Late Neuroborreliosis Research Articles

Modern concepts on the pathogenesis of neuroborreliosis

The analysis of publications on the websites PubMed, ClinicalKey, devoted to the pathogenesis of neuroborreliosis (NB), using keywords for search: «pathogenesis of neuroborreliosis», «neuroborreliosis in children», «pathogenesis of Lyme disease», as well as an analysis of the results of the published research results of the staff of the Research Institute of Pediatric Infections, St-Petersburg, Russia is presented. Syndromes of early and late NB are more often observed among the forms without migrating erythema, and their development can be caused by all representatives of the species B. burgdorferi s.l. (B.b.), but more often - B. garinii, since it most effectively suppresses the factors of innate and adaptive immune response, reducing interferon production, phagocytosis and complement synthesis. The cause of immunosuppression with the development of NB may be simultaneous infection with several genovids and borrelia species or pathogens of other infections transmitted by Ixodes ticks, for example, infection with B.b. and tick-borne encephalitis virus. The ability to move along peripheral nerves, the change of surface antigens of the VlsE protein, as well as the formation of atypical cysts and granular forms allows B.b. to affect different structures of the peripheral and central nervous system, avoid an immune response and persist for a long time, causing chronic neuroinfection. Both the B.b. themselves, capable of being outside and inside glial cells and neurons, and inflammatory reactions developing in response to their introduction and associated with the synthesis of cytokines and chemokines and mimicry, cause damage to the vascular endothelium, vasculitis and impaired blood supply to the brain, demyelination, autoimmune inflammation and degeneration, leading to the development of NB syndromes, the spectrum of which varies depending on the duration of neuroinfection. In the development of NB and its outcomes, the following are also important: early initiation of treatment, the effectiveness of antibacterial drugs, the use of immunotropic agents that optimize the patient's immune response to the fight against neuroinfection, as well as the timely use of pathogenetic drugs, such as Cytoflavin, which have a complex effect on the vascular endothelium.

Is Borrelia Associated with Post-Infectious Autoimmune-Mediated Acute and Chronic Inflammatory Demyelinating Polyneuropathy? A Case Series

A variety of neurological syndromes—occurring more frequently in Europe because of the greater neurotropism of Borrelia garinii—have been described in neuroborreliosis. Recent case reports and two cohort studies describe the probable association between Lyme disease and inflammatory demyelinating polyneuropathy. Our case series reports on 3 patients with Guillain-Barre syndrome (GBS), and 2 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) which are most probably linked to neuroborreliosis as antecedent infection. These cases originate from a series of n = 53 with Lyme neuroborreliosis diagnosed in the period 2011-2017. Cerebrospinal fluid analysis and serological and chemokine testing suggest GBS and CIDP are part of late neuroborreliosis rather than acute neuroborreliosis. We discuss if Lyme disease, known for its neurotropism, is a mimicker of Guillain-Barre syndrome or its variants due to active infection of the nervous system or if Borrelia sp. is only one of the many pathogens known to induce these syndromes as a consequence of its immunogenic capacity. Our case series and earlier reported cases suggest that among other infections, Lyme disease could trigger autoimmune response with anti-neuronal reactivity leading to neurologic injury. Such post-infectious autoimmune-mediated acute and chronic inflammatory demyelinating polyneuropathy could be more frequent/important than radiculoneuropathies occurring in the acute stadium of neuroborreliosis.

Анализ эффективности иммунотерапии раннего и позднего нейроборрелиоза у детей

Immunostimulants are drugs that increase the effectiveness of antimicrobial therapy, improve outcomes, and participate in the process of repairing damaged tissues. Objective. To evaluate the effectiveness of the inclusion of immunostimulants in the therapy of early and late neuroborreliosis (NB) in children: glucosaminylmuramyldipeptide (Licopid), recombinant interferon α-2b in combination with antioxidants vitamins E and C (Viferon®) and recombinant interleukin-2 (Roncoleukin). Patients and methods. Forty-two patients with NB aged 2–17 years were examined and received therapy. The diagnosis included clinical-epidemiological and laboratory-etiological methods (enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR)) for Borrelia burgdorferi s.l. (Bb). Electroneuromyography was performed in early NB, and magnetic resonance imaging (MRI) of the brain and spinal cord was performed in late NB. The main group included children with early NB (n = 13) who received 1 mg of Licopid orally and Viferon® rectal suppositories 150,000 or 500,000 IU (depending on age) twice a day for 10 days. In late NB, children in the main group (n =1 2) received drip intravenous injection of Roncoleukin №3 at a dosage of 0.5 mg for 3 days. The comparison groups included 9 children with early NB and 8 children with late NB who received antimicrobial and pathogenetic therapy without immunostimulants. Results. In early NB (n = 22), children with aseptic meningitis and Bannwarth syndrome were observed, and in late NB (n = 20) – children with leukoencephalitis and disseminated encephalomyelitis. The prescription of Licopid and Viferon® ensured the eradication of Bb in the cerebrospinal fluid (CSF) by PCR results and led to the complete recovery of facial and peripheral nerve function in all cases, whereas in the comparison group, in 11.1% (n = 1), Bb remained in CSF on day 15, and after 6 months, a neurological deficit was detected in 2 (40%) of 5 children with Bannwarth syndrome: in the form of facial muscle contraction (n = 1) and polyneuropathy (n = 1). In late NB, the presription of Roncoleukin reduced the duration of bed days (by an average of 13 days) and mean neurological deficit on the EDSS scale after 1, 6 and 12 months. After 1 year, ¼ of children had complete regression of foci on MRI, and 41.6% (n = 5) had regression of both foci and clinical symptoms. During the year, there were no exacerbations, and CSF PCR was negative. In the comparison group, 3 (37.5%) children had clinical and/or radiation exacerbation. Conclusion. The inclusion of immunostimulants (Licopid, Viferon®) in therapy in early NB and the drug Roncoleukin in late NB accelerates the eradication of Borrelia, reduces neurological deficit, avoids exacerbations, progression of infection and repeated courses of antibiotics. Key words: neuroborreliosis, immunotherapy, Licopid, Viferon, Roncoleukin, children

Diagnostic problems of neuroborreliosis

Nowadays a significant increase in Lyme disease incidence rate in Ukraine ensures the relevance of the problem. The difficulties of clinical and laboratory diagnostics of early and late neuroborreliosis have been analyzed, the main clinical differences between the lesion of the nervous system of borrelia etiology and the similar neurological syndromes of other genesis are indicated.

Not So Common? Late Neuroborreliosis in a Referred Population

BackgroundThe nervous system is known to be the third most commonly (12–15%) affected site in Lyme disease (LD) in the U.S. Though previous studies reported peripheral neuropathy, encephalopathy, and encephalitis with some frequency in later stage LD, limited contemporary data exist on the frequency, presentation, and outcomes of these entities.MethodsRetrospective review of 1261 patients referred (2000–2013, single center) for presumptive LD was performed for neuroborreliosis. Symptoms less than 3 months were designated early LD. Patients with remote history of treated neuroborreliosis (> 2 years) were excluded. The diagnosis of LD followed CDC criteria. Response to antibiotics was assessed at the last clinical visit.ResultsOf 185 diagnosed with LD, 19% (35/185) had neuroborreliosis, including 29 early LD (ELD) and 6 late LD (LLD). The mean age was 44 yrs (±20) in ELD and 61(±11) in LLD. The median symptom duration was 14d (1–69) in ELD and 182d (140–2570) in LLD. Facial nerve palsy was most common, 54% (19/29 in ELD vs. 0/6 in LLD), followed by meningitis 20% (4/29 vs. 3/6), radiculopathy 20% (6/29 vs. 1/6), encephalopathy 3% (0/29 vs. 1/6), and peripheral neuropathy 3% (0/29 vs. 1/6) (P = 0.001). No encephalitis was identified. The median treatment duration (days) was 30 (10–135) in ELD and 56 (28–230) in LLD. All 35 patients were treated with doxycycline and/or ceftriaxone (16, 46% IV). Of the 32 followed patients, 28/32 (88%) responded to antibiotics, whereas 4/32 (12%) remained symptomatic with median follow-up duration of 72 days. Four non-responsive cases included 1 ELD (radiculopathy) and 3 LLDs (meningitis, encephalopathy, and peripheral neuropathy). The rate of non-response to antibiotics was higher in late LD (4% of ELD vs. 60% of LLD; P = 0.008). There was no statistically significant difference between outcome groups when comparing age, treatment duration, history of anxiety/depression, and route of treatment (p > 0.05, respectively).ConclusionEncephalopathy, encephalitis, and peripheral neuropathy ascribed to LD were uncommon in this population and poorly responsive to antibiotics. This raises the question whether LD truly was causal or if irreversible damage occurs by late stage LD. Future studies are needed in this regard.Disclosures All authors: No reported disclosures.

Lyme Neuroborreliosis.

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common tick-borne illness in the United States and Europe. Lyme disease usually begins with the characteristic skin lesion, erythema migrans, at the site of the tick bite. Following hematogenous dissemination, neurologic, cardiac, and/or rheumatologic involvement may occur. Neurologic involvement occurs in up to 15% of untreated B. burgdorferi infection and neurologists should be familiar with its diagnosis and management. The most common early neurologic manifestations of Lyme disease are cranial neuropathy (particularly facial palsy), lymphocytic meningitis, and radiculoneuritis, which often occur in combination. Late neuroborreliosis occurs much less frequently than early disease. A combination of clinical and laboratory findings is recommended for the diagnosis of Lyme neuroborreliosis. Treatment with recommended antibiotic regimens is effective in Lyme neuroborreliosis, and patients with early disease usually have excellent outcomes. Recovery is slower and may be incomplete in patients with late disease. Nervous system involvement occurs in up to 15% of patients with untreated B. burgdorferi infection. This article reviews clinical aspects of the diagnosis and treatment of Lyme neuroborreliosis, with focus on the United States.

Lyme neuroborreliosis-epidemiology, diagnosis and management.

Lyme disease, caused by the Borrelia burgdorferi bacterium, is the most common vector-borne disease in the northern hemisphere. The clinical presentation varies with disease stage, and neurological manifestations (often referred to as Lyme neuroborreliosis) are reported in up to 12% of patients with Lyme disease. Most aspects of the epidemiology, clinical manifestation and treatment of Lyme neuroborreliosis are well known and accepted; only the management of so-called chronic Lyme disease is surrounded by considerable controversy. This term is used for disparate patient groups, including those who have untreated late-stage infection (for example, late neuroborreliosis), those with subjective symptoms that persist after treatment (termed 'post-treatment Lyme disease syndrome' [PTLDS]), and those with unexplained subjective complaints that may or may not be accompanied by positive test results for B. burgdorferi infection in serum (here called 'chronic Lyme disease'). The incidence of PTLDS is still a matter of debate, and its pathogenesis is unclear, but there is evidence that these patients do not have ongoing B. burgdorferi infection and, thus, do not benefit from additional antibiotic therapy. Chronic Lyme disease lacks an accepted clinical definition, and most patients who receive this diagnosis have other illnesses. Thus, a careful diagnostic work-up is needed to ensure proper treatment.

Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study

BackgroundPrevious studies indicate that successful resolution of Lyme neuroborreliosis (NB) is associated with a strong T helper (Th) 1-type cytokine response in the cerebrospinal fluid (CSF) followed by a down-regulating Th2 response, whereas the role of the recently discovered Th17 cytokine response is unknown.MethodsTo investigate the relative contribution of different Th associated cytokine/chemokine responses, we used a multiple bead array to measure the levels of CXCL10 (Th1 marker), CCL22 (Th2 marker), IL-17 (Th17 marker) and CXCL8 (general inflammation marker), in serum and in CSF from untreated patients with confirmed NB (n = 133), and non-NB patients (n = 96), and related the findings to clinical data. Samples from patients with possible early NB (n = 15) and possible late NB (n = 19) were also analysed, as well as samples from an additional control group with orthopaedic patients (n = 17), where CSF was obtained at spinal anaesthesia.ResultsThe most prominent differences across groups were found in the CSF. IL-17 was elevated in CSF in 49% of the patients with confirmed NB, but was not detectable in the other groups. Patients with confirmed NB and possible early NB had significantly higher CSF levels of CXCL10, CCL22 and CXCL8 compared to both the non-NB group and the control group (p < 0.0001 for all comparisons). Patients in the early NB group, showing a short duration of symptoms, had lower CCL22 levels in CSF than did the confirmed NB group (p < 0.0001). Furthermore, patients within the confirmed NB group showing a duration of symptoms <2 weeks, tended to have lower CCL22 levels in CSF than did those with longer symptom duration (p = 0.023). Cytokine/chemokine levels were not correlated with clinical parameters or to levels of anti-Borrelia-antibodies.ConclusionOur results support the notion that early NB is dominated by a Th1-type response, eventually accompanied by a Th2 response. Interestingly, IL-17 was increased exclusively in CSF from patients with confirmed NB, suggesting a hitherto unknown role for Th17 in NB. However, for conclusive evidence, future prospective studies are needed.

Neuroborreliosis in the South West of England.

Although Lyme borreliosis is increasingly diagnosed in the United Kingdom, few systematic studies have been performed there. UK data suggest that the commonest complications are neurological, but inadequate information exists about their nature and the incidence of late neuroborreliosis. Local data are necessary because clinical presentations may show geographical variation. This study aimed to provide data on clinical manifestations in an area of South West England and to estimate treatment delay. We reviewed clinical records of 88 patients in the Royal Devon and Exeter Hospital catchment area who had positive Borrelia antibody tests during a 5-year period. Fifty-six (64%) reported tick bites. The commonest presentations were erythema migrans (65%) and arthralgia/myalgia (27%). However, 22 patients (25%) had neurological symptoms other than headache alone. Fourteen had facial palsy, eight had confusion/drowsiness, four had meningism, five had radiculopathy, two had sixth nerve palsies, and two had peripheral neuropathies. No late, progressive or atypical neurological syndromes were found. Neurological manifestations were generally predictable and usually included either (or all) of meningoencephalitis, facial palsy or radiculopathy.

Pathogenesis of Lyme neuroborreliosis in the rhesus monkey: the early disseminated and chronic phases of disease in the peripheral nervous system.

The histopathologic and immunohistochemical features of early and late neuroborreliosis of the peripheral nervous system were investigated in rhesus macaques infected with the JD1 strain of Borrelia burgdorferi. Infection was proven by culture or polymerase chain reaction analysis of skin biopsies and indirectly by Western blot analysis. Three months after infection, neuritis involving multiple nerves was the most consistent neurologic manifestation. Both macrophages and B lymphocytes but not T lymphocytes were present in the cellular infiltrates. Axonal structures surrounding infiltrates had changes consisting of demyelination and axonal phagocytosis. Some of the Schwann cells in lesions stained with anti-nitrotyrosine and anti-tumor necrosis factor-alpha antibodies. B. burgdorferi, or antigens thereof, were visualized immunohistochemically within macrophages. Forty-six months after infection, the most common changes were regenerative, whereas neuritis was infrequent. Aberrant axonal regeneration, irregularly sized myelinated fibers, and fibrosis were frequently observed. Possible mechanisms to explain the appearance and subsidence of Lyme neuritis are discussed.

Lymphocyte reactivity against purified Lyme disease Borrelia cell components in individuals with neuroborreliosis

Lymphocyte proliferative responses to whole-cell antigen and three subcellular protein fractions of Lyme disease Borrelia were investigated. The lymphocytes were obtained from patients previously diagnosed as having early or late neuroborreliosis. Patients with late neuroborreliosis were tested 1–7 yr after antibiotic treatment of the disease. One of the subcellular protein fractions contained 12 proteins of defined molecular weights, the second fraction contained predominantly the outer surface proteins (Osp) A and OspB, and the third fraction contained, as the major component, the flagellum of Lyme disease Borrelia. This study demonstrated that the lymphocyte proliferative assay had a sensitivity of 88% in late neuroborreliosis patients and 75% in patients with previous early neuroborreliosis when whole cells were used as antigen. A similar sensitivity had previously been seen when the sera of these patients had been analysed for Borrelia burgdorferi-specific IgG antibodies. Of the three subcellular fractions, the flagellin fraction demonstrated the highest sensitivity, 64% in late neuroborreliosis patients and 62% in patients with previous early neuroborreliosis. Furthermore, the whole-cell antigen and the flagellin fraction showed matching specificity (73%) in this lymphocyte proliferative assay. The results of the present study show that the determination of lymphocyte proliferative responses to subcellular components of Borrelia is a useful complement to the determination of serological responses for the diagnosis of Lyme borreliosis. This study also showed that the lymphocyte proliferative assay had a sensitivity similar to that of serology, irrespective of whether patients had active borreliosis or if testing successfully treated patients.

Serological follow-up after treatment of patients with erythema migrans and neuroborreliosis

To investigate the duration and kinetics of immunoglobulin M (IgM) and IgG antibodies against Borrelia burgdorferi in serum after treatment of Lyme borreliosis, consecutive serum samples from 30 seropositive patients with erythema migrans and 91 seropositive patients with neuroborreliosis were analyzed with a capture IgM enzyme-linked immunosorbent assay (ELISA) and an indirect IgG ELISA, both using B. burgdorferi flagella as the antigen. All the patients improved after treatment: 97 patients had a complete clinical recovery, while 24 patients had sequelae. The results showed that patients with erythema migrans and early neuroborreliosis more often initially had highly elevated IgM optical density (OD) values and low IgG OD values against B. burgdorferi, while the opposite was found in patients with late neuroborreliosis. During follow-up, the majority of patients had developed negative or significantly declining IgM ODs after 1 to 1.5 years but persistently positive IgM ODs were found up to 17 months after treatment of erythema migrans and 3 years after treatment of neuroborreliosis. IgG antibody levels declined more slowly and remained elevated to a larger extent, but more than half of the patients had developed negative IgG ODs within 5 years after therapy. However, positive IgG OD values were found after 9 to 10 years for patients treated for neuroborreliosis as well as erythema migrans. Both IgM and IgG antibodies against B. burgdorferi may persist for months to years after successful treatment of Lyme borreliosis. Consequently, a single serum sample with antibodies against B. burgdorferi must always be carefully evaluated and correlated to clinical symptoms.