Effects of sex hormones on brain GABA and glutamate levels in a cis- and transgender cohort.

Sex hormones affect the GABAergic and glutamatergic neurotransmitter system as demonstrated in animal studies. However, human research has mostly been correlational in nature. Here, we aimed at substantiating causal interpretations of the interaction between sex hormones and neurotransmitter function by using magnetic resonance spectroscopy imaging (MRSI) to study the effect of gender-affirming hormone treatment (GHT) in transgender individuals. Fifteen trans men (TM) with a DSM-5 diagnosis of gender dysphoria, undergoing GHT, and 15 age-matched cisgender women (CW), receiving no therapy, underwent MRSI before and after at least 12 weeks. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (combination of GABA and macromolecules) and Glx (combination of glutamate and glutamine) ratios to total creatine (GABA+/tCr, Glx/tCr) were calculated in five predefined regions-of-interest (hippocampus, insula, pallidum, putamen and thalamus). Linear mixed models analysis revealed a significant measurement by gender identity effect (pcorr. = 0.048) for GABA+/tCr ratios in the hippocampus, with the TM cohort showing decreased GABA+/tCr levels after GHT compared to CW. Moreover, analysis of covariance showed a significant sex difference in insula GABA+/tCr ratios (pcorr. = 0.049), indicating elevated GABA levels in cisgender women compared to cisgender men. Our study demonstrates GHT treatment-induced GABA+/tCr reductions in the hippocampus, indicating hormone receptor activation on GABAergic cells and testosterone-induced neuroplastic processes within the hippocampus. Moreover, elevated GABA levels in the female compared to the male insula highlight the importance of including sex as factor in future MRS studies. DATA AVAILABILITY STATEMENT: Due to data protection laws processed data is available from the authors upon reasonable request. Please contact rupert.lanzenberger@meduniwien.ac.at with any questions or requests.

Association of norepinephrine transporter methylation with in vivo NET expression and hyperactivity-impulsivity symptoms in ADHD measured with PET.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a robust genetic influence. The norepinephrine transporter (NET) is of particular interest as it is one of the main targets in treatment of the disorder. As ADHD is a complex and polygenetic condition, the possible regulation by epigenetic processes has received increased attention. We sought to determine possible differences in NET promoter DNA methylation between patients with ADHD and healthy controls. DNA methylation levels in the promoter region of the NET were determined in 23 adult patients with ADHD and 23 healthy controls. A subgroup of 18 patients with ADHD and 18 healthy controls underwent positron emission tomography (PET) with the radioligand (S,S)-[18F]FMeNER-D2 to quantify the NET in several brain areas in vivo. Analyses revealed significant differences in NET methylation levels at several cytosine-phosphate-guanine (CpG) sites between groups. A defined segment of the NET promoter ("region 1") was hypermethylated in patients in comparison with controls. In ADHD patients, a negative correlation between methylation of a CpG site in this region and NET distribution in the thalamus, locus coeruleus, and the raphe nuclei was detected. Furthermore, methylation of several sites in region 1 was negatively associated with the severity of hyperactivity-impulsivity symptoms. Our results point to an epigenetic dysregulation in ADHD, possibly due to a compensatory mechanisms or additional factors involved in transcriptional processing.

Machine learning classification of ADHD and HC by multimodal serotonergic data.

Serotonin neurotransmission may impact the etiology and pathology of attention-deficit and hyperactivity disorder (ADHD), partly mediated through single nucleotide polymorphisms (SNPs). We propose a multivariate, genetic and positron emission tomography (PET) imaging classification model for ADHD and healthy controls (HC). Sixteen patients with ADHD and 22 HC were scanned by PET to measure serotonin transporter (SERT') binding potential with [11C]DASB. All subjects were genotyped for thirty SNPs within the HTR1A, HTR1B, HTR2A and TPH2 genes. Cortical and subcortical regions of interest (ROI) were defined and random forest (RF) machine learning was used for feature selection and classification in a five-fold cross-validation model with ten repeats. Variable selection highlighted the ROI posterior cingulate gyrus, cuneus, precuneus, pre-, para- and postcentral gyri as well as the SNPs HTR2A rs1328684 and rs6311 and HTR1B rs130058 as most discriminative between ADHD and HC status. The mean accuracy for the validation sets across repeats was 0.82 (±0.09) with balanced sensitivity and specificity of 0.75 and 0.86, respectively. With a prediction accuracy above 0.8, the findings underlying the proposed model advocate the relevance of the SERT as well as the HTR1B and HTR2A genes in ADHD and hint towards disease-specific effects. Regarding the high rates of comorbidities and difficult differential diagnosis especially for ADHD, a reliable computer-aided diagnostic tool for disorders anchored in the serotonergic system will support clinical decisions.

Repetitive enhancement of serum BDNF subsequent to continuation ECT.

INTRODUCTION: Continuation electroconvulsive therapy (c-ECT) is highly effective for the prevention of depressive symptom relapse. There is a lack of understanding, about how c-ECT works in humans, particularly with regard to its effects on brain derived neurotrophic factor (BDNF) concentrations. Here, we aimed to close a gap in the literature by evaluating BDNF levels in patients receiving c-ECT. METHODS: We included 13 patients with either unipolar or bipolar depression (mean age ± SD: 55.5 ± 17.1; f/m: 10/3; unipolar/bipolar: 10/3) who received between one and four c-ECT (average per patient: 2.8). Serum BDNF (sBDNF) levels were assessed before and after each c-ECT sessions. Clinical assessments were also administered both before and after treatment. RESULTS: Our analysis revealed a significant increase in sBDNF after each treatment (c-ECT 1-3: P < 0.001, c-ECT 4: P = 0.018). The application of multiple c-ECT treatments was not, however, associated with further sBDNF enhancements. Psychometric scores were not significantly altered following c-ECT. DISCUSSION: An increase in sBDNF concentrations subsequent to c-ECT parallel data from the animal literature, which has linked regularly applied electrical stimulation to neuroplastic processes. This finding suggests a relationship between ECT-induced sBDNF concentrations and (sustained) remission status, considering a stable clinical condition across c-ECT.

Clinical factors predicting treatment resistant depression: affirmative results from the European multicenter study.

OBJECTIVES: Clinical variables were investigated in the 'treatment resistant depression (TRD)- III' sample to replicate earlier findings by the European research consortium 'Group for the Study of Resistant Depression' (GSRD) and enable cross-sample prediction of treatment outcome in TRD. EXPERIMENTAL PROCEDURES: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. RESULTS: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. CONCLUSION: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I.

The influence of the rs6295 gene polymorphism on serotonin-1A receptor distribution investigated with PET in patients with major depression applying machine learning.

Major depressive disorder (MDD) is the most common neuropsychiatric disease and despite extensive research, its genetic substrate is still not sufficiently understood. The common polymorphism rs6295 of the serotonin-1A receptor gene (HTR1A) is affecting the transcriptional regulation of the 5-HT1A receptor and has been closely linked to MDD. Here, we used positron emission tomography (PET) exploiting advances in data mining and statistics by using machine learning in 62 healthy subjects and 19 patients with MDD, which were scanned with PET using the radioligand [carbonyl-11C]WAY-100635. All the subjects were genotyped for rs6295 and genotype was grouped in GG vs C allele carriers. Mixed model was applied in a ROI-based (region of interest) approach. ROI binding potential (BPND) was divided by dorsal raphe BPND as a specific measure to highlight rs6295 effects (BPDiv). Mixed model produced an interaction effect of ROI and genotype in the patients' group but no effects in healthy controls. Differences of BPDiv was demonstrated in seven ROIs; parahippocampus, hippocampus, fusiform gyrus, gyrus rectus, supplementary motor area, inferior frontal occipital gyrus and lingual gyrus. For classification of genotype, 'RandomForest' and Support Vector Machines were used, however, no model with sufficient predictive capability could be computed. Our results are in line with preclinical data, mouse model knockout studies as well as previous clinical analyses, demonstrating the two-pronged effect of the G allele on 5-HT1A BPND for, we believe, the first time. Future endeavors should address epigenetic effects and allosteric heteroreceptor complexes. Replication in larger samples of MDD patients is necessary to substantiate our findings.

Imaging the neuroplastic effects of ketamine with VBM and the necessity of placebo control.

In the last years a plethora of studies have investigated morphological changes induced by behavioural or pharmacological interventions using structural T1-weighted MRI and voxel-based morphometry (VBM). Ketamine is thought to exert its antidepressant action by restoring neuroplasticity. In order to test for acute impact of a single ketamine infusion on grey matter volume we performed a placebo-controlled, double-blind investigation in healthy volunteers using VBM. 28 healthy individuals underwent two MRI sessions within a timeframe of 2 weeks, each consisting of two structural T1-weighted MRIs within a single session, one before and one 45min after infusion of S-ketamine (bolus of 0.11mg/kg, followed by an maintenance infusion of 0.12mg/kg) or placebo (0.9% NaCl infusion) using a crossover design. In the repeated-measures ANOVA with time (post-infusion/pre-infusion) and medication (placebo/ketamine) as factors, no significant effect of interaction and no effect of medication was found (FWE-corrected). Importantly, further post-hoc t-tests revealed a strong "decrease" of grey matter both in the placebo and the ketamine condition over time. This effect was evident mainly in frontal and temporal regions bilaterally with t-values ranging from 4.95 to 5.31 (FWE-corrected at p<0.05 voxel level). The vulnerabilities of VBM have been repeatedly demonstrated, with reports of influence of blood flow, tissue water and direct effects of pharmacological compounds on the MRI signal. Here again, we highlight that the relationship between intervention and VBM results is apparently subject to a number of physiological influences, which are partly unknown. Future studies focusing on the effects of ketamine on grey matter should try to integrate known influential factors such as blood flow into analysis. Furthermore, the results of this study highlight the importance of a carefully performed placebo condition in pharmacological fMRI studies.

Gender transition affects neural correlates of empathy: A resting state functional connectivity study with ultra high-field 7T MR imaging.

Sex-steroid hormones have repeatedly been shown to influence empathy, which is in turn reflected in resting state functional connectivity (rsFC). Cross-sex hormone treatment in transgender individuals provides the opportunity to examine changes to rsFC over gender transition. We aimed to investigate whether sex-steroid hormones influence rsFC patterns related to unique aspects of empathy, namely emotion recognition and description as well as emotional contagion. RsFC data was acquired with 7Tesla magnetic resonance imaging in 24 male-to-female (MtF) and 33 female-to-male (FtM) transgender individuals before treatment, in addition to 33 male- and 44 female controls. Of the transgender participants, 15 MtF and 20 FtM were additionally assessed after 4 weeks and 4 months of treatment. Empathy scores were acquired at the same time-points. MtF differed at baseline from all other groups and assimilated over the course of gender transition in a rsFC network around the supramarginal gyrus, a region central to interpersonal emotion processing. While changes to sex-steroid hormones did not correlate with rsFC in this network, a sex hormone independent association between empathy scores and rsFC was found. Our results underline that 1) MtF transgender persons demonstrate unique rsFC patterns in a network related to empathy and 2) changes within this network over gender transition are likely related to changes in emotion recognition, -description, and -contagion, and are sex-steroid hormone independent.

Intramuscular distribution of botulinum toxin--visualized by MRI.

OBJECTIVE: A precise knowledge of the spread of botulinum toxin (BoNT) in muscle tissue is required to efficiently access endplate zones and increase BoNT's therapeutic efficacy. Here, we aimed to understand the spatiotemporal dynamics of BoNT distribution in skeletal muscle and its modulating factors, such as injected volume and exercise after injection. METHODS: To visualize distribution in muscle tissue, sagittal, dynamic, balanced fast field echo (BFFE) MRI imaging was performed during injection of 1 ml BoNT/NaCl bolus in spastic biceps brachii muscles (SBB, n=4), and 1 ml NaCl in the right and 2 ml NaCl in the left healthy biceps brachii (HBB, n=6), with or without successive muscle exercise. The pattern of extracellular fluid distribution was evaluated by T2-weighted and diffusion tensor imaging (DTI) sequences. RESULTS: BFFE indicated an immediate increase in hyperintensity, parallel to the muscle fibers, in the shape of a long (5.3±1.7 cm) and thin (0.52±1.3 cm) layer in HBB. The layer in SBB was shorter (3.25±0.6 cm, p=0.01) and tended to be thicker (0.74±2.9 cm, p=0.27). In HBB, an increase in volume (2 ml) resulted in an increase in thickness (0.95±0.2 cm, p=0.015), but a consistent length (5.67±1.3 cm, p=0.54). DTI visualized a change of diffusion, which exceeded the bolus region by approximately 0.5 cm. Redistribution occurred 10 min after injection and was more prominent in HBB, compared to SBB. Additional muscle activity did not alter the diffusion pattern or bolus distribution. CONCLUSION: Injecting BoNT at different depths perpendicular to the direction of the muscle fiber might optimize the efficacy of BoNT treatment. Additional sites along muscle fibers should be considered in SBB.

[The effects of hormone replacement therapy on mind and brain]. / Hormonersatztherapie und deren Wirkung auf Psyche und Gehirn.

Hormonal fluctuations during the perimenopausal transition lead to physical discomfort but are also frequently accompanied by mood swings, depressive symptoms, anxiety and sleeping disorders. The important role of the neurotransmitter serotonin in the pathogenesis of anxiety disorders and major depression is unquestioned, but only little is known about the influence of sex hormones on the serotonergic system. This review provides an overview of potential risk factors for the occurrence of affective disorders in the menopausal transition and discusses possible therapeutic options. Current research findings from longitudinal studies testing the efficacy of hormone replacement therapy and antidepressants with effects on the serotonergic neurotransmission on physical and mental discomforts during menopause are presented. Furthermore, studies using positron emission tomography and genetic methods that explore the effects of sex steroids on different components of the serotonergic system are shown. The interactions between estrogen, progesterone and the serotonergic system are described, and possible neurobiological and endocrinological mechanisms underlying depressive symptoms in the perimenopause are elucidated.

Long-term efficacy and respective potencies of botulinum toxin A and B: a randomized, double-blind study.

BACKGROUND: Mouse units (mU) are used for quantification of the biological activity of botulinum A and B toxin preparations. However, in human tissue, mU values between preparations are not equivalent and lack of clarity concerning efficacy and safety remains with regard to their respective potencies, duration of drug effect and diffusion qualities. OBJECTIVES: To compare short-term and long-term effects of Botox(®) (BOT; Allergan Inc., Irvine, CA, U.S.A.) and Neurobloc(®)/Myobloc(®) (NBC; Solstice Neurosciences Inc., Malvern, PA, U.S.A.) in different doses and dilutions in a human skin model. METHODS: In this prospective randomized double-blind study, 18 healthy volunteers (eight women and 10 men; mean ± SD age 28·4 ± 5·7 years) were injected intradermally with pure saline, BOT and NBC at 10 points in the abdomen in random order, using the BOT/NBC conversion ratio 1 : 75 and different dilution schemes. For an objective outcome, the ninhydrin sweat test was used to compare the anhidrotic areas (action halos). Ten measurements were taken during a time period of 54 weeks. RESULTS: Both preparations showed a peak effect at week 3, with significantly larger anhidrotic areas for NBC. Thereafter, however, the rate of decline was lower in BOT and after week 24, mean BOT areas were larger. The effect of dilution was higher in NBC and the mean dose equivalence conversion ratio (BOT/NBC) was 1 : 29 (area under the curve). Gender effects were seen in both products, with smaller action halos in women. CONCLUSIONS: These results have important implications in clinical routine, especially for autonomic indications.

Transcranial magnetic brain stimulation modulates blepharospasm: a randomized controlled study.

BACKGROUND: Benign essential blepharospasm (BEB) is a common form of focal dystonia. Besides pathology in the basal ganglia, accumulating evidence suggests pathologic changes in the anterior cingulate cortex (ACC). METHODS: This is a randomized, sham-controlled, observer-blinded prospective study. In 12 patients with BEB, we evaluated the effects of a 15-minute session of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the ACC with stimulation intensities at 100% active motor threshold with 3 stimulation coils: a conventional circular coil (C-coil), a sham coil (S-coil), and a Hesed coil (H-coil, which allows stimulation of deeper brain regions. Primary outcome was the clinical effects on BEB (blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after, and 1 hour after stimulation); secondary outcome was the blink reflex recovery curve. RESULTS: Subjective stimulation comfort was similar for each coil with no stimulation-associated adverse events. Stimulation with the H- and C-coils resulted in a significant improvement in all 3 outcome measures and was still detectable in physician rating and patient rating 1 hour after stimulation. S-coil stimulation had no effects. The active motor threshold was significantly lower for the H-coil compared to the other 2 coils. CONCLUSIONS: rTMS could be used as a therapeutic tool in BEB. Further studies will be necessary to show whether repeated stimulation applications result in lasting clinical effects. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with BEB, H- and C-coil rTMS is safe and improves clinical symptoms of BEB immediately and 1 hour after stimulation.

Reward and the serotonergic system.

Anhedonia, as a failure to experience rewarding stimuli, is a key characteristic of many psychiatric disorders including depression and schizophrenia. Investigations on the neurobiological correlates of reward and hedonia/anhedonia have been a growing subject of research demonstrating several neuromodulators to mediate different aspects of reward processing. Whereas the majority of research on reward mainly focused on the dopamine and opioid systems, a serotonergic mechanism has been neglected. However, recent promising results strengthen the pivotal role of serotonin in reward processing. Evidence includes electrophysical and pharmacological as well as genetic and imaging studies. Primate research using single-unit recording of neurons within the dorsal raphe nucleus argues for a serotonergic mediation of reward value, whereas studies using intracranial self-stimulation point to an important contribution of serotonin in modulating motivational aspects of rewarding brain stimulation. Pharmacological studies using agonists and antagonists of serotonergic receptor subtypes and approaches investigating an increase or decrease of the extracellular level of serotonin offer strong evidence for a serotonergic mediation, ranging from aversion to pleasure. This review provides an argument for serotonin as a fundamental mediator of emotional, motivational and cognitive aspects of reward representation, which makes it possibly as important as dopamine for reward processing.

Blepharospasm and the modulation of cortical excitability in primary and secondary motor areas.

BACKGROUND: Traditionally, benign essential blepharospasm (BEB) is considered a disorder caused by basal ganglia dysfunction. Electrophysiologic and brain imaging studies suggest pathologic changes in excitability in the primary motor cortex (MC), anterior cingulate (AC), and secondary motor areas, such as premotor (PMC) and supplementary motor cortices (SMA). METHODS: In this pilot study of 7 patients with BEB, we experimentally reduced cortical excitability of 4 areas: MC (first dorsal interosseus area), PMC, SMA, and AC, each with 3 noninvasive techniques: low-frequency repetitive transcranial magnetic stimulation (lfrTMS), continuous theta burst stimulation (cTBS), and cathodal transcranial direct current stimulation (tDCS). Primary outcome was the clinical effects on blepharospasm (blink rate observation by an investigator blinded to the intervention and subjective rating by the patient); secondary outcome was the blink reflex recovery curve (BRR). RESULTS: lfrTMS resulted in a significant improvement over all 4 brain areas for physician rating, patient rating, and BRR, whereas cTBS and tDCS showed only trends for improvement in physician rating, but no improvements for patient rating and BRR. lfrTMS had a significantly higher effect over AC than MC for physician rating, but no differences were seen for other pairwise comparisons of stimulated brain areas. CONCLUSIONS: Electrophysiologic and clinical improvements by functional inhibition of the medial frontal areas using low-frequency repetitive transcranial magnetic stimulation suggests that hypersensitivity of the anterior cingulate is directly or indirectly involved in the pathophysiology of benign essential blepharospasm. Inhibition of these areas using low-frequency repetitive transcranial magnetic stimulation could provide a therapeutic tool and is worthy of a larger study.

Neutralizing antibodies in dystonic patients who still respond well to botulinum toxin type A.

BACKGROUND: Complete secondary therapy failure due to antibodies against botulinum toxin A (BoNT/A-ABs) may raise extensive treatment difficulties. We tested whether neutralizing BoNT/A-ABs can be detected in dystonic patients with good clinical responses to botulinum toxin A (BoNT/A) treatment. METHODS: We used the ninhydrin sweat test (NST) and the mouse diaphragm test (MDT) in 28 subjects. Of 119 dystonic patients who responded well to BoNT/A, we randomly selected 14 and compared the results of the NST and MDT with 14 healthy controls. RESULTS: Higher BoNT/A-AB titers correlated significantly with smaller anhidrotic areas. We found seven patients with borderline antibody (AB) values (MDT 0.4 to 0.8 mU/mL) with significantly smaller anhidrotic areas (NST) compared with healthy controls and AB-negative patients. Risk factors for smaller anhidrotic areas were short injection intervals but not prolonged exposure to BoNT/A or high injection doses. CONCLUSIONS: These data demonstrate that >40% of dystonic patients who respond well to botulinum toxin A (BoNT/A) show partial nonresponsiveness on the ninhydrin sweat test and have low titers of neutralizing BoNT/A antibodies.

Botulinum toxin in the treatment of rare head and neck pain syndromes: a systematic review of the literature.

BACKGROUND: Botulinum neurotoxin (BoNT) is used to treat various neurological disorders associated with pathologically increased muscle tone. Botulinum toxin inhibits the release of the neurotransmitter acetylcholine at the neuromuscular junction thereby inhibiting striatal muscle contractions. Besides the reduction in muscle tone BoNT tends to reduce pain in pain syndromes associated with muscle spasm. In addition, BoNT has been proposed as an analgesic, suggesting alternative non-cholinergic mechanisms of action.Surprisingly, BoNT was reported as a potential treatment for tension-type headache and migraine-both primary headache syndromes without an apparent muscular component-however, varying responses to BoNT have been found, overall without sufficient evidence for a general treatment. In this systematic review we set out to clarify the efficacy and safety of BoNT in the treatment of rare head and neck pain syndromes (e. g. cervicogenic headache, chronic paroxysmal hemicrania, cluster headache, trigeminal neuralgia, temporomandibular disorders, cervical dystonia and whiplash injuries). OBJECTIVES: To assess the analgesic efficacy and safety of botulinum toxins versus other medicines, placebo or no treatment in rare head and neck pain syndromes. SEARCH STRATEGY: We searched the bibliographic databases MEDLINE, EMBASE and PASCAL Biomed to May 2003. We also reviewed the reference lists from identified articles including reviews and meta-analyses of treatment studies. Furthermore we searched booklets of scientific congresses in the field of neurology for potentially relevant studies. Additional reports were identified from the reference list of the retrieved papers, and by contacting experts in the field. SELECTION CRITERIA: Randomized controlled trials (RCTs) with any dose of BoNT for rare head and neck pain syndromes, describing subjective pain assessment as either the primary or a secondary outcome, were included in this review. DATA COLLECTION AND ANALYSIS: All trials were quality scored and two independent reviewers extracted data. Results were compared for differences, and discrepancies were resolved by discussion. MAIN RESULTS: Fourteen RCTs of BoNT in cervical dystonia were included in this review. All except one showed significant pain relief following BoNT treatment compared to placebo. Studies providing dichotomous outcome data were pooled using the Peto method. The overall effect was found to be highly significant (OR 4.795 [95% CI 5.551-6.473]). For cervicogenic headache, two RCTs-one positive study and one negative study-were included. Two studies addressing chronic neck pain were included in this review. Both studies did not reveal significant effects. Furthermore, one small trial (N = 15 patients) focussing BoNT in temporomandibular disorders was included,without demonstrating significant effectiveness but a high proportion of patients lost to follow-up and a high rate of adverse effects. For the use of BoNT in cluster headache, chronic paroxysmal hemicrania and trigeminal neuralgia no RCTs were identified. Adverse effects (AEs) were found to be mild to moderate and dose-dependent. They were summarized where possible, irrespective of the formulation used and condition treated (OR = 5.066 [95% CI 2.770-9.265], number-needed-to-harm (NNH) = 5.5 [range 4.4-17]). REVIEWERS' CONCLUSIONS: There is convincing evidence for the effectiveness of BoNT in the treatment of pain associated with cervical dystonia. Due to the frequent adverse effects predominantly observed with higher doses, the trade off in risk and benefit should be carefully considered in each case. For all other rare head and neck pain syndromes we found no RCTs (cluster headache, chronic paroxysmal hemicrania, trigeminal neuralgia) and only a few small sized trials (cervicogenic headache, chronic neck pain, temporomandibular disorders). We were therefore unable to draw any definite conclusions.

Treatment of focal hyperhidrosis with botulinum toxin type A: long-term follow-up in 61 patients.

BACKGROUND: The blocking action of botulinum toxin type A (BTX-A) on cholinergically innervated sweat glands has been used successfully to treat patients with focal hyperhidrosis. OBJECTIVES: To investigate the long-term efficacy and safety of intradermal injections of BTX-A. METHODS: We performed an open-label study in 61 patients treated over a period of 3 years for axillary or palmar hyperhidrosis. A total dose of 400 mU BTX-A (Dysport) was injected into both axillae or 460 mU BTX-A (Dysport) into both palms. The injections were repeated after relapse. Objective quantification of sweat production was performed using digitized ninhydrin-stained sheets. RESULTS: Four weeks after BTX-A treatment the median reduction in sweat production was 71% compared with baseline (P < 0.001) in the axillary group and 42% (P = 0.005) in the palmar group. Subjective assessment of sweat production by the patients using a visual analogue scale (0, no sweating; 100, the most severe sweating) showed a significant reduction in both the axillary (P < 0.001) and palmar groups (P < 0.001). Secondary disturbances due to focal hyperhidrosis interfering with daily activities were markedly improved in both groups. The median time interval between the sets of injections was 34 weeks for axillary hyperhidrosis and 25 weeks for palmar hyperhidrosis. The treatment of palmar hyperhidrosis was complicated by transient but not disabling weakness of the small hand muscles in nine of 21 patients. CONCLUSIONS: Repeated intradermal injections of BTX-A in patients with axillary and palmar hyperhidrosis are as effective as first treatments.

[Botulinum toxin in the treatment of focal hyperhidrosis]. / Intradermale Botulinumtoxininjektionen in der Behandlung fokaler Hyperhidrosen.

INTRODUCTION: Botulinum A toxin (BTX-A) acts primarily at peripheral cholinergic synapses, inhibiting the release of acetylcholine. Initially it has been used to block the neuromuscular junction in focal dystonic and spastic syndromes. Recently there has been suggestions for potential clinical indications in non-muscular diseases where cholinergic terminals play a role. GUSTATORY SWEATING: In 1995 physicians reported a long-lasting anhidrotic effect of intracutaneous BTX-A injections in patients suffering from gustatory sweating (Frey's syndrome). Consequently, a number of clinical studies demonstrated good efficacy of intradermal injections of botulinumtoxin in patients with focal hyperhidrosis. FOCAL HYPERHIDROSIS OF THE PALMS AND AXILLAE: Focal hyperhidrosis is usually confined to the palms and axillae. Excessive sweating may be a social handicap and an occupational hazard. The management of focal hyperhidrosis remains controversial. Topical antiperspirants are only effective in very mild cases. Iontophoresis with tap water or anticholinergic drugs is messy and time consuming with only short-lived effect. Sympathectomy, the cornerstone of surgical management, is usually effective in palmar hyperhidrosis. Complications of this technique include surgical risks, postoperative and cosmetic problems and compensatory hyperhidrosis. AXILLARY HYPERHIDROSIS: Several studies confirmed that intracutaneous injections of botulinum toxin are useful in the majority of patients with axillary hyperhidrosis resistant to conventional treatment. In axillary hyperhidrosis total doses are ranging from 200-400 mU Dysport or from 80 to 130 mU Botox to reach a good clinical response. Injections are usually well tolerated and no serious side-effects have been observed. The mean duration of anhidrotic effect ranges between 3 and 9 weeks. PALMAR HYPERHIDROSIS: The use of botulinumtoxin in patients with palmar hyperhidrosis is rather difficult. The therapeutic window is smaller because injections are complicated by transient weakness of the small hand-muscles. Furthermore the injections at the palms are painful which can be overcomed by application of local anaesthetics or the blockade of the ulnar and median nerves. The duration of anhidrotic effect ranges from 20 to 50 weeks. CONCLUSION: Intracutaneous injections of botulinum-toxin should be offered to patients with focal hyperhidrosis of the palms and axillae causing serious social, psychologic and occupational problems, resistant to other conventional treatment options.

Kidney function during common carotid artery occlusion in anaesthetized cats: influence of vagotomy, constant ventilation, blood pressure stabilization, and carotid body chemoreceptor inactivation.

The reactions of kidney function elicited by bilateral common carotid artery occlusion were studied in six groups of chloralosed cats in which the Nn. vagi, the breathing reaction, the increase of the mean systemic arterial blood pressure, and the carotid body chemoreceptors were excluded successively. Carotid occlusion in the control animals caused a rise of the mean systemic arterial blood pressure, hyperventilation, and an increase in renal sodium and water excretion, resulting from an inhibition of tubular reabsorption. Bilateral cervical vagotomy, relaxation and constant artificial ventilation only slightly modified this renal response. Inactivation of the carotid body chemoreceptors in vagotomized and constantly ventilated cats attenuated the natriuresis due to carotid occlusion regardless of the behaviour of the renal perfusion pressure. On the other hand, keeping the mean arterial blood pressure during carotid occlusion constant by the bleeding technique also reduced the natriuretic reaction. Cats with both inactivated carotid body chemoreceptors and constant renal perfusion pressure exhibited an antinatriuretic reaction during carotid clamping. From these data it is concluded that in narcotized cats the natriuretic response during carotid occlusion is the result of both a stimulation of the carotid body chemoreceptors and the rise of the renal perfusion pressure. In contrast, in dogs this so-called carotid-sinus-polyuria seems to be induced solely by the increase of the systemic arterial blood pressure. The findings additionally indicated that the arterial chemoreceptors may be involved in the physiological daily control of renal sodium excretion already at normal arterial oxygen tension under sea-level conditions.