Lyme disease, or Lyme borreliosis, is a bacterial disease occurring worldwide, spread by ticks and manifesting in various organs.
The primary manifestation of Lyme disease is a characteristic skin rash known as erythema migrans (EM). Recognizing EM and starting antimicrobial medication without delay form the basis of treatment for preventing later symptoms. No laboratory tests are needed at this stage.
If there is an area of erythema more than 5 cm in diameter at the site of a tick bite and more than one week has elapsed since the bite, it should be regarded as EM.
About half of patients with untreated EM will have later manifestations of the disease.
At later stages, diagnosis must always be based on three factors: the possibility of having been bitten by a tick carrying Borrelia bacteria, clinical findings and laboratory tests.
The clinical picture shows varying progression. Various symptoms may occur simultaneously. The main skin, nervous system and musculoskeletal symptoms caused by borreliosis should be kept in mind.
There is a separate guideline for antimicrobial treatment of later stages of the disease.
Persistent or chronic Borrelia infection is extremely rare in patients who have received appropriate treatment. If diagnosis and treatment are significantly delayed, symptoms associated with the convalescent phase may occur after the infection has been cured. In such cases repeated antimicrobial treatments are not indicated.
Prevalence
In Finland, thousands of people every year have a primary infection. The incidence is about 120 cases per 100 000 persons per year.
Based on laboratory samples, slightly over 2 000 cases of later stages are reported annually in Finland. The average incidence has been about 40/100 000, but great variation exists between different regions of the country.
Because of travel and the long latency period of the late stages of the disease, patients with Lyme disease may be encountered anywhere in Finland. Due to the climate warming, ticks exist in more northern areas than before.
The incidence of Lyme disease in various areas depends on the frequency of ticks, the extent to which they carry Borrelia (0 to 40%) and the lifestyles of the population. About 1 tick bite in 50 causes disease.
Lyme disease has been reported in North America, all over Europe and parts of Asia.
Infection
Lyme disease (LD) is caused by the spirochete Borrelia burgdorferi sensu lato and its subspecies. The most common species in Europe are B. afzelii, B. garinii and B. burgdorferi sensu stricto, as well as B. bavariensis and B. spielmanii. In the USA, nearly all cases are caused by B. burgdorferi sensu stricto. New and potentially pathogenic Borrelia species found in ticks are B. valaisana of the group B. burgdorferi s.l. and B. miyamotoi of the febris recurrentis group.
Spirochetes are transmitted to humans through the bite of an infected tick (Ixodes ricinus). In Finland, another type of tick, the so-called taiga tick (Ixodes persulcatus) has been seen in places. The taiga tick may also be a vector of Borrelia bacteria but has more significance in spreading a more dangerous eastern form of tick-borne encephalitis.
Borrelia bacteria are spread by adult ticks and by nymphs that are more difficult to detect.
In most cases, the infection initially produces no symptoms. Infection occurs slowly, within 12 to 72 hours after the bite.
As being infected with Borrelia will not produce immunity, repeated infection may lead to repeated disease.
Symptoms
At an early stage, borreliosis causes local skin symptoms. Spirochetes spread into tissues and within 6 months about 25% of untreated patients show second phase symptoms of borreliosis of the nervous system, joints or skin. Ocular and cardiac borreliosis do occur in Europe but relatively rarely.
If early infection is not treated, as many as 50% of patients may develop late symptoms. These may occur several weeks, months or even years after the EM skin rash. Absence of a rash does not necessarily exclude disseminated disease.
Early skin manifestations of Borrelia infection
Erythema migrans (EM) skin rash
Erythema migrans, "migrating redness", (pictures 12345678) is an early local manifestation of Borrelia infection, occurring in about 75% of all cases. It appears within a few days to a couple of weeks after tick bite. EM often expands and disappears within a few weeks but it may persist for a couple of months or even longer.
EM is not a dermatological disease but the first stage of Borrelia infection.
EM spreads centrifugally around the bite and may appear annular, homogeneous or as a "bull's eye lesion". Local symptoms, such as itching, lymphadenitis or pain, are mild, occurring in about 50% of cases. Unspecific general symptoms, such as fatigue, joint or muscle pain or a slight rise in body temperature are even rarer.
If there is an area of erythema more than 5 cm in diameter at the site of a tick bite and more than one week has elapsed since the bite, it should be regarded as EM. The lesion should not be confused with a small area of erythema around the bite that is caused by tissue irritation and subsides within a few days.
Even erythema with a diameter of less than 5 cm may be due to EM if it occurs at the bite site after a period without symptoms and is expanding.
EM is the only phenomenon due to borreliosis that can be identified purely clinically and treated immediately without the need for further examinations. Antibody assays are not useful for diagnosis.
Early spread of infection is very common: culture or PCR have shown 40 to 50% of patients to already have Borrelia in their blood at the EM stage.
EM may sometimes also be absent or appear to be so (because the bite is at a site where it goes undetected, such as a skin fold).
Foreign body granuloma may develop after tick removal due to parts of the tick's mouth remaining in the skin. Treatment is surgical.
Multiple lesions
EM may cause multiple lesions, in children more often than in adults. If so, it should be classified as disseminated Lyme disease.
25% of children with multiple EM have been found to have mild lymphocytic pleocytosis (presence of an abnormally large number of lymphocytes) in their CSF.
5 to 15% of patients have multiple lesions (picture 9), which is a sign of early hematogenic spread of infection from the bite site. These should also be treated without delay and without laboratory tests (cf. below).
Benign cutaneous lymphocytoma
Lymphocytoma is a rarer (less than 10%) form of cutaneous borreliosis appearing later than EM as a soft, painless, bluish or reddish swelling (picture 10). It may appear at or near the tick bite (in which case it is classified as disseminated infection) in soft tissue, such as the earlobe, nipple or scrotum. Lymphocytoma is 3 times more common in children than in adults.
Borrelia antibodies are found in serum in nearly every case. In unclear cases, histological examination is necessary.
Lymphocytoma rarely resolves without treatment.
Chronic atrophic acrodermatitis (ACA), late cutaneous form of borreliosis
ACA is a late form of disseminated cutaneous Lyme disease (pictures 1112), 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.
Diagnostic work-up
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.
Clinical details
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.
Treatment
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.
Amoxicillin 500 mg 3 times daily for patients weighing less than 70 kg, and 1 g 3 times daily for those weighing more than 70 kg Treatment of Early Lyme Disease. More even plasma levels are achieved by dosage three times rather than twice daily.
Phenoxymethyl penicillin (penicillin V) is not recommended because the serum concentrations reached with it are possibly not high enough to prevent the spirochetes from spreading into the central nervous system in the EM phase.
Children
50 mg/kg body weight per day of amoxicillin divided into three daily doses, see above
For children over 8 years 4 mg/kg doxycycline once daily
Azithromycin has been recommended as a second-line alternative in children. Consulting a specialist in infectious diseases or a paediatrician is recommended.
Doxycycline should always be prescribed with caution because of its adverse effects, especially sensitivity to sunlight. As always, clear and accurate instructions for administration should be given.
Pregnant women
Lyme borreliosis during pregnancy has not been shown to damage the fetus. Nevertheless, the importance of treating the infection also in pregnant women should be generally emphasized.
The recommended drug is amoxicillin, 500 mg 4 times daily for 14 to 21 days.
If a pregnant woman has LD, a specialist in infectious diseases should always be consulted!
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.
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.
Persistent symptoms after treatment
If symptoms persist after appropriate treatment of Lyme disease, they are most often caused by something other than continued Borrelia infection. This condition is often inappropriately called 'post-treatment Lyme disease', which may be misleading because the patient is going through symptomatic recovery from the infection and may possibly also have even permanent tissue damage.
The feared chronic active Borrelia infection is highly unlikely in patients treated according to guidelines. The situation is challenging for a physician and requires thorough assessment by experienced experts.
Patients may suffer from fatigue, cognitive dysfunction and impaired exercise tolerance as long as 3 to 6 months after the treatment of neuroborreliosis. This does not indicate continued infection, and further antimicrobial treatment is not warranted.
Symptomatic treatment, planned rehabilitation and support are important for avoiding chronic fear of borreliosis.
After Lyme arthritis, persistent arthritis may continue in the absence of infection, and the situation may not have improved after 2 months despite two appropriate courses of treatment. The causative mechanism behind such arthritis resistant to antimicrobial drugs is not fully understood. Individual characteristics related to the regulation of inflammatory reactions, such as the HLA-DR4 genotype, are often decisive. In animal tests, molecules of Borrelia antigen, without living bacteria, have been found to have established themselves in tissues, causing inflammatory reactions. This, however, does not mean a chronic infection.
The condition name "post-Lyme disease syndrom" or PLDS should be used with caution, since often the symptoms may be caused by some other underlying aetiology that has not been noticed in differential diagnosis.
Symptoms should never be downplayed; they may be due, for example, to permanent tissue damage or other disease. Psychophysical stress is another possible cause but this should not be used as an excuse for stopping examinations too soon.
Prevention
Ixodes ricinus thrives in forests, smaller wooded areas rich in alder trees, grass areas, pastures, meadows, and generally in terrain favoured by its host animals and in moist micro-atmosphere.
Obviously, the best prevention is to avoid being bitten by ticks. There are no ticks in rocky and dry terrain and there is thus no danger in such areas.
When walking in terrain favoured by ticks, the middle of the footpath should be used and long trousers (light-coloured to help identifying the ticks), tucked into the socks, should be worn.
The skin should be inspected and any ticks removed every day.
An embedded tick should be mechanically removed by pulling it straight out with tweezers. Scraping off embedded ticks should be avoided, as parts of ticks may remain in the skin and cause a purulent infection. Such remaining parts will eventually come out spontaneously with wound discharge. The method of removing the tick is not currently considered to influence the risk of Borrelia infection.
An embedded tick should be detected and removed within the first day, as the risk of infection increases with time.
Experiments have been performed with vaccines against Borrelia burgdorferi in many places, including Finland. So far, the development of a practicable vaccine has not been successful.
Pictures
References
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