A general model for the motion of multivalent cargo interacting with substrates.

Multivalent interactions are common in biology at many different length scales, and can result in the directional motion of multivalent cargo along substrates. Here, a general analytical model has been developed that can describe the directional motion of multivalent cargo as a response to position dependence in the binding and unbinding rates exhibited by their interaction sites. Cargo exhibit both an effective velocity, which acts in the direction of increasing cargo-substrate binding rate and decreasing cargo-substrate unbinding rate, and an effective diffusivity. This model can reproduce previously published experimental findings using only the binding and unbinding rate distributions of cargo interaction sites, and without any further parameter fitting. Extension of the cargo binding model to two dimensions reveals an effective velocity with the same properties as that derived for the one-dimensional case.

Migraine patients in Germany - need for medical recognition and new preventive treatments: results from the PANORAMA survey.

BACKGROUND: Migraine is a primary headache disorder characterized by recurrent attacks that may have a significant impact on patients' daily life. Treatment options must often be re-evaluated in light of efficacy, tolerability and compliance issues. Few data on commonly applied treatment algorithms and treatment failures have existed in Germany in 2017/2018. The PANORAMA survey was designed to explore and characterize the migraine healthcare landscape and to demonstrate the medical treatment need at that time in Germany. METHODS: Three different questionnaires were used to assess the profile of the 119 participating centers, characterize migraine patients at centers and evaluate qualitative aspects of the current migraine healthcare situation from a physician´s professional perspective. Data were analyzed as observed and summarized by descriptive statistics. RESULTS: The results demonstrate that once referred to a migraine specialist, the majority of patients continue to be treated at a specialist. At specialized centers, 41.6 % of migraine patients receive prophylactic treatment. 45.4 % of prophylactic treatments are initiated with a beta-blocker and 28.1 % with an anti-epileptic. Pivotal factors to initiate prophylactic treatment are migraine attack frequency and intensity (58.0 %). Treatment decisions are largely based on prior / concomitant diseases and physical constitution of the patient (52.1 %). Following an inadequate treatment, most patients either switch substance class or discontinue prophylactic treatment. CONCLUSIONS: PANORAMA gives a comprehensive overview of the migraine healthcare landscape in Germany in 2017/2018, elucidates a lack of common treatment algorithms and reveals a high demand for defined therapy strategies and new prophylactic treatment going forwards.

[Treatment of chronic migraine with botulinum neurotoxin A : Expert recommendations of the German Migraine and Headache Society]. / Therapie der chronischen Migräne mit Botulinumneurotoxin A : Expertenempfehlung der Deutschen Migräne- und Kopfschmerzgesellschaft.

BACKGROUND: Injection of botulinum neurotoxin A (BoNT-A) according to the PREEMPT (Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy) paradigm has been approved for the treatment of refractory chronic migraine in Germany in 2011. OBJECTIVE: The practical application raises some questions, such as the choice of dose and injection intervals during the course of the treatment, and the appropriate time point for discontinuation of BoNT-A treatment. MATERIAL AND METHODS: Taking into account the existing literature, the German Migraine and Headache Society (Deutsche Migräne- und Kopfschmerzgesellschaft, DMKG) gives recommendations for the treatment of chronic migraine with BoNT-A. RESULTS: Treatment is usually started with a dose of 155 U BoNT-A. During the first year of treatment, 3­month injection intervals are recommended. Goal of the treatment is an improvement of migraine by ≥30%. If needed, dose escalation up to 195 U can be used to reach this goal. If improvement by ≥30% is not reached after the third injection cycle, the treatment is usually considered to be insufficiently efficient and discontinuation is recommended. If a stable success is reached during the first year of treatment, prolongation of injection intervals to 4 months can be considered. If success continues to be stable for at least two 4­month intervals, discontinuation of BoNT-A treatment can be tried. CONCLUSION: The literature on these points is insufficient for recommendations at the guideline level. The present recommendations are based on an expert consensus of the DMKG for the structured approach to the treatment of chronic migraine with BoNT-A.

Children with migraine: Provocation of headache via pressure to myofascial trigger points in the trapezius muscle? - A prospective controlled observational study.

BACKGROUND: The objective was to evaluate a supposed clinical interdependency of myofascial trigger points and migraine in children. Such interdependency would support an interaction of spinal and trigeminal afferences in the trigemino-cervical complex as a contributing factor in migraine. METHODS: Children ≤18 years with the confirmed diagnosis of migraine were prospectively investigated. Comprehensive data on medical history, clinical neurological and psychological status were gathered. Trigger points in the trapezius muscle were identified by palpation and the threshold of pressure pain at these points was measured. Manual pressure was applied to the trigger points, and the occurrence and duration of induced headache were recorded. At a second consultation (4 weeks after the first), manual pressure with the detected pressure threshold was applied to non-trigger points within the same trapezius muscle (control). Headache and related parameters were again recorded and compared to the results of the first consultation. RESULTS: A total of 13 girls and 13 boys with migraine and a median age of 14.5 (Range 6.3-17.8) years took part in the study. Manual pressure to trigger points in the trapezius muscle led to lasting headache after termination of the manual pressure in 13 patients while no patient experienced headache when manual pressure was applied to non-trigger points at the control visit (p < 0.001). Headache was induced significantly more often in children ≥12 years and those with internalizing behavioural disorder. CONCLUSION: We found an association between trapezius muscle myofascial trigger points and migraine, which might underline the concept of the trigemino-cervical complex, especially in adolescents. SIGNIFICANCE: In children with migraine headache can often be induced by pressure to myofascial trigger points, but not by pressure to non-trigger points in the trapezius muscle. This supports the hypothesis of a trigemino-cervical-complex in the pathophysiology of migraine, which might have implications for innovative therapies in children with migraine.

[Modern non-cosmetic treatment with botulinum toxins]. / Moderne, nichtkosmetische Therapie mit Botulinumtoxinen.

Botulinum toxin has been known in medical history for a long time. The first scientific investigations and thoughts on possible indications in the treatment of muscular disorders were published by the German physician and poet Justinus Kerner in 1822. The physiological effect of botulinum toxin was identified in the middle of the twentieth century and the first clinical use was reported in 1977. It was first used in ophthalmology for the correction of strabismus and some years later the therapy of blepharospasm and cervical dystonia was established. Further indications, all supported by randomized controlled studies, are spastic tone increase of the limbs after lesions of the central nervous system, idiopathic axillar hyperhidrosis, chronic migraine and neurogenic or idiopathic bladder hyperactivity. In addition to these indications, a large number of further possible options have been published in the literature. Beside its effect on transmission at the neuromuscular synapses, botulinum toxin has also been shown to affect the sensory transmission of nociceptive fibers.

Pupillary autonomic dysfunction in patients with ANCA-associated vasculitis.

OBJECTIVE: To assess autonomic function by infrared dynamic pupillometry in patients with ANCA-vasculitis (AAV) in correlation to autonomic symptoms, disease specific clinical parameters and cardiovascular reflex tests. METHODS: Patients with AAV and healthy controls underwent pupillometry at rest and after sympathetic stimulation (cold pressor test). Three parasympathetic parameters (amplitude, relative amplitude, maximum constriction velocity) and one sympathetic parameter (late dilatation velocity) were assessed. Results were correlated with clinical parameters, symptoms of autonomic dysfunction (COMPASS31 questionnaire), heart rate variability during deep breathing test and blood pressure response to pain. RESULTS: 23 patients and 18 age-matched controls were enrolled. Patients had a smaller amplitude (1.44 vs. 1.70 mm; p = 0.009) and a slower constriction velocity (4.15 vs. 4.71 mm/s; p = 0.028) at baseline and after sympathetic stimulation (1.47 vs. 1.81 mm, p = 0.001; 4.38 vs. 5.19 mm/s, p = 0.006, respectively). Relative amplitude was significantly smaller in patients after sympathetic stimulation (28.6 vs. 32.5%; p = 0.043), but not at baseline. There was no difference in sympathetic pupillary response between the groups. In patients, parasympathetic pupil response was correlated negatively with age and positively with parasympathetic cardiac response. After adjusting for age, no significant correlation was observed with clinical parameters. However, there was a trend towards a negative correlation with disease duration, vasculitis damage index and CRP. CONCLUSION: Patients with AAV exhibit parasympathetic pupillary autonomic dysfunction. Although correlations were weak and not significant, pupillary autonomic dysfunction is rather linked to chronic damage than to active inflammation or symptoms of autonomic dysfunction.

Intracellular Cargo Transport by Kinesin-3 Motors.

Intracellular transport along microtubules enables cellular cargoes to efficiently reach the extremities of large, eukaryotic cells. While it would take more than 200 years for a small vesicle to diffuse from the cell body to the growing tip of a one-meter long axon, transport by a kinesin allows delivery in one week. It is clear from this example that the evolution of intracellular transport was tightly linked to the development of complex and macroscopic life forms. The human genome encodes 45 kinesins, 8 of those belonging to the family of kinesin-3 organelle transporters that are known to transport a variety of cargoes towards the plus end of microtubules. However, their mode of action, their tertiary structure, and regulation are controversial. In this review, we summarize the latest developments in our understanding of these fascinating molecular motors.

[Migraine in children and adolescents-brain and muscle? : Another example of why children are not small adults]. / Migräne im Kindes- und Jugendalter ­ Gehirn und Muskel? : Warum Kinder einmal mehr keine kleinen Erwachsenen sind.

Migraine as primary headache is a life-long disease which is relevant for the quality of life and is based on complex genetics. It often starts in childhood with symptoms typical for the specific age. These show different nuances compared to the migraine symptoms in adults, for example, regarding (bilateral/unilateral) localization of the acute migraine headache. Only over the course of years-during adolescence and young adulthood-do the more specific symptoms as defined by the International Classification of Headache Disorders (ICHD 3 beta) develop. In this article we focus on the clinical specifics of children and adolescents with migraine. We elaborately refer to the trigeminocervical complex (TCC) because it forms a conceptual bridge for the understanding of migraine, for psychoeducation, and for therapeutic options. We pragmatically discuss options and limits of treatments.

[Headache in the emergency department]. / Kopfschmerz in der Notaufnahme.

Headache is one of the most frequent symptoms leading to visits at the emergency department. Here, we aim at presenting a pragmatic algorithm for headache patients at the emergency department. The basic principle is taking a detailed history of the current headache with a focus on dynamics, phenotype and trigger factors as well as a possible preexisting headache. "Red flags" should be interrogated specifically. Hypotheses of the etiology of the headache should be generated in combination with the clinical examination (vital signs, neurological exam, otorhinolaryngological and ophthalmological exams) and should be tested appropriately with imaging, laboratory, cerebral spinal fluid studies and ultrasound. Secondary headache have to be treated with a causal approach, if necessary also symptomatically. When a secondary headache can be excluded, we recommend aiming for a primary headache diagnosis with subsequent specific therapy. When a headache patient can be discharged, we recommend scheduling a follow-up appointment to understand the development of a secondary headache and its cause. In case of a primary headache, optimizing prophylaxis and acute therapy is important to prevent future emergency department visits.

Learned control over spinal nociception in patients with chronic back pain.

BACKGROUND: Descending pain inhibition suppresses spinal nociception, reducing nociceptive input to the brain. It is modulated by cognitive and emotional processes. In subjects with chronic pain, it is impaired, possibly contributing to pain persistence. A previously developed feedback method trains subjects to activate their descending inhibition. Participants are trained to use cognitive-emotional strategies to reduce their spinal nociception, as quantified by the nociceptive flexor reflex (RIII reflex), under visual feedback about their RIII reflex size. The aim of the present study was to test whether also subjects with chronic back pain can achieve a modulation of their descending pain inhibition under RIII feedback. METHODS: In total, 33 subjects with chronic back pain received either true (n = 18) or sham RIII feedback (n = 15), 15 healthy control subjects received true RIII feedback. RESULTS: All three groups achieved significant RIII suppression, largest in controls (to 76 ± 26% of baseline), intermediate in chronic back pain subjects receiving true feedback (to 82 ± 13%) and smallest in chronic back pain subjects receiving sham feedback (to 89 ± 14%, all p < 0.05). However, only chronic pain subjects receiving true feedback significantly improved their descending inhibition over the feedback training, quantified by the conditioned pain modulation effect (test pain reduction of baseline before training: to 98 ± 26%, after: to 80 ± 21%, p < 0.01). CONCLUSION: Our results show that subjects with chronic back pain can achieve a reduction of their spinal nociception and improve their descending pain inhibition under RIII feedback training. SIGNIFICANCE: Subjects with chronic back pain can learn to control their spinal nociception, quantified by the RIII reflex, when they receive feedback about the RIII reflex.

[Relaxation techniques and behavioural therapy for the treatment of migraine : Guidelines from the German Migraine and Headache Society]. / Entspannungsverfahren und verhaltenstherapeutische Interventionen zur Behandlung der Migräne : Leitlinie der Deutschen Migräne- und Kopfschmerzgesellschaft.

Besides pharmacological and interventional possibilities nonpharmacological options, deriving from behavioural approaches may be helpful in the treatment of migraine. Already consulting a patient reduces frequency of attacks. Relaxation (especially progressive muscle relaxation), endurance sports, and biofeedback as well as cognitive behavioural therapy are effective in treatment of migraine. The combination of these treatment options also with pharmacological treatment increase the positive effects.

Assessment of autonomic function in a cohort of patients with ANCA-associated vasculitis.

OBJECTIVE: To assess symptoms and objective parameters of autonomic dysfunction (AD) in patients with ANCA-associated vasculitides. METHODS: Symptoms and objective parameters of AD were assessed in patients with ANCA-associated vasculitis and in age-matched healthy controls. Autonomic symptoms were explored by COMPASS31, a validated questionnaire addressing symptoms of six autonomic domains (orthostatic, vasomotor, secretomotor, gastrointestinal, pupillomotor, and bladder dysfunction). Objective autonomic parameters consisted of expiratory/inspiratory (E/I) ratio during the deep breathing test (DBT), blood pressure response to cold pressor test (CPT), and skin conductance changes during mental arithmetic. RESULTS: 27 patients and 27 healthy controls have been enrolled. 27 patients and 27 controls completed COMPASS31. 21 patients and 18 controls underwent objective autonomic testing. Vasculitis patients had significantly higher COMPASS31 total scores than controls (median 10.4 vs 3.0; p = 0.005). In the sub-domain analysis, significant differences were seen in the vasomotor and the bladder domain (p = 0.004; p < 0.001, respectively). No correlation was found between COMPASS31 score and disease duration, number of affected organs, or Birmingham vasculitis activity score (BVAS). There was no significant difference in any of the objective autonomic parameters between patients and controls. In a subgroup analysis, no difference in objective autonomic parameters was found between patients with active disease (n = 12) and patients in remission (n = 7). CONCLUSION: Patients with ANCA-associated vasculitides commonly have symptoms of autonomic dysfunction that are independent of disease duration and disease severity. However, at least in this single-centre observation, there was no evidence of impaired autonomic regulation in three autonomic function tests in vasculitis patients.

[Botulinum toxin type A in headache treatment : Established and experimental indications]. / Botulinumtoxin A in der Kopfschmerztherapie : Bewährte und experimentelle Indikationen.

In recent years botulinum toxin type A has been used increasingly more in the treatment of specific headache disorders. Especially regarding chronic migraine with and without combined medication overuse, convincing randomized studies have proven the efficacy of this treatment option and have led to approval for this indication. Regarding other headache entities, such as episodic migraine, tension-type headache, trigeminal autonomic cephalalgia (TAC), neuralgic, neuropathic and myofascial pain, currently available scientific data on the efficacy of botulinum toxin type A are scarce and often ambiguous. The exact underlying mechanisms of the influence of botulinum toxin type A on the pathophysiology of headache are not completely clear but an influence on the release of calcitonin gene-related peptide (CGRP) seems to play a crucial role. This article summarizes the most important studies as well as experiences of treatment with botulinum toxin type A regarding different headache entities.

[Pain - a neglected neurological issue]. / Schmerz - ein vernachlässigtes neurologisches Thema.

Chronic pain represents a great challenge; according to epidemiological data increasing numbers of patients should be expected. Based on recent advances, a better understanding of the pathophysiology of chronic pain has been achieved and neurologists have made a major contribution to this understanding. Chronic pain is accompanied by substantial maladaptive plastic alterations in both the peripheral and central nervous systems; therefore, neurological knowledge is of paramount importance for pain therapists but this contrasts with the current treatment situation of pain patients in Germany. There are basically too few departments and practices undertaking treatment, and neurologists are an exception in most pain centers. Furthermore, due to economic reasons neurological hospitals are currently experiencing a dearth of inpatients suffering from chronic pain. Diagnostic and/or treatment procedures for neurological pain entities (e.g. headaches or neuropathic pain) are insufficiently represented in the German diagnosis-related groups (DRG) reimbursement system and the obstacles for an efficient pain therapy in neurological practices are too high. Finally, there are too few academic positions for pain medicine in neurological hospitals; therefore, career opportunities for motivated young neurologists with an interest in pain are lacking. In order to address the unmet therapeutic needs of patients with chronic pain there is a high demand for (i) establishment of departments for neurological pain medicine, (ii) modification of the German DRG system and (iii) education of young neurologists with expertise in pain. Pain medicine in particular should be especially appealing to neurologists .

[Physician Counseling about Physical and Sports Activity in Neurological Practices in Germany: Results of a Survey Among Members of the German Neurological Society]. / Beratung zu körperlicher und sportlicher Aktivität in neurologischen Praxen in Deutschland. Ergebnisse einer Umfrage unter den Mitgliedern der Deutschen Gesellschaft für Neurologie e.V.

Physical inactivity is a major but modifiable risk factor for morbidity and mortality. Regular physical activity has preventive and therapeutic effects on numerous diseases including neurological disorders. Therefore, it is desirable that physicians motivate their patients to increase their physical and sports activities and that they help them to overcome barriers to exercising. The present study is a survey of neurologists who are members of the German Neurological Society with their own practices; they were asked whether they advised their patients on the benefits of physical activity. Details on physician counseling on physical activity were obtained, such as the frequency of counseling, the neurological disorders considered by the practitioners to be worth the effort of counseling, and the barriers to exercise on the part of patients. More than 80 % of the participants who responded to the survey stated that they frequently provide their patients with advice on the preventive and therapeutic aspects of physical activity. Almost all of them recommended endurance sports; this was followed by Far Eastern types of sport such as tai chi or yoga (70 % of all physicians who advice sports activities). The frequency of counseling about physical activity significantly correlated to the physician's own sports activity. Frequency of counseling was reduced if the physician assessed the patients to be incapable of adopting and maintaining a lifestyle of habitual physical activity. Lack of time as well as an insufficient reimbursement of the counseling, however, did not significantly influence the frequency of counseling. The physician's own sports activity matched that of individuals with similar social status. Thus, a selection bias does not seem to be of importance regarding the results of the survey. However, since only 169 of the 784 invited neurologists (21.6 %) responded to the questionnaire, the representativeness of the survey may be limited. Counseling about physical activity seems to be an essential part of consultations in neurological practices.

Cryopyrin-associated periodic fever syndrome manifesting as Tolosa-Hunt syndrome.

BACKGROUND: Tolosa-Hunt syndrome (THS) is characterized by unilateral orbital pain, ipsilateral oculomotor paresis and a prompt response to treatment with corticosteroids. Several reports have demonstrated that the clinical features of THS are not specific to one causal aetiology and can lead to misdiagnosis. CASE REPORT: We report the case of a patient diagnosed with THS after an episode of unilateral orbital pain and diplopia with demonstration of granulomatous inflammation of both cavernous sinus on cerebral magnetic resonance imaging and an immediate response to treatment with corticosteroids. Progression of the disease over the following years, accompanied by increasing signs of inflammation on cerebral magnetic resonance imaging and cerebrospinal fluid pleocytosis, led to further diagnostic tests. Genetic analyses revealed a heterozygote low-penetrance mutation (Q703K) of the cryopyrin/NLRP3 gene compatible with a cryopyrin-associated periodic fever syndrome. DISCUSSION: This case report demonstrates that THS can be a central nervous system manifestation of cryopyrin-associated periodic fever syndrome, which therefore represents a differential diagnosis of THS, even in elderly patients.

Noise-Enhanced Vestibular Input Improves Dynamic Walking Stability in Healthy Subjects.

BACKGROUND: White noise galvanic vestibular stimulation (GVS) is thought to enhance the sensitivity of vestibular organs. OBJECTIVE: To examine the effects of noise-enhanced vestibular input on the walking performance in healthy subjects walking with eyes closed. METHODS: Walking performance of 17 healthy subjects (mean age 28.8 ± 1.7 years) at slow, preferred, and fast speeds was examined during three different conditions: (1) walking with eyes open (EO) as baseline condition, (2) walking with eyes closed and sham noisy GVS (EC), and (3) walking with eyes closed and non-zero amplitude noisy GVS set to 80% of the individual sensory threshold for GVS (EC-GVS). Ten gait parameters were examined: stride time, stride length, base of support, swing time percentage, double support time percentage as well as gait asymmetry, bilateral phase coordination and the coefficient of variation (CV) of stride time, stride length and base of support. RESULTS: Noisy GVS improved stride time CV by 36% (p < 0.034), stride length CV by 31% (p < 0.037), base of support CV by 14% (p < 0.009), and bilateral phase coordination by 23% (p < 0.034). The ameliorating effects of noisy GVS on locomotion function were primarily observable during slow walking speeds. CONCLUSION: Noise-enhanced vestibular input is effective in improving locomotion function and is accompanied by a subjectively felt improvement of walking balance. It predominantly targets the variability and bilateral coordination characteristics of the walking pattern, which are critically linked to dynamic walking stability. Noisy GVS might present an effective treatment option to improve walking performance in patients with bilateral vestibular dysfunction.

[Cognitive Function in Patients Before and After Micro-neurosurgical Resection of Frontal Brain Tumors]. / Kognitive Funktion bei Patienten vor und nach mikrochirurgischer Resektion von frontalen Hirntumoren.

Patients with lesions of the prefrontal cortex as a result of frontal brain tumors (intra- and extra-axial) can show impairments of executive functions 1 2 3 4. Although there are a large number of psychological tests, the detection of impairments of relevant everyday executive functions in these patients is still extremely difficult. In 30 patients with lesions of the prefrontal cortex, the executive functions were tested with the Behavioral Assessment of Dysexecutive Syndrome (BADS) and 21 patients were also followed up postoperatively. Additionally, if possible, the Wisconsin Card Sorting Test (WCST), a widely used executive function test, and the Wechsler Adult Intelligence Scale (WAIS) for general cognitive performance were conducted. Pre- and postoperatively, a total of 16 patients were followed up with all three tests. The aim was to investigate the neuropsychological assessment pre- and postoperatively, to evaluate it in terms of deficits and changes in performance and to ensure that no new relevant everyday cognitive deficits arose. Preoperatively, only one patient, who could not be tested post-surgery, showed a reduced overall profile value in the BADS.  In all tested patients, there was no evidence of deterioration of cognitive status 8 - 12 weeks postoperatively. Further investigations using fMRI should be used to clarify whether the results obtained should be interpreted as neuroplastic adaptations of prefrontal cognitive functions or as a failure to detect deficits due to a lack of sensitivity of the tests used.