Common and uncommon neurological manifestations of neuroborreliosis leading to hospitalization

In this study we classified patients with neuroborreliosis depending on neurological deficits that were the reason for presentation in a hospital. Here, we found that signs of meningitis were often found in patients with neuroborreliosis, but usually did not cause admission to a hospital (Fig. 3). In our cohort, cranial nerve palsy was the most frequent deficit which caused admission to a hospital followed by painful radiculitis, encephalitis, myelitis, and meningitis.

Patients presented either with isolated symptoms/deficits or a combination of multiple neurological symptoms. In patients with a combination of deficits, back pain (radiculitis) was the first symptom, followed by meningitis (headache), and finally by cranial nerve palsy in all but one patients. Our results are in line with a previous report showing that cranial nerve palsy is not the initial symptom when multiple neurological symptoms are present [23]. The diagnosis of cranial nerve palsy and myelitis is straightforward for neurologists and lumbar puncture is usually performed. However, diagnosis of neuroborreliosis can be difficult in other cases. Patients with radiculitis either reported back pain only or radiating pain into the limbs with or without paresis. Pain symptoms were rather unspecific and could therefore be easily misinterpreted e.g. as herniated disc. In three patients limb palsy due to radiculitis occurred suddenly, which led to initial misdiagnosis stroke.

Encephalitis seems to be another diagnostic challenge in neuroborreliosis. In our cohort, one patient presented with severely altered consciousness suggesting delirium for hours with the need of intensive care. MRI of the brain showed signs of basal vasculitis without infarction. Stroke on the basis of cerebral vasculitis is indeed a rare manifestation of neuroborreliosis in both adults and children and was predominantly described in case reports or series [4, 7, 24‐43]. In these cases typical stroke-like symptoms such as paresis, dysarthria, and/or aphasia have been reported. Only in few cases paresis combined with delirium were described. Interestingly, our patient presented with acute delirium due to vasculitis without stroke. Since such patients are frequently hospitalized in psychiatric institutions, psychiatrists should be aware of possible neuroborreliosis in patients with acute delirium. Another five patients in our cohort showed symptom duration of more than 6 months and were classified as chronic encephalitis. These patients were older than 65 years and suffered from cognitive impairment and gait disorder suspicious for normal pressure hydrocephalus (NPH). However, lumbar puncture with drainage of CSF did not change their symptoms. Instead, CSF analysis revealed pleocytosis and intrathecal synthesis of Borrelia specific antibodies indicating neuroborreliosis. Improvement of clinical symptoms after antibiotic treatment occurred in all of these cases. Similar cases of neuroborreliosis with symptoms mimicking NPH were already described in some case reports [44‐48]. Pseudotumor cerebri presents another disease which might be related to neuroborreliosis. In several reports typical symptoms of pseudotumor cerebri such as headache and papilledema and an elevated CSF opening pressure have been described predominantly affecting children [49‐60]. In these patients antibiotic treatment led to normalization of symptoms and CSF pressure.

The seasonal distribution of symptom onset might be of some help in suspicious cases. The majority of our patients (60%) presented between July and September. Similar results were communicated in earlier studies in Danish, Swedish, and Finish populations [6, 23, 61, 62]. Nevertheless, in our cohort neuroborreliosis was diagnosed in every month of the year except February. Therefore, low-risk months are unreliable for ruling out neuroborreliosis as already suggested [23].

For detection of Borrelia burgdorferi sensu lato infection serum is usually analyzed using ELISA with subsequent confirmation by immunoblot. Remarkably, four of our patients with neuroborreliosis lacked positive results for Borrelia infection in the blood (6%) but additional analysis of the CSF revealed pleocytosis and intrathecal production of antibodies against Borrelia burgdorferi sensu lato. Thus, negative blood results do not necessarily rule out neuroborreliosis. The same conclusion was drawn in previous studies [63‐65]. Henningsson and collegues found Borrelia specific antibodies in the CSF but not in serum in 25 of 150 patients (17%) by using ELISA at the time of diagnosis [64].

Our CSF data are largely in line with previous observations [10, 64, 66, 67]. We found elevated CSF cell counts in all but one patient. Blood-CSF barrier dysfunction occurred in 87% patients. Oligoclonal bands restricted to the CSF were found in 90% patients indicating intrathecal IgG synthesis. Quantitatively elevated intrathecal synthesis of immunoglobulins (either IgM, or IgG, or IgA) based on the calculation method of Reiber-Felgenhauer prevailed in 81% of the patients. Intrathecal synthesis of IgM was found in 74%, IgG synthesis was found in 47%, and IgA in 32% of the patients. Interestingly, isolated intrathecal synthesis of IgM or IgA was not found and was accompanied by positive oligoclonal bands in all cases. These results demonstrate that neuroborreliosis is accompanied by pronounced immunological CSF changes.

Active neuroborreliosis without pleocytosis is controversially discussed and three scenarios are suggested [3, 64, 66, 68]. The most common interpretation is that the majority of cases with intrathecal Borrelia specific antibody production without CSF pleocytosis are due to a previous neuroborreliosis. However, other authors attribute the absence of pleocytosis in some cases to a prolonged disease. Henningsson and colleagues described four cases with normal CSF cell count and a long history of illness (from 36 weeks till 6 years) [64]. Remarkably these four patients displayed the highest Borrelia specific IgG indices in their cohort and they have speculated that the initial pleocytosis might have been already resolved by the time of lumbar puncture probably reflecting the natural course of the disease. Conversely, others suggested that the lack of elevated CSF cell count may be associated with the brevity in disease duration in some cases. Rupprecht and colleagues described two cases with normal cell counts who were successfully treated with antibiotics [68]. Repeated CSF analyses after 6 or 14 days indeed discovered an increase in cell counts and an elevation of the Borrelia specific antibody index confirming active neuroborreliosis. Our cohort included only one patient without pleocytosis whose symptoms resolved completely after treatment with ceftriaxone. However, this patient did not undergo a second lumbar puncture, and thus, according to the diagnostic criteria there is a limitation regarding a definitive diagnosis. In our opinion, antibiotic treatment in such cases is justified with the important restriction that such a therapy has not been conducted before. The chemokine CXCL13 has been evaluated as a possible CSF biomarker for detection of acute neuroborreliosis [69‐71]. CXCL13 analysis might help in such cases to differentiate between acute neuroborreliosis and previous infection. However, CXCL13 is not yet in use as a routine parameter due to concerns about the specificity [68].