Perceptions on the value of bodily functions in multiple sclerosis.

BACKGROUND: In neurological diseases presenting with a plethora of symptoms, the value of bodily functions for a given patient might be a guide for clinical management. Multiple sclerosis (MS) is paradigmatic in this respect, and little is known about the value of different bodily functions of patients and their physicians' perceptions. METHODS: In a multicenter study, 171 patients with relapsing-remitting multiple sclerosis (RRMS), 61% with a clinically active disease within the last 2 years were followed over up to 3 years and yearly patients and their study physician rated on the perceived value of 13 bodily functions via a priority list. Differences between patients and physicians as well as modulating disease demographic factors were analyzed. RESULTS: Patients with RRMS rated visual function followed by thinking and memory and walking highest while physicians stressed mobility, followed by thinking and memory and alertness most. Ratings were independent from disease duration or disability. Strongest value judgment differences were seen in swallowing regarded more relevant by patients and hand function regarded more relevant by physicians. In general, patients' and physicians' ratings through time were quite stable. Collapsing physical items into a physical functioning scale and mental items in a mental function scale, both dimensions were regarded equally important by patients while physicians underscored physical functioning (P = .016). CONCLUSION: There are differences between patients and physicians in value statements of bodily functions in MS. In particular, visual functioning is under-recognized by physicians.

[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.

Effects of stress and relaxation on pain perception in subjects with pain-free occlusional disharmony compared with healthy controls.

OBJECTIVES: The significance of occlusal disharmony for the development of painful temporomandibular disorder (TMD) is controversial. The ongoing biomechanical strain caused by occlusal disharmony might lead to sensitization processes in the nociceptive system. Understanding these processes might be an important step toward understanding the possible relationship between occlusal disharmony and TMD. In this study, we therefore investigated whether subjects with occlusal disharmony (n = 22) differ from healthy controls (n = 26) in their pain perception and pain modulation by stress and relaxation. MATERIALS AND METHODS: Trigeminal and extratrigeminal experimental pain perception (pinprick, heat, and pressure pain) was assessed before and after stress (mental arithmetic) and relaxation (viewing of low-arousal pictures). RESULTS: There were no group differences in pain perception at baseline or during the stress task. Compared with controls, the occlusal disharmony group exhibited an inadequate reduction in pain perception during relaxation, which was significant for the extratrigeminal site (P < 0.01) and reached a trend for significance at the trigeminal site (P = 0.1). CONCLUSIONS: These results suggest that subjects with occlusal disharmony show signs of disturbed endogenous pain inhibition during relaxation. CLINICAL RELEVANCE: There is evidence for the presence of sensitization of the nociceptive system in subjects with occlusal disharmony. Possibly, deficient inhibition of extratrigeminal and trigeminal pain perception by relaxation might contribute to the development of TMD or other chronic pain disorders.

[Consensus paper of the German Migraine and Headache Society on the structure of headache care facilities in Germany]. / Konsensuspapier der Deutschen Migräne- und Kopfschmerzgesellschaft zur Struktur von Kopfschmerzzentren und Kopfschmerzschwerpunktpraxen in Deutschland.

This consensus paper introduces a classification of headache care facilities on behalf of the German Migraine and Headache Society. This classification is based on the recommendations of the International Association for the Study of Pain (IASP) and the European Headache Federation (EHF) and was adapted to reflect the specific situation of headache care in Germany. It defines three levels of headache care: headache practitioner (level 1), headache outpatient clinic (level 2) and headache centers (level 3). The objective of the publication is to define and establish reliable criteria in the field of headache care in Germany.

[Therapy and care of patients with chronic migraine: expert recommendations of the German Migraine and Headache Society/German Society for Neurology as well as the Austrian Headache Society/Swiss Headache Society]. / Therapie und Versorgung bei chronischer Migräne : Expertenempfehlung der Deutschen Migräne- und Kopfschmerzgesellschaft/Deutsche Gesellschaft für Neurologie sowie der Österreichischen Kopfschmerzgesellschaft/Schweizerischen Kopfwehgesellschaft.

Chronic migraine (CM) was first defined in the second edition of the International Headache Society (IHS) classification in 2004. The definition currently used (IHS 2006) requires the patient to have headache on more than 15 days/month for longer than 3 months and a migraine headache on at least 8 of these monthly headache days and that there is no medication overuse. In daily practice the majority of the patients with CM also report medication overuse but it is difficult to determine whether the use is the cause or the consequence of CM. Most the patients also have other comorbidities, such as depression, anxiety and chronic pain at other locations. Therapy has to take this complexity into consideration and is generally multimodal with behavioral therapy, aerobic training and pharmacotherapy. The use of analgesics should be limited to fewer than 15 days per month and use of triptans to fewer than 10 days per month. Drug treatment should be started with topiramate, the drug with the best scientific evidence. If there is no benefit, onabotulinum toxin A (155-195 Units) should be used. There is also some limited evidence that valproic acid and amitriptyline might be beneficial. Neuromodulation by stimulation of the greater occipital nerve or vagal nerve is being tested in studies and is so far an experimental procedure only.

Reduced intraepidermal nerve fibre density in lesional and nonlesional prurigo nodularis skin as a potential sign of subclinical cutaneous neuropathy.

BACKGROUND: Prurigo nodularis (PN) is a highly pruritic condition characterized by multiple hyperkeratotic nodules. Previous immunohistochemical studies demonstrated increased numbers of dermal nerve fibres. OBJECTIVES: Given that the sensation of pruritus is transmitted mainly by thin, unmyelinated epidermal nerves, the aim of our study was to investigate the intraepidermal nerve fibre (IENF) density. METHODS: Biopsies taken from lesional and nonlesional skin of 53 patients (37 women and 16 men; mean ± SD age 60·6 ± 14·9 years) with PN of diverse origin were immunostained for protein gene product 9·5. According to the guideline of the European Federation of Neurological Societies, the IENF density per millimetre was determined and compared with that in 20 healthy volunteers. RESULTS: Lesional and uninvolved PN skin biopsies showed significantly decreased IENF density (P < 0·001) regardless of patient age, origin of PN, intensity or quality of pruritus. CONCLUSIONS: Hypoplasia of epidermal sensory nerves independently of clinical parameters is a new finding in PN and suggests involvement of epidermal nerves in PN pathophysiology. To date, it cannot be ruled out that reduced IENF density is due to repeated scratching. However, the presence of hypoplasia in nonlesional PN skin suggests the presence of a subclinical small fibre neuropathy.

Cluster headache and Alpha 1-antitrypsin deficiency.

Little is known about the pathophysiology of cluster headache (CH), one of the most debilitating primary headaches. Interestingly, associations of lung affecting diseases or lifestyle habits such as smoking and sleep apnoea syndrome and CH have been described. Certain genotypes for alpha 1-antitrypsin (alpha(1)-AT) are considered risk factors for emphysema. Our aim was to investigate possible associations between common genotypes of the SERPINA1 gene and CH. Our study included 55 CH patients and 55 controls. alpha(1)-AT levels in serum and the genotype were analysed. Patients CH characteristics were documented. We could not detect any association between CH and a genotype that does not match the homozygous wild type for alpha(1)-AT. Interestingly, there is a significant difference of CH attack frequency in patients who are heterozygous or homozygous M allele carriers. We conclude that the presence of an S or Z allele is associated with higher attack frequency in CH.

Placebo efficacy in childhood and adolescence migraine: an analysis of double-blind and placebo-controlled studies.

Studies on the treatment of migraine in children and adolescents are rare and difficult to design. In particular, the high placebo response in some trials makes it difficult to prove efficacy of a verum drug. We analysed all available placebo-controlled trials on acute and on prophylactic migraine treatment in children and adolescents with respect to different placebo rates (pain free and pain relief at 2 h; rate of responders with >or= 50% attack frequency decrease). We identified eight crossover and 11 parallel group trials on acute treatment. The placebo response rates were considerably lower in crossover trials than in parallel group trials (19.2% vs. 27.1% for pain free after 2 h and 39.4% vs. 56.9% for pain relief after 2 h). In the 10 prophylactic trials included in this analysis, only a small trend towards a lower placebo rate in crossover trials could be observed. Further significant factors associated with a lower placebo rate in childhood and adolescence trials on the acute treatment of migraine were single-centre (vs. multicentre) trials and small sample size. Age and sex were not associated with the placebo response. Our study suggests that parallel group trials on the acute treatment of migraine in children and adolescents show a very low therapeutic gain due to a high placebo rate. The verum response rates, however, are very similar to those seen in adulthood trials. In conclusion, trial designs on the acute and prophylactic treatment of migraine in children and adolescents should consider the specific findings of this analysis in order to exhibit a higher probability of showing significant differences between placebo and verum drug.

An association of migraine with hereditary haemorrhagic telangiectasia independently of pulmonary right-to-left shunts.

Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder characterized by epistaxis, telangiectasia and visceral vascular manifestations. It is associated with migraine with aura due to pulmonary arteriovenous malformations (pAVMs). The aim of the study was to evaluate headache prevalence in 106 consecutive HHT patients (67 female, 39 male, age 53.5 +/- 14.5 years) and age- and gender-matched controls. An extensive clinical work-up was performed and headache prevalence was determined. Lifetime prevalence of migraine was higher in HHT patients (39.6%) than in controls (19.8%) [P < 0.001, chi(2) = 12.17, odds ratio (OR) 3.0; 95% confidence interval 1.6 < OR < 5.7]. A positive association was confirmed between HHT patients with pAVMs and migraine with aura (38.5% vs. 10%). Furthermore, HHT patients without pAVMs had a higher prevalence of migraine without aura (11.5% vs. 26.3%; chi(2) = 11.85; d.f. = 2; P = 0.003). We speculate that pathophysiological mechanisms, including dysfunction of the transforming growth factor-beta pathways and resulting vascular changes, contribute to the higher prevalence of migraine without aura in HHT patients without pAVMs.

The incidence and prevalence of cluster headache: a meta-analysis of population-based studies.

Cluster headache is a trigemino-autonomic cephalgia with a low prevalence. Several population-based studies on its prevalence and incidence have been performed, but with different methodology resulting in different figures. We analysed all available population-based epidemiological studies on cluster headache and compared the data in a meta-analysis. The pooled data showed a lifetime prevalence of 124 per 100,000 [confidence interval (CI) 101, 151] and a 1-year prevalence of 53 per 100,000 (CI 26, 95). The overall sex ratio was 4.3 (male to female), it was higher in chronic cluster headache (15.0) compared with episodic cluster headache (3.8). The ratio of episodic vs. chronic cluster headache was 6.0. Our analysis revealed a relatively stable lifetime prevalence, which suggests that about one in 1000 people suffers from cluster headache, the prevalence being independent of the region of the population study. The sex ratio (male to female) is higher than published in several patient-based epidemiological studies.

Migraine and left-handedness are not associated. A new case-control study and meta-analysis.

To investigate the possible association between migraine and left-handedness, we enrolled 100 patients with a diagnosis of migraine according to the International Headache Society diagnostic criteria and 100 age- and sex-matched control subjects into a case-control study. Handedness was determined by the Edinburgh Handedness Inventory. There was no significant difference in the frequency or grade of left-handedness between the two groups. Additionally, we pooled our data with those from five similar studies, which did not alter the result. Thus, neither our study nor the meta-analysis support Geschwind and Behan's hypothesis of an association between migraine and left-handedness.

Functional polymorphisms of the 5-HT1A and 5-HT1B receptor are associated with clinical symptoms in migraineurs.

Migraine is regarded as a polygenic disease and serotonergic pathways appear to play a major role in its pathogenesis. In the present study, the role of the 5-HT1A and 5-HT1B receptors in migraine was evaluated. The human 5-HT1A receptor gene transcription is modulated by a functional C-1019G promoter polymorphism. The 5-HT1B receptor is the main effector of vasoconstriction in meningeal and cerebral arteries and its functional G861C promoter polymorphism was investigated. We report a positive association of the GG genotype of the 5-HT1A promoter polymorphism with avoidance of physical activity during a migraine attack in comparison to the CC genotype (p = 0.008). Moreover, a positive association of the CC genotype of the G861C polymorphism of the 5-HT1B receptor with the reported intensity of the headache attack on the visual analogue scale was observed (CC 8.3 +/- 1.5 vs. GG 6.9 +/- 1.8; p < 0.05). An association of either polymorphism with migraine with or without aura could not be found. For the first time, our results indicate a role of allelic variation of the 5-HT1A receptor in motion related discomfort in migraineurs and a role of the 5-HT1B receptor polymorphism in headache intensity.

Control over spinal nociception as quantified by the nociceptive flexor reflex (RIII reflex) can be achieved under feedback of the RIII reflex.

BACKGROUND: Descending pain modulatory systems control transmission of nociceptive information at the spinal level, and their activity can be modified by cognitive and emotional processes. Thus, it may be possible to learn using cognitive-emotional strategies to specifically target descending pathways in order to achieve pain reduction. METHODS: The present study used visual feedback of the nociceptive flexor reflex (RIII reflex) to train healthy subjects over three sessions to reduce their spinal nociception (RIII reflex size) by self-selected cognitive-emotional strategies. The study included two feedback groups (fixed vs. random stimulation intervals) and a control group without feedback (15 subjects each). RESULTS: While all three groups successfully reduced their RIII reflexes (p < 0.01), reductions were larger in the feedback groups (p < 0.05). Success increased over training sessions in the feedback groups (p < 0.05). In the third session, RIII was reduced to 90 ± 15% of baseline in the control group, and to 72 ± 24 and 66 ± 22% in the feedback groups. Most subjects used mental imagery or relaxation to achieve RIII reduction. Pain reduction correlated with RIII reduction in the feedback groups, but was not significantly different between feedback and control groups. CONCLUSIONS: The present results suggest that healthy subjects are able to learn using cognitive and emotional strategies to reduce their spinal nociception under feedback of their RIII reflex size. However, future studies will have to include a sham feedback group to differentiate true learning effects from expectancy effects induced by the feedback procedure.

Combined epineurial therapy with neutralizing antibodies to tumor necrosis factor-alpha and interleukin-1 receptor has an additive effect in reducing neuropathic pain in mice.

Monotherapy with antibodies to tumor necrosis factor-alpha (TNF) or interleukin-1 receptor 1 (IL-1R1) reduces hyperalgesia in an animal model of painful neuropathy. Here we investigated whether combined therapy with epineurial anti-TNF and anti-IL-1R1 antibodies produces a further advantage. C57BL/6 mice with a chronic constrictive injury of one sciatic nerve were treated epineurially with neutralizing antibodies to either IL-1R1 or TNF alone or with a combined application of neutralizing antibodies to TNF and IL-1R1. Combined treatment with anti-IL-1R1 and anti-TNF antibodies markedly reduced thermal hyperalgesia and mechanical allodynia more effectively than monotherapy with either antibody. There were no detectable differences in IL-1beta and TNF endoneurial protein expression between animals with monotherapy and combined treatment. We conclude that combined anti-cytokine therapy may be a useful strategy in the treatment of neuropathic pain.

Reproducibility of contact heat evoked potentials (CHEPs) over a 6 months interval.

OBJECTIVE: Contact heat evoked potentials (CHEPs) mediated by primary afferent Aδ-fibers can be recorded at the vertex. CHEPs are reduced in small fibre neuropathy and considered as a noninvasive measure of small fibre function. As long-term stability of CHEPs has not been examined, it is presently not clear if CHEPs may also be useful for following the course of small fibre neuropathy. METHODS: Here, we analyzed CHEPs from 60 healthy subjects recorded at two occasions separated by 6 months. RESULTS: There was a systematic shift towards larger amplitudes (from 40.2 ± 13.8 µV to 53.3 ± 17.5 µV, p<0.001) and towards shorter latencies (from 425.0 ± 28.8 ms to 387.2 ± 30.3 ms, p<0.001) after six months, while CHEP areas were more constant over time. CONCLUSIONS: The present results show that systematic changes of CHEP amplitudes and latencies may occur over time. Possible reasons include seasonal differences in skin conductivity for heat and psychological effects. SIGNIFICANCE: CHEP areas seem to be more stable over time than amplitudes or latencies, however, it remains to be determined if CHEP areas differentiate between subjects with lesions of the nociceptive system and healthy controls as reliably as CHEP amplitudes.

[Copper deficiency as a treatable cause of myelopathy]. / Kupfermangel - eine behandelbare Ursache der Myelopathie.

Copper deficiency myelopathy is an important and treatable differential diagnosis of vitamin B12 deficiency, of degenerative diseases presenting with the cardinal sign ataxia, and less often of motor neuron diseases. We report a 30-year-old female who presented with progressive gait disorder and sensory disturbances in her feet. Neurological examination showed tetraparesis with spastic ataxia. Laboratory investigations showed malabsorption, anemia, and leukopenia. Further extensive diagnostic investigations revealed copper deficiency due to malabsorption as the probable cause of the neurological deterioration. After oral copper substitution was started, the progression of her neurological symptoms could be stopped.

An adenosine A2A receptor gene haplotype is associated with migraine with aura.

The adenosine A2A receptor A2AR facilitates effects of calcitonin gene-related peptide and vasoactive intestinal peptide, two important neuropeptides in migraine pathophysiology, and is the molecular target of caffeine, which is used in migraine treatment. We therefore determined whether A2AR gene variation might influence migraine susceptibility. Migraine patients (n = 265) with or without aura and migraine-free controls (n = 154) were assessed and genotyped for six genetic variants spanning the A2AR gene. A six-marker haplotype was more frequent in migraine patients with aura (P < 0.01) but not in patients without aura, compared with the control group. This indicates that A2AR gene variation may contribute to the pathogenesis of migraine with aura.