About Lyme Disease:
Lyme Borreliosis (LB), the most frequent diseases transmitted by ticks in Europe and North America is a zoonosis, the etiological agent circulating in ticks from Ixodes ricinus species complex and a great variety of vertebrate animals. The reservoir animal gives the pathogen agent (Borrelia burgdorferi sensu lato) to the vector, that transmits it to another reservoir hosts or to humans that may accidentally invade the natural source and closes the infection cycle without turning into a reservoir hosts. The disease was previously described for the first time in 1977, in USA, even though mentioning of it exist in Europe starting with the end of 19th century, and recent molecular studies have identified DNA sequences of B. burgdorferi in “ice man” from Tyrol, a human body discovered in Alps , having an age of 5300 years. During the last years LB has become a public health problem in the northern hemisphere.
Epidemiology. The distribution of the disease is correlated with the presence of vector tick species, the disease being described in the temperate climate of northern hemisphere: North America, Europe, part of North Africa (Maghreb) and North Asia (Siberia, Japan, China and Korea).
Clinical signs. LB, “the disease with 1000 faces”, may affect a large variety of organs, and the clinical signs and the evolution may be different from one patient to the other.

  • Early Lyme Borreliosis
    • Early localized infection: the spirochetes ate localized at skin level; the symptoms of a viral infection and local adenopathy can be associated 
    • Early disseminated infection: organs where the spirochetes have disseminated are involved (skin tissue, nervous system, joints, heart)
  • Late Lyme Borreliosis (persistent infection): starts after months or years from infection, the diseases affecting joints, skin tissue and nervous system.

This staging has more a didactical value and it is not coordinated with the clinical practice and incorrectly suggests that the patient has to go through all stages. In reality LB follows a variable course with a large spectrum of symptoms and clinical signs.
Main clinical signs of Lyme Borreliosis (after Stanek et al., 2002).

Affected Organ

Clinical Sign


Migrating erythema
Multiple Migrating Erythema
Borrelia Lymphocytom
Atrophic chronic acrodermatitis

Nervous system

Meningioradiculonevritis (Bannwarth syndrome)
Cranial nerves paresis
Peripheral neuropathy

Musculoskeletal System





Conjunctivitis, keratitis, endophtalmitis, panophtalmitis

Skin symptoms

  • Migratory erythema (ME) is defined as an erythema skin lesion that develops in 7-10 days after the patient has been bitten by a tick, at the site of B. burgdorferi penetrates the skin. ME stats with a macula or a papulae at the biting site and transforms into an erythema plaque in several days. An elevated or an excavated area (punctum) may remain in the centre of the lesion (days, even weeks), or a clarified area may appear. A high percentage of the patients may present associated asthenia, myalgia, headaches, fever, shivers or local lymphadenopathy.
  • Multiple migrating erythema is caused by blood dissemination of initial infection and in characterized by two or more skin lesions similar in morphology to the initial one, but smaller and without center rough area.  
  • Borrelia Lymphocytoma. The aspect is of a tumoral lesion of reddish-blue color with a few centimeters diameter that appears after weeks/months after the tick bite. The favorite location is behind the ear, nipple and scrotum in children and breast in adults.
  • Chronic Artophic Acrodermatitis (CAA) is a chronic skin sign of LB. it appears more frequently in lower limbs, on dorsal sides of hands and legs. Initially color skin changes appear, sweats and painful edema. In a few months or years the edema disappears, the skin turns athropic, hyperpigmented or depigmented, and varicose tracks may have a prominent look. Peripheral nerves and joits may be also interested in the affected area.

Nervous system lesions
Lyme neuroborreliosis (LNB) can be classified in early LNB (signs and symptoms lasting less than 6 months) or late LNB (lasts between 6 months and several years) (Mygland et al., 2010).

  • Early Lyme Neuroborrelisis. Lesions of peripheral nervous system (PNS). Meningopoliradiculonevritis (Bannwarth syndrome) implies the inflammatory lesions of the meninges as well as the cranial and peripheral nerves. The most encountered clinical sign is pain as a result of the radiculonevritis. The lesions of the motor nerves get to paresis. Patients with meningitis report moderate headaches, the meningeal signs are light or absent, the evolution of the disease being similar to the viral meningitis. Facial nerve is the most affected one but other nerves can be also affected: oculomotor, trochlear, abducesn, vestibule-cochlear and optical. The lesions on the central nervous system (CNS) are rare as mielitis or encephalitis.
  • Late Lyme Neuroborreliosis. Implies the modifications of PNS (mononeuropaties, radiculopaties and polineuropaties) or of CNS (symptoms of disseminated encephalomyelitis that can look like the ones from multiple sclerosis).

Joints lesions
Spectrum of joints symptoms in LB can be classified in 3 categories:

  • (1) joints pain without clinical signs;
  • (2) joints pain with clinical signs;
  • (3) chronic lesions of the joints under the lesions of CAA. Symptoms tend to be migratory affecting mainly the large joints, especially knees, but are also possible the symptoms in small joints. Arthritis is mono- or oligo-, rarely poli. Up to 10% of Lyme arthritis from USA have not adequately responded to antibiotic therapy (in Europe, the epidemiogical data do not permit a correct appreciation of data). In case of these resistant arthritis immunopathogenetic mechanisms appear to be involved that are triggered by Borrelia burgdorferi infection.

Lyme Carditis
Most frequently it is presented as inetrminted atrio-ventricular block of varying degrees of acute onset. The complete heart block is the only cause is the only decease cause in LB patiente, and is a very rare event.
Ocular signs
The eyes may be primarily affected as a result of inflammation (conjunctivitis, keratitis, iridocyclitis, retinian vasculitis, corioretinitis, optical neuropathy, episcleritis, panuveita, panoftalmitis) or secondary as a result of extra-ocular manifestations like cranial nerve paresis or orbital myositis. Symptoms include pain, vision decrease, photophobia, diplopia or lack of accommodation.
Chronic Lyme Borreliosis
The term of Chronic LB is reserved to the patients with objective manifestations of late LB, like CAA, chronic arthritis and late NLB. It is not used for (Marques, 2008): (a) Symptoms with unknown causes without connection with Borrelia infection (even in presence of specific serum antibodies); (c) Symptoms with unknown cause, with specific Borrelia antibodies, but without history or clinical signs of LB; (d) Post Lyme disease syndrome (PLDS). The definition of PLDS has been proposed in American Society of Infection Diseases Guide (Wormser et al., 2006): appearance of subjective signs (fatigue, parestezia, cognitive signs, headaches, myalga, joints pain, sleep disorders) during 6 months after standard therapy of some well knowned signs of LB and their persistence more than 6 months. Symptoms are of high intensity and affect daily activities but the differential diagnosis is essential.
Lyme Borreliosis in pregnancy
At the moment, even if it is known that B. burgdorferi can be present in blood there are no data of any adverse fetal effects resulting in gestational.
Diagnosis of Lyme Borreliosis
Is based on epidemiological data (tick bites or exposure of endemic areas), clinical and direct or indirect laboratory methods for highlighting the etiological agent.
Direct methods for pathogen detection

  • Culturing. It’s performed on special mediums (different varieties of modified Kelly medium) from skin specimens, LCR, synovial liquid, blood, aqueous humor. The method sensibility is 10-30% in LCR, NBL, 50-70% in skin biopsies and <10% in blood, cardiac tissues, and in synovial fluid. Represents the attribution of research laboratories.
  • DNA amplification techniques. The sensibilities of this method is much lower in biological liquids than in tissues and depends from analyzed biological specimens.

Indirect methods for diagnosis
Currently in clinical practice the serology represents the first and mostly used laboratory method for diagnosis, performed in two steps: ELISA screening followed in case of positive or uncertain cases by immunoblot method (Western Blot). The application of immunoblot test for serodiagnosis of lyme borreliosis it’s rejected due to the increase of asymptomatic seroprevalence of pathogen when the clinical value of the results it’s decreasing.
The limits of the serological diagnosis. Sensibility. The ATC response in previous phase of LB could be low or absent, especially in the first phase of eritema migrans. Specificity. It’s influenced by: (1) the low level of cut-off; (2) cross-reactions with other antibodies (Syphilis); (3) IgM testing can give false-positive results due to the presence of rheumatoid factor. The observed oligoclonal stimulation in some infections (ex. EBV, Mycoplasma pneumoniae) may increase the antibody titer at a high number of antigens. IgM false-positive results were observed in clinical practice (ex. autoimmune diseases). One of the research studies shows a high frequency of IgM tested by immunoblot. It’s recommended the analyses the IgM specific antibodies in case of patients with signs and symptoms. Numerous tests are available without independent evaluation system. There are known variations between results of different tests and between batches of the same kit.
The detection of intrathecal antibody production

It’s recommended by European guidelines (Mygland et al., 2010) the support of the NBL. This requires measurement of specific antibodies in blood and LCR by quantitative methods, ELISA, followed by determination of the factor of intrathecal antibody index (IAI). The criteria for NBL diagnosis: (1) neurological symptoms (excluding other causes); (2) pleocytosis of liquid cephalorahidian; (3) Intrathecal produced Bb specific antibodies. This criteria are applicable in all cases of NBL manifestations with exception of late NBL  with polyneuropathy - in this case the next criteria should be applied: (1) peripheral neuropathy; (2) Clinical diagnosis of Acrodermatitis chronica atrophicans (ACA); (3) Bb specific antibodies in serum.

Recommendations in diagnosis of LB in clinical practice (Stanek et al., 2012)


Essential laboratory tests

Supportive laboratory tests

Supportive clinical data

Erithema migrans

ATC testing it’s not recommended. Exception: in case of atypical lesions  it’s recommended ATC testing in acute and  coavalescent-phase.

 B. burgdorferi  detection by culturing or PCR from skin biopsy*

Recognized tick bite

Borrelial lymphocitoma


Seroconversion or positive serology

Histology for neoplasm exclusion. Detection of B. burgdorferi  by culturing or PCR from skin biopsy*

Tick bites, recent or concomitant EM


High level of IgG specific ATC

Histology. Detection of B. burgdorferi  by culturing or PCR from skin biopsy*

LB well defined past manifestation.

Neuroborrelioza Lyme (NBL)

Pleocytosis and demonstration of intrethecal production of specific ATC. The serology tests are generally positives at presentation; in case of negative cases, convalescent serum will be tested (2-6 weeks)

Detection of B. burgdorferi  by culturing or PCR from LCR. Intrathecal synthesis of total IgM or IgG antibodies.

Recent or concomitant EM

Lyme Arthritis

IgG specific ATC in serum, generally in high concentrations

Synovial liquid analysis. Detection of B. burgdorferi  by PCR or synovial fluid or tissue culture

Past well defined LB manifestations

Lyme carditis

Specific antibodies in serum; in negative cases it will be tested the convalescent-phase serum (after 2-6 weeks)

Detection of B. burgdorferi  by PCR or endomyocardial biopsy culture*

Recent or concomitant EM and/or NBL

Ocular affectation

Specific antibodies in serum 

Detection of B. burgdorferi  by PCR or aqueous humor culture

Recent or concomitant manifestations of LB

* in research, it’s not recommended in clinical practice
Due to the sensibility, specificity, standardization and low reproducibility some of the tests are not recommended for diagnosis (Mygland et al., 2010):

  • Microscopic methods for B. burgdorferi visualization in LCR, blood,  tegument (darkfield microscopy, histological staining).
  • CXCL13 chemokine and specific antibodies detection in LCR, urinate, ATC detection which binds to circulate immune complexes, lymphocytes transformation tests after incubation with borrelial ATC, cyst in vitro formation in stress conditions (temperature, pH) or lymphocytes markers (lymphocyte subpopulations CD57+/CD3-).

Differential diagnosis it’s performed in function of organic damage:

Eritema migrans

Hypersensitive reaction after tick bite or insect;  tineea, erysipelas, hives, contact eczema, folliculitis, celulită, erythema multiforme, pityriasis rosea,  parvovirus B19 infection (children)

Borrelial lymphocitoma

Neoplasm breast cancer (location in the breast), B cell lymphoma, pseudolimfom


Skin aging, chronic vascular insufficiency, superficial phlebitis, acrcyanosis, livedo reticularis, lymphedema, rheumatoid nodules, tophus, erythema nodosum


Viral meningitis, other facial paresis cases, mechanical radiculopathy, multiple sclerosis, lupus erythematosus, neurosarcoidosis

Lyme Arthritis

Septic arthritis, gout, reactive arthritis, psoriatic arthritis, rheumatoid and enteropathy arthritis

Cardiac affectation

Infection causes or noninfectious cases of conduction disorders.

Treatment of Lyme borreliosis
Recommended antibiotics in LB therapy (Wormser et al., 2006; Hansmann, 2009; Mygland et al., 2010; Stanek et al., 2012).


Doze (adults)

Doze (children)

Preferred oral therapy


2x100 mg/day

it's not recommended < 8 years
>8 years, 4 mg/kg/day in 2 dose (max.100 mg/dose)


3x1000 mg/day

50 mg/kg/day divided in 3 (max.500 mg/dose)

Cefuroxim axetil

2x500 mg/day

30mg/kg/day in 2 dose (max.500mg/dose)

Alternative oral therapy


500 mg first day, 250mg/day after

20 mg/kg/day first day, 10 mg/kg/day after (max.500 mg/day)

Preferred parenteral therapy


2 g/ day intravenous dose only

50-75 mg/kg/day intravenous, dose only, max. 2 g

Alternative parenteral therapy

Cefotaxime *

2 g intravenous  at 8 h

150-200 mg/kg/day intravenous, 3-4 dose, max. 6 g/day

Penicillin G            

18-24 mil.UI/day intravenous at  4 h

200 000-400 000 UI/kg/day at 4 h, max.18-24mil UI/day

*Recommended therapy for patients with Lyme borreliosis.

Clinical manifestation



Eritema migrans
Borrelial lymphocitoma

Cefuroxim axetil

14 - 21 days

5 day

Multiple eritema migrans


14 day 
14  - 21 days

 Acrodermatitis chronica atrophicans


21 (14 - 30) days

Lyme carditis

Temporary pacemaker

14 - 21 days

Precocious or late NBL with SNC affection

Penicillin G            

14 - 30 days

Precocious or late NBL with cranial nerve affection, peripheryc or meningeal nerves


14 - 21 days

Arthritis without neurological disease


21 - 28 days

Recurrent arthritis after oral therapy


21 - 28 days

Antibiotic-refractory Lyme arthritis

Symptomatic NSAIDs

Ocular Lyme Borreliosis 


14 - 21 days

Post Lyme disease syndrome (PLDS)



The therapy for pregnancy women is administered in function of affecting organs with antibiotics allowed in pregnancy.
What must be done in case of symptom persistence after adequate antibiotic therapy of LB
Lack of therapy response suggests the possibility of an initial wrong diagnosis (ex. hypothyoidism, autoimmune disease, rheumatoid polimyalgia, multiple sclerosis) and the need of a clinical re-evaluation better than a new cure with antibiotics (Puéchal and Sibilia, 2009). In the case of an initial inadequate regime an antibiotic cure as indicated in guides is recommended. Patients management with persistent symptoms after adequate LB treatment:

  • a. EM that persist more that 3 months need skin biopsy
  • b. In Lyme arthritis corticosteroids intra-articular administration is efficient in reduction of the intra-articular collection and reduction of symptoms. Systemic cortico-therapy is not indicated, instead NSAI are indicated, reducing the symtomatology.
  • c. It is difficult to establish a cause – effect relation between B. burgdorferi infection and poli-neuropathy except CAA because 5-25% of healthy persons can present anti B. burgdorferi antibodies and poli-neuropathy is a frequent common condition with diverse etiology. In this situation an anti-microbial therapy is used, but with a reduced efficiency (Mygland et al., 2006).
  • d. Persistence of the symptoms after antibiotic therapy of LB is a well debated and studied phenomenon, a subject being the irreversible affection of nervous system especially if the disease has evolved for a long period of time. At the moment, repeated and prolonged cures are not indicated because their lack of efficiency and possible side effects (catheter infections, lung embolism, digestive hemorrhages, enterocolitis with Clostridium difficile). In these patients management pain killers, neuropathic pain therapy, psychological support.

Therapy of patients with no symptoms but positive serology
There is no data sustaining the use of antibiotics in case of patients with no symptoms but with positive serology to Borrelia (seroprevalence varies according to area endemicity and to occupational or recreational risk). In the context of erroneous or contradictory information that they receive, patients keep returning, requesting cure repeating because of the positive serology persistence or of clinical signs. Patient must be informed of the risk of a prolonged antibiotic therapy that have no proven efficiency and with possible adverse reactions. Public presentations of some patients with degenerative neurologic signs such as amyotrophic lateral sclerosis or multiple sclerosis as being LB does nothing but creates confusion and fear from the patients. An important role in LB management is played by doctors with other specialties that must know the aspects concerned by limits of serological tests (false positive results, high seroprevalence in healthy population). Because anti B. burgdorferi antibodies can persist 10 to 20 years after first infection (Kalish et al., 2001), and seroprevalence in general population is low, in these patients evaluation other facts must be taken into account: co-morbidities, physiologic aging, stress, publicity regarding LB.
Polymorphism of clinical manifestations is indeed a known fact, but removal of any other diagnosis, as long as positive serology persists, may deprive the patient of specific therapy, for other treatable disease. Stanek et al. (2011) says about LB: “Public perception of the disease in Europe has been distorted by media and activist groups by exaggerating some data regarding the disease’s pathogenicity and difficulties in diagnosis and treatment. Even if it is true that LB may raise some diagnosis and treatment problems, many of those result from a wrong diagnosis of LB in patients with other diseases. This may appear by lack of specificity of some clinical signs of the disease but also by the fact that some laboratories use non-standardized diagnosis methods”.

Lyme Borreliosis Prophylaxis

  • Prevention of tick bites. The best existing method of prophylaxis for B. burgdorferi infection is represented by avoiding and reduction of time spent in tick infested area. In case in which this is not possible protective clothes are recommended (long sleeves shirt, long trousers tucked in socks, boots, light colored clothes) and of repellents. Repellents can be chemical (DEET, permetrin, picaridin) or botanical components (citronella, eucalyptus oil).
  • Removal of attached ticks. Attached ticks must be extracted as soon as possible because the risk of infection transmission rises significantly after 24 hours of attachment. It is indicated to use pointed tweezers (to grad the tick as close to the skin and to eliminate the risk of pressure on the body, followed by regurgitation) and the tick is extracted directly up, with no twist. In cases in which parts of the tick’s head remain in the skin their extraction is not recommended, only the local disinfection. The use of chemical methods (alcohol, oil, acetone) or physical ones (matches, duck tape) are not recommended because of their inefficiency and they induce regurgitation. After extraction the area is disinfected. Signs and symptoms of early BL are looked for (EM or pseudo-flu syndrome) in the next 30 days. Evaluation by molecular diagnosis of B. burgdorferi infection of ticks is not indicated because: not all attached ticks are detected, proof of infection in tick does not mean presence of human disease, PCR methods are not standardized.
  • Chemical prophylaxis. In Europe, based on existent studies antibiotic prophylaxis in not recommended and “wait and watch” politics is preferred, respectively tracking the patient. Antibiotic therapy is indicated just in case of disease signs.
  • Antibodies testing at biting moment and at 3-6 weeks, followed by antibiotic therapy in case of seroconversion are not indicated because of serological testing limits. Besides, seroconverions does not mean disease, proven by the large number of positive serology in endemic areas.
  • Vaccination. At the moment there is no available vaccine against LB.
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