Lymes disease

Lyme borreliosis (LB) is a zoonotic disease caused by Gram-negative bacteria Borrelia burgdorferi sensu lato (B. burgdorferi s.l.), belonging to the Spirochaetaceae family. A typical clinical picture of LB may include symptoms involving skin, joints, nervous system, and more rarely heart and eyes. Some infected patients are asymptomatic. The majority of reported cases of LB originate in the northern hemisphere, mostly in the US and Europe. Clinical presentation of LB includes three stages: early localised infection, early disseminated infection, and late disseminated infection. Various musculoskeletal symptoms may be present in a wide array of conditions, while the presence of anti-borrelial antibodies in the general population could contribute to misdiagnosis. Lyme arthritis (LA) is one of the fundamental LB symptoms; it can be defined as the presence of arthritis with swelling and pain of one or several large joints, sometimes also pain in tendons, muscles, and/or bones in patients with serologically confirmed LB.

Erythema migrans

Lymes disease Summary

There are approximately 300,000 new Lymes disease (LD) cases reported each year in the United States. The disease is reaching near epidemic proportions, especially in the Northeast and upper Midwest, where LD cases appear to cluster. These patients with suspected (or diagnosed) LD are showing up in pain practices in increasing numbers and tend to fall into 4 categories. The first category encompasses patients who have pain and documented LD by serologic test results. The second category is composed of patients with pain without an identifiable, obvious cause, in whom serologic testing later documents the presence of disseminated LD. The third category includes patients who investigated LD on their own and determined they may have it based on symptoms that are compatible with disseminated LD (unconfirmed). The fourth category encompasses pain patients with post-treatment Lymes disease syndrome (PTLDS), which presents as an autoimmune disorder that progressively destroys tissue, such as joint cartilage.

Pain treatment of LD generally follows the step-up regimen of multimodal analgesic therapy with oral and topical agents. A chronic infectious or autoimmune disorder always is accompanied by inflammation, making NSAIDs essential. Clinicians are reminded to incorporate physical and complementary modalities to improve function, diminish pain, and enhance patient well-being. All pain practitioners should educate themselves about LD and its treatment, and stay abreast of future clinical recommendations.

Pathogenesis Of Lyme Arthritis (la)

The basis of LA pathogenesis is a strong inflammatory reaction. This reaction results in a perivascular collection of lymphocytes, macrophages, as well as scattered mast cells in the interstitium, typically found on histopathology in patients with severe LA. The inflammatory reaction is paramount in LA development because Bb spirochetes do not produce toxins. It has been suggested that in an inflammatory reaction, this leads to progressive degradation of aggrecan by host mechanisms, advancing chondral destruction and subsequent joint damage in LA.

Three Stages Of Active Infection

Infection following a tick bite causes 3 stages of disease:

Stage One -Early Localized (3-30 days after tick bite)

  • Bull’s-eye rash
  • Heat, Inflammation
  • Chills and fever, flu-like symptoms (headache, muscle and joint aches, and swollen lymph nodes)

The early localized infection causes a rash called “erythema migrans,” commonly called a “bull’s-eye rash,” which eventually resolves, even without antibiotic treatment. Although diagnostic following a tick bite, the rash only occurs in about half of LD cases. In the early stages of infection, the spirochete can spread to other tissues and organs (eg, skin, nervous system, joints, and heart), causing more severe symptoms. LD has a predilection to attack the facial nerve and cause Bell’s palsy. The disease also commonly affects the neck and cervical spine, causing pain, stiffness, headache, and possible radicular symptoms. Joint, muscle and nerve pain begin to occur during active infection, with the knee being a favoured site of joint pain.

Stage Two- Early Disseminated (untreated infection days to weeks after tick bite)

  • Expanded rash (up to 12 in across)
  • Pain in the bite area
  • Paralysis, weakness in face muscles (Bell’s palsy)
  • Severe headache and neck stiffness (meningitis)
  • Pain and swelling in large joints
  • Muscle pain
  • Heart palpitations

Stage Three- Late Disseminated (months to years after tick bite)

  • Abnormal muscle movement (spasms)
  • Joint swelling/pain (arthritis)
  • Myalgia
  • Numbness and tingling
  • Cognitive impairments
  • Neuralgia
  • Weakness

The late, disseminated stage of infection is characterized by neurologic manifestations and severe arthritic pain in the joints. There may be shooting pains, myalgias, numbness or tingling in the hands or feet, insomnia, and problems with short-term memory. Tragically, the spirochete may have a predilection for the central nervous system (CNS). Once infected, CNS LD may cause several symptoms that may mimic other neurologic diseases, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. Many physicians refer to CNS infection by LD as “neuroborreliosis.”

Clinical Presentation

Musculoskeletal symptoms may appear in any of the three stages, even early localised infection, often leading to miscategorisation of patients into the wrong stage.

In the early localised stage, during which erythema migrans (EM) is a classic symptom, some patients experience migratory muscle and joint pain. Nadelman et al., in a prospective assessment of 79 patients with culture-confirmed EM, showed the presence of myalgia and arthralgia in almost half of the cases (correspondingly, 44% and 44%). Those symptoms are a non-specific reaction of the immune system to the infection and cannot function as a basis for diagnosis of LA.

In the early disseminated stage, arthritis may appear from a few days to months after the point of infection. The time between tick bite and the onset of LA may vary. In the US, in patients having exhibited EM and not treated with an antibiotic, LA developed in a period of 4 days to 2 years, 6 months on average; in Europe, it was from 10 days to 16 months, 3 months on average. LA affects almost exclusively those not treated while EM was present or those who did not notice the EM altogether. Musculoskeletal symptoms in patients who had received prompt and appropriate treatment are extremely unlikely. Prompt treatment means starting antibiotic therapy before dissemination of infection, which usually occurs a few weeks (rarely – days) after the appearance of EM. Therefore, immediate antibiotic therapy in the first days of EM virtually eliminates the possibility of LB dissemination.

Arthritis is the main component of LA, and arthralgia may precede, accompany, or follow the inflammation, and sometimes it can be the only rheumatic manifestation of LB. In LA, usually, there is one or few joints affected (oligoarthritis), normally no more than five, and involvement of many or most joints is atypical. Ordinarily, the joint involvement is asymmetrical and concerns mostly large joints, particularly the knee; small joints may be affected as a component of oligoarthritis, whereas an isolated involvement of small joints (e.g. of the hand) points to a cause other than LA. Apart from the knees, LA commonly affects the shoulder, elbow, wrist, and ankle joints. Early research into the course of LA frequently noted involvement of the temporomandibular joint. According to Heir and Fein, it was the fourth most involved joint, following the knee, shoulder, and elbow. Typically, arthritis in the course of LB is accompanied by inflammation of the synovial membrane, and less often erosion and destruction of joint structures, which can be present in longer-duration arthritis.

Diagnostic Considerations

Diagnosis of LA must be started with a thorough history and examination of the patient. The history should contain information on previous stays in tick-endemic regions, tick bites, length of time the tick had remained attached, and method of removal. It bears noting that approximately 27–42% of European patients do not remember the tick bite at the site of the EM, and up to 75% in the US; therefore, its absence in history does not exclude LB.

The next diagnostic step is laboratory testing, performed only in patients whose reported symptoms correspond to the clinical picture of LB. Serology detects specific IgM, appearing in the blood 1–2 weeks after infection, peaking at 2– 6 weeks, and specific IgG, appearing 2–6 weeks after infection, peaking at 4–6 months. The standard is two-tier serological testing in which the first step is a sensitive enzyme-linked immunosorbent assay (EIA). If the EIA is positive or equivocal, then separate IgM and IgG immunoblots should be performed. A positive immunoblot test with a positive or borderline EIA test confirms the presence of specific Bb antibodies. Because both the EIA and immunoblot may be falsely positive, it is not recommended to skip the first step.

When the symptoms are relatively recent (2–4 weeks) and serological testing is negative, it should be repeated after an additional 2 weeks. High antibody titre (IgM and IgG) may exist for many years, even with successful antibiotic therapy; therefore, serology does not differentiate between active infection and past infection or exposition to Bb in the past. With that in mind, it is not recommended to test antibody levels post-treatment, given that they have no relation to the clinical picture of the disease.

The next diagnostic step in LA may be employing polymerase chain reaction (PCR), detecting DNA of Bb spirochetes in synovial fluid and/or membrane. However, it has some constraints. The PCR test result will be positive in the presence of both alive and dead spirochetes. Its sensitivity for synovial fluid approximates 60–85%, meaning that a negative result does not exclude LA. In the majority of patients pre-treatment, Bb DNA is usually found in the synovial fluid and the synovial membrane, whereas post-treatment with antibiotics, that result is usually negative.

The synovial fluid itself is also employed in the diagnostic process of LA. It would be inflammatory, characterised by an increased WBC count, typically from 46,000/mm3 to 60,000/mm3 (in rare cases reaching more than 100,000/mm3) and dominated by neutrophils. It is usually collected to exclude other causes of arthritis, such as gout or bacterial arthritis. It is not recommended to use synovial fluid for Borrelia cultures. Bb culturing is possible; however, the technique is expensive, requires additional laboratory conditions, and yields results after 2–6 weeks.

Complete blood count usually yields normal results for WBC, platelets, haemoglobin, and haematocrit. Only at an early stage of LA, in approximately 20% of patients in Europe, a small increase in aspartate transaminase and alanine transaminase may be observed. Every stage of LA may show a slight increase in erythrocyte sedimentation rate and/or C-reactive protein.

Sonography or MRI might show fluid in the affected joint and thickening of the synovial membrane. X-rays of patients with chronic LA may show destruction of the joints, such as joint space narrowing, geodes, or erosion of cartilage; however, those signs are not LA-specific and their prevalence is unknown. Therefore, having found joint deterioration, it is recommended to look for causes other than LA first.

Serological methods used in diagnosing LB have their limitations. Seroreactivity after successful treatment of Lyme borreliosis may persist for years. Another diagnostic challenge is the possibility of false-positive test results, possibly caused by cross-reactivity with other spirochaetal or bacterial antigens, as well as viral antigens, autoantigens.

Treatment

When musculoskeletal manifestations are present in patients with EM, the treatment is essentially the same as EM alone. First-line drugs include the following: doxycycline, amoxicillin, or cefuroxime orally. Dosing: doxycycline 100 mg every 12 h, amoxicillin 500 mg every 8 h, or cefuroxime 500 mg every 12 h – duration of treatment 14 days. In LA, however, that duration is longer, at 28 days. The dosing of doxycycline and cefuroxime is as given above; however, doses of amoxicillin are 500–1000 mg each 8 h. Second-line treatment in LA is IV ceftriaxone, 2 g every 24 h for 14–28 days. It has been established that if the symptoms subside only partially with oral antibiotic therapy, second-line treatment should consist of another recommended oral antibiotic while reserving parenteral antibiotic treatment for those without any substantial clinical response.

Untreated arthritis usually subsides on its own; however, it can take years – there have been cases where this form of LB persisted for 7–8 years. There is insufficient proof of the effectiveness of additional antibiotic therapy courses; moreover, the potential side effects of such antibiotics need to be considered. Long-term antibiotic therapy, its frequent repetition, as well as combined therapy with multiple antibiotics, do not offer any benefit and should not be used. At the start of therapy, approximately 7–30% of patients may experience aggravation of symptoms due to the Jarisch-Herxheimer reaction. It usually develops for 12–24 hours from the start of treatment and is caused by the sudden destruction of a large number of spirochetes. It does not require cessation of treatment and usually subsides in 48 hours. Pregnant and breastfeeding women should be treated the same as the general population with the exception of doxycycline, which should not be used (as well as in children up to 8 years of age). Patients who have been demonstrated to have specific antibodies but are symptomless should not be treated.

Post-antibiotic Lyme Arthritis

One course of therapy is sufficient for LA to dissipate in most cases, although for some patients the symptoms subside gradually even after completion of therapy; therefore, an assessment of outcome should be performed 3 months after its end. Some patients do not experience any improvement after antibiotic therapy; hence, the term ‘antibiotic refractory LA’ was created, defined as persisting synovitis for > 1 month after two four-week oral antibiotic courses or > 2 months after completion of intravenous ceftriaxone treatment. This form of persistent joint inflammation is now being called “post-antibiotic Lyme arthritis” (p-a LA), not to suggest antibiotic resistance as a cause of such a disease course.

There are two fundamental circumstances in which antibiotic therapy fails. The first is an erroneous diagnosis of LA, meaning a not uncommon situation where anti-Bb antibodies are found in a patient with musculoskeletal symptoms attributable to a different condition. The exclusion of other causes of the symptoms prompts us to consider the second option: p-a LA. The pathogenesis of p-a LA is not fully clear. The patients are characterised by a higher prevalence of HLA-DRB1*0401 and related alleles. A similar mechanism exists in rheumatoid arthritis, which suggests an autoimmune component to p-a LA. Another idea is spirochete persistence. It has been demonstrated that in rare cases, Bb genetic material may be found in muscle tissue and synovial fluid many months after antibiotic therapy.

It is recommended initially, in instances where the above-mentioned treatment proves to be unsuccessful, for patients to be referred to a rheumatologist for additional diagnostics and symptomatic treatment, and the search for other causes of symptoms should be considered Possible methods of treatment for patients with p-a LA include the following: non-steroidal anti-inflammatory agents, disease-modifying anti-rheumatic drugs (DMARDS), biologic agents, intra-articular steroids, and arthroscopic synovectomy.

Pain Treatment Of Active Disease

Pain may be severe enough to require specific analgesic therapy at any stage of LD. The first line of pain treatment is anti-inflammatory agents because inflammation is always present with LD. The agents can be delivered topically or systemically. Topical anaesthetics such as lidocaine also help manage joint pain. In addition to anti-inflammatory agents, standard, step-wise multimodal pain treatment is recommended—starting with agents such as acetaminophen, muscle relaxants (when needed), various neuropathic drugs, and complementary therapies. Opioid analgesics may be required for severe pain if non-opioid measures are ineffective.

Post-treatment Ld Syndrome (ptld)

Approximately 10% to 20% of patients with LD have symptoms that may last months to years after treatment with antibiotics. These symptoms can include muscle and joint pain, cognitive defects, sleep disturbances, and fatigue. The cause of these symptoms is not precisely known, since there is no evidence that there is ongoing infection with the spirochete. As noted, this condition is referred to as PTLDS. It is an autoimmune disorder in which a person’s immune system continues to respond, doing damage to the body’s tissues even after the infection has been cleared. Further antibiotic therapy is not helpful.

PTLDS appears to be similar to other infections that produce an autoimmune condition after the active infection has resolved. Included here are Campylobacter jejuni (polyneuropathy, Guillain-Barre Syndrome), chlamydia (reactive arthritis, Reiter’s Syndrome), Streptococcus (glomerulonephritis), and Epstein-Barr virus (infectious mononucleosis). These post-infectious syndromes are of great importance to pain practitioners because they may produce severe pain in joints, nerves, and muscles that require potent analgesics. Also, many patients who are given a diagnosis of fibromyalgia, myofacial pain syndrome, or degenerative joint disease may, in fact, have PTLDS.

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Dr Murli Krishna

Consultant Pain Medicine