never having occurred or it was not recognized by the patient or correctly diagnosed by the physician.

Epidemiologic and seasonal context is extremely important in elucidating the diagnosis of Lyme disease, and a number of important details are diagnostically useful, such as associated symptoms, and the size, shape, location, evolution, and color and morphology of lesions.

Go to Pediatric Lyme Disease for complete information on this topic.

Associated symptoms

A paucity of pain or pruritus exists in most patients. When present, these localized symptoms tend to be mild. Associated systemic symptoms include low-grade fever, chills, fatigue, and neck stiffness. Very high fever or toxicity suggests an alternative diagnosis or an additional tick-borne infection such as babesiosis or ehrlichiosis.

Size

Erythema migrans varies in size (lesions are up to 70 cm; median is 16 cm). Some of the conditions in the differential diagnosis (eg, bacterial cellulitis) become more unlikely with larger lesions, especially in a patient who does not appear ill. Although the Centers for Disease Control and Prevention (CDC) surveillance criteria for erythema migrans state that it must be greater than 5 cm in size, culture-proven cases have been occasionally documented that are smaller,[22] and this size cutoff is only meant to be used for epidemiologic purposes.

Shape

Erythema migrans typically is round or oval and monocyclic. Occasionally, lesions can be triangular or linear, but this is seen less frequently.

Location

Location of the bite is an important diagnostic clue. Ticks tend to feed in areas in which natural barriers prevent their forward progress, such as the popliteal fossa, groin, and axilla, or in areas in which elastic clothing or bra straps impede their journey. The thorax and trunk are also common spots. In children, the hairline and scalp are especially common locations.

Evolution

Erythema migrans usually enlarges by a few centimeters per day and eventually fades within a few weeks, even without antibiotic treatment. Occasionally, the rash can be fleeting. Erythema migrans does not enlarge over hours, and it very rarely remains constant over weeks to months.

Color and morphology

Most lesions are red. Although central clearing has been emphasized in the past, the color of the lesion more commonly is uniform. Occasionally, the center is darker than the periphery. Lesions usually are flat but may be slightly raised (see the image below). Scaling does not usually occur. In some patients mistakenly treated with topical steroids, the rash may be quite pale.

The rash on the ankle seen in this photo is consisThe rash on the ankle seen in this photo is consistent with both cellulitis (deep red hue, acral location, mild tenderness) and erythema migrans (July presentation in an area highly endemic for Lyme disease). In this situation, treatment with a drug that covers both diseases (eg, cefuroxime or amoxicillin and clavulanate combination) is one effective strategy.

Special Considerations

Failure to diagnose Lyme disease correctly can result in legal ramifications, as malpractice cases have been brought centering on missed diagnoses of Lyme disease. Carefully complete the process of differential diagnosis. Monitor patients to ensure that the disease resolves in both early-stage and late-stage disease. Lack of resolution with antibiotics suggests an error in diagnosis, lack of compliance with the treatment by the patient, or inadequate therapy.

Differential Diagnoses

  • Ankylosing spondylitis and rheumatoid arthritis
  • AV nodal block
  • Babesiosis, human granulocytic anaplasmosis (previously termed ehrlichiosis), and Rocky Mountain spotted fever
  • Bacterial and viral meningitis
  • Cellulitis, contact dermatitis, and granuloma annulare
  • Chronic fatigue syndrome and fibromyalgia
  • Confusional states and acute memory disorders
  • Gout and pseudogout
  • Prion-related diseases
  • Systemic Lupus Erythematosus
Proceed to Workup
 
 
Contributor Information and Disclosures
Author

John O Meyerhoff, MD  Assistant Professor, Department of Internal Medicine, Johns Hopkins University School of Medicine; Clinical Scholar in Rheumatology, Department of Medicine, Sinai Hospital of Baltimore

John O Meyerhoff, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD  Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Additional Contributors

Lawrence H Brent, MD Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, and American College of Rheumatology

Disclosure: Abbott Honoraria Speaking and teaching; Centocor Consulting fee Consulting; Genentech Grant/research funds Other; HGS/GSK Honoraria Speaking and teaching; Omnicare Consulting fee Consulting; Pfizer Honoraria Speaking and teaching; Roche Speaking and teaching; Savient Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching

Eugene Y Cheng, MD, FCCM Consulting Staff, Department of Anesthesiology, The Permanente Medical Group

Disclosure: Nothing to disclose.

Jonathan A Edlow, MD Associate Professor of Medicine, Department of Emergency Medicine, Harvard Medical School; Vice Chairman, Department of Emergency Medicine, Beth Israel Deaconess Medical Center

Jonathan A Edlow, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Cindy R Hennen, RPh Assistant Director of Clinical Pharmacy Practice, Froedtert Hospital, Medical College of Wisconsin

Disclosure: Nothing to disclose.

R Philip Kinkel, MD, FAAN Associate Professor of Neurology, Harvard Medical School; Director, Multiple Sclerosis Center, Beth Israel Deaconess Medical Center; Consultant Neurologist, Children's Hospital of Boston

Disclosure: Nothing to disclose.

Kristine M Lohr, MD, MS Professor, Department of Internal Medicine, Center for the Advancement of Women's Health and Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

Tarun Madappa, MD, MPH Attending Physician, Department of Pulmonary and Critical Care Medicine, Elkhart General Hospital

Tarun Madappa, MD, MPH is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society

Disclosure: Nothing to disclose.

Augusto A Miravalle, MD Fellow, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School

Augusto A Miravalle, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Christen M Mowad, MD Associate Professor, Department of Dermatology, Geisinger Medical Center

Christen M Mowad, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Wendy Peltier, MD Program Director, Assistant Professor, Department of Neurology, Medical College of Wisconsin

Disclosure: Nothing to disclose.

Julie L Puotinen, PharmD Clinical Coordinator of Pharmaceutical Services, Department of Pharmacy, Clinical Instructor, Saint Luke's Medical Center

Disclosure: Nothing to disclose.

Karen L Roos, MD John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Karen L Roos, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Nothing to disclose.

Michael J Schneck, MD Associate Professor, Departments of Neurology and Neurosurgery, Stritch School of Medicine, Loyola University; Associate Director, Stroke Program, Director, Neurology Intensive Care Program, Medical Director, Neurosciences ICU, Loyola University Medical Center

Michael J Schneck, MD is a member of the following medical societies: American Academy of Neurology, American Society of Neuroimaging, Neurocritical Care Society, and Stroke Council of the American Heart Association

Disclosure: Boehringer-Ingelheim Honoraria Speaking and teaching; Sanofi/BMS Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; UCB Pharma Honoraria Speaking and teaching; Talecris Consulting fee Other; NMT Medical Grant/research funds Independent contractor; NIH Independent contractor; Sanofi Grant/research funds Independent contractor; Boehringer-Ingelheim Grant/research funds Independent contractor; Baxter Labs Consulting fee Consulting

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Suyung Wu, MD Consulting Staff, Neuroscience Department, Elkhart Clinic

Suyung Wu, MD is a member of the following medical societies: American Academy of Neurology and American Academy of Sleep Medicine

Disclosure: Nothing to disclose.

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Normal and engorged Ixodes ticks.
Erythema migrans, the characteristic rash of early Lyme disease.
Magnified ticks at various stages of development.
Erythema migrans in a woman who presented to the emergency department after treatment with cephalexin for 2 days, which was prescribed by another physician for treatment of cellulitis. On history, she was found to live in an endemic area for ticks and to pull ticks off her dog daily. The location and size of the rash are typical of erythema migrans and the central punctum can be seen at the lateral margin of the inferior gluteal fold. The uniform color is common.
Hematoxylin and eosin stained section from a biopsy performed at the periphery of an eruption from a woman with erythema migrans who presented to the emergency department after treatment with cephalexin for 2 days. Note the perivascular lymphocytic infiltrate, a pattern that is not specific for, but is characteristic of, erythema migrans.
Photomicrograph demonstrates perivascular infiltrate in a biopsy specimen from the border of an erythema migrans lesion (hematoxylin and eosin stain). Courtesy of J. Edlow.
Photo of the torso of a young man who had been working outdoors in northern New Jersey in late June. He was under treatment for a spider bite, although he did not have a history of a bite and had no pain, as is typical in a spider bite. The location, size, and epidemiologic context favor a diagnosis of erythema migrans. Examination was remarkable for a palpable right axillary lymph node. His symptoms resolved within 48 hours of initiating doxycycline.
Photo of the left side of the neck of a patient who had pulled a tick from this region 7 days previously. Note the raised vesicular center, which is a variant of erythema migrans. The patient had a Jarisch-Herxheimer reaction approximately 18 hours after the first dose of doxycycline.
Classic target lesion with concentric rings of erythema, which often show central clearing. Although this morphology was emphasized in earlier North American literature, it only represents approximately 40% of erythema migrans lesions in the United States. This pattern is more common in Europe. Courtesy of Lyme Disease Foundation, Hartford, Conn.
Typical appearance of erythema migrans, the bull's-eye rash of Lyme disease.
Bulls-eye rash.
rash. Courtesy of M. Fergione, B. Tucker, and L. Zernel; Pfizer Laboratories
Borrelial lymphocytoma of the earlobe, which shows a bluish red discoloration. The location is typical in children, as opposed to the nipple in adults. This manifestation of Lyme disease is uncommon and occurs only in Europe. Courtesy of Lyme Disease Foundation, Hartford, Conn.
Acrodermatitis chronica atrophicans is found almost exclusively in European patients and comprises an early inflammatory phase and a later atrophic phase. As the term suggests, the lesion occurs acrally and ultimately results in skin described as being like cigarette paper. Courtesy of Lyme Disease Foundation, Hartford, Conn.
: Photo of erythema migrans on the right thigh of a toddler. The size and location are typical of erythema migrans, as is the history of the patient vacationing on Fire Island, NY, in the month of August. No tick bite had been noted at this location. Approximately 25% of patients with Lyme disease are children, which is the same percentage of patients who do not recall a tick bite. Courtesy of Dr John Hanrahan.
Multiple lesions of erythema migrans occur in approximately 20% of patients. A carpenter from Nantucket who worked predominantly outside had been treated with Lotrisone for 1 week before presenting to the emergency department with the rashes seen in this photo. The patient had no fever and only mild systemic symptoms. He was treated with a 3-week course of oral antibiotics.
The rash on the ankle seen in this photo is consistent with both cellulitis (deep red hue, acral location, mild tenderness) and erythema migrans (July presentation in an area highly endemic for Lyme disease). In this situation, treatment with a drug that covers both diseases (eg, cefuroxime or amoxicillin and clavulanate combination) is one effective strategy.
Blood smear showing likely babesiosis. Babesiosis can be difficult to distinguish from malaria on a blood smear.
This is an ECG from a 21-year-old man with severe weakness and near syncope. Ten days earlier, while in upstate New York, he had a febrile illness without rash. No tick bite was known to occur, and the serologic result for Lyme disease was negative at the time. Seroconversion occurred when this ECG was obtained. He was admitted to a telemetry unit, had a temporary pacemaker inserted, and was given 2 g of intravenous ceftriaxone daily. He was well and did not need the pacemaker after 4 days
The bacterium Borrelia burgdorferi (darkfield microscopy technique, 400X; courtesy of the US Centers for Disease Control and Prevention).
To remove a tick, use fine-tipped forceps and wear gloves. Grasp the tick as close to the skin surface as possible, including the mouth parts, and pull upward with steady, even traction. Do not twist or jerk the tick because this may cause the mouth parts to break off and remain in the skin; however, note that the mouth parts themselves are not infectious. When removing, wear gloves to avoid possible infection. Children, elderly persons, and immunocompromised persons may be at greater risk for infection and should avoid removing ticks if possible. A common misperception is that pressing a hot match to the tick or trying to smother it with petroleum jelly, gasoline, nail polish, or other noxious substances is beneficial. This only prolongs exposure time and may cause the tick to eject infectious organisms into the body. Additionally, using lidocaine (subcutaneously or topically) may actually irritate the tick and prompt it to regurgitate its stomach contents. Finally, do not squeeze, crush, or puncture the body of the tick because its fluids (saliva, hemolymph, gut contents) may contain infectious organisms. Once the tick is removed, wash the bite area with soap and water or with an antiseptic to destroy any contaminating microorganisms. Additionally, the person who removed the tick should wash his or her hands.
Tick-borne disease prevention can be divided into environmental and personal measures. Patients exposed to tick-endemic areas should wear long-sleeved, light-colored clothing when outside. Lighter colors allow for easier identification of ticks. Chemical repellents with DEET (N,N-diethyl-3-methylbenzamide) and picaridin are available in numerous over-the-counter skin preparations as sprays or lotions. Permethrin is an acaricide that can be applied to clothing and is used in conjunction with chemical repellents. All individuals should perform regular skin checks. Ticks prefer warm, moist areas, such as the beltline, groin, and axilla, although in children, the hairline is a common site. Environmental prevention involves clearing underbrush and spraying acaricides in the spring around property sites. These measures prevent both mice and ticks from encroaching on properties. Studies involving the treatment of wild deer and mice have not been conclusive in reducing tick-borne diseases in humans. Currently, no Lyme disease vaccines are available in the United States. Lyme disease vaccine (Lymerix™) was discontinued in 2002, so some patients may still have residual protective antibodies. Image courtesy of the National Library of Medicine.
Approximately 90% of Lyme disease cases are reported from the northeastern and upper midwestern United States. A rash that can be confused with early Lyme disease sometimes occurs following bites of the lone star tick (Amblyomma americanum). These ticks, which do not transmit the Lyme disease bacterium, are common human-biting ticks in the southern and southeastern United States.
Peripheral smear showing babesiosis.
 
 
 
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