An antibody capture enzyme-linked immunosorbent assay was developed to measure directly intrathecal immunoglobulin (Ig) G, A, and M synthesis specific for Borrelia burgdorferi. Purified, biotin-avidin-peroxidase-labeled B. burgdorferi flagella was used as test antigen. Paired cerebrospinal fluid and serum specimens from 100 patients with clinically definite neuroborreliosis and 35 control subjects with neurological diseases were examined. Significant B. burgdorferi-specific intrathecal IgG, A, and M production was found in 89%, 65% and 67% of patients with neuroborreliosis. Local synthesis of specific IgA was only seen in patients with significant local IgG synthesis. Antibody production in cerebrospinal fluid began by 2 weeks after onset of neurological symptoms. At the end of the second week specific IgM, IgG, or both, was detected in 88% of the patients. Specific IgG synthesis was present in all patients by 6 weeks after onset. Specific local IgM synthesis usually disappeared by 3 to 6 months after therapy, whereas specific IgG synthesis persisted after recovery. Even in patients with a severely altered blood-brain barrier, the assay discriminated between intrathecal antibody synthesis and antibody leakage from serum. The assay makes diagnostic measurement of B. burgdorferi-specific intrathecal antibody synthesis reliable, rapid, and accessible as a routine serological test.

This prospective study reports the clinical and epidemiological features of 187 consecutive patients with neuroborreliosis recognized in Denmark over the 6-yr period, 1985-1990. Only patients with intrathecal Borrelia burgdorferi specific antibody synthesis were included. In 1990 regional incidences varied between 5.7 and 24.1 per million. Ninety-four percent of the patients had early (second stage) neuroborreliosis. The most common manifestation was a painful lymphocytic meningoradiculitis (Bannwarth's syndrome) either with paresis (61%) or as a radicular pain syndrome only (25%). Central nervous system (CNS) involvement in early neuroborreliosis was rare; 4% had signs of myelitis and only one patient had acute encephalitis. Children showed a different course of the disease. Six percent of the patients suffered a chronic course with a disease duration between 6 mths and 6 yrs either as chronic lymphocytic meningitis (1.6%) or as third stage chronic encephalomyelitis (4.3%). Meningeal signs were rare despite pronounced inflammatory cerebrospinal fluid (CSF) changes (median cell count 160/microliters; median protein concentration 1.13 g/l). High dose i.v. penicillin G was administered to 91% of the patients. Based on the clinical outcome and normalization of CSF no treatment failures were recognized. The final morbidity after a median follow-up of 33 mths was low; disabling sequelae were reported in nine patients, mainly those with previous CNS involvement. We conclude that neuroborreliosis is a common and characteristic neurological disorder. The diagnosis should be based on the demonstration of inflammatory CSF changes and B. burgdorferi specific intrathecal antibody production.

The isolation of Borrelia burgdorferi flagella and an enzyme-linked immunosorbent assay (ELISA) for detection of immunoglobulin G (IgG) and IgM to the B. burgdorferi flagellum are described. The diagnostic performance of the flagellum ELISA for serodiagnosis of Lyme disease was compared with the performance of a traditional whole cell B. burgdorferi sonic extract ELISA. We examined sera and cerebrospinal fluid (CSF) from 56 patients with lymphocytic meningoradiculitis (Bannwarth's syndrome), the most frequent secondarystage manifestation of Lyme disease in Europe. Two hundred healthy individuals and patients with aseptic meningitis, encephalitis, Guillain-Barré syndrome, and syphilis served as controls. The flagellum ELISA was significantly more sensitive than the sonic extract ELISA. The diagnostic sensitivities were increased from 41.1 to 76.8% (P < 0.01) for IgG and from 35.7 to 67.9% (P < 0.05) for IgM detection in serum. The increase in sensitivity was most pronounced in patients with a short duration of disease (<20 days after onset). The diagnostic specificity increased for IgG detection but was almost unaltered for IgM. The flagellum ELISA did not improve the diagnostic sensitivity of measuring antibodies to borreliae in CSF, most likely owing to the low level of unspecific antibodies in CSF compared with serum. The cross-reactivity of sera and CSF from patients with syphilis decreased significantly. The flagellum antigen of B. burgdorferi shows no strain variation, is easy to purify in sufficient quantity, and is therefore a suitable reference antigen for routine serodiagnosis of Lyme disease.

We used a capture ELISA with biotinylated Borrelia burgdorferi flagella as antigen to analyze the kinetics of intrathecal antibody production against B burgdorferi in 27 patients with neuroborreliosis. All patients had lymphocytic pleocytosis, 13/27 had intrathecal specific IgM production, and 26/27 had intrathecal IgG synthesis against B burgdorferi before therapy. All patients improved after antibiotic treatment. At follow-up, 11 months to 8 years later (median, 1 1/2 years), 20 patients had had a complete clinical recovery, and seven suffered from sequelae. One patient without sequelae had persistent specific intrathecal IgM synthesis. Ten of 20 patients without sequelae and five of seven patients with sequelae had persistent intrathecal IgG production against B burgdorferi. None of the 16 patients with persistent specific intrathecal antibody synthesis had pleocytosis at follow-up. Therefore, intrathecal immunoglobulin production against B burgdorferi, especially IgG, may persist for years after treatment of neuroborreliosis without clinical signs of active disease.

Objective To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. Methods We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. Results From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. Conclusion CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.