Neuroborreliosis

Neuroborreliosis is the result of a disseminated (systemic) infection with Borrelia burgdorferi involving the nervous system. In this context, it is important to note that around 50 % of tick bites go unnoticed! Only around 60-70% of those infected develop an early symptom typical of the disease, erythema migrans!

Borrelia burgdorferi has a large number of immunologically relevant antigens (see Borrelia antigens below), which can be detected with varying sensitivity depending on the stage and in some cases have varying specificity. Knowledge of these is important for the interpretation of the serological test results.

Early immune response (mainly IgM)

• Flagellar protein(flagellin, p41)
• OspC (associated with outer membrane)
• VlsE

late immune response (mainly IgG)

• p83/100, p58, p43, p39, p30, p21, DbpA (Osp17) and p14 (overall reactive with approx. 80% of the sera)
• VlsE (detectable in more than 90% of sera)

Early neuroborreliosis

• Lymphocytic menigitis: in children - frequency approx. 30% - more frequent than in adults Frequency 4-5%. Headache, meningismus, photophobia, nausea, vomiting, fatigue, emotional instability; rarely chronic course.
• Garin-Bujadoux-Bannwarth syndrome (meningoradiculoneuritis): Garin-Bujadoux-Bannwarth syndrome, also known as meningoradiculoneuritis or Bannwarth syndrome, is the most common manifestation of acute Lyme borreliosis in adults in Europe after erythema migrans. The symptoms of radiculitis develop on average 4-6 weeks (maximum 1-18) after the tick bite or after the erythema migrans. Segmental pain occurs first, which is worse at night and can change its localization. Initially, the pain is often localized in the extremity where the tick bite or erythema migrans was previously observed. The pain has a burning, drilling, biting or tearing character and responds only slightly to conventional analgesics. It often reaches a maximum within a few hours or days.
• Cranial nerve paresis weeks to months after infection (tick bite!): In three quarters of patients, neurological deficits develop after 1-4 weeks, paresis more frequently than sensory disturbances. In about 60% of patients with Bannwarth syndrome, cranial nerve deficits are found. With the exception of the olfactory nerve, all cranial nerves can be involved. In over 80% of cases with cranial nerve involvement, the facial nerve is affected, although bilateral manifestations are frequently described (approx. 1/3 of cases). The sense of taste may be spared. In unilateral cases, differentiation from idiopathic facial nerve palsy can be difficult; however, there are sometimes symptoms or anamnestic data (e.g. erythema migrans, radicular pain) that provide an indication of neuroborreliosis. CSF diagnostics can provide clarity here. Regardless of the severity of the facial nerve palsy, a complete recovery is observed in most cases within 1-2 months. Residues or defect healing with facial synkinesia (pathological co-movements) are seen in around 5-10% of patients. Neuroborreliosis can also affect the abducens nerve and very rarely the vestibulocochlear nerve, the optic nerve (optic neuritis, papilledema), the oculomotor system (Nn. III, IV), the trigeminal nerve and the caudal cranial nerves (Nn. IX-XII).

Late neuroborreliosis:

• Polyneuropathy/polyneuritis: Polyneuropathy/polyneuritis as an expression of a Borrelia infection is usually seen in European patients in association with acrodermatitis chronica atrophicans (ACA) in a frequency of 48-64%. Isolated polyneuropathies/polyneuritis without other clear symptoms of Lyme borreliosis have been described in 39-52% of American patients with Lyme borreliosis.
• CNS involvement: Involvement of the central nervous system is rare in the context of neuroborreliosis (approx. 4%). This often begins insidiously and is often chronic.
  • Myelitis: The symptoms are very varied. The most frequent manifestation is myelitis with spastic-ataxic gait and bladder dysfunction. The symptoms can develop over days or several months. Some patients develop severe tetra- or paraparesis. About 60% of patients with myelitis have additional signs of encephalitis and about 40% have cranial nerve involvement.
  • Encephalitis: Encephalitis has no clinical characteristics that are specific to the pathogen. Encephalitis can lead to psychiatric symptoms or organic brain psychosyndromes. Cases of acute psychosis (Csaszar T et al. 1994) or Tourette's syndrome have been reported.
• Vascular symptoms: In very rare cases, cerebral symptoms (e.g. strokes) may be caused by a borrelia-induced vasculitis.
• Myositis: Another very rare manifestation of Lyme borreliosis is myositis, which has only been reported in isolated cases.

Inflammatory CSF changes (pleocytosis, blood CSF barrier disorder and intrathecal immunoglobulin synthesis) are to be expected in all cases of neuroborreliosis (possible exceptions: very early stage of the disease or distally symmetrical polyneuropathy). The CSF typically shows a lymphocytic pleocytosis with plasma cells, activated lymphocytes and a significant increase in the total protein or albumin quotient (barrier disorder) (Djukic M et al. 2011). The average cell count is between 170 and 220/µl up to 1100 cells/µl.

Intrathecal antibody synthesis: The detection of borrelia-specific intrathecal antibody synthesis (positive borrelia-specific antibody index [AI]) in conjunction with inflammatory changes in the cerebrospinal fluid can be used to confirm the suspected clinical diagnosis of neuroborreliosis. Borrelia-specific intrathecal antibody synthesis begins around the 2nd week of illness and is detectable in over 99% of patients after 6-8 weeks. A borrelia-specific AI without accompanying inflammatory CSF changes may remain positive for years after neuroborreliosis has been cured.

Serodiagnostics, antibody detection: In early Lyme borreliosis, borrelia-specific IgM antibodies are found from the 3rd week p.i. and IgG antibodies from the 6th week p.i. However, the use of the VlsE or C6 peptide as a test antigen means that IgG antibodies can now often be detected as early as IgM antibodies.

High IgG antibody concentrations are generally found in the late manifestations of Lyme borreliosis. The detectable humoral immune response does not always follow the usual course of other infectious diseases: in the early localized manifestation (erythema migrans), the measurable antibody response may (still) be absent, or the measurable IgM response may be completely absent, for example in the case of reinfection. A measurable humoral immune response may also be suppressed as part of very early antibiotic treatment. On the other hand, the positive finding of Borrelia-specific IgM and/or IgG antibodies alone does not prove a disease with Borrelia burgdorferi, as Borrelia infections with asymptomatic seroconversion occur and elevated IgG and IgM antibody titres (in serum and/or cerebrospinal fluid) that persist for years after sufficiently treated Lyme disease are not uncommon in healthy individuals. It follows that borrelia serology is not suitable for monitoring the antibiotic therapy of Lyme borreliosis and is therefore not recommended.

Chemokine CXCL13: The chemokine CXCL13 increases significantly in the CSF of almost all patients with acute neuroborreliosis, even before a specific antibody response is generated. Immediately after the start of antibiotic administration, the chemokine level drops again very quickly, long before the CSF pleocytosis regresses. Studies on patients with suspected neuroborreliosis showed sensitivities/specificities of 100%/99% and positive or negative predictive values of 88% and100%, so that the parameter can be helpful in unclear cases of very early neuroborreliosis (Lintner H et al. (2020) Sensitivity and specificity of cerebrospinal fluid CXCL13 for diagnosing Lyme neuroborreliosis - a study on 1410 patients and review of the literature. J Neurol Sci 414:116843. It should be noted that the CXCL13 value is not specific for neuroborreliosis; elevated CSF values have also been found in neurolues, tuberculous meningitis and CNS lymphomas.

Neuroborreliosis is suspected on the basis of typical clinical symptoms and is subsequently supported by laboratory tests (serum and cerebrospinal fluid tests) (Fingerle V et al. 2008).

Early neuroborreliosis: Doxycycline 2x100mg/day or beta-lactam antibiotic for 21 days.

Late neuroborreliosis: Doxycycline 2x100mg/day or beta-lactam antibiotic for 28-30 days. Severe course: Ceftriaxone 2g/day i.v.. Duration: 2-3 weeks.

Immunization: No vaccine available

Complete cure with sufficient therapy. Mortality low!

1. Csaszar T et al. (1994) Differential diagnostic problems in Lyme disease (Borrelia infection resulting in acute exogenous psychosis). Orv Hetil 135: 2269-2271.
2. Dersch R et al. (2015) Quality of life, fatigue, depression and cognitive impairment in Lyme neuroborreliosis. JNeurol 262: 2572-2577
3. Dersch R et al. (2016) Prevalence and spectrum of residual symptoms in Lyme neuroborreliosis after pharmacological treatment: a systematic review. JNeurol 263: 17-24).
4. Djukic M et al. (2011) The diagnostic spectrum in patients with suspected chronic Lyme neuroborreliosis - the experience from one year of a university hospital's Lyme neuroborreliosis outpatients clinic Eur J Neurol 18:547-555).
5. Fingerle V et al. (2008) Epidemiological aspects and molecular characterization of Borrelia burgdorferi s.l. from southern Germany with special respect to the new species Borrelia spielmanii sp. nov. Int J Med Microbiol298: 279-290.
6. Lintner H et al. (2020) Sensitivity and specificity of cerebrospinal fluid CXCL13 for diagnosing Lyme neuroborreliosis - a study on 1410 patients and review of the literature. J Neurol Sci 414:116843.