Neurologic manifestations of Lyme Borreliosis.

In the first part of this review, a summarized description of the typical clinical manifestation as well as less frequent symptoms of early (acute) Lyme Neuroborreliosis (LNB) are presented. In the second part, insights into the controversial topic of "Post-Treatment Lyme Disease Syndrome" are given and the quite rare, but clearly defined picture of late (chronic) LNB is described.

Diagnostic value of cerebrospinal fluid CXCL13 for acute Lyme neuroborreliosis. A systematic review and meta-analysis.

OBJECTIVES: The utility of cerebrospinal fluid (CSF) CXCL13 for diagnosis of acute Lyme neuroborreliosis (LNB) has been debated and the test is not yet routinely performed. This study's aim was to evaluate its overall diagnostic accuracy through meta-analysis. METHODS: Electronic searches in PubMed MEDLINE and Web of Science were performed to identify relevant articles published before January 2018. A summary receiver operating characteristic curve and an optimal cut-off were estimated modelling multiple cut-offs. Publication bias was evaluated using a funnel plot and the associated regression test. RESULTS: A total of 18 studies involving 618 individuals with acute LNB and 2326 individuals with other neurological disorders meeting the eligibility criteria were identified. The pooled sensitivity for CSF CXCL13 was 89% (95% CI 85%-93%) and the pooled specificity was 96% (95% CI 92%-98%), using the identified optimal cut-off value of 162 pg/mL. There was marked heterogeneity between studies, caused by differences in the designs of the study populations and age distribution. The optimal cut-off in the seven studies with a cross-sectional design was 91 pg/mL (sensitivity 96%, 95% CI 92%-98%; specificity 94%, 95% CI 86%-97%) and in the 11 case-control studies it was 164 pg/mL (sensitivity 85%, 95% CI 78%-91%; specificity 95%, 95% CI 90%-98%). CSF CXCL13 values above the optimal cut-off level (determined in this meta-analysis) were also detectable in some other central nervous system disorders, namely neurosyphilis and central nervous system lymphoma. CONCLUSIONS: Our meta-analysis shows that CSF CXCL13 has the potential to become a useful adjunct in the diagnosis of acute LNB.

To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis: a position paper of ESGBOR, the ESCMID study group for Lyme borreliosis.

BACKGROUND: Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato. The most frequent clinical manifestations are erythema migrans and Lyme neuroborreliosis. Currently, a large volume of diagnostic testing for LB is reported, whereas the incidence of clinically relevant disease manifestations is low. This indicates overuse of diagnostic testing for LB with implications for patient care and cost-effective health management. AIM: The recommendations provided in this review are intended to support both the clinical diagnosis and initiatives for a more rational use of laboratory testing in patients with clinically suspected LB. SOURCES: This is a narrative review combining various aspects of the clinical and laboratory diagnosis with an educational purpose. The literature search was based on existing systematic reviews, national and international guidelines and supplemented with specific citations. IMPLICATIONS: The main recommendations according to current European case definitions for LB are as follows. Typical erythema migrans should be diagnosed clinically and does not require laboratory testing. The diagnosis of Lyme neuroborreliosis requires laboratory investigation of the spinal fluid including intrathecal antibody production, and the remaining disease manifestations require testing for serum antibodies to B. burgdorferi. Testing individuals with non-specific subjective symptoms is not recommended, because of a low positive predictive value.

[CXCL13: a biomarker for acute Lyme neuroborreliosis: investigation of the predictive value in the clinical routine]. / CXCL13 als Biomarker der akuten Neuroborreliose : Überprüfung des prädiktiven Wertes in der klinischen Routine.

BACKGROUND: The level of CXCL13 is a cerebrospinal fluid (CSF) biomarker for acute Lyme neuroborreliosis (LNB) with a high sensitivity. As the concentration rapidly declines during antibiotic therapy CXCL13 can also be used as a follow-up parameter. However, CXCL13 is not yet in use as a routine parameter due to concerns about the specificity. OBJECTIVES: The sensitivity, specificity and predictive value of CXCL13 in the clinical routine work-up of suspected LNB was analyzed. MATERIAL AND METHODS: Since July 2010 the CSF of all patients (n = 204) with suspected acute LNB was not only analyzed for the routine parameters (i.e. pleocytosis and intrathecal production of Borrelia-specific antibodies, AI) but also for CXCL13. In cases of incongruent findings, a follow-up puncture after antibiotic therapy was carried out. The cut-off level for acute LNB was set at 250 pg/ml. RESULTS: This study included 179 patients who were not pretreated with antibiotics. Of these patients 15 suffered from definite LNB, 3 had a probable LNB and all had a CXCL13 value above the cut-off level. Only 2 of the 161 patients with a non-LNB diagnosis (both with a lymphoma) had a CXCL13 value in the CSF higher than 250 pg/ml. Especially noteworthy were two patients without pleocytosis in the CSF but with CXCL13 levels above the cut-off level in whom LNB could be confirmed in the follow-up CSF analysis. CONCLUSIONS: The biomarker CXCL13 has a higher sensitivity (100 % vs. 87 %) with a specificity (99 %) comparable with the established diagnostic markers for LNB, e.g. CSF pleocytosis and Borrelia-AI in the investigated patient population. The negative predictive value of CXCL13 is 100 %. Therefore, a normal CXCL13 level virtually excludes LNB. In the clinical routine CXCL13 is a valuable and practical diagnostic marker for LNB and can even detect an acute LNB in patients without CSF pleocytosis.

A case of relapsing-remitting neuroborreliosis? Challenges in the differential diagnosis of recurrent myelitis.

We report the case of a 31-year-old woman with 4 episodes of myelitis with pleocytosis, a positive Borrelia burgdorferi serology with positive antibody indices, and full recovery each time after antibiotic and steroid treatment, suggesting neuroborreliosis. We nevertheless believe that recurrent neuroborreliosis is improbable based on the levels of the chemokine CXCL13 in cerebrospinal fluid and favor the diagnosis of post-infectious autoimmune-mediated transverse myelitis possibly triggered by an initial neuroborreliosis as the cause of the relapses observed in our patient. We demonstrate the diagnostic steps and procedures which were important in the differential diagnosis of this unusual and challenging case.

A prospective study on the role of CXCL13 in Lyme neuroborreliosis.

BACKGROUND: The definite diagnosis of acute Lyme neuroborreliosis (LNB) requires detection of an increased Borrelia burgdorferi-specific antibody index (AI). The B burgdorferi AI, however, is negative in up to 20% of patients with early LNB and can remain elevated for years after adequate therapy; both of these factors can make the diagnosis difficult. Recent retrospective studies suggested the chemokine CXCL13 as a potential biomarker for LNB. To evaluate its diagnostic value, we conducted a prospective study. METHODS: From March 2008 to August 2009, CSF and serum samples from all patients in whom a B burgdorferi-specific AI was requested (n=692) and CSF analysis revealed CSF pleocytosis (n=192) were included in the study. Because of the low number of patients with untreated LNB, 13 additional retrospectively selected samples of patients with untreated LNB were added. CXCL13 concentrations were measured by ELISA and receiver operating characteristic curves were generated. RESULTS: CSF CXCL13 was highly elevated in all patients with untreated acute LNB (mean=15,149 pg/mL) compared with that in the patients without LNB (mean=247 pg/mL). At a cutoff of 1,229 pg/mL, the sensitivity of CXCL13 was 94.1%, which is higher than the AI (85.7%). Only 7 patients (5 with a CNS lymphoma and 2 with bacterial meningitis) had a CXCL13 level above the cutoff, resulting in a specificity equal to the AI of 96.1%. CONCLUSIONS: CXCL13 shows high sensitivity and specificity for acute, untreated LNB. This novel marker appears to be helpful in clinically atypical cases and, in particular, in early stages of the disease when the B burgdorferi AI is (still) negative.

Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues.

In all known congenital imprinting disorders an association with aberrant methylation or mutations at specific loci was well established. However, several patients with transient neonatal diabetes mellitus (TNDM), Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) exhibiting multilocus hypomethylation (MLH) have meanwhile been described. Whereas TNDM patients with MLH show clinical symptoms different from carriers with isolated 6q24 aberrations, MLH carriers diagnosed as BWS or SRS present only the syndrome-specific features. Interestingly, SRS and BWS patients with nearly identical MLH patterns in leukocytes have been identified. We now report on the molecular findings in DNA in three SRS patients with hypomethylation of both 11p15 imprinted control regions (ICRs) in leukocytes. One patient was a monozygotic (MZ) twin, another was a triplet. While the hypomethylation affected both oppositely imprinted 11p15 ICRs in leukocytes, in buccal swab DNA only the ICR1 hypomethylation was visible in two of our patients. In the non-affected MZ twin of one of these patients, aberrant methylation was also present in leukocytes but neither in buccal swab DNA nor in skin fibroblasts. Despite mutation screening of several factors involved in establishment and maintenance of methylation marks including ZFP57, MBD3, DNMT1 and DNMT3L the molecular clue for the ICR1/ICR2 hypomethylation in our patients remained unclear. Furthermore, the reason for the development of the specific SRS phenotype is not obvious. In conclusion, our data reflect the broad range of epimutations in SRS and illustrate that an extensive molecular and clinical characterization of patients is necessary.

Polyneuropathy associated with cholesterol crystal embolism.

INTRODUCTION: Cholesterol crystal embolism complicating arterial catheterization usually presents as a multiorgan disease with renal failure, abdominal problems, and skin manifestations. METHODS: We present a patient with hypertension and generalized arteriosclerosis who presented with muscle weakness, diffuse pain in the extremities, and renal failure 3 weeks after coronary catheterization and angioplasty of the right coronary artery. Muscle weakness progressed during the following months. RESULTS: Nerve conduction studies and nerve biopsy showed severe axonal nerve injury. Biopsy of the kidney revealed the diagnosis of cholesterol crystal embolism. CONCLUSION: The clinical presentation indicates a direct association of cholesterol crystal embolism and polyneuropathy. Although cholesterol crystal embolism represents a rare cause of polyneuropathy, it should be considered in patients with acute onset polyneuropathy and sudden onset multiorgan disease after arterial catheterization.

EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis.

BACKGROUND: Lyme neuroborreliosis (LNB) is a nervous system infection caused by Borrelia burgdorferi sensu lato (Bb). OBJECTIVES: To present evidence-based recommendations for diagnosis and treatment. METHODS: Data were analysed according to levels of evidence as suggested by EFNS. RECOMMENDATIONS: The following three criteria should be fulfilled for definite LNB, and two of them for possible LNB: (i) neurological symptoms; (ii) cerebrospinal fluid (CSF) pleocytosis; (iii) Bb-specific antibodies produced intrathecally. PCR and CSF culture may be corroborative if symptom duration is <6 weeks, when Bb antibodies may be absent. PCR is otherwise not recommended. There is also not enough evidence to recommend the following tests for diagnostic purposes: microscope-based assays, chemokine CXCL13, antigen detection, immune complexes, lymphocyte transformation test, cyst formation, lymphocyte markers. Adult patients with definite or possible acute LNB (symptom duration <6 months) should be offered a single 14-day course of antibiotic treatment. Oral doxycycline (200 mg daily) and intravenous (IV) ceftriaxone (2 g daily) are equally effective in patients with symptoms confined to the peripheral nervous system, including meningitis (level A). Patients with CNS manifestations should be treated with IV ceftriaxone (2 g daily) for 14 days and late LNB (symptom duration >6 months) for 3 weeks (good practice points). Children should be treated as adults, except that doxycycline is contraindicated under 8 years of age (nine in some countries). If symptoms persist for more than 6 months after standard treatment, the condition is often termed post-Lyme disease syndrome (PLDS). Antibiotic therapy has no impact on PLDS (level A).

Mimicking of cerebral herniation through gamma-hydroxybutyric acid therapy.

Besides being a treatment option for narcolepsy, gamma-hydroxybutyrate is used as an adjuvant during anesthesia in Europe. In addition, it is illegally used as a recreational drug. Fixed and dilated, asymmetric pupils developed in 2 patients during continuous therapy with intravenous gamma-hydroxybutyrate, which was added to the long-term anesthetics fentanyl and midazolam. Cerebral herniation as an alternative cause for the pupillary changes was ruled out by using continuous intracranial pressure monitoring and computed tomography. In both patients, the pupillary abnormalities resolved after discontinuation of gamma-hydroxybutyrate. Thus, fixed and dilated pupils that are asymmetric seem to be an important side effect of gamma-hydroxybutyrate therapy that may mimic cerebral herniation in deeply anesthetized patients.

[Pain and neuroborreliosis: significance, diagnosis and treatment]. / Schmerzen bei Neuroborreliose: Bedeutung, Diagnostik und Therapie.

Lyme neuroborreliosis is a tick-borne infection of the central nervous system caused by the spirochete Borrelia burgdorferi. The most frequent manifestation of neuroborreliosis in Europe is meningoradiculitis or Bannwarth's syndrome. One of its hallmarks is intense, lancinating, radicular pain, especially at night. Its characteristics are rather different to other forms of neuropathic pain in respect to the dynamics, localisation and therapeutic responses. This review therefore summarises not only the general symptoms, diagnostic procedures and therapy of Lyme neuroborreliosis, but also revises the characteristics and therapeutic options of painful meningoradiculitis in Bannwarth's syndrome.

[Is there a correlation between the clinical, radiological and intrasurgical findings of osteoarthritis of the knee? A Prospective study on 103 patients]. / Korrelieren die klinischen, radiologischen und intraoperativen Befunde der Gonarthrose? Eine prospektive Studie an 103 Patienten.

AIM: The aim of this study was to compare the different diagnostic features (symptoms, physical examination, radiographic features and intraoperative findings) of osteoarthritis of the knee before total joint replacement and consequently relate them with each other. METHOD: Patients with primary osteoarthritis of the knee, who where accepted for total joint replacement in our clinic, were integrated in our study. The medical conditions were recorded by using the Womac score, the knee subscore (KS) of the Knee Society Clinical Rating System and a visual analogue scale (VAS). A physical examination was also performed. The radiological evaluation was performed by using standardised radiographs. Joint space narrowing, subchondral sclerosis, osteophytes, knee alignment and the Kellgren score were recorded. During surgery an orthopaedic specialist documented the progression of cartilage lesions using the classification of chondromalacia described by Outerbridge. The analysis of correlation was performed by using the Spearman correlation (SpK) coefficient. RESULTS: 103 patients were integrated in the study (mean age: 68 years, 70 women). No significant correlation could be found between the Womac score or VAS and the results of the radiological examination (SpK [Womac - Kellgren score]: - 0.04; SpK [VAS - Kellgren score]: 0.08). There was a significant correlation between the KS and the results of the radiological examination as well as the progression of the cartilage lesions, caused by the results of the physical examination documented in the KS (SpK [KS - Kellgren score]: - 0.39). The radiographic features, with the exception of subchondral sclerosis, showed a significant correlation with the degree of chondromalacia (SpK [Kellgren score - chondromalacia]: 0.43). The amount of osteophytes correlated the most with the cartilage lesions: SpK: 0.43. CONCLUSION: The knee subscore appears to be an efficient method for staging the clinical progression of osteoarthritis of the knee for clinical practice as well as for clinical trials. The Womac score especially serves to record the level of pain. We were able to confirm that the presence of osteophytes is the most significant radiographic feature of osteoarthritis of the knee. The Kellgren score turned out to be a reliable method for monitoring the radiographic progression of osteoarthritis of the knee.

[Cytokine CXCL13--a possible early CSF marker for neuroborreliosis]. / Zyktokin CXCL13 : Ein früher Liquormarker für die Neuroborreliose?

The definitive diagnosis of acute neuroborreliosis (NB) is based upon the presence of lymphomonocytic CSF pleocytosis and intrathecal Borrelia burgdorferi (B.b.)-specific antibody production (expressed by an antibody index of >2). However, the latter might be absent in early stages of the disease. Now a recently discovered additional CSF marker-the cytokine CXCL13-was found to be positive in every initial CSF sample from patients with NB and therefore could be a valuable tool for early diagnosis and initiation of antibiotic therapy. We report an unusual case of NB in a patient with a history of metastatic carcinoma of the prostate and unilateral polyradiculitis. While no intrathecal B.b.-specific antibody production could be demonstrated initially, the CSF CXCL13 level was high (>500 ng/g vs <1.7 ng/g in healthy controls). During the course of the disease, the antibody index turned positive (4.8) and the patient responded to antibiotic therapy, thus confirming the diagnosis. In this case, measuring CXCL13 in the CSF would have led to earlier diagnosis and treatment of NB.

The chemokine CXCL13 (BLC): a putative diagnostic marker for neuroborreliosis.

Using protein expression profiling, the authors identified an upregulation of the chemokine B lymphocyte chemoattractant (BLC) in the CSF of patients with neuroborreliosis but not in patients with noninflammatory and various other inflammatory neurologic diseases. This upregulation was confirmed by ELISA, showing increased BLC levels in every neuroborreliosis patient while being undetectable in patients with noninflammatory neurologic diseases. These results point to BLC as a putative additional diagnostic marker for neuroborreliosis.

Ascending arterial blood flow velocities during cardiac diastole in critical care patients--a characteristic flow pattern with a bad prognosis.

AIM: Pulsed Doppler ultrasound is a standard noninvasive investigation to measure the velocity and pulsatility of blood flow within the major intracranial and organ-supplying arteries in critical care patients. The normal arterial flow pattern in organ-supplying vessels is characterised by a systolic-diastolic forward flow which is caused by the aortic "Windkessel" function and the low peripheral resistance of the parenchymatous organs. A variety of well known pathological conditions may cause a change of the vascular characteristics within the perfused organs which are diagnosed by the typical changes of the flow pattern in the supplying arteries. In the cardiac diastole, however, there is always a slow decrease of the flow velocity which is terminated by the onset of the following systole. METHOD AND RESULTS: We report on 11 patients investigated by Doppler ultrasound during their stay in our intensive care unit. All these patients presented a markedly different flow pattern measured in their intra- and/or extracerebral vessels. This very distinctive flow pattern is characterised by a diastolic ascent of the arterial flow velocity and is caused by an excessively increased venous pressure within the draining veins of the affected organs. All patients died due to (multiple) organ failure. CONCLUSION: It is of major importance to be aware of the rare but very characteristic flow pattern described here because of the poor prognosis associated with it.

Clinical experience with linezolid for the treatment of central nervous system infections.

Linezolid, an oxazolidinone, exhibits bacteriostatic activity against virtually all Gram-positive bacteria and even covers atypical organisms like mycobacteria and Nocardia. However, little is known about its effectiveness for central nervous system (CNS) infections. We report on our good experience with linezolid for the treatment of CNS infections in 10 patients, amongst whom three were caused by mycobacteria. While six of our patients clinically improved during linezolid therapy even after failure of various antibiotics, it was unsuccessful in one case. Side-effects were only mild gastrointestinal problems in one patient after long term-treatment, which however led to the cessation of therapy. Linezolid appears to be a safe alternative to vancomycin for therapy-resistant CNS infections because of its good CSF penetration and few side-effects.