eMedicine Specialties > Neurology > Neurological Infections

Lyme Disease: Differential Diagnoses & Workup

Author: Augusto A Miravalle, MD, Fellow, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School
Coauthor(s): 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
Contributor Information and Disclosures

Updated: Jul 23, 2009

Differential Diagnoses

Acute Disseminated Encephalomyelitis
Multiple Sclerosis
Alzheimer Disease
Persistent Idiopathic Facial Pain
Ankylosing Spondylitis
Prion-Related Diseases
Aseptic Meningitis
Toxic Neuropathy
Bell Palsy
Trigeminal Neuralgia
Confusional States and Acute Memory Disorders
Viral Meningitis
Fibromuscular Dysplasia

Other Problems to Be Considered

Atypical facial pain
Babesiosis
Bacterial meningitis
Chronic fatigue syndrome
Dementia
Depression
Gout or pseudogout
Human granulocytic anaplasmosis (previously termed ehrlichiosis)
Infectious mononucleosis
Mononeuropathy multiplex
Plant dermatitis
Radiculopathy
Reiter syndrome
Rheumatoid arthritis
Rocky Mountain spotted fever

Workup

Laboratory Studies

  • Laboratory diagnosis: According to US Centers for Disease Control and Prevention surveillance criteria, patients presenting with a clinical picture compatible with early LD (ie, erythema migrans, constitutional flulike symptoms) and a history of exposure to an area in which tick exposure is likely do not require laboratory confirmation of the disease before receiving treatment. Erythema migrans is the only manifestation of LD in the United States that allows clinical diagnosis in the absence of laboratory confirmation.
  • Serologic testing: Serologic testing typically involves enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assay (IFA). If results from either of these tests are positive or indeterminate, Western blotting should be performed to confirm LD.
    • Seroconversion can take as long as 6-8 weeks after a tick bite. The false-negative rate for ELISA is 32% in early disease. Vaccination with the LD vaccine and a variety of diseases, including Rocky Mountain spotted fever, syphilis, systemic lupus erythematosus, and rheumatoid arthritis, can cause false-positive results. Late disease is tentatively diagnosed when at least 1 objective clinical manifestation of disseminated disease is present and is supported by ELISA or IFA results. These tests have 89% sensitivity but only 72% specificity for detecting LD.
    • A positive result on Western blotting after ELISA or IFA is an indication for treatment. Likewise, a negative result is highly suggestive of a false-positive ELISA finding, and therapy is not indicated.
    • Inadequate antibiotic therapy for early LD can suppress the antibody response, potentially yielding a false-negative result on ELISA, IFA, or Western blotting. Serum concentrations of immunoglobulin M (IgM) antibodies usually peak 6-8 weeks after infection and disappear within 4-6 months, although levels sometimes remain elevated for several months or years. IgM titers are useful in evaluating early disease and are considered positive if 2 of the 8 most common bands associated with early disease (ie, 18, 21, 28, 37, 41, 45, 58, or 93 kd) are present.
    • In patients with a high probability of having early LD, IgM testing is 96% specific and 93% predictive. Immunoglobulin G (IgG) antibodies are typically detectable within 6-8 weeks after infection, peak within 4-6 months, and remain elevated indefinitely. In late-stage disease (>4-6 wk after infection), IgG results are more useful than IgM results and are considered diagnostic if 5 of 10 IgG bands common in late disease (ie, 18, 21, 28, 30, 39, 41, 45, 58, 66, or 93 kd) are present. Careful consideration of both IgG and IgM antibodies is essential because the IgG response may be negative in as many as 50% of patients (particularly those with early disease), whereas a persistence of IgM antibodies can lead to false-positive findings in patients infected for more than 1 month who subsequently receive effective treatment. Of note, serologic results can remain positive years after adequate treatment and cannot be used to distinguish active from inactive disease.
  • CSF evaluation
    • If a clinical diagnosis of neuroborreliosis is suspected, lumbar puncture is considered essential to evaluate the presence of specific antibodies to B burgdorferi.5
    • Although CSF cultures are positive in less than 10% of patients with apparent meningitis, intrathecal antibodies and a lymphocytic pleocytosis (approximately 100 cells/µL) are present in more than 80%. Patients with meningitis typically have elevated protein concentrations (>50 mg/dL) but normal glucose levels (45-80 mg/dL). Oligoclonal bands specific for B burgdorferi may be present.
    • Ongoing controversy surrounds the diagnosis of neurologic LD. One of the most important concepts to understand is that a positive LD serology in CSF does not mean that the person has neuroborreliosis. It could represent evidence of a previous infection or simply reflect potential leakage of serum antibodies across the blood-brain barrier.6
    • Intrathecal anti-Borrelia antibody production is typically seen within 3-6 weeks of infection.
    • Anti-Borrelia antibody CSF-to-serum index has recently shown a 97% specificity and 75% sensitivity for the diagnosis of neuroborreliosis7 CSF-to-serum index greater than 1.0 suggests synthesis of antibody in the CNS.
    • Recent publications propose that 4 of the following 5 criteria should be present in order to diagnose neuroborreliosis:7
      • No past history of neuroborreliosis
      • CSF anti-B burgdorferi antibodies
      • Positive anti-B burgdorferi antibody index
      • Favorable clinical outcome after proper antibiotic therapy
      • Absence of alternative diagnosis
  • Advanced techniques
    • LD multiplex polymerase chain reaction (PCR)
      • Lyme multiplex PCR has not been standardized; therefore, it is not currently used in routine testing.
      • PCR is used to detect B burgdorferi DNA in the blood, CSF, urine, or synovial fluid within weeks of infection.
      • The result is positive in approximately 30% of patients with active LD.
      • A notable disadvantage of PCR testing is the likelihood of false-negative results because of a sparsity of spirochetes in infected tissues. Likewise, inexperience with the PCR technique can yield false-positive findings when care is not taken to prevent contamination and when incorrect primers are used in preparing the specimen.
      • Although most PCR results become negative within 2 weeks of antimicrobial therapy, results can remain positive for years after apparent cure.
      • One of the most compelling uses of PCR may be in confirming persistent or recurrent disease because a positive result is highly specific for exposure to B burgdorferi.
    • LD urine antigen testing: This test has not been studied sufficiently. It has not been proven reliable or accurate and therefore should not be used as a diagnostic tool.
    • Flow cytometric borreliacidal antibody test: This test is used to detect highly specific borreliacidal antibodies that formed after exposure to B burgdorferi. The specificity of borreliacidal antibody test results far exceeds those of ELISA. One study of 572 patients showed a specificity of greater than 99%, although its sensitivity is marginal, at 72%. Although borreliacidal antibodies are detectable in the serum soon after infection, the number of antibodies increases with the duration and severity of illness; therefore, borreliacidal antibody testing is most useful in late disease. It should not be performed in patients who recently received antimicrobial therapy.

Imaging Studies

  • MRIs show abnormalities in approximately 15-20% of patients in the United States who have neurologic manifestations of LD.
    • Punctate lesions of the periventricular white matter are common and resemble changes seen in demyelinating or inflammatory disorders. In an attempt to differentiate radiological manifestations of neuroborreliosis and multiple sclerosis, a recent study proposed that occult brain tissue damage (seen by brain magnetization transfer and diffusion tensor magnetic resonance) are not common in neuroborreliosis, as opposed to multiple sclerosis.
    • Space-occupying lesions have also been reported as a rare manifestation.
    • In European patients with CSF-confirmed LD, imaging findings have suggested that microvasculitis and macrovasculitis in the CNS may be responsible for neurologic sequelae and the MRI changes seen in patients with neuroborreliosis.
    • Functional brain imaging, such as single-photon emission CT scanning, may contribute to the diagnosis of chronic neurologic LD.

Other Tests

  • Electrophysiologic studies: Abnormal results are often consistent with axonal degeneration in patients presenting with peripheral neuropathy in stage 3 disease.

Procedures

  • Approximately 60-80% of specimens isolated from the leading edge of a suspected erythema migrans lesion by means of saline-lavage needle aspiration or 2-mm punch biopsy reveal B burgdorferi. However, because the presence of a lesion along with a compatible history and clinical presentation are sufficient to initiate treatment, these skin biopsy procedures are seldom performed. However, histological examination is recommended in patients with suspected borrelial lymphocytoma, when the location of the lesion or the clinical history is not clear to make a diagnosis.

Histologic Findings

Marked perivascular lymphocytic and plasmocytic infiltration is a key histologic finding in all affected tissues. Lymphocytoma is characterized by marked lymphocytic infiltration replacing or nearly replacing the dermis.

Photomicrograph demonstrates perivascular infiltr...

Photomicrograph demonstrates perivascular infiltrate in a biopsy specimen from the border of an erythema migrans lesion (hematoxylin and eosin stain). Courtesy of J. Edlow.

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Photomicrograph demonstrates perivascular infiltr...

Photomicrograph demonstrates perivascular infiltrate in a biopsy specimen from the border of an erythema migrans lesion (hematoxylin and eosin stain). Courtesy of J. Edlow.

More on Lyme Disease

Overview: Lyme Disease
Differential Diagnoses & Workup: Lyme Disease
Treatment & Medication: Lyme Disease
Follow-up: Lyme Disease
Multimedia: Lyme Disease
References
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Further Reading

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Keywords

Lyme arthritis, Lyme borreliosis, Garin-Boujadoux-Bannwarth syndrome, Garin-Bujadoux-Bannwarth syndrome, Bannwarth syndrome, Borrelia burgdorferi sensu lato, B burgdorferi sensu lato, Borrelia burgdorferi sensu stricto, B burgdorferi sensu stricto, Ixodes ricinus, I ricinus, Borrelia garinii, B garinii, Borrelia afzelii, B afzelii ticks, tick-borne disease, Lyme disease

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Contributor Information and Disclosures

Author

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.

Coauthor(s)

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
R Philip Kinkel, MD, FAAN is a member of the following medical societies: American Academy of Neurology and Consortium of Multiple Sclerosis Centers
Disclosure: Nothing to disclose.

Medical Editor

Aashit K Shah, MD, Associate Professor of Neurology, Wayne State University; Program Director, Clinical Neurophysiology Fellowship, Department of Neurology, Detroit Medical Center
Aashit K Shah, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, and American Epilepsy Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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; Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Paraplegia Society, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Michael K Racke, MD, Professor of Neurology and Molecular Virology, Immunology, and Medical Genetics, Chairman of Neurology, Chief of Neurology Service, Ohio State University Medical Center
Michael K Racke, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for the Advancement of Science, American Association of Immunologists, and American Neurological Association
Disclosure: Teva Neuroscience Consulting fee Consulting; Peptimmune Inc. Consulting fee Consulting; Bristol Myers Squibb Consulting fee Consulting; EMD Serono Honoraria Speaking and teaching

 
 
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