B3 agonists or anticholinergics in the treatment of the lower urinary tract dysfunction in patients with multiple sclerosis?-A randomized study.

INTRODUCTION AND OBJECTIVE: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system. MS patients usually present with lower urinary tract dysfunction (LUTD). Objective of this study is to evaluate and compare the efficacy and safety of treating MS patients with LUTD with either a b3 agonist (mirabegron) or anticholinergics. The study's primary outcome is the LUTD symptom improvement. MATERIAL AND METHODS: This is a multi-center, single-blinded, comparative study including 91 MS patients with LUTD. At baseline, patients underwent thorough clinical examination, urine cultivation and abdominal ultrasound and completed urination diaries and specific, validated questionnaires (NBSS, MusiQoL). At second visit, patients were administered either mirabegron or anticholinergics. Treatment was always carried out alongside with MS treatment. Reevaluation was performed 3 months after first visit. Patients underwent the same clinical and imaging tests that were carried out at first visit. RESULTS: We compared several clinical and imaging parameters between the two groups at first visit and month 3 after treatment. Νo statistical difference was noted between the mirabegron group and the anticholinergic group in terms of LUTD improvement. In both groups, improvement from baseline regarding LUTD was recorded. Statistical analysis was performed using the paired and unpaired t test method. No patient discontinued either medication due to side effects. CONCLUSIONS: MS patients receiving either mirabegron or anticholinergic therapy for LUTD showed improvement. Nevertheless, no statistical difference was noted between the two cohorts at 3 months in terms of drug efficacy in all the statistically significant parameters.

Nocebo phenomena may be enhanced in aging: Implications for clinical practice.

Nocebo effects, denoting unfavourable outcomes after a medical intervention because of negative expectations rather than a direct pharmacologic action, are an important cause of dropout from clinical trials and non-adherence to medication, and may be especially pertinent for older adults. Several characteristics of aging individuals and their medical care have a potential to augment nocebo susceptibility, such as depression and anxiety, neurodegenerative diseases and chronic pain states, adverse healthcare experiences, generic drug use, age-related stereotypes, and strained patient-physician communication. Nocebo-related research in older adults is hindered by under-representation in clinical trials, medical complexity of geriatric patients, and lack of validated tools to accurately assess susceptibility and efficacy of preventive efforts.

Pitfals in recognition and management of trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) is a severe, disabling form of painful cranial neuropathy. Even though TN has a typical clinical picture, diagnosis it is often missed or delayed in clinical practice. In order to investigate the occurrence of diagnostic and therapeutic errors in TN, we studied 102 patients suffering from TN recruited through a multicentric survey. METHODS: We performed a Pubmed database search on errors and pittfalls in TN diagnosis and management. Then, patients with TN were consecutively enrolled in the period from February 2017 to October 2019, by several European Headache Centers participating in the study, following a call of the Headache and Pain Scientific Panels of the European Academy of Neurology (EAN). Diagnosis of Classical Trigeminal Neuralgia (CTN) was made according to the International Headache Society (IHS) criteria (Tölle et al., Pain Pract 6:153-160, 2006). All the patients were evaluated using telephone/frontal interviews conducted by headache/pain specialists using an ad hoc questionnaire. RESULTS: A number of 102 patients were recruited, mostly females (F:M ratio 2.64:1). Eighty-six percent of the patients consulted a physician at the time they experienced the first pain attacks. Specialists consulted before TN diagnosis were: primary care physicians (PCP) (43.1%), dentists (in 30.4%), otorhinolaryngologists (3.9%), neurosurgeons (3.9%), neurologists or headache specialists (14.7%), others (8%). The final diagnosis was made mainly by a neurologist or headache specialist (85.3%), and the mean interval between the disease onset and the diagnosis made by a specialist was 10.8 ± 21.2 months. The "diagnostic delay" was 7.2 ± 12.5 months, and misdiagnoses at first consultation were found in 42.1% of cases. Instrumental and laboratory investigations were carried out in 93.1% of the patients before the final diagnosis of TN. CONCLUSION: While TN has typical features and it is well defined by the available international diagnostic criteria, it is still frequently misdiagnosed and mistreated. There is a need to improve the neurological knowledge in order to promptly recognize the clinical picture of TN and properly adhere to the specific guidelines. This may result in a favorable outcome for patients, whose quality of life is usually severely impaired.

Headache and pregnancy: a systematic review.

This systematic review summarizes the existing data on headache and pregnancy with a scope on clinical headache phenotypes, treatment of headaches in pregnancy and effects of headache medications on the child during pregnancy and breastfeeding, headache related complications, and diagnostics of headache in pregnancy. Headache during pregnancy can be both primary and secondary, and in the last case can be a symptom of a life-threatening condition. The most common secondary headaches are stroke, cerebral venous thrombosis, subarachnoid hemorrhage, pituitary tumor, choriocarcinoma, eclampsia, preeclampsia, idiopathic intracranial hypertension, and reversible cerebral vasoconstriction syndrome. Migraine is a risk factor for pregnancy complications, particularly vascular events. Data regarding other primary headache conditions are still scarce. Early diagnostics of the disease manifested by headache is important for mother and fetus life. It is especially important to identify "red flag symptoms" suggesting that headache is a symptom of a serious disease. In order to exclude a secondary headache additional studies can be necessary: electroencephalography, ultrasound of the vessels of the head and neck, brain MRI and MR angiography with contrast ophthalmoscopy and lumbar puncture. During pregnancy and breastfeeding the preferred therapeutic strategy for the treatment of primary headaches should always be a non-pharmacological one. Treatment should not be postponed as an undermanaged headache can lead to stress, sleep deprivation, depression and poor nutritional intake that in turn can have negative consequences for both mother and baby. Therefore, if non-pharmacological interventions seem inadequate, a well-considered choice should be made concerning the use of medication, taking into account all the benefits and possible risks.

European Headache Federation consensus on technical investigation for primary headache disorders.

The diagnosis of primary headache disorders is clinical and based on the diagnostic criteria of the International Headache Society (ICHD-3-beta). However several brain conditions may mimic primary headache disorders and laboratory investigation may be needed. This necessity occurs when the treating physician doubts for the primary origin of headache. Features that represent a warning for a possible underlying disorder causing the headache are new onset headache, change in previously stable headache pattern, headache that abruptly reaches the peak level, headache that changes with posture, headache awakening the patient, or precipitated by physical activity or Valsalva manoeuvre, first onset of headache ≥50 years of age, neurological symptoms or signs, trauma, fever, seizures, history of malignancy, history of HIV or active infections, and prior history of stroke or intracranial bleeding. All national headache societies and the European Headache Alliance invited to review and comment the consensus before the final draft. The consensus recommends brain MRI for the case of migraine with aura that persists on one side or in brainstem aura. Persistent aura without infarction and migrainous infarction require brain MRI, MRA and MRV. Brain MRI with detailed study of the pituitary area and cavernous sinus, is recommended for all TACs. For primary cough headache, exercise headache, headache associated with sexual activity, thunderclap headache and hypnic headache apart from brain MRI additional tests may be required. Because there is little and no good evidence the committee constructed a consensus based on the opinion of experts, and should be treated as imperfect.

Nocebo as a potential confounding factor in clinical trials for Parkinson's disease treatment: a meta-analysis.

BACKGROUND AND PURPOSE: Nocebo refers to adverse events (AEs) generated by patient's negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo-controlled randomized controlled trials (RCTs). We examined AEs following placebo administration in RCTs for Parkinson's disease (PD). METHODS: After a systematic Medline search for RCTs for PD pharmacologic treatments published between 2000 and 2010, we assessed percentages of placebo-treated patients reporting at least one AE or discontinuing due to placebo intolerance and searched for factors influencing nocebo's extent. RESULTS: Data were extracted from 41 RCTs fulfilling search criteria. Of 3544 placebo-treated patients, 64.7% (95% CI: 53.6-74.4) reported at least one AE and 8.8% (95% CI: 6.8-11.5) discontinued placebo treatment due to intolerance. The number of AEs per 100 person-months was 25.9 (95% CI: 16.8-39.8). Nocebo dropout rate was positively related to study population size and year of publication. Increased number of AEs per 100 person-months was negatively correlated with the duration of treatment. AE rates, dropout rates, and AEs per 100 person-months in placebo- and active drug-treated patients were strongly correlated (r = 0.941, 0.695, and 0.824, respectively). CONCLUSIONS: Our analysis indicates a significant dropout rate related to nocebo in trials for PD treatment. Adherence and efficacy may be adversely affected with additional implications for clinical practice.

Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice.

BACKGROUND: Nocebo refers to adverse effects (AEs) generated by negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo-controlled randomized clinical trials (RCTs). We examined AEs following placebo administration in RCTs for fibromyalgia (FM), a condition characterized by patients' poor medication adherence, which may affect outcome and/or increase healthcare costs. METHODS: Following a systematic Medline search for RCTs for FM pharmacologic treatment published between 2001 and 2010, we assessed percentages of placebo-treated patients reporting at least one AE or discontinuing because of placebo intolerance and searched for factors influencing nocebo's extent. Percentages were compared with those revealed by similar meta-analyses of RCTs for multiple sclerosis and primary headaches. RESULTS: Data were extracted from 16 RCTs fulfilling search criteria. Of 2026 placebo-treated patients, 67.2% (95%CI: 51.0-81.5%) reported at least one AE, and 9.5% (95%CI: 8.3-10.9%) discontinued placebo treatment because of intolerance. AEs in placebo arms corresponded quantitatively and qualitatively to those in active drug arms (ρ > 0.88, P < 0.0001). Younger age and larger placebo arm size were associated with increased dropout rates. Patients with depression were more likely to withdraw from trials. Nocebo dropouts in FM trials were fourfold and twofold higher than in RCTs for multiple sclerosis treatment and migraine preventive treatment, respectively. CONCLUSIONS: Nocebo is remarkably prevalent in FM patients participating in RCTs. Because nocebo contributes to drug intolerance and treatment failure in clinical practice, identification of predisposing factors and efforts to prevent nocebo by educating these patients appropriately may be important for FM outcome.

Acute transverse myelitis and antiphospholipid antibodies in lupus. No evidence for anticoagulation.

Current views suggest that prothrombotic properties of antiphospholipid antibodies (aPL) have a role in the development of acute transverse myelitis (ATM) in patients with systemic lupus erythematosus (SLE). Consequently, empiric anticoagulation may be included in these patients' treatment. We performed a systemic review of the literature to explore the clinical value of the presence of aPL in patients with lupus myelitis and the possible effectiveness of anticoagulation. We analyzed clinical and laboratory data extracted from published cases of SLE-associated ATM, fulfilling the Transverse Myelitis Consortium Working Group diagnostic criteria, that provided information on aPL. We report on a total of 70 patients. aPL, detected upon ATM onset in 54% of patients, neither predicted the involvement of the thoracic part of the spine, which has been postulated to reflect a predominantly thrombosis-induced injury, nor correlated with relapsing ATM, additional lupus CNS manifestations, or worse clinical outcome. An unfavorable outcome could be predicted by paralysis (P=0.02) and abnormal CSF findings at presentation (P=0.02). Whilst all patients received major immunosuppressive regimens, severe neurologic impairment (estimated Expanded Disability Status Scale score>7) was found primarily in aPL-negative patients (P=0.03). Anticoagulation was more frequently applied in aPL-positive patients (P=0.04), but any additional therapeutic effect was not evident. Detection of circulating aPL at ATM onset appears unreliable to suggest a thrombotic cause and perhaps not enough to dictate therapeutic anticoagulation. Registry creation of ATM in patients with SLE is needed to obtain more definite answers on the role of aPL in this condition.

Nocebo effects in multiple sclerosis trials: a meta-analysis.

OBJECTIVE: To estimate the incidence and severity of nocebo responses in trials of symptomatic treatments (STs) and disease-modifying treatments (DMTs) for multiple sclerosis (MS). METHODS: We conducted a systematic Medline search for all randomised, placebo-controlled MS trials published between 1989 and 2009. Meta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events. Nocebo severity was calculated from the percentage of placebo-treated patients that dropped-out due to drug-related adverse events. RESULTS: Data were extracted from 56 DMT and 44 ST eligible trials. The pooled incidence of nocebo responses was 74.4% (95% CI: 69.92-88.30) in DMT trials and 25.3% (95% CI: 15.24-36.90) in ST trials and was significantly higher in the former (p < 0.0001). The pooled nocebo severity was 2.1% (95% CI: 1.6-2.67) in DMT and 2.34% (95% CI: 1.54-3.29) in ST trials. Meta-regression analysis revealed a higher nocebo incidence in parallel design ST studies compared to crossover ones (p = 0.013) and a higher nocebo severity in phase II ST studies compared to phase III ones (p = 0.0001). Nocebo severity in DMT trials exhibited an association with the year of study publication (p = 0.011) and the frequency of drug administration (p = 0.0082). CONCLUSIONS: Nocebo responses in MS trials are substantial and appear to have increased significantly in recent years with important implications for both trial design and clinical practice. Furthermore, nocebo responses exhibit an association with medication and trial-related factors.

Migraine recurrence is not associated with depressive or anxiety symptoms. Results of a randomized controlled trial.

In order to investigate the plausible association of migraine recurrence with anxiety and depressive symptoms, a multicentre, randomized, double-blind, placebo-controlled, crossover clinical trial was conducted using sumatriptan as a vehicle drug. Migraineurs were randomly assigned to receive either 50 mg sumatriptan or placebo for three consecutive migraine attacks, and then cross over to the other treatment for three more migraine attacks. The primary measurements were the observed rate of migraine recurrence in relation to (i) patient's mood condition, measured by the Hamilton rating scales for depression and anxiety and (ii) patient's general health and functioning measured by the Symptom Checklist (SCL)-90-R. Migraine recurrence was defined as any migrainous headache that occurred within 24 h post treatment, only when pain free at 2 h was achieved. The analysis of efficacy was performed on 376 migraine attacks treated with sumatriptan and 373 attacks treated with placebo. Recurrence ratio was 14.1% and 5.1%, respectively (P = 0.045). The number needed to treat for pain free at 2 h post dose was 5.4. Recurrence was not affected by Hamilton scores for depression or anxiety, SCL-90-R scores or treatment. Apparently, depressive or anxiety symptoms do not influence headache recurrence in acute pharmaceutical migraine treatment, but further investigation is required.

EFNS guideline on the treatment of tension-type headache - report of an EFNS task force.

BACKGROUND: Tension-type headache (TTH) is the most prevalent headache type and is causing a high degree of disability. Treatment of frequent TTH is often difficult. OBJECTIVES: To give evidence-based or expert recommendations for the different treatment procedures in TTH based on a literature search and the consensus of an expert panel. METHODS: All available medical reference systems were screened for the range of clinical studies on TTH. The findings in these studies were evaluated according to the recommendations of the EFNS resulting in level A, B or C recommendations and good practice points. RECOMMENDATIONS: Non-drug management should always be considered although the scientific basis is limited. Information, reassurance and identification of trigger factors may be rewarding. Electromyography (EMG) biofeedback has a documented effect in TTH, whilst cognitive-behavioural therapy and relaxation training most likely are effective. Physical therapy and acupuncture may be valuable options for patients with frequent TTH, but there is no robust scientific evidence for efficacy. Simple analgesics and non-steroidal anti-inflammatory drugs are recommended for the treatment of episodic TTH. Combination analgesics containing caffeine are drugs of second choice. Triptans, muscle relaxants and opioids should not be used. It is crucial to avoid frequent and excessive use of analgesics to prevent the development of medication-overuse headache. The tricyclic antidepressant amitriptyline is drug of first choice for the prophylactic treatment of chronic TTH. Mirtazapine and venlafaxine are drugs of second choice. The efficacy of the prophylactic drugs is often limited, and treatment may be hampered by side effects.

Guidelines for controlled trials of drugs in tension-type headache: second edition.

The Clinical Trials Subcommittee of the International Headache Society published its first edition of the guidelines on controlled trials of drugs in tension-type headache in 1995. These aimed 'to improve the quality of controlled clinical trials in tension-type headache', because 'good quality controlled trials are the only way to convincingly demonstrate the efficacy of a drug, and form the basis for international agreement on drug therapy'. The Committee published similar guidelines for clinical trials in migraine and cluster headache. Since 1995 several studies on the treatment of episodic and chronic tension-type headache have been published, providing new information on trial methodology for this disorder. Furthermore, the classification of the headaches, including tension-type headache, has been revised. These developments support the need for also revising the guidelines for drug treatments in tension-type headache. These Guidelines are intended to assist in the design of well-controlled clinical trials in tension-type headache.

Apraxia related with subcortical lesions due to cerebrovascular disease.

OBJECTIVES: To examine whether ideomotor apraxia exists in patients with subcortical ischemic lesions. PATIENTS AND METHODS: A matched-control, prospective and multi-centered research design was used. Ideomotor apraxia, anxiety and depression were assessed by the Movement Imitation Test and the Hamilton scales, respectively. RESULTS: Forty two consecutive patients with subcortical ischemic stroke and an equal number of healthy participants, matched in age and sex were included. Paired-sample t-tests showed that patients had significantly more apractic elements in their movements (t = 5.03, P < 0.01), higher anxiety (t = -2.55, P = 0.0014) and depression levels (t = -2.61, P = 0.012) than their healthy matched participants. Participants with higher anxiety and depression scores performed worse on the Movement Imitation Test. CONCLUSIONS: Ischemic damage of subcortical modular systems may affect praxis.

Refractory chronic headache associated with obstructive sleep apnoea syndrome.

The aim was to investigate the comorbidity of chronic refractory headache with obstructive sleep apnoea syndrome (OSAs). Seventy-two patients (51 women and 21 men) with chronic and refractory headaches, whose headache occurred during sleep or whose sleep was accompanied by snoring, were submitted to polysomnography. Patients diagnosed with OSAs (respiratory disturbance index > 10) began continuous positive airway pressure (C-PAP) treatment and were followed up for >or= 6 months. Twenty-one cases of OSAs were identified (29.2% of the total investigated, 13.7% of the women and 66.6% of the men). Headaches were classified into several headache disorders, medication overuse headache and cluster headache being the most prevalent (nine and six of the 21 cases, respectively). In one case (1.4% of the total sample, 4.7% of all the men), the criteria for hypnic headache were fulfilled. Multivariate regression analysis revealed that age, male gender and body mass index were associated with OSAs. C-PAP treatment improved both sleep apnoea and headache in only a third of the cases. Patients suffering from chronic refractory headache associated with sleep or snoring, in particular those who are also middle-aged, overweight men, should be considered for polysomnography. C-PAP treatment alone does not seem to improve headache, but further investigation is needed.

Methodology of clinical trials in multiple sclerosis.

The scope of the paper is to summarise key issues in methodology used in clinical trials on multiple sclerosis (MS) treatment and help clinicians to better understand articles reporting the results of these trials. Relapsing ratio and disability progression based on the Expanded Disability Status Scale are currently used as clinical efficacy primary outcomes, but more global measurements should be used in future such as the MS Functional Composite. For magnetic resonance imaging (MRI) outcomes, new MRI composites and indexes are already available (Z4 score, conventional MRI-derived end-points) that, together with new MRI techniques (magnetisation- transfer MRI and proton resonance spectroscopy), offer more precise neuroimaging assessments of the disease. These efficacy measurements should be presented in articles as number needed to treat, which assists the reader to calculate and compare the treatments' power and safety.

Animal models of migraine: looking at the component parts of a complex disorder.

Animal models of human disease have been extremely helpful both in advancing the understanding of brain disorders and in developing new therapeutic approaches. Models for studying headache mechanisms, particularly those directed at migraine, have been developed and exploited efficiently in the last decade, leading to better understanding of the potential mechanisms of the disorder and of the action for antimigraine treatments. Model systems employed have focused on the pain-producing cranial structures, the large vessels and dura mater, in order to provide reproducible physiological measures that could be subject to pharmacological exploration. A wide range of methods using both in vivo and in vitro approaches are now employed; these range from manipulation of the mouse genome in order to produce animals with human disease-producing mutations, through sensitive immunohistochemical methods to vascular, neurovascular and electrophysiological studies. No one model system in experimental animals can explain all the features of migraine; however, the systems available have begun to offer ways to dissect migraine's component parts to allow a better understanding of the problem and the development of new treatment strategies.

Add-on topiramate in the treatment of refractory partial-onset epilepsy: clinical experience of outpatient epilepsy clinics from 11 general hospitals.

An open, prospective, observational study was performed to assess efficacy and adverse-event profile of topiramate as add-on therapy in epilepsy. Outpatient neurology clinics from 11 general hospitals in Greece participated in the study. In total, 211 patients with treatment resistant partial-onset seizures who met the inclusion criteria, were studied. After baseline evaluation, topiramate was given at a target dose of 200mg/day over a 1-month titration period. In the subsequent maintenance period, the topiramate dose could be varied according to the clinical results. Patients were followed for in total 6 months, with monthly visits and regular physical, neurological and laboratory examinations. Seizure frequencies decreased to 35--40% of baseline values following 3 months of treatment and remained relatively constant thereafter. The average monthly seizure frequency over the 6-month study period was 4.61, compared to 9.21 at baseline. The number of responders (patients with at least 50% reduction in seizure frequency) followed a similar pattern, i.e., increase during the first 3 months levelling off at a final 80--85% response rate. Of those completing the study, 30% had been seizure-free for at least 3 months and 12% for 5 months. Topiramate was well tolerated, no deviations in laboratory values were found. Adverse events appeared to occur less frequently, and antiepileptic effects were more pronounced in this prospective open-label study than in earlier reports from randomised controlled trials. The nature of the patient population and the application of individualised dose optimisation are proposed as contributing factors to explain the favourable results of this study.

Time perception in migraine sufferers: an experimental matched-pairs study.

Despite occasional case reports, the influence of migraine on time perception has not been systematically investigated. We used an experimental technique to study the estimation of auditory duration in 40 migraineurs at different tone intervals in the ms and in the 1-s range and compared their performance with 40 matched normal subjects. With a time awareness questionnaire we also evaluated the subjective experience of elapsing time for long durations involving long-term memory processes. Migraine did not influence temporal judgements in either of the tests, suggesting that migraineurs do not generally over- or underestimate temporal events. The subgroup of migraineurs with a depressive disorder, however, showed a marked speeding up of their internal timekeeping mechanisms, pointing to depression as an important covariable in time perception.