Cognitive, behavioral, and psychological phenotypes in small fiber neuropathy: A case-control study.

OBJECTIVE: Small fiber neuropathy (SFN) is a well-defined chronic painful condition causing severe individual and societal burden. While mood disorders have been described, cognitive and behavioral profiles of SFN patients has not been investigated. METHODS: Thirty-four painful SFN patients underwent comprehensive cognitive, behavioral, psychological, quality of life (QoL), and personality assessment using validated questionnaires. As control samples, we enrolled 36 patients with painful peripheral neuropathy (PPN) of mixed etiology and 30 healthy controls (HC). Clinical measures of neuropathic pain, duration, frequency, and intensity of pain at the time of assessment were recorded. Between-group and correlation analyses were performed and corrected for multiple comparisons. RESULTS: No differences in clinical measures were found between SFN and PPN, and all groups had similar cognitive profiles. SFN patients showed higher levels of anxiety and alexithymia (p < .005) compared to PPN and HC, considering also pain intensity. Maladaptive coping strategies characterized both patient groups, but only SFN revealed higher levels of acceptance of pain (p < .05). Pain intensity and neuropathic symptoms were associated with mood, low QoL and catastrophism (p < .001), particularly, the higher the perceived pain intensity, the higher the use of maladaptive coping strategies (p < .001). The personality assessment revealed significant feelings of worthlessness and somatization traits both in SFN and PPN (p < .002 vs HC). DISCUSSIONS: our results suggest that SFN patients had a normal-like cognitive profile, while their behavioral profile is characterized by mood disorders, alexithymia, maladaptive coping strategies, and poor QoL, as other chronic pain conditions, possibly related to pain intensity. Personality assessment suggests that somatization and feelings of worthlessness, which may worsen the neuropsychological profile, deserve clinical attention when considering patients' therapeutic approaches. At the same time, the high level of acceptance of pain is promising for therapeutic approaches based on psychological support.

OnabotulinumtoxinA in elderly patients with chronic migraine: insights from a real-life European multicenter study.

INTRODUCTION: Although migraine prevalence decreases with aging, some older patients still suffer from chronic migraine (CM). This study aimed to investigate the outcome of OnabotulinumtoxinA (OBT-A) as preventative therapy in elderly CM patients. METHODS: This is a post hoc analysis of real-life prospectively collected data at 16 European headache centers on CM patients treated with OBT-A over the first three treatment cycles (i.e., Cy1-3). We defined: OLD patients aged ≥ 65 years and nonOLD those < 65-year-old. The primary endpoint was the changes in monthly headache days (MHDs) from baseline to Cy 1-3 in OLD compared with nonOLD participants. The secondary endpoints were the responder rate (RR) ≥ 50%, conversion to episodic migraine (EM) and the changes in days with acute medication use (DAMs). RESULTS: In a cohort of 2831 CM patients, 235 were OLD (8.3%, 73.2% females, 69.6 years SD 4.7). MHDs decreased from baseline (24.8 SD 6.2) to Cy-1 (17.5 SD 9.1, p < 0.000001), from Cy-1 to Cy-2 (14.8 SD 9.2, p < 0.0001), and from Cy-2 to Cy-3 (11.9 SD 7.9, p = 0.001). DAMs progressively reduced from baseline (19.2 SD 9.8) to Cy-1 (11.9 SD 8.8, p < 0.00001), to Cy-2 (10.9 SD 8.6, p = 0.012), to Cy-3 (9.6 SD 7.4, p = 0.049). The 50%RR increased from 30.7% (Cy-1) to 34.5% (Cy-2), to 38.7% (Cy-3). The above outcome measures did not differ in OLD compared with nonOLD patients. CONCLUSION: In a population of elderly CM patients with a long history of migraine OBT-A provided a significant benefit, over the first three treatment cycles, as good as in non-old patients.

The cost and the value of treatment of medication overuse headache in Italy: a longitudinal study based on patient-derived data.

BACKGROUND AND PURPOSE: The cost of medication overuse headache (MOH) is underestimated. Our aim was to address the cost-effectiveness of a structured treatment protocol and to present annual cost estimates. METHODS: Patients were enrolled on the occasion of a structured treatment protocol, were administered a research protocol addressing direct and indirect costs and were followed up for 3 months. RESULTS: Of 176 enrolled patients, 138 completed the study. The 3-month cost per patient fell from €2989 to €1160: the difference was €696 per month for patients treated in the ward and €466 for those treated in day-hospital; thus it takes 2-3 months to compensate for the protocol's cost. The per-person annual costs of MOH were €10 533 (95% confidence interval €8700-12 406): direct healthcare costs accounted for 44.8% and indirect costs for 51.5% of the total MOH cost. The annual MOH cost for Italy is estimated at €13.5 billion (95% confidence interval €11.1-15.9 billion). CONCLUSION: The cost of MOH around the period of a structured treatment protocol is much higher compared to previous estimates. Our protocol is cost-effective for reducing the economic burden of MOH.

Pharmacotherapy for acute migraines in children and adolescents.

INTRODUCTION: Migraine is increasingly recognized as an extremely burdensome and disabling disorder in both children and adolescents. A proper treatment plan is needed to improve the quality of life of both children and families as well as to minimize the risk of disease progression. AREAS COVERED: This review focuses on the current pharmacotherapy for acute migraine in pediatric populations, taking into account specific considerations for those drugs tested in randomized, placebo-controlled trials (RCTs). EXPERT OPINION: A large number of RCTs have documented the efficacy, tolerability, and safety of different compounds. Triptans appears more effective than placebo but results are variable and inconsistent. Almotriptan and rizatriptan are effective as oral formulations, as well as sumatriptan and zolmitriptan as both oral and nasal spray formulations. Adding non-steroidal anti-inflammatory drugs (NSAIDs) reinforces triptan's effectiveness. Furthermore, small RCTs have documented both the efficacy of ibuprofen and the ineffectiveness of acetaminophen. Naproxen, ketoprofen, diclofenac, and indomethacin - NSAIDs effective in acute migraines in adults - should be tested also in pediatric subjects. Furthermore, the authors suggest that dopamine receptor antagonists should be considered in cases of severe migraines. Lastly, better designed RCTs are needed to fine-tune current therapeutic resources.

Establishment of an Italian chronic migraine database: a multicenter pilot study.

To optimize chronic migraine (CM) ascertainment and phenotype definition, provide adequate clinical management and health care procedures, and rationalize economic resources allocation, we performed an exploratory multicenter pilot study aimed at establishing a CM database, the first step for developing a future Italian CM registry. We enrolled 63 consecutive CM patients in four tertiary headache centers screened with face-to-face interviews using an ad hoc dedicated semi-structured questionnaire gathering detailed information on life-style, behavioral and socio-demographic factors, comorbidities, and migraine features before and after chronicization and healthcare resource use. Our pilot study provided useful insights revealing that CM patients (1) presented in most cases symptoms of peripheral trigeminal sensitization, a relatively unexpected feature which could be useful to unravel different CM endophenotypes and to predict trigeminal-targeted treatments' responsiveness; (2) had been frequently admitted to emergency departments; (3) had undergone, sometime repeatedly, unnecessary or inappropriate investigations; (4) got rarely illness benefit exemption or disability allowance only. We deem that the expansion of the database-shortly including many other Italian headache centers-will contribute to more precisely outline CM endophenotypes, hence improving management, treatment, and economic resource allocation, ultimately reducing CM burden on both patients and health system.

Approaches to treatments of chronic migraine associated with medication overuse: a comparison between different intensity regimens.

Treatment of chronic migraine with medication overuse requires withdrawal from acute medications. However, guidelines and clear indications for different intensity regimens, i.e., day hospital (DH) vs. inpatient treatment, are not available. Patients completed disability, quality of life (QoL) and depression questionnaires; headaches frequency and overused medications category were collected. Mann-Whitney U test and Chi square were used to assess differences between inpatients and DH patients; Bonferroni correction was applied. 194 patients aged 43.9 ± 12 (160 females) were enrolled (100 from DH, 94 inpatients). Inpatients were older, less educated and with lower employment rates. Inpatients had higher MIDAS scores (P = 0.003) and headache frequency (P = 0.002). They had lower QoL for restrictive (P = 0.002) and preventive components; no difference was found for disability, mood state and QoL emotional component. Patients treated during hospitalization had higher disease severity and lower quality of life, but similar disability and mood state than those treated in DH.

Difficulties in work activities and the pervasive effect over disability in patients with episodic and chronic migraine.

Migraine is associated with reduced productivity in work-related activities. The degree to which problems with work are, in turn, associated to the level of migraine-related disability as well as to headache frequency has been poorly explored. The aim of the study was to assess if migraine patients with different degrees of work difficulties showed a different level of migraine-related disability. A consecutive sample of patients with episodic migraine (EM) or with chronic migraine (CM) with medication overuse (MO) attending the Headache Centre of the Neurological Institute C. Besta of Milan was studied. All patients completed the MIDAS and the WHODAS 2.0 questionnaires. The total scores of both questionnaires, frequency of headaches, average pain intensity, and the scores of each subscale of the WHODAS 2.0 were calculated separately for EM and CM patients. The score of WHODAS 2.0 "Work difficulties" subscale was used to divide the studied patients into two groups, i.e. those above and those below the median "Work difficulties" subscale score. Independent sample t test was used to compare these two groups as far as all the other studied variables. A total of 296 patients (102 with EM and 194 with CM-MO) were enrolled. Patients with higher work difficulties score also displayed higher scores in the other WHODAS 2.0 subscales; for those with CM-MO, the differences were significant. The results of this study indicate that having more and more severe workplace problems is associated to a higher disability level in migraineurs. Further studies are needed to better understand workplace disability in different migraine forms, particularly in a qualitative way.

Onabotulinum toxin A (Botox) for chronic migraine treatment: an Italian experience.

Chronic migraine is a common and debilitating headache syndrome. Botulinum neurotoxin, a potent toxin produced by the anaerobic bacterium clostridium botulinum, used largely for treatment of disorders associated with increased muscle tone and hyperhidrosis, is used for patients suffering from chronic migraine. In this study, a group of patients suffering from chronic migraine with medication overuse was treated with onabotulinum toxin A (Botox) to verify its efficacy for chronic migraine. The results confirmed the efficacy of onabotulinum toxin A (Botox) when used at the dosage of 155 UI according to the PREEMPT protocol. Although these results are preliminary, they led to intense efforts to evaluate the analgesic properties of onabotulinum toxin A (Botox) and to assess its use in clinical practice, in particular in migraine field.

Role of neurostimulation in migraine.

Chronic forms of headache characterized by daily or almost daily headache, affect almost 3 % of general population. They represent the most disabling forms of headache inducing high degree of disability, poor quality of life for patients. During the last decades, several neuromodulatory surgical techniques have been developed for the management of headaches that are unresponsive to medical treatment. Invasive and non invasive central and/or peripheral neurostimulation techniques have been developed by different research groups with encouraging results for different type of headaches. In this report, the acute effect of non invasive vagus nerve stimulation (nVNS) (gammacore) was evaluated to treat migraine attacks in a population of patients affected by high-frequency episodic migraine or chronic migraine. The aim of this study was to verify the efficacy of nVNS to treat migraine attacks in this specific category of patients.

Proposal of a model for multidisciplinary treatment program of chronic migraine with medication overuse: preliminary study.

The treatment of patients with chronic migraine associated with medication overuse is challenging in clinical practice; different strategies of treatment have been recently developed, multidisciplinary treatment approaches have been developed in academic headache centers. Education and support of patients are necessary to improve patients' adherence to pharmacological treatments as well as to non-pharmacological therapies. This study reports a clinical experience conducted at our Headache center with a group of female patients, suffering from chronic migraine complicated by medication overuse, treated by a multidisciplinary approach and followed for a period of 1 year after withdrawal. Results confirm the efficacy of a multifaceted treatment to manage this problematic category of patients.

Difficulties in work-related activities among migraineurs are scarcely collected: results from a literature review.

Migraine affects work productivity in terms of missed workdays and days with reduced productivity. In this literature review, we looked for papers addressing specific difficulties in work-related activities. Twenty-three papers were included in the review, reporting data on 51,135 patients. Results showed that there is some evidence for limitations in skills such as problem solving, and activities such as speaking and driving. However, the way in which problems with remunerative employment are addressed is limited to concepts such as reduced performance or inability to work as usual. Given the paucity of data, a return to patient-derived data will be needed to develop an assessment instrument that is able to collect information on headache-related problems in work activities.

Evaluation of immune parameters in chronic migraine with medication overuse.

It has been postulated that chronic pain and chronic migraine in particular, can be connected to immunologic disturbances. Moreover the psychiatric comorbidity is often responsible of migraine chronification, but also of developing of particular immune function alterations. The role of the immune system in migraine precipitation is still under debate also if speculations about the evidence of infections in migraine patients has been performed, but not always corroborated by clinical and scientific explanations. In this report we present an evaluation of specific immune parameters in patients suffering from different forms of migraine respect to controls in order to determine possible alterations in immune function: speculations about the evidenced abnormalities are attempted.

Disability and quality of life in headache: where we are now and where we are heading.

Headache disorders determine relevant personal and societal burden, and thus the use of patient-reported outcome measures (PROMs) investigating the level of disability and health-related quality of life (HRQoL) have been increasingly used in headache research. The aim of this review was to address the status of research on disability and HRQoL, by addressing results from recently published clinical trials as well as in longitudinal observational studies on headache patients. PubMed has been searched for papers in which measures of HRQoL and/or disability were used as primary or secondary outcome on adult subjects with primary headache, and published in 2010-2012. Among the 70 records retrieved, 12 papers were selected for narrative synthesis. They included data on 2,621 patients with episodic migraine with and without aura, chronic daily headache, and/or chronic migraine with and without medication overuse. The selected trials investigated the efficacy of different pharmacological prophylaxis, of some surgical approaches, of education programmes and osteopathic manipulative treatment; two studies reported longitudinal observations of patients currently under treatment. Overall, the results of our review showed that headache frequency as well as HRQoL and disability were positively impacted by treatment interventions; positive outcomes were less evident in two studies, and similar results were found in the two observational studies. Our findings confirmed that the most commonly used PROMs, including disease-specific tools to assess disability and HRQoL and SF-36, are sensitive to the beneficial effects occurring over time in functioning and quality of life domains in headache patients. They also suggest that the personal and societal costs of headache disorders are likely to be reduced when headache patients receive appropriate treatments and when continuity of care is offered. In terms of future directions, we note that the systematic use of appropriate PROMs should be encouraged both in the clinical practice and in the research field, as they offer a valid option to assess the global effect of treatments on patient-perceived sense of well-being and quality of performance.

Multidisciplinary approach to patients with chronic migraine and medication overuse: experience at the Besta Headache Center.

The question concerning treatment of chronic forms of migraine associated with medication overuse has been largely debated and discussed in the last years and clinical experience has indicated the withdrawal as the first step to treat these patients as the withdrawal is useful so that a preventive pharmacologic therapy can be effective. Moreover, in the last 15 years it has been realized that chronic migraine with medication overuse is clearly a biobehavioral disorder. This clinical condition is not only a painful condition residing in an abnormality of receptor physiology; it is more aptly recognized as a condition wherein emotion and pain are intermingled. For this reason a multidisciplinary strategy of treatment which considers every aspect of individual life, social and emotional, is needed.

Onabotulinum toxin A for treatment of chronic migraine with medication overuse.

Chronic migraine is a common and debilitating headache syndrome. Botulinum neurotoxin (BoNT), a potent toxin produced by the anaerobic bacterium Clostridium botulinum, used largely for treatment of disorders associated with increased muscle tone and hyperidrosis, has been recently used for patients suffering from chronic migraine. In this study, two groups of patients were treated with different dosages of BoNT A to verify the efficacy for chronic migraine. The results confirmed the efficacy of BoNT A when used at the dosage of 150 U. In the second group of patients treated with 100 U, results were not significant. Although these results are preliminary, they led to intense efforts to evaluate the analgesic properties of BoNT A and to assess their clinical applicability.

Understanding the relationship between pain and emotion in idiopathic headaches.

The aim of this paper is to review hypotheses regarding pain mechanisms in headache and relationships between headache pain and the brain's emotional network. There is evidence that chronic pain in idiopathic headaches is, in part, an emotional response induced by alterations in the homeostasis of the interoceptive system--a system that integrates nociceptive information with the emotional network (mediating emotional awareness). These findings suggest that idiopathic headaches are probably due to both an altered pain matrix on the one hand, and an altered affective-cognitive state on the other.

Psychiatric screening for migraine patients.

Psychiatric disorders in migraine patients have a higher prevalence than general population. The presence of psychiatric comorbidities may influence the complexity of the migraine pictures and be related to medication overuse. Severely impaired chronic migraineurs presenting with medication overuse are a challenge for headache clinics. Psychiatric comorbities, such as dependency-like behaviors, anxiety and mood symptoms, might account for headache-related disability and recurrent relapses into medication overuse after a successful detoxification. Within a sample of 63 chronic migraineurs with medication overuse and severe disability, we investigated to which extent clinical severity, affective states and attitudes about medication impact the overall functioning at time of detoxification. To unravel whether some of these factors could predict their long-term outcome, we followed and retest them 1 year after withdrawal. We hypothesized that the detoxification would have led to a partial improvement and not modified the attitudes toward medication and dependence. Detoxification improves most of the clinical and affective measures, but does not free from significant levels of pain intensity and headache-related disability. The partial benefit from detoxification, the severity bias and the maladaptive cognitive profile led us to believe that subgroups of chronic-relapsing migraineurs deserve a multidisciplinary approach that addresses not only the reduction of clinical severity but also specific cognitive and behavioral impairments.

A 14-month study of change in disability and mood state in patients with chronic migraine associated to medication overuse.

This paper aims to evaluate changes in disease severity, disability and mood state in patients with chronic migraine associated to medication overuse (CM-MO). MIDAS was used for assessing disease activity, WHO-DAS-2 for disability, DBI-2 for mood state. ANOVA was used to test change over time; t-test to assess follow-up differences in WHO-DAS-2 and BDI-2 between patients with MIDAS ≤20 and ≥21. Change in MIDAS, WHO-DAS-2 and BDI-2 scores were computed: Pearson's index was used to assess correlation between them; linear regression to assess change in WHO-DAS-2, using MIDAS and BDI-2 change as predictors. Mean MIDAS decreased significantly (from 101.9 to 52.0). In 26.1 % of the sample, MIDAS fell below 21 at follow-up: these patients had lower WHO-DAS-2 score. WHO-DAS-2 change was little correlated to MIDAS change and strongly correlated to changes in BDI-2 scores. 57.1 % of WHO-DAS-2 change variance is explained by change in BDI-2 and MIDAS scores. There was a clear clinical improvement 14 months after detoxification, and a modest reduction in disability which is explained by reduced disease activity and improved mood state. An appropriate treatment of CM-MO, based on detoxification and prophylaxis, is likely to reduce disease burden: recognition and treatment of mood problems may be a key factor to reduce disability.

Day-hospital withdrawal for chronic migraine with medication overuse: results at 3 years follow-up.

Patients with chronic headache and medication overuse are particularly difficult to treat, with no one approach being universally accepted. Some type of withdrawal program, however, is typically implemented before beginning a pharmacological prophylaxis treatment. Different withdrawal modalities have been performed for managing these patients: at first step, in-patient withdrawal has been confirmed effective in preceding clinical experiences. In recent years, new modalities for withdrawal have been developed as day-hospital setting. Purpose of this study was to determine the clinical course of a sample of chronic migraine patients with medication overuse 3 years after day-hospital withdrawal. A group of 202 patients were treated. Patients were suffering from chronic migraine with medication overuse according with IHS criteria. All patients were submitted to a day-hospital withdrawal and then they were followed with meetings every 3 months until the first year and then every 6 months until the last follow-up 3 years after withdrawal. Eighty patients achieved the last follow-up meeting 3 years after withdrawal. Patients clinically improved, significantly, both for days of headache per month and consumption of medications per month. From these results, the day-hospital setting for withdrawal, followed by periodic clinical meetings, seems to be effective for this category of patients to improve significantly at long-term headache frequency and analgesics intake.