Post-treatment Lyme disease syndrome G93.3

In 2006, the Infectious Disease Society of America (IDSA) published a case definition for Post-Lyme Disease Syndrome (PLDS), which is now commonly referred to as Post-Treatment Lyme Disease Syndrome (PTLDS) (Wormser GP et al. 2006). This definition includes the occurrence of fatigue, generalized musculoskeletal pain or complaints of cognitive impairment within 6 months of confirmed B. burgdorferi infection, the persistence of symptoms for ≥ 6 months (persistent or recurrent) after adequate antibiotic therapy that has resulted in the disappearance or stabilization of objective manifestations, and that the symptoms are so severe that, if present, they result in a significant limitation of the previous level of occupational, educational, social or personal activities.

Lyme borreliosis (LB) is an important tick-borne disease caused by spirochetes of the Borrelia burgdorferi sensu lato (s.l.) complex. As the spirochetes can infect different parts of the body, the disease can manifest itself with a variety of clinical symptoms. Asymptomatic infections must be expected (Steere AC et al. 2016; Stanek G et al. 2012).

The most common clinical manifestation of Lyme borreliosis is erythema migrans (EM), an early, localized infection that may be associated with flu-like symptoms. If left untreated, early disseminated Lyme borreliosis (LB) or late Lyme borreliosis can develop, which is characterized by multiple erythema migrans (MEM), as Lyme neuroborreliosis (LNB), Lyme arthritis (LA), Lyme carditis or acrodermatitis chronica atrophicans (ACA), among others (Steere AC et al. 2016; Stanek G et al. 2012).

In addition to these objectively recognizable symptoms, persistent non-specific symptoms such as fatigue, ubiquitous diffuse musculoskeletal pain or cognitive difficulties occur in a subgroup of patients despite adequate antibiotic therapy. If these symptoms persist for more than 6 months and lead to a restriction of daily activities, this symptomatology is referred to as post-treatment Lyme disease syndrome (PTLDS). Of all nonspecific symptoms, the following were observed in various cohorts of Lyme patients. Of all non-specific symptoms, a higher risk of pain and fatigue was found in various cohorts of Lyme disease patients compared to controls.

Clinical symptoms of PTLDS (as defined by the Infectious Disease Society of America):

• Muscle pain (> 1 body part)
• Joint pain (> 1 body part)
• Fatigue, memory problems (forgetfulness)
• Difficulty concentrating and finding words.
• Word-finding problems
• There are also effects on daily activities.

The following non-specific symptoms that are suspected to be associated with PTLDS can be used to assess PTLDS status (Nemeth J et al. 2016):

• Headache
• Joint swelling
• Paresthesias (e.g. tingling)
• Night sweats (on waking)
• Excessive sleep and problems falling asleep

The proportion of patients with PTLDS is estimated at 5.9% for acute Lyme disease (patients with erythema chronicum migrans) and 20.9% for patients with disseminated/late Lyme disease (Geebelen L et al. 2022; Aucott JN et al. 2013).

The cause of PTLDS is still unknown. One of the hypotheses is that it is a post-infectious syndrome, as observed in other infectious diseases such as Epstein-Barr virus infections, Q fever and COVID-19 (Hickie I et al. 2006; Lancet T 2020).

An autoimmune process has not yet been proven.

In view of the negative or at best marginal effects of repeated antibiotics (see Therapy), a chronic persistent infection is unlikely. This assumption is further supported by the following arguments: no accompanying objective clinical signs of disease and/or inflammation with progression, persistence of symptoms independent of a positive Borrelia serology, no pathogen detection by culture and/or PCR, no proven resistance of Borrelia burgdorferi sensu lato to the commonly used antibiotics.

Ultimately, the so-called PTLDS cannot yet be defined as a disease entity due to inconsistent data.

The host immune response to Norrelia infection:

Despite the expression of CRASPs and antigenic variation in B. burgdorferi surface lipoproteins that allow the bacterium to evade host immune defenses, B. burgdorferi is still recognized and killed by both innate and adaptive immune responses. Since B. burgdorferi does not produce toxins or extracellular matrix-degrading proteases, most manifestations of human Lyme borreliosis in each of the three disease stages are due to inflammation triggered by these immune responses.

In stage 1, erythema migrans, biopsies taken in the first days of infection show papillary skin edema and a mixed infiltrate consisting predominantly of T cells, neutrophils, dendritic cells and monocytes or macrophages (Duray PH 1989). Cytokine expression at this stage is predominantly pro-inflammatory and includes elevated levels of tumor necrosis factor(TNFalpha), interleukin-2, interleukin-6 and type I interferons (IFN). Levels of chemokines that attract neutrophils (e.g. CXC chemokine ligand 1(CXCL1 - also known as growth-regulated alpha protein), macrophages (e.g. CC chemokine ligand 3(CCL3) and CCL4) and T cells (e.g. CXCL9, CXCL10 and CXCL11) are also elevated in erythema migrans lesions.

In both animal and human studies, neutrophil granulocytes, which are highly effective in killing B. burgdorferi, are no longer detectable after 24 hours, while T cells, dendritic cells and monocytes are still present (Müllegger RR et al. 2000). In animals expressing artificially elevated levels of the neutrophil chemoattractant KC, B. burgdorferi is rapidly cleared after inoculation into the dermis. This suggests that the disappearance of neutrophils is important to establish the infection (Xu Q et al. 2007). Complement also plays an early role in controlling infection, probably by enhancing phagocytosis and opsonization via the classical pathway. As erythema migrans lesions develop over days, dense perivascular and interstitial infiltrates consisting of lymphocytes, plasma cells and occasionally mast cells develop. The anti-inflammatory cytokine interleukin-10 can be found in these lesions (Sjöwall J et al. 2011). In animals, IL-10 deficiency is associated with increased inflammation and reduced numbers of B. burgdorferi, suggesting that while induction of IL-10 may result in reduced inflammation and tissue damage, it may enable B. burgdorferi to escape the immune system.

B cells are crucial for the control of infection. In the spleen, marginal zone B cells produce antibodies against T cell-independent antigens and are a source of B. burgdorferi-specific IgM antibodies in stage 1 disease (Oliver AM et al. 1997). The subsequent development of B. burgdorferi-specific IgG antibodies correlates with a reduction in spirochete numbers in mice. Passively administered IgG antibodies can prevent the establishment of infection in animal models.

Within a few weeks to months, innate and adaptive immune mechanisms can reduce bacterial numbers to such an extent that the systemic symptoms of Lyme borreliosis are reduced even without antibiotic treatment. Spirochaetes can survive in local niches for several years in untreated patients, which can lead to persistent symptoms in some cases. In humans, however, all inflammatory manifestations of the disease, with the possible exception of acrodermatitis chronica atrophicans, eventually resolve without antibiotic therapy.

Wild B. burgdorferi reservoirs, such as mice, do not develop infection-related pathology despite lifelong persistence of the bacteria. This finding suggests that their immune system has evolved to "ignore" the presence of the organism, which, since the bacteria do not produce toxins or degradative factors, poses less of a threat than continued activation of the immune system. In humans, who are not reservoir hosts, the bacteria may evade eradication for months or years in localized niches, but are eliminated more efficiently over time.

Several randomized, controlled treatment trials have not provided sufficient evidence for the benefit of prolonged antibiotic treatment in patients with persistent symptoms (Klempner MS et al. 2001; Berendes A et al. 2016).

For other types of symptoms, such as joint pain, symptomatic therapy with NSAIDs is recommended. However, optimal approaches for symptomatic treatment have not been defined, as systematic studies - with the exception of studies evaluating re-treatment with antibiotics - are rare or lacking in these patients.

Following treatment trials for fibromyalgia, multidisciplinary approaches combining medications such as gabapentin or amitriptyline with non-pharmacological therapies such as cognitive behavioral therapy, acupuncture or massage have also been advocated (Steere AC et al. 2015).

Effects on daily activities: A standardized EQ-5D-5L questionnaire can be used to get an overview of the usual activities.

A 60-year-old, sporty woman who enjoys hiking presented with dizziness, which was unusual for her, general muscle stiffness, occasional chills, headaches with nausea, night sweats and noticeable difficulty sleeping and falling asleep. Because of these symptoms, she had been receiving 10mg diazepam for some time, which was now to be reduced. At a further contact one month later, she still complained of dizziness and "feelings of shock" in her head, she was stiff in her movements and movements were generally painful. A ADR was considered. Screening blood tests (CBC, hemoglobin, platelets, C-reactive protein (CRP), creatinine, creatine kinase (CK), liver enzymes, electrolytes were performed with normal results. At a consultation four months later, she mentioned that her right foot was so swollen that she had to wear a whole shoe size larger. Dizziness, body stiffness and dull headaches persisted. She also reported "occasional palpitations", exhaustion/fatigue, pain under the sole of her foot, so that she "no longer felt like exercising or walking".

Findings: Diffuse swelling over the dorsal part of the right foot and toes to just above the ankle. The skin was hyperesthetic, reddish-bluish in color, wrinkled and shiny. Sonography performed by the GP revealed normal findings in the tendons and joints of the ankle and foot. New screening blood tests including thyroid hormones and rheumatology tests showed no abnormalities. A punch biopsy of the skin revealed interstitial lympho-plasma cell infiltrates (CD68 positive), with somewhat thickened and homogenized collagen bundles, as well as a band-like infiltrate of CD4 positive T lymphocytes. Vacuolated degeneration of the basal cell layer in places. No interface dermatitis. The PCR test of the biopsy was positive for Borrelia burgdorferi sensu lato. Serology: detection of several bands of IgG antibodies. Supplementary CSF examination revealed no evidence of infection/inflammation or intrathecal production of Borrelia-specific antibodies. In accordance with current guidelines, treatment with doxycycline (200 mg daily) was administered for 3 weeks. Almost a year after the onset of symptoms and about 6 months after the end of treatment, the patient still suffered from headaches, fatigue, fatigue, memory problems (forgetfulness), concentration difficulties, word-finding problems, tingling paresthesias, difficulty falling asleep and night sweats. Her right foot was still slightly larger than her left. She wore thicker socks in her left shoe to cushion it better.

The diagnosis is now: condition after acrodermatitis chronica atrophicans. Post-Lyme disease syndrome.

Therapy: cognitive behavioral therapy, acupuncture and massages. A trial with amitriptyline is planned.

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