Resumption of migraine preventive treatment with CGRP(-receptor) antibodies after a 3-month drug holiday: a real-world experience

BackgroundMigraine frequency increases after the cessation of successful preventive treatment with CGRP(-receptor) monoclonal antibodies (mAbs). In this study, we aimed to evaluate the course of migraine after treatment resumption.MethodsPatients with migraine, who started treatment with the same CGRP(-R) mAb after a three-month drug holiday were included in this analysis. We collected headache data at four prospective visits: 1) during the four weeks before the initial mAb treatment (baseline); 2) during the four weeks before the last mAb injection; 3) in weeks 13–16 of the drug holiday; 4) in weeks 9–12 after treatment restart. Outcomes were the changes in monthly migraine days (MMD), monthly headache days (MHD), monthly days with acute medication use (AMD) and Headache Impact Test-6 (HIT-6) scores across the observation period.ResultsThis study included 39 patients (erenumab n = 16; galcanezumab/ fremanezumab n = 23). MMD decreased from 12.3 ± 6.3 at the end of the drug holiday to 7.8 ± 5.5 three months after treatment restart (p = 0.001). The improvement after treatment resumption was similar to the response in the initial treatment period (baseline: 12.3 ± 6.3 MMD vs. 7.5 ± 5.2 MMD before treatment interruption). MHD and AMD showed a significant improvement after treatment restart. HIT-6 scores decreased, indicating a diminished impact of headache on everyday life.ConclusionsReinitiation of treatment with CGRP(-R) mAbs after a drug holiday leads to a significant reduction of migraine frequency and medication use as well as improvement in quality of life.     

Comparison of six commercial tick-borne encephalitis IgM and IgG ELISA kits and the molecular characterization of their antigenic design

Tick-borne encephalitis virus (TBEV) diagnosis is mainly based on the detection of viral-specific antibodies in serum. Several commercial assays are available, but published data on their performance remain unclear. We assessed six IgM and six IgG commercial enzyme-linked immunosorbent assay (ELISA) kits (ELISA-1 through ELISA-6) using 94 samples, including precharacterized TBEV-positive samples (n=50) and -negative samples (n=44). The six manufacturers showed satisfactory sensitivity and specificity and high overall agreement for both IgM and IgG. Three manufacturers showed better reproducibility and were the most sensitive (100%) and specific (95.5–98.1%) for both IgM and IgG. Two of them were also in agreement with the clinical interpretation in more than 90% of the cases. All the assays use inactivated virus as antigen, with strains showing approximately 94% homology at the amino acid level. The antigenic format of the assays was discussed to further improve this TBEV diagnostic tool.     

Intracisternal injection of inflammatory soup activates the trigeminal nerve system

The release of calcitonin gene-related peptide (CGRP) and sensitization of the trigeminal nerve system are important elements in migraine pathophysiology. Sensitization can be induced by topical meningeal administration of inflammatory soup (IS). CGRP release is a marker of trigeminal nerve activation. We examined the effect of intracisternal IS administration on CGRP release in rat jugular vein blood at baseline, 2 and 15 min after the beginning of IS infusion. IS administration caused a significant increase of CGRP levels after 2 and 15 min compared with baseline. Daily oral treatment with topiramate for 4 and 8 weeks led to a dose- and time-dependent reduction of IS-induced CGRP release. Sumatriptan also attenuated stimulated neuropeptide release. These results indicate that intracisternal IS administration leads to activation of the trigeminal system. The inhibition of CGRP release by topiramate offers a possible mechanism that may in part account for the preventative antimigraine activity of this drug.     

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF^Val/Val) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF^Met/Met). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF^Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF^Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.     

Glyceroltrinitrate facilitates stimulated CGRP release but not gene expression of CGRP or its receptor components in rat trigeminal ganglia

Nitric oxide (NO) donors induce delayed headaches in migraineurs. In a corresponding rat model NO donors cause delayed ongoing activity in central trigeminal neurons which process intracranial afferent input. Cellular models indicate that NO may increase the release or production of calcitonin gene-related peptide (CGRP), a key mediator in primary headaches. CGRP release from intact isolated trigeminal ganglia of adult male Wistar rats was investigated in vitro. Exposure to high NO donor concentrations did not affect basal or stimulated CGRP release. After a two hour infusion of the NO donor glyceroltrinitrate (250 μg/kg/h), however, inflammatory mediators-induced CGRP release was 80% higher compared to control animals. Administration of the soluble guanylate cyclase inhibitor ODQ or the application of 8Br–cGMP revealed a cGMP-independent mechanism. In four groups of separate experiments total mRNA was extracted from rat trigeminal ganglia up to 6 h after glyceroltrinitrate or saline infusion. Gene expression of CGRP and the CGRP-receptor components, receptor activity-modifying protein 1, receptor component protein and calcitonin receptor-like receptor was measured by quantitative RT-PCR. Glyceroltrinitrate infusion did not change mRNA levels of these genes compared to infusion of saline. The present data suggest that prolonged increase in NO levels facilitates stimulated CGRP release from trigeminal ganglion neurons. The underlying mechanism appears to be independent of the cGMP pathway and not to interact with CGRP in the trigeminal ganglion. Delayed headaches induced by NO may change CGRP or CGRP-receptor expression.     

Nocturnal penile tumescence and penile responses in the waking state in diabetic and nondiabetic sexual dysfunctionals

This study compared diabetics with sexual dysfunction, nondiabetics with sexual dysfunction, and a group of controls on nocturnal penile tumescence (NPT) during three nights in a sleep laboratory, and penile response to erotic stimulation in the waking state on one of the nights. Both diabetic and nondiabetic dysfunctionals showed less erectile response to erotic films and tape than controls but did not differ from each other. In contrast, the diabetic dysfunctionals showed significantly weaker NPT response than both the nondiabetic dysfunctionals and the controls, and 58% of them (contrasted with 23% of nondiabetic dysfunctionals and 0% of controls) would be classified as organic using minimal NPT (less than 11.5 mm maximal increase in penile circumference during any nocturnal erection) as the sole criterion. There was a significant relationship between NPT and waking erections in response to erotic stimuli, especially in the diabetic dysfunctionals and the controls.The research on which this report is based was supported in part by NIMH Grant No. 1-R01-MH31908. Parts of this report were presented at the Seventh Annual Meeting of the Society for Sex Therapy and Research, March 20–22, 1981, New York, N.Y., and at the International Congress Therapy in Andrology: Pharmacological, Surgical and Psychological Aspects, June 21–24, 1982, Pisa, Italy.     

Analyse der Behandlungsergebnisse von 1127 Patienten mit Oberschenkelfrakturen aus der Bundesrepublik Deutschland und der Schweiz

Under the aspect of quality control of the surgical treatment the results of femur-fractures of 1127 patients were scrutinized. These patients were treated in 16 German and in 21 Swiss AO-hospitals. Different complications are discussed. The study shows that not so much the chosen method of osteosynthesis is of paramount importance, but the way it is performed, especially if the surgical technic is done according to standardized principles and biomechanical rules. As the injuries are in many cases very severe and as in many patients the fracture of the femur is only part of a polytrauma, the results are satisfying.     

A new method for fast quantitative mapping of absolute water content in vivo

The presence of brain edema, in its various forms, is an accompanying feature of many diseased states. Although the localized occurrence of brain edema may be demonstrated with MRI, the quantitative determination of absolute water content, an aspect that could play an important role in the objective evaluation of the dynamics of brain edema and the monitoring of the efficiency of treatment, is much more demanding. We present a method for the localized and quantitative measurement of absolute water content based on the combination of two fast multi-slice and multi-time point sequences QUTE and TAPIR for mapping the T(2)* and T(1) relaxation times, respectively. Incorporation of corrections for local B(1) field miscalibrations, temperature differences between the subject and a reference probe placed in the FOV, receiver profile inhomogeneities and T(1) saturation effects are included and allow the determination of water content with anatomical resolution and a precision >98%. The method was validated in phantom studies and was applied to the localized in vivo measurement of water content in a group of normal individuals and a patient with brain tumor. The results demonstrate that in vivo measurement of regional absolute water content is possible in clinically relevant measurement times with a statistical and systematic measurement error of <2%.