Lyme Borreliosis (LB)

Early skin manifestations of Borrelia infection

Chronic atrophic acrodermatitis (ACA), late cutaneous form of borreliosis

• ACA is a late form of disseminated cutaneous Lyme disease (pictures 11 12), appearing several months or years after infection, most often on the extensor surfaces of arms or legs.
• Unspecific signs include slowly developing blueish swelling of the skin and atrophy developing with time. Fibrotic lumps can often be found. The inflamed area may be tender and painful. Local sensory nerve disorder is common. Symptoms in joints and tendons are common.
• In ACA patients, antibody tests are always positive. In unclear cases, histological examinations and PCR study of skin biopsy specimen should be performed.
• There is a wide range of differential diagnoses: nodular gout, rheumatoid arthritis, chronic venous insufficiency, scleroderma, etc.

Neuroborreliosis, early and late

• Early neuroborreliosis is the most common clinical form of disseminated infection and appears within 6 months after the bite, often at the EM stage, already.
• The infection damages peripheral and cranial nerves, most often through axonal mononeuritis but also through neuritis affecting the brachial or lumbosacral plexus.
• CNS infection appears as meningitis with few symptoms or as painful meningoradiculitis (Bannwarth's syndrome).
• A rare but important form of acute borreliosis is cerebral vasculitis, which is associated with circulatory disturbances and causes TIA or stroke symptoms. Pleocytosis in the CSF may lead to the diagnosis of borreliosis.
• Encephalitis observed in MRI or symptomatic myelitis is present in less than 10% of patients with neuroborreliosis.
• If neuroborreliosis is suspected, the examinations needed to confirm the diagnosis or for differential diagnosis must be performed before treatment but without delaying it.
• Facial nerve palsy caused by Borrelia is a form of peripheral neuroborreliosis; about two patients in three are found to have lymphocytic meningitis. Immediate antimicrobial treatment is needed. This must be distinguished from Bell's palsy Peripheral Facial Paralysis, requiring quite different treatment (immediate administration of glucocorticoids).
• Neuroborreliosis is considered late if the symptoms have continued untreated for more than 6 months. Tissue damage will then have proceeded, focal symptoms may have developed and there may be permanent functional impairment. If the ependyma, the inner lining of the brain, is inflamed, obstructive hydrocephalus may develop.

Musculoskeletal symptoms of borreliosis

• Migrating joint and muscle pain may already occur at the EM stage of borreliosis, without any objective evidence of inflammation. The symptoms disappear as the skin rash is treated.
• If the primary stage is not treated, children as well as adults may develop arthritis a few weeks or months (6 months, on an average) after tick bite. This is often preceded by general symptoms and pain around the joints, as well as in muscles and tendons. Patients typically have fluctuating mono- or oligoarthritis of large joints with abundant fluid. They may simultaneously show symptoms of tendinitis, bursitis or enthesitis but with notably little pain or local inflammatory symptoms. Lyme arthritis is rarely seen in several joints at a time.
• Symptoms continue for several weeks or months, calm down for a few weeks and recur. This pattern may continue for a couple of years, after which spontaneous recovery may occur. After initial symptoms, chronic erosive arthritis causing permanent functional impairment occurs in less than 3% of patients.
• Patients with Lyme arthritis are usually in good general health. Slightly elevated body temperatures and local lymph node reactions are relatively frequent. The joint is swollen and tender, often with abundant fluid, and the local skin temperature is elevated. Swelling impairs movement.
• The differential diagnosis includes various types of reactive arthritis, psoriatic arthropathy, other forms of bacterial arthritis, viral arthritis, osteoarthritis, gout, pseudogout, atypical rheumatoid arthritis, sarcoidosis, trauma, etc. It is important to perform immediately any differential diagnostic examinations that are required.
• Unspecific inflammatory markers, i.e. ESR, blood leukocytes and plasma CRP, are usually only slightly elevated.
• If Lyme arthritis is suspected, intra-articular glucocorticoid injections should not be given.
• Arthritis responds well to antimicrobial treatment: more than 90% of patients recover. Persistent arthritis resistant to antimicrobial drugs is rare.

Principles

• The absolute requirements for the diagnosis of borreliosis are
  • exposure (knowledge that the patient has moved in terrain where tick bite is possible)
  • clinical symptoms consistent with Lyme disease
  • serological findings.
• Erythema migrans forms the only exception to these. EM should be diagnosed and treated without preceding laboratory tests. This also applies to multiple lesions.
• Serology is the most important diagnostic tool for identifying disseminated or late Lyme disease. The principal laboratory test is the determination of specific antibodies to one or more Borrelia antigens.
  • Different laboratories still use different serological methods and antibodies. Therefore, the laboratory should always provide instructions for interpretation or, alternatively, an individual statement based on the clinician's referral.
  • The use of recombinant antigens is recommended.
  • The testing should be based on the assay of Bb IgG antibodies.
  • IgM antibodies are not useful for diagnosis and have not been shown to reflect disease activity.
  • Assaying Borrelia antibodies in CSF is very important and should be done without too much hesitation because antibodies may be produced in the CNS in patients with minor clinical symptoms.
  • If doubts remain as to the specificity of detected antibodies, for instance, the result can be confirmed by immunoblot assay, which can usually be performed on the first sample stored at the laboratory.
• Increased concentrations of the chemokine CXCL13 in CSF are a sign of active inflammation. See Central nervous system neuroborreliosis below.
• Detection of Borrelia DNA by PCR is an accurate method for examining untreated patients. However, it should be remembered that this test measures DNA, not just live bacteria. The test done on a skin biopsy sample is valuable for the diagnosis of EM, lymphocytoma and ACA, with a sensitivity of 70 to 80% and specificity of nearly 100%.
  • PCR is a good further examination particularly for the diagnosis of Lyme arthritis. When performed on synovial fluid, the sensitivity of PCR is 65 to 90%, on synovial biopsy samples even higher, and its specificity is close to 100%.
• Borrelia culture is not clinically feasible due to the long incubation time and low sensitivity.
• In areas endemic for Borrelia, seropositivity is common in the population, reducing the diagnostic specificity considerably. In hyperendemic regions the prevalence of seropositivity may be 50% or even higher, particularly in older age groups, and even in less endemic areas it may be 5 to 10%.
• The probability of Lyme disease should be assessed in advance according to the Bayesian principles, i.e. considering the epidemiological situation, time from infection to symptoms and clinical picture. The probability is low (20%) if the clinical picture is vague and there is no history of exposure to ticks Laboratory Diagnosis of Lyme Disease. The probability is moderate (50%) if there is a history of tick exposure and neurological or joint symptoms. The probability is high (80%) if in addition to exposure and symptoms, tick bite and EM have been observed. If the probability exceeds 80%, treatment must be started without delay (picture 13).
• Pharmacies sell rapid tests to detect the presence of Borrelia bacteria in a tick. These are, however, not to be recommended because the tests are poorly documented. In addition, only a fraction, i.e. about 7.5% of bites by ticks that carry Borrelia bacteria lead to an infection. Using these tests and starting antimicrobial medication in every positive case would thus lead to significant overtreatment. Therefore, ESGBOR (European Study Group for Lyme Borreliosis) explicitly advises against using these and other rapid tests http://www.escmid.org/fileadmin/src/media/PDFs/3Research_Projects/ESGBOR/Tick_tests_discouragement_ESGBOR2013.pdf.
• Tests suggested by some, such as so-called direct microscopy, ELISPOT, CD57+ NK cells, or Borrelia antigen-induced IL-1 production by macrophages should not be used, since they have been found unfit for the purpose.

Erythema migrans (EM)

• No laboratory tests are needed to diagnose erythema migrans. All patients with erythema exceeding 5 cm in diameter are immediately treated. An erythema less than 5 cm in diameter is monitored for a week and treated if it grows, or if a known bite is followed by an asymptomatic period and the erythema appears only after the asymptomatic period. In uncertain cases the situation may be further monitored for a couple of days; the erythema grows approximately 1 cm/day. If there are general symptoms, however, treatment may be started immediately. A patient with multiple lesions (see above) is always treated immediately.
• If, for some reason, it is necessary to try to make an objective diagnosis of EM, Borrelia DNA in a skin biopsy sample can be examined by PCR technique. This is not a routine examination and must not delay the beginning of treatment.
• Lymphocytoma at the tick bite site is diagnostic for primary borreliosis and requires immediate treatment. Histological examination, PCR and antibody assay may be necessary for differential diagnosis.

Neuroborreliosis

Peripheral neuroborreliosis

• Facial nerve palsy is the most typical manifestation of peripheral nervous system borreliosis. It may begin soon after infection, during EM already, when serum IgG antibodies may still be negative. Positive IgM antibodies may be suggestive but are not suitable for diagnosis here, either. Facial nerve palsy does not always mean that the patient has meningitis; CSF is normal in about 30% of cases.
• CSF assays and examinations of intrathecal antibody production are important.
• For differential diagnosis versus other peripheral nerve damage, such as axonal neuropathy and plexitis, electrophysiological examinations, for example, are needed.
• In Lyme neuritis, IgG antibodies are positive but the examination is not sufficiently specific for diagnosis.

Central nervous system neuroborreliosis

• The symptom picture is very multifaceted, and same symptoms occur also in other infections of the central nervous system, which is why serological testing is necessary.
• CSF must always be examined.
• Lymphocytic pleocytosis in CSF is a definite diagnostic finding.
• Serum and CSF concentrations of IgG Borrelia antibodies should be examined. Serum IgG antibody concentrations are always increased 4 weeks after the onset of symptoms.
• Intrathecal antibody production should be calculated. In CNS neuroborreliosis, the index is elevated 10 to 14 days after the onset of symptoms. After neuroborreliosis, the index may remain elevated for several years, which reduces its diagnostic usefulness.
• Increased concentrations of the chemokine CXCL13 in the CSF are a useful and important general sign of inflammatory activity, with clearly increased concentrations in CNS neuroborreliosis. This can be found earlier than pleocytosis and an elevated antibody index, and helps decisively in diagnosis. Slight increase is also seen in patients with multiple sclerosis (MS), the clinically isolated syndrome (CIS) and optic neuromyelitis, as well as in viral and bacterial meningitis. In addition to borreliosis, high levels are also seen in syphilis and meningeal lymphoma.
• Imaging (cranial MRI) should be considered for differential diagnosis.

Lyme arthritis

• Serum IgG antibody concentrations are always clearly increased. There is no point in determining antibody levels in synovial fluid because they are at the same level as in serum.
• Synovial fluid PCR is recommended.
• Blood and synovial fluid tests and imaging for differential diagnosis form part of the diagnostic workup.

Acrodermatitis

• Serum IgG antibody concentrations are always increased.
• The histological findings are typical, and PCR of a skin biopsy sample is an alternative that can be recommended for diagnosis.

Mere tick bite without any kind of symptoms suggestive of Lyme borreliosis

• There is no indication for an antimicrobial drug in a healthy patient!
• Serological examinations are not performed. Even seroconversion would not be a sign of a disease in the absence of symptoms.
• During pregnancy, prophylactic antimicrobial treatment may be considered if exposure to ticks is probable (consult a specialist in infectious diseases).

Primary stage (EM or lymphocytoma)

• The treatment duration is usually 2 weeks. It may be extended to 3 weeks if symptoms are still present at the end of the normal period of treatment.
• Three weeks of medication are recommended for the treatment of multiple lesions.
• The drug of first choice is amoxicillin or doxycycline.

Disseminated and later stages of Lyme disease

• The most common duration of treatment is 21 days but if symptoms persist, extending the treatment to four weeks may be considered. Excessive durations of treatment should be avoided.
• ACA and Lyme arthritis are usually treated with oral amoxicillin or doxycycline.
• Oral treatment can be used for neuroborreliosis if no more than 4 to 6 weeks have elapsed since the onset of symptoms and there are no focal symptoms.
• For persistent symptoms and/or long delay or for patients with focal symptoms, 2 g ceftriaxone i.v. should be given once daily for 21 days. If ceftriaxone needs to be interrupted, treatment can be continued with oral antimicrobial agents.

Assessment of treatment results

• Assessment of response to treatment requires patience from both patient and doctor. The main criterion is the final clinical status, which can often only be seen 2 to 3 months after the end of treatment.
• IgM antibody assays are not useful here, either, and are therefore unnecessary.
• Decrease of IgG antibody concentrations to no more than a half of baseline concentrations indicates successful treatment, but this may take as long as 6 months and occurs in only 50% of cases.
• Assay of the inflammatory marker CXCL13 in CSF if useful; the concentrations decrease significantly as soon as 2 weeks after successful treatment even if pleocytosis persists.
• Borrelia DNA may be found by the PCR method as late as one or two months after antimicrobial treatment but it may consist of spirochete debris and does not, in principle, show continued infection.