Background and PurposeWe need more knowledge on clinical presentations, time course, biomarkers, and prognosis in European Lyme neuroborreliosis (LNB).MethodsA prospective 12‐month follow‐up of predetermined clinical and laboratory parameters was undertaken in 105 patients with LNB.ResultsAt presentation, 79% had radiculopathy, 49% had facial palsy, and 13% had solely subjective symptoms (predominately pain). Intrathecally produced Borrelia burgdorferi (Bb) antibodies were demonstrated and cerebrospinal fluid (CSF) CXCL13 was positive in 85% and 82% pretreatment, in 73% and 10% at 6 months, and in 58% and 14% at 12 months, respectively. CSF Bb polymerase chain reaction (PCR) was positive in 40% pretreatment. In four patients who tested negative for Bb antibodies in both serum and CSF, the diagnosis was supported by typical clinical features, pleocytosis, CSF Bb‐PCR (n = 1), or CSF CXCL13 (n = 2). The proportion with symptoms influencing daily life was 91% pretreatment, 25% at 10 weeks, 20% at 6 months, and 15% at 12 months. Fatigue was the most common complaint at 12 months. A high burden of symptoms before and after treatment was associated with residual complaints at 12 months, whereas background data, other clinical features, and laboratory features were not.ConclusionsLNB can present with solely subjective symptoms, especially pain. Many LNB patients have persistent Bb antibodies in serum and CSF. In seronegative LNB, CSF Bb‐PCR and CXCL13 may give diagnostic support. CXCL13 may be persistently positive after treatment in some patients. Most of the clinical improvement occurs during the first 10 weeks. High initial clinical score is associated with poorer outcome.