CXCL13 as a biomarker in the diagnostics of European lyme Neuroborreliosis - A prospective multicentre study in Austria.

Background: 'Definite Neuroborreliosis (NB)' is diagnosed with the presence of NB-specific symptoms, cerebrospinal fluid (CSF) pleocytosis and an elevated Borrelia Burgdorferi antibody index. However, some diagnostic uncertainties exist. The B-cell chemokine CXCL13 represents an emerging biomarker for the diagnosis and treatment of NB because its intrathecal concentration rises prior to the Borrelia antibody index and drops rapidly after antibiotic therapy. Nevertheless, due to lacking prospective data, a definite CXCL13 cut-off for the diagnosis of NB is still pending. Objective: Definition of a CSF CXCL13 cut-off for the diagnosis of acute and untreated NB in a prospective study setting. Design and methods: This multicentre prospective study involved 6 neurological departments treating patients in the Lower Austria district (1.7 million inhabitants). The controls were patients scheduled for a spinal tap but not clinically diagnosed with NB. Demographic data, clinical characteristics and blood counts, as well as inflammatory CSF values and CSF CXCL13-concentration were analysed. Results: We recruited 440 adult patients, of whom 42 have been diagnosed as having an acute and untreated 'definite NB'. Three hundred ninety-eight patients were assigned to the control group. The median intrathecal CXCL13 concentration was 2384 pg/ml for patients with NB and 0 pg/ml for controls. The difference was highly statistically significant (P ≤ .001). A CSF CXCL13 cut-off of 271 pg/ml resulted in a sensitivity of 95.2% and a specificity of 97.2% for the confirmation or exclusion of NB. Conclusion: Based on our results, we propose a CSF CXCL13 cut-off of 271 pg/ml with Euroimmun-Elisa for the diagnosis of acute and untreated NB. Due to its high sensitivity and specificity, CXCL13 is a strong candidate biomarker for routine NB assessment, especially in clinically unclear cases.

Analysis of inflammatory markers and tau deposits in an autopsy series of nine patients with anti-IgLON5 disease.

Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with a specific tauopathy. Only a few post-mortem neuropathological studies have been reported so far. Little is known about the pathogenic mechanisms that result in neurodegeneration. We investigated the neuropathology of anti-IgLON5 disease and characterized cellular and humoral inflammation. We included nine cases (six of them previously published). Median age of patients was 71 years (53-82 years), the median disease duration was 6 years (0.5-13 years), and the female to male ratio was 5:4. Six cases with a median disease duration of 9 years presented a prominent tauopathy. Five of them had a classical anti-IgLON5-related brainstem tauopathy and another presented a prominent neuronal and glial 4-repeat tauopathy, consistent with progressive supranuclear palsy (PSP). Three cases with short disease duration (median 1.25 years) only showed a primary age-related neurofibrillary pathology. Inflammatory infiltrates of T and B cells were mild to moderate and did not significantly differ between anti-IgLON5 disease cases with or without tauopathy. In contrast, we found an extensive neuropil deposition of IgG4 in the tegmentum of the brainstem, olivary nucleus, and cerebellar cortex that was most prominent in two patients with short disease duration without the typical IgLON5-related tauopathy. The IgG4 deposits were particularly prominent in the cerebellar cortex and in these regions accompanied by mild IgG1 deposits. Activated complement deposition (C9neo) was absent. Our study indicates that IgLON5-related tau pathology occurs in later disease stages and may also present a PSP-phenotype with exclusively 4-repeat neuronal and glial tau pathology. The prominent deposition of anti-IgLON5 IgG4 at predilection sites for tau pathology suggests that anti-IgLON5 antibodies precede the tau pathology. Early start of immunotherapy might prevent irreversible neuronal damage and progression of the disease, at least in a subgroup of patients.

A pilot study into the effects of music therapy on different areas of the brain of individuals with unresponsive wakefulness syndrome.

The global cerebral network allows music " to do to us what it does." While the same music can cause different emotions, the basic emotion of happy and sad songs can, nevertheless, be understood by most people. Consequently, the individual experience of music and its common effect on the human brain is a challenging subject for research. Various activities such as hearing, processing, and performing music provide us with different pictures of cerebral centers in PET. In comparison to these simple acts of experiencing music, the interaction and the therapeutic relationship between the patient and the therapist in Music Therapy (MT) provide us with an additional element in need of investigation. In the course of a pilot study, these problems were approached and reduced to the simple observation of pattern alteration in the brains of four individuals with Unresponsive Wakefulness Syndrome (UWS) during MT. Each patient had three PET investigations: (i) during a resting state, (ii) during the first exposure to MT, and (iii) during the last exposure to MT. Two patients in the MT group received MT for 5 weeks between the 2nd and the 3rd PET (three times a week), while two other patients in the control group had no MT in between. Tracer uptake was measured in the frontal, hippocampal, and cerebellar region of the brain. With certain differences in these three observed brain areas, the tracer uptake in the MT group was higher (34%) than in the control group after 5 weeks. The preliminary results suggest that MT activates the three brain regions described above. In this article, we present our approach to the neuroscience of MT and discuss the impact of our hypothesis on music therapy practice, neurological rehabilitation of individuals in UWS and additional neuroscientific research.

Prevention of poststroke cognitive decline: ASPIS--a multicenter, randomized, observer-blind, parallel group clinical trial to evaluate multiple lifestyle interventions--study design and baseline characteristics.

BACKGROUND: Cognitive impairment after stroke is a considerable burden to patients and their caregivers and occurs in one-third of stroke survivors. No strategy to prevent cognitive decline after stroke exists thus far. Established vascular risk factors have been associated with cognitive decline and may be a target for therapeutic interventions in stroke survivors. AIM: To test whether intensive multifactorial non-pharmacologic interventions based on lifestyle modification can reduce the risk of cognitive decline in patients who recently suffered ischemic stroke. METHODS: A randomized, controlled, multicenter, observer-blind trial was designed. The reference group obtains stroke care according to standard guidelines. The intervention group additionally receives intensive control and motivation for better compliance with prescribed evidence-based medication, regular blood pressure measurements, healthy diet, regular physical activity and cognitive training. Primary outcomes are the rate of cognitive decline at 24 months, assessed by a neuropsychological test battery and the cognitive subscale of the Alzheimer's Disease Assessment Scale. RESULTS: 202 patients (29% women), aged 62 ± 9 years, were recruited during 2010 to 2012. Stroke related impairment at inclusion was low (mean National Institutes of Health Stroke Scale: 1.9±1.8, median modified Rankin Scale: 1 (0-1)). At baseline, groups did not differ significantly in demographic, clinical or lifestyle characteristics. CONCLUSION: The recruitment was successful and the groups are balanced regarding potential confounding variables. The study will provide essential data about the feasibility and efficacy of lifestyle intervention after stroke in order to develop a new approach to prevent cognitive decline in patients with mild ischemic stroke.

European consensus table on the use of botulinum toxin type A in adult spasticity.

A group of clinicians from across Europe experienced in the use of botulinum toxin type A for the treatment of spasticity following acquired brain injury gathered to develop a consensus statement on best practice in managing adults with spasticity. This consensus table summarizes the current published data, which was collated following extensive literature searches, their assessment for level of evidence and discussion among the whole group. Published information is supplemented by expert opinion based on clinical experience from 16 European countries, involving 28 clinicians, who treat an average of approximately 200 patients annually, representing many thousand spasticity treatments with botulinum toxin per year.

Respective potencies of Botox and Dysport in a human skin model: a randomized, double-blind study.

Mouse units used to quantify the activity of botulinum A toxin preparations are not equivalent and issues concerning efficacy and safety remain with regard to their respective potencies and diffusion qualities in human tissue. We compared the effects of Botox (BOT) and Dysport (DYS) in different doses and dilutions in a human skin model. Eighteen (8 women, 10 men) healthy volunteers, aged 28.4 years +/- 5.7 years were injected intradermally with pure saline, BOT and DYS at 16 points in the abdomen in random order and in a double-blind condition, using two conversion ratios (1:3 and 1:4) and three different dilution schemes. For an objective outcome, the Ninhydrin sweat test was used to compare the anhidrotic areas. Both preparations showed a linear dose and dilution relationship with similar variances of responses for anhidrosis and hypohidrosis, indicating the same reliability of response. The dose equivalence conversion ratios (BOT: DYS) were 1:1.3 for anhidrosis and 1:1.6 for hypohidrosis (1:1.1-1.5 and 1:1.4-1.8 95% confidence intervals). The diffusion characteristics of both products were similar. A dose equivalence factor of more than 1:2 (BOT:DYS) is not supported by these objective and reproducible data.

UV-B irradiation attenuates dermal effects of botulinum toxin A: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Botulinum toxin type A (BoNT/A) is frequently used for cosmetic indications and hyperhidrosis. OBJECTIVES: We investigated whether UV-B irradiation alleviates the BoNT/A effect on local sudomotor activity. MATERIALS AND METHODS: In a randomized, double-blinded trial, the anhidrotic areas after BoNT/A (100 mU) injection 48 hours before and 14 days after UV-B irradiation were compared in six healthy volunteers. RESULTS: UV-B irradiation alleviated BoNT/A effect by approximately 30% (p=.0017). The UV-B-evoked reduction of anhidrotic areas was constant over the observation period of 14 weeks. CONCLUSIONS: When BoNT/A is applied intradermally, excessive exposure to UV-B and sunburn should be reconsidered. The authors have indicated no significant interest with commercial supporters.

Pain sensation during intradermal injections of three different botulinum toxin preparations in different doses and dilutions.

BACKGROUND: Pain sensation associated with injections of botulinum neurotoxin (BoNT) is commonly reported. To date differences in pain sensation between the commercially available products containing BoNT have not been quantified. OBJECTIVES: The pain sensations during injection of Dysport, Botox, Neurobloc, and pure saline (control) were compared. In addition, the nociceptive effect of different volumes used for the dilution of the same BoNT dose was investigated. METHODS: In a prospective, double-blind, controlled trial, 10 healthy subjects were injected intradermally with Dysport (12 U), Botox (3 and 4 U), Neurobloc (150 and 300 U) reconstituted in 0.9% saline, and pure saline. Pain sensation was quantified during injections. RESULTS: Neurobloc injections caused significantly more injection pain than Botox, Dysport, and saline. No significant differences between Dysport, Botox, and saline were found, although there was a trend toward less pain with pure saline injections. Higher pain levels with higher volumes could not be demonstrated significantly. CONCLUSION: Our data demonstrate that BoNT type B injections are associated with substantial pain. There is a considerable difference between the commercially available BoNT type B compared to the two BoNT type A preparations. Therefore, considering mitigation of injection pain seems necessary when using BoNT type B.

A lack of antinociceptive or antiinflammatory effect of botulinum toxin A in an inflammatory human pain model.

Several in vitro and in vivo investigations have shown that botulinum toxin A (BoNT/A) can inhibit the release of substance P and excitatory amino acids. Recently, a marked antinociceptive effect of BoNT/A and inhibition of glutamate release was observed in an animal pain model with inflammatory sensitization. In the present study, we tested the antiinflammatory and antihyperalgetic effect of BoNT/A in a well-characterized human inflammatory pain model. Using a randomized, double-blind, paired study design, we compared the effects of 100 mouse units of BoNT/A versus pure saline. Thermal and mechanical pain testings and superficial skin blood flow measurements were performed at baseline, at 48 h (in normal skin), and at 72 h (in inflamed skin) thereafter. Ultraviolet B irradiation resulted in a local inflammation with significant primary and secondary hyperalgesia. However, despite the evidence of efficacy on sudomotor function, BoNT/A had no effect on pain measures in either normal or inflamed skin. Signs of inflammation and primary and secondary hyperalgesia were found to be unaffected by BoNT. We have confirmed that BoNT/A has no direct effect on acute, noninflammatory pain. Furthermore, despite highly promising data from animal research, we have not observed antiinflammatory or antinociceptive effects of BoNT/A in human inflammatory pain.

Ninhydrin sweat test: a simple method for detecting antibodies neutralizing botulinum toxin type A.

Approximately 5% of patients with cervical dystonia receiving repeated botulinum neurotoxin A (BoNT/A) injections develop secondary loss of treatment benefit. Currently available tests to directly detect neutralizing BoNT/A antibodies (BoNT/A-AB) are either expensive or time consuming. To establish a simple, clinically useful test for antibody detection, we adapted the ninhydrin sweat test (NST). Eighteen dystonic patients with secondary nonresponse and clinically suspected BoNT/A-AB formation were tested for BoNT/A-AB in the mouse diaphragm test (MDT). In addition, the size of the anhidrotic area was determined by the NST 21 days after an intradermal dose of 10 U Dysport into the hypothenar region of the left palm. In nine patients, positive BoNT-AB titers were found in the MDT. There was a significant correlation between the BoNT/A-AB titers and the anhidrotic area (Spearman's rho = -0.9, P < 0.0001). Both tests provided comparably good results with respect to qualitative antibody detection. In the clinical situation of secondary nonresponse to BoNT/A therapy, the economical NST may be a helpful tool to detect neutralizing BoNT/A-AB.

Tension-type headache in different age groups at two headache centers.

At two headache centers, one for children and adolescents and the other for adults, we investigated patients aged 5-80 years with episodic or chronic tension-type headache to evaluate the relation between age and headache characteristics as well as analgesics intake. We found an increasing headache frequency and duration, an increasing variability of the headache location, and an increasing frequency of nausea with increasing age. All other headache features did not depend on age. Additionally, our study revealed a marked increase of analgesics use in adults compared to children and adolescents. In conclusion, children, adolescents, and adults referred for tension-type headache show minor differences in some headache features, but a marked change of analgesics intake. The different headache symptoms may be causally related to age, but an influence of medication or other factors must also be considered.