Clue to what makes lyme bacteria tick

During this time, she had two episodes of a swollen right knee which lasted for more than 1 month. Physical examination revealed skin involvement of the distal parts of the limbs: distal to the midpoint of the left upper arm, distal to the right elbow and distal to the middle of the right lower leg. In the proximal parts of the involved skin, the changes were disseminated in the form of patches, while more distally skin was involved homogeneously.

The skin was bluish, atrophic, in some parts—in particular on the back of her hands—it was wrinkled, translucent and with numerous prominent veins. A neurologist diagnosed the presence of polyneuropathy, X-ray examination disclosed subluxation of fingers of the right foot.

Histologic examination of the skin revealed teleangiectasias, interstitial infiltration of the dermis and subcutaneous tissue with lymphocytes and plasma cells and thin hyperkeratotic epidermis.

Serological testing revealed high levels of specific IgG serum antibodies. Comment: A course of ACA with the involvement of skin, peripheral nerves and joints. The lesion is most often located on acral parts of the body, usually on the extensor part of hands or feet, and initially is usually unilateral, later on it may become more or less symmetrical.

A previous other manifestation of Lyme borreliosis is usually not recalled by these patients. ACA is more often diagnosed in women than in men and occurs only very exceptionally in children. Patients are usually over 40 years old Asbrink and Hovmark ; Strle et al. Because of the long incubation time and the long duration of the skin lesions prior to diagnosis, a history of tick bites is not supportive. Histological findings in the early lesions are non-specific perivascular lymphocytic infiltrates; the epidermis is frequently thinned.

Band-like and perivascular infiltrates consisting of lymphocytes and plasma cells are seen in the upper and middle portions of the dermis, often combined with oedema de Koning and Duray Dilated blood vessels can be found in the superficial dermis. Peri-articular fibroid nodules may be present in the deeper portions of the dermis extending into the subcutaneous fat. The nodules consist of a homogeneous eosinophilic centre surrounded by irregular fascicles of collagen, onion-like.

Perivascular infiltrates of lymphocytes and plasma cells are present predominantly in the peripheral parts of the lesion, and fibrosis is pronounced. In the late stage of ACA, cutaneous atrophy is present with more or less pronounced inflammation Fig.

In very long-standing atrophic lesions, the inflammatory infiltrates are sparse or may even be absent; collagen and elastic fibres are strongly reduced and degenerated. In general, histologically constant findings in active ACA lesions are telangiectases and a lymphocytic infiltrate with a moderate-to-rich admixture of plasma cells Asbrink, Hovmark and Olsson ; Asbrink et al. However, the histopathological pattern is not diagnostic in itself Brehmer-Andersson, Hovmark and Asbrink Clinically, the involved region is usually oedematous; initially erythema and swelling may vary in intensity.

In some patients, the cutaneous manifestations are confined to a heel that is swollen, sometimes discoloured and painful Asbrink et al. After the initial months to years, the oedema slowly vanishes and gradually atrophy becomes more and more prominent.

The skin becomes increasingly vulnerable, thin and wrinkling, with prominently visible underlying vessels. When exposed to a cold environment, the skin becomes pronouncedly bluish. Band-like fibrous indurations may occur in the involved regions, usually in ulnar or tibial regions, or they may be nodular, preferably localised prepatellarly or next to the olecranon Asbrink, Hovmark and Olsson ; Asbrink et al.

In some cases of ACA, sclerotic lesions are clinically and histologically indistinguishable from localised scleroderma morphea or lichen sclerosus et atrophicus. About every tenth patient with typical inflammatory ACA also has a lichen sclerosus et atrophicus-like lesion Asbrink and Hovmark , and the histopathological picture of some of these patients is compatible with that of lichen sclerosus et atrophicus Asbrink, Hovmark and Olsson , Asbrink et al.

Peripheral nerves and joints are quite often involved in the regions of affected skin Asbrink and Hovmark Sensory and motor mononeuropathy or polyneuropathy or patchy dysaesthesia may develop at the site of the cutaneous lesions. A smaller proportion of patients with long-lasting disease show periosteal thickening of bones similar to dactylitis syphilitica in the late phase of syphilis Asbrink, Hovmark and Olsson ; Asbrink et al.

Bursitis of the knee or elbow, epicondylitis, retro- or subcalcaneal bursitis and Achilles tendinitis may precede or accompany ACA Asbrink and Hovmark ; Herzer The proper diagnosis of ACA is based on clinical, serological and histological criteria. Absence of IgG antibodies to B.

Histological examination of the involved skin additionally consolidates the diagnosis. Routine laboratory tests are usually in the normal range and thus not of substantial diagnostic help. The diagnosis of ACA can be further supported by the isolation of B. Fibrous nodules may be misinterpreted as rheumatoid nodules and gout or even as erythema nodosum.

A borrelial aetiology of scleroderma circumscripta and lichen sclerosus et atrophicus, sclerotic skin lesions of unknown aetiology, has been implicated on the basis of humoral and cellular immune responses to B. However, proof of the aetiological role of B. Further, the results of a case—control study in Denmark and Sweden suggest an association between B. However, researchers from the USA did not find any such association in molecular or epidemiological studies Munksgaard et al.

Although the association has not been scientifically confirmed, the European Organization for Research and Treatment of Cancer and the International Society for Cutaneous Lymphoma suggest in a consensus paper that cutaneous marginal-zone lymphoma in European areas endemic for B. However, the efficacy of antibiotic treatment in borrelia-associated primary cutaneous marginal-zone lymphoma is poorly documented.

LNB appears mostly early, during the first few weeks or months after infection, only rarely appearing late in the course of Lyme borreliosis. Early LNB typically shows lymphocytic meningitis and involvement of cranial and peripheral nerves. Case 6. A year old farmer—who remembered several tick bites each year—became unwell in the middle of July.

He suffered from myalgia, joint pain and mild headaches, was tired and occasionally very sleepy. At the end of September, after a short improvement for about 3 weeks, he developed chest pain, which expanded in extent during the first few days and became more and more intense.

He reported an approximately 25 cm wide belt with a burning sensation over the upper part of the abdomen and lower part of the thorax that became worse during the night. It was hard for him to move because of the pain. He became impatient, agitated and experienced episodes of weeping for no obvious reason.

He felt exhausted and totally without willpower. Problems were especially severe at night. For nearly 4 weeks, he was almost sleepless. There was no fever, no headache and no nausea. He visited his doctor several times but examinations revealed no abnormality. Sedatives and painkillers did not bring any relief.

At the end of September, a day before admission to the hospital, he noticed that he was not able to close his left eye, to raise his left eyebrow, to frown on the left side of his forehead and that the left side of his mouth was not moving properly.

On admission to hospital, the patient moved slowly and very carefully; he was in distress and seemed to be exhausted. He had left-sided peripheral facial palsy, but no other significant abnormality was found. Meningeal signs were not expressed. Results of the blood tests were within normal limits.

CSF was clear, open pressure was normal. Comment: Typical presentation of meningoradiculoneuritis Gadin-Bujadoux-Bannwarth syndrome with radicular pain, peripheral facial palsy and lymphocytic pleocytosis. The syndrome has been known in Europe for more than 90 years, i. Borrelial aetiology was definitely established by the isolation of B. Meningoradiculoneuritis is the most prominent clinical manifestation of LNB in adult patients in Europe. It begins gradually with increasing pain, later on accompanied by palsies and other neurological signs and symptoms that will, if untreated, not diminish for many weeks Kristoferitsch, Spiel and Wessely ; Pachner and Steere ; Kristoferitsch , ; Hansen ; Stanek et al.

Radicular pain is the most pronounced clinical symptom of meningoradiculoneuritis; it is usually severe and most intense during the night. In children isolated meningitis and peripheral facial palsy are more common than in adults.

In addition, involvement of motor nerves may lead to paresis Kristoferitsch ; Hansen ; Hansen, Crone and Kristoferitsch Case 7. A year-old boy felt completely well during the first few weeks after a tick bite. However, 6 days after the bite he noticed a small redness at the site of the bite on his right thigh. After 3 weeks, it spontaneously disappeared.

Six weeks after the tick bite, headaches, nausea, vomiting and low fever appeared. The patient became sensitive to light and had pain when moving the eyes.

The headache was predominantly frontal and varied in intensity. Five days later, he was admitted to the hospital due to the suspicion of aseptic meningitis. The only abnormalities found on admission were that he looked tired, had a body temperature of The diagnosis of borrelial meningitis was indicated by the history of EM and was further supported by the demonstration of serum antibodies to B.

The patient was treated with doxycycline mg bid for 14 days and had an uneventful recovery. Comment: Characteristic presentation of borrelial CNS involvement in a child. Patients with borrelial meningitis usually suffer from mild intermittent headache, resembling relatively mild but unusually protracted viral meningitis with intermittent improvements and deterioration. Excruciating headache occurs exceptionally. In adult patients, fever, nausea and vomiting and meningeal signs are usually absent Kristoferitsch ; Hansen ; Stanek and Strle Protein concentration is normal or slightly to moderately elevated; glucose concentration is usually normal or mildly depleted.

Case 8. An year-old girl was bitten by a tick while collecting blueberries in June. No skin lesion developed at the site of the bite.

Three days later, similar changes occurred on the other side of her face. She had no headache, no vomiting nor fever. At examination bilateral peripheral facial palsy was established. Meningeal signs were absent; basic laboratory blood tests were in normal range. CSF examination revealed normal opening pressure. She was treated with i. Comment: In about half of patients with borrelial meningitis, peripheral facial palsy develops.

In some patients, the paralysis is bilateral; in such cases, pareses usually do not appear at the same time. Patients often report a tingling sensation on the affected side and pain around the ear or jaw. Disorder of taste is rare facial nerves are usually affected distally from the branching of the chorda tympani nerve. Palsies are of sudden onset, lasting from a few days to several months average 8 weeks ; they usually heal spontaneously and completely.

Borrelial peripheral facial palsy responds very well to antibiotic treatment but prognosis is also good in untreated patients Pachner and Steere ; Hansen However, in clinical and neurophysiological examination, mild sequelae were found in about half of Swedish children who had borrelial peripheral facial palsy 3—5 years earlier Bagger-Sjobak et al. Shortly after onset of neurological symptoms, intrathecal synthesis of antibodies may not be detectable and CSF pleocytosis may be absent especially in children with isolated facial palsy Millner et al.

Involvement of most other cranial nerves has been described, particularly nervus oculomotorius, n. A close topical association between the cutaneous region of the tick bite, subsequent EM and the radicular lesion has been established in European patients Kristoferitsch et al.

An unusual manifestation of LNB is pseudotumour cerebri which is seen primarily in children Steenhoff et al. Encephalitis resulting from a B. Subtle encephalopathy has been reported predominantly by American authors Logigian, Kaplan and Steere LNB in Europe is most often caused by B.

The clinical presentation of patients with a CSF culture-proven B. Borrelia garinii causes what, in Europe, is diagnosed as typical early LNB i. In contrast to the B. The findings of the study might indicate that, although B. The significance of this genospecies in LNB remains to be elucidated. Histopathological findings in the CNS are limited. In peripheral neuropathy accompanying ACA, lymphocytes and plasma cells are present around blood vessels in the perineurium, with occasional sparse lymphocytes in vessel walls which show no signs of necrosis but may become thickened and obliterated, thrombosis may develop de Koning and Duray Fibres within the nerve eventually lose myelin.

The most striking finding is axonal degeneration Kristoferitsch et al. Late LNB is most probably very rare. The only exception is peripheral neuritis in association with ACA. Peripheral neuritis occurs in more than half of patients with long-lasting ACA Kristoferitsch , Careful sight of the literature suggests that peripheral neuritis without ACA is an extremely rare condition, if it exists at all Hansen, Crone and Kristoferitsch ; Wormser et al.

The diagnosis of early LNB should be based on clinical characteristics, the presence of lymphocytic pleocytosis and demonstration of CNS borrelial infection, as evidenced by intrathecal production of antibodies against B. Wilske et al. Further, procedures for DNA detection are not standardised and may give false-positive results Wilske et al.

In everyday European clinical practice, demonstration of intrathecally synthesised antibodies to B. However, physicians should be aware that intrathecal synthesis may not be demonstrable shortly after the onset of LNB Hansen ; Aguero-Rosenfeld et al.

In the presence of strong clinical evidence together with CSF pleocytosis and preceding EM, the clinician should stay with the clinical diagnosis despite absence of proof of intrathecal antibody production. This may be demonstrable in later samples. Differential diagnosis comprises a list for each main manifestation of LNB, such as meningitis, radiculoneuritis, cranial nerve involvement and so forth.

However, an exact medical history and meticulous clinical examination can often substantially narrow the possibilities. Case 9. A year-old previously healthy housewife was bitten by a tick in the middle of May. At the end of May, intermittent migratory myalgia and arthralgia appeared and a month later burning belt-like pain in the middle of the chest emerged; the pain was very severe and nearly unbearable at night.

The patient was not able to sleep and was suicidale due to pain. She also had difficulties with concentration and thinking and was afraid of making mistakes when performing even the simplest daily tasks. She did not have headache, nausea or fever. On 27 August, she woke up with pressing retrosternal pain spreading to the neck. She was dizzy when standing up but dizziness disappeared when she lay down.

She was examined at the emergency department and admitted to hospital. ECG showed second degree atrio-ventricular A-V block.

Ultrasound examination of heart revealed no substantial abnormalities. In the following 2 days, the patient had changing third to second degree A-V blocks. On 31 August, the block was predominantly of second degree and occasionally also of first degree, and on 1 September only first degree A-B block was registered. In the following week, P-Q interval shortened from ms to normal values.

The further clinical course was smooth and the outcome was uneventful. From the second day of hospitalisation, the patient was treated with ceftriaxone 2 g i. The diagnosis of Lyme carditis was substantiated by high levels of IgG serum antibodies to B. Comment: A typical course and outcome of Lyme carditis. In patients with suspected Lyme carditis, the diagnostic approach should include active search for other manifestations of Lyme borreliosis such as EM and LNB and exclusion of other explanations for cardiac abnormalities.

Heart involvement related to a borrelial infection usually presents with the acute onset of varying degrees of intermittent atrioventricular A-V heart block, sometimes in association with clinical evidence of myopericarditis Steere et al. The frequency of heart involvement in relation to the other manifestations of Lyme borreliosis appears to be very low Rubin et al. No evidence of carditis was found among cases with definite Lyme borreliosis in two prospective studies evaluating a recombinant OspA vaccine in the USA Sigal et al.

In an epidemiological study in southern Sweden, only 7 of 0. Histopathology shows interstitial infiltrates of lymphocytes and plasma cells involving the myocardium, pericardium and endocardium. Muscle fibres are usually intact Steere et al.

The heart conducting system may show localised oedema and slight lymphocytic infiltration of sinoatrial and A-V nodes, focal oedema in the bundle of Hiss, fibrotic lesions, and vasculitis of small and large intramyocardial vessels de Koning and Duray ; Fish, Pride and Pinto Spirochaetal forms have been found in endomyocardial biopsy de Koning et al.

Lyme carditis occurs between June and December, usually within 2 months after the onset of infection, men being affected more often than women Steere et al. The prognosis is usually favourable Sigal Hospitalisation is needed for patients with first-degree A-V block with P-Q interval longer than 0. In a case of complete heart block, insertion of a temporary heart pacemaker may be life saving. Diffuse ST segment and T wave changes on surface electrocardiograms were noted in the majority of a first series of patients with Lyme carditis Steere et al.

In most cases, myocardial dysfunction is mild and self-limited Steere et al. The isolation of B. However, there is as yet no convincing evidence of such an association. The diagnosis also requires corroboration by demonstration of borrelial infection; in practice the presence of typical manifestation s of Lyme borreliosis such as EM or LNB is the most reliable.

A diagnosis of Lyme carditis should be further substantiated by the absence or exclusion of other obvious explanations for cardiac abnormalities. Case A year-old accountant developed migratory myalgias and arthralgias in mid of September that he attributed to pronounced physical activities during the previous months. At the beginning of October, he woke up with severe pain in the right knee.

The joint was heavily swollen, warm, skin colour was normal. The pain, which was quite severe at rest, deteriorated with movement. He was treated with anti-inflammatory drugs. Five days later, and 2 days before right knee swelling vanished, effusion of his left knee appeared, and somewhat later the right ankle became painful and swollen.

The duration of attacks of individual joint involvement was 5—14 days. Synovial fluid culture was negative for the presence of bacteria, and no crystals were found.

However, the patient had high serum IgG antibody levels to B. The patient was treated with doxycycline mg bid for 4 weeks. Before the end of antibiotic therapy, attacks of arthritis vanished and later on he only occasionally had mild-to-moderate arthralgias of large joints.

Lyme arthritis is mostly monoarticular or oligoarticular, typically involving the knee. In Europe, the aetiological relationship of certain cases of arthritis to a B.

However, Lyme arthritis has ever since been considered a less common manifestation in Europe than in the USA. Seven per cent of patients diagnosed with Lyme borreliosis in a study from southern Sweden had Lyme arthritis Berglund et al.

The isolation rate of borreliae from joint fluid and synovia is very low; thus, data on the infecting agent are based predominantly on molecular detection of borrelial DNA in synovial fluid or synovial tissue.

The genospecies identified in Lyme arthritis cases in Europe were B. The synovial fluid from 13 of 20 patients with the diagnosis of Lyme arthritis in Germany was processed for borrelial DNA by OpsA typing and revealed B.

Similar results were obtained in another study from Germany where B. Acute arthritis results from Borrelia -induced infiltration of mononuclear cells into the synovial tissue and the accumulation of neutrophils, immune complexes, complement and cytokines in the synovial fluid.

In untreated Lyme arthritis, host factors involved may include autoantigens like endothelial cell growth factor and apolipoprotein B, arthritogenic factors such as TLR2 and MyD88, adhesion molecules P66 that bind the extracellular matrix, decorin-binding proteins A and B, Bgp and BKK, T and B-cell responses to annexin A2, and annexin A2 autoantibodies Coburn, Fischer and Leong ; Guerau-de-Arellano and Huber ; Drouin et al. In addition, matrix metalloproteinases may be involved in the pathogenesis of erosive processes in the joint in long-standing infection and possibly also in antibiotic-refractory arthritis Hu et al.

Excessive TH17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory Lyme arthritis Strle et al. Persistent or antibiotic-refractory Lyme arthritis may be observed in a subset of patients who have already received standard antibiotic treatment. Models for the immune-pathogenesis proposed comprise persistent infection, T-cell epitope mimicry and bystander activation of T cells. However, none of these has enabled a complete explanation for all patients.

The aetiology is most probably multifactorial and may vary from patient to patient Steere and Glickstein ; Puius and Kalish The main and the most important joint manifestation of Lyme borreliosis is arthritis. Arthralgia may precede, accompany or follow arthritis but may sometimes be the only rheumatic manifestation of Lyme borreliosis.

Indicative of Lyme arthritis in Europe are the succession or coexistence of intermittent attacks of musculoskeletal pain and arthritis Herzer In a subset of patients, episodes of severe pain in joint and periarticular sites may precede arthritis for several weeks or months, or may precede and continue after arthritis, or may develop with arthritis.

Episodes of arthralgias may alternate with attacks of arthritis. Large joints are predominately affected but also small joints in an often migratory pattern; however, involvement of only small joints is very rare. Mostly only one or two sites are affected at any one time Herzer Arthralgias usually vanish during the first few weeks after standard treatment Cerar et al. The incubation period for Lyme arthritis, from tick bite to clinical manifestation, cannot be easily assessed.

In patients from North America who had EM without antibiotic treatment and were followed up for years, arthritis occurred from 4 days to 2 years after onset of infection, with a mean of 6 months Steere, Schoen and Taylor In a European series of patients, the period from tick bite or EM to the onset of arthritis ranged from 10 days to 16 months, with a mean of 3 months Herzer Lyme arthritis can be preceded or accompanied by other manifestations of Lyme borreliosis.

Results of a prospective epidemiological study of Lyme borreliosis in southern Sweden showed that of 98 patients diagnosed with Lyme arthritis 7. Six patients with arthritis had two additional main manifestations of Lyme borreliosis Berglund et al. For clinical diagnosis, it should be considered that Lyme arthritis usually consists of intermittent attacks of inflammation of one or a few large joints and is often preceded by intermittent migratory joint pain.

Joint involvement is usually asymmetric, the onset of arthritis is acute and with effusion, and skin over the affected joint is warm but of normal colour Steere, Schoen and Taylor The knee is most often involved. However, some patients with pronounced knee effusions have only mild pains Steere, Schoen and Taylor Joint inflammation usually lasts a few days to weeks, sometimes several months Steere, Schoen and Taylor The course of Lyme arthritis is usually recurring and may continue for several years.

Fatigue, malaise, low fever or night sweats may accompany Lyme arthritis in a small proportion of patients Herzer , Routine laboratory parameters are often completely normal in Lyme arthritis. Concentration of CRP is usually in the normal range.

The pronounced elevation of laboratory inflammation parameters in a patient with arthritis points strongly against Lyme arthritis. Some patients have slightly elevated counts of white blood cells, and some elevated serum IgM.

Cryoglobulins and circulating immune complexes may be present. Rheumatoid factors and antinuclear antibodies are usually negative. Synovial fluid shows elevated white cell counts with a range of 0. Total protein concentration commonly ranges from 3. Cryoglobulins and abnormal C1q binding consistent with antigen—antibody complexes are commonly present in synovial fluid Hardin and Steere ; Steere et al. Specific radiographic findings for Lyme arthritis have not been reported Lawson and Steere Serum IgG antibodies to B.

Serological investigation of synovial fluid is of no value because of the absence of a blood—synovial barrier; IgG antibody concentration in serum and synovial fluid will be the same.

What would additionally support the diagnosis of Lyme arthritis is the demonstration of borrelial DNA in synovial fluid or in synovial tissue. Diagnosis of Lyme arthritis is based on the medical history other manifestations of Lyme borreliosis such as EM, LNB or ACA , clinical features, laboratory findings, exclusion of other causes of arthritis and demonstration of serum IgG antibodies to B.

One should nevertheless be aware that IgG seropositivity is not diagnostic for Lyme arthritis as it does not inform about active or past infection nor about the location of the disease process. The differential diagnosis of Lyme arthritis includes inflammatory rheumatic diseases, bacterial septic arthritis, viral arthritis and crystal-induced arthritis Steere, Schoen and Taylor ; Herzer ; Rees and Axford Other differential diagnoses include psoriatic arthritis, early rheumatoid arthritis and systemic lupus erythematosus in patients who have borrelial antibodies in serum.

Musculoskeletal pain in Lyme borreliosis may be mistaken for psychogenic rheumatism or fibromyalgia. However, fibromyalgia is characterised by more generalised chronic pain and by symmetric tender points, and thus more often fibromyalgia in seropositive persons is often wrongly diagnosed as Lyme borreliosis Herzer Eye involvement in the course of Lyme borreliosis appears to occur very rarely and is associated with EM, LNB or Lyme arthritis, although it can be the sole manifestation of the disease Steere ; Strle ; Mikkila et al.

Often, the clinical ocular features may not be recognised Karma et al. Since human intraocular material is usually unavailable, serology remains the main diagnostic aid with all its interpretation problems. Onset of eye involvement is difficult to assess; the interval from EM may range from a few days to years. Primary borrelial-induced inflammation of the eye includes conjunctivitis, keratitis, iridocyclitis, retinal vasculitis, chorioiditis, optic neuropathy, episcleritis, panuveitis and panophthalmitis.

Secondary effects are results of extra-ocular manifestations of borrelial infection, including pareses of certain cranial nerves, pseudotumour cerebri and orbital myositis Steere et al. In later published cases of EM, conjunctivitis was reported only rarely or not mentioned at all. Intraocular involvement resulting from borrelial infection has been described in 19 European patients. To Read the Full Story. Subscribe Sign In. Continue reading your article with a WSJ membership.

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What this means, says de Silva, is that "the bacteria essentially adapts during the transmission process to maximize the chance of infecting the host. The team suggests that future efforts to develop better vaccines could focus either on antigens produced within the tick before the bacteria population diversifies or on surface proteins common to all of the otherwise variable bacteria.

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