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Background and objectives The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8–14 days/month) or chronic migraine (CM). Methods This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician’s choice, or patient’s preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. Results Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57–11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05–2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15–3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04–2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07–0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42–8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14–2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22–3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. Conclusions A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.

Italian Migraine Registry (I-GRAINE) is a multicenter (n = 38), prospective, observational, non-interventional study aimed at providing big data on migraine to ensure proper clinical disease management, according to scientific, and sustainability criteria. We enrolled consecutive patients affected by episodic or chronic migraine according to the systematic random method. Information on sociodemographic characteristics, lifestyle, migraine features, patient's journey, and healthcare resource use were gathered using face-to-face interviews.On the date of 31 December 2021, we enrolled 231 patients at 12 headache centers. Most of them were women (84.4%), with high migraine frequency (9.6 +/- 6.9 days/month) and severe disability (MIDAS score: 43.0 +/- 40.8; HIT-6 score: 60.4 +/- 10.6). Only a minority of patients (38.1%) had previously visited a headache center.A clear-cut difference emerged in the proportion of responders to nonspecific acute treatments (43.5-66.7%) compared to triptans (76.3%) and in responders to unspecific prophylaxis (5.4-35%) compared to anti-CGRP monoclonal antibodies (69.2-78.6%). Most patients underwent >= 1 specialist visit (66.9%) or diagnostic investigation (77.4%) over the last 3 years-mostly subsidized by our national health system-inappropriate in 64.9% and 25% of the cases, respectively.The I-GRAINE registry is expected to provide a large and exponentially increasing collection of clinical, biological, and epidemiologic information and will contribute to moving migraine out of the shadow cone of marginalization, which has been often relegated up to now.

Objective: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. Background: Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. Methods: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18–65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70mg, administered subcutaneously every 4weeks. Treatment duration was planned to last from 6 to 12months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9–12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). Results: In total, 372 migraine patients were treated with at least one dose of erenumab 70mg. At weeks 9–12, erenumab decreased MMDs by 4.5±4.1days (mean±SD) in patients with HFEM and by 9.3±9.1 (mean±SD) days in those with CM compared to baseline. At weeks 9–12 VAS score was reduced by 1.9±1.9 (mean±SD), HIT score by 10.7±8.8 (mean±SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0–14.0) to 5.0 (IQR 3.0–7.0) in HFEM. In CM patients, VAS was reduced by 1.7±2.0 (mean±SD), HIT by 9.7±10.4 (mean±SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0–30.0) to 8.0 (IQR 5.0–15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24–7.40; p=0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02–1.11; p=0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14–3.52; p=0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20–0.93; p=0.003). Conclusions: Erenumab 70mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

To investigate in real-life the conversion from chronic migraine (CM) to episodic migraine (EM), specifically to EM with High-Frequency (HFEM: 8-14 monthly migraine days, MMDs), Medium-Frequency (MFEM, 4-7 MMDs), and Low-Frequency EM (LFEM, 0-3 MMDs), and its persistence during 1 year of treatment with galcanezumab.Consecutive CM patients treated with galcanezumab completing 1 year of observation were enrolled. We collected data on MMDs, pain intensity (Numeric Rating Scale, NRS score), and monthly acute medication intake (MAMI) from baseline (V1) to the 12-month visit (V12).Of the 155 enrolled patients, 116 (around 75%) reverted to EM at every visit and 81 (52.3%) for the entire 1-year treatment. Patients with older onset age (p = 0.010) and fewer baseline MMDs (p = 0.005) reverted more frequently to EM. At V12, 83 participants (53.5%) presented MFEM or LFEM. Patients reverted to MFEM or LFEM for 7 months (25th 1, 75th 11). The medication overuse discontinuation rate at V12 was 82.8% and occurred for 11 months (25th 8, 75th 12). From baseline to V12, the MAMI decreased by 17 symptomatic drugs (p 0.000001) while the NRS score reduced by almost 2 points (p 0.000001). A consistent transition to EM for the entire treatment year was observed in 81 (52.3%) patients.The 1-year GARLIT experience suggests that more than half of CM patients treated with galcanezumab persistently reverted to EM in real life.ClinicalTrials.gov NCT04803513.

Botulinum toxin (BT) is an effective and safe treatment for spasticity, with limited evidence in multiple sclerosis (MS). We aim to describe the use of BT for the management of MS spasticity in the clinical practice, its combination with other anti-spastic treatments in MS and possible MS clinical correlates. This is a multicentre cross-sectional observational study including 386 MS patients, receiving BT for spasticity in 19 Italian centres (age 53.6 ± 10.9 years; female 228 (59.1%); disease duration 18.7 ± 9.2 years; baseline Expanded Disability Status Scale (EDSS) 6.5 (2.0–9.0)). BT was used for improving mobility (n = 170), functioning in activities of daily living (n = 56), pain (n = 56), posturing-hygiene (n = 63) and daily assistance (n = 41). BT formulations were AbobotulinumtoxinA (n = 138), OnabotulinumtoxinA (n = 133) and IncobotulinumtoxinA (n = 115). After conversion to unified dose units, higher BT dose was associated with higher EDSS (Coeff = 0.591; p

The diagnostic framework and the therapeutic management of patients with adult dystonia can represent a challenge for clinical neurologists. The objective of the present paper is to delineate diagnostic and therapeutic recommendations for dystonia provided by a panel of Italian experts afferent to the Italian Society of Neurology, the Italian Academy for the Study of Parkinson's Disease and Movement Disorders, and the Italian Network on Botulinum Toxin. We first discuss the clinical approach and the instrumental assessment useful for diagnostic purpose. Then, we analyze the pharmacological, surgical, and rehabilitative therapeutic options for adult dystonia. Finally, we propose a hospital-territory network model for adult dystonia management.

The aim of this study is to assess changes in the body distribution and the semeiology of functional motor disorder (FMD) in patients who reported only one or more than one body site affected at FMD onset. Data were obtained from the Italian Registry of Functional Motor Disorders, which included patients with a diagnosis of clinically definite FMDs. The relationship between FMD features and spread to other body sites was estimated by multivariate Cox regression analysis. We identified 201 (49%) patients who reported only one body site affected at FMD onset and 209 (51%) who reported multiple body sites affected at onset. FMD spread from the initial site to another site in 43/201 (21.4%) patients over 5.7 ± 7.1 years in those with only one site affected at FMD onset; FMD spread to an another body site in 29/209 (13.8%) over 5.5 ± 6.5 years. The spread of FMD was associated with non-motor functional symptoms and psychiatric comorbidities only in the patients with one body site affected at FMD onset. Our findings provide novel insight into the natural history of FMD. The number of body sites affected at onset does not seem to have a consistent influence on the risk of spread. Furthermore, our findings suggest that psychiatric comorbidities and non-motor functional symptoms may predict the spread of FMD symptoms, at least in patients with one body site affected at onset.

Background Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM. Methods This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9-12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥50%, ≥75% and 100% responder rates at the same time intervals. Results 67 migraine patients had received ≥1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p

Objective\ud We aimed to describe the prevalence and clinical-demographical features of patients with functional gait disorders (FGDs) and to compare them to patients with functional motor disorders (FMDs) without FGDs (No-FGDs).\ud \ud Methods\ud In this multicenter observational study, we enrolled patients with a clinically definite diagnosis of FMDs in 25 tertiary movement disorders centers in Italy. Each subject with FMDs underwent a comprehensive clinical assessment, including screening for different subtypes of functional gait disorders. Multivariate regression models were implemented in order to estimate the adjusted odds ratio (OR; 95% confidence interval) of having FGDs in relation to sociodemographic and clinical characteristics.\ud \ud Results\ud Out of 410 FMDs, 26.6% (n = 109) of patients exhibited FGDs. The most frequent FGDs were slow gait (n = 43, 39.4%), astasia-abasia (n = 26, 23.8%), and knee buckling (n = 24, 22%). They exhibited single FGDs in 51.4% (n = 56) or complex FGDs (more than one type of FGDs) in 48.6% (n = 53) of cases. On multivariate regression analysis, the presence of FGDs was more likely associated with older age (OR 1.03, 95% CI 1.01–1.04), functional visual symptoms (OR 2.19, 95% CI 1.08–4.45), and the diagnosis of somatic symptoms disorder (OR 2.97, 95% CI 1.08–8.17). FGDs were also more likely to undergo physiotherapy (OR 1.81, 95% CI 1.08–3.03).\ud \ud Conclusions\ud People with FMDs may present with different and overlapping types of FGDs, which may occur in older age. The association of FGDs with functional visual symptoms and somatic symptoms disorder opens up to new avenues to the understanding of the neural mechanisms of these disorders.

Objective: To develop a dedicated Italian chronic migraine (CM) database (IRON project) to overcome disease misconceptions, improve clinical administration, reduce patients' burden, and rationalize economic resource allotment.Background: Proper CM management requires a comprehensive appraisal of its full clinical, social, and economic complexity.Methods: In this cross-sectional study, CM patients were screened in 24 certified headache centers with face-to-face interviews. Information on sociodemographic factors, medical history, characteristics of CM, and of prior episodic migraine (EM), and healthcare resource use was gathered using a semistructured web-based questionnaire.Results: A total of 866 CM patients were enrolled. CM started similar to 20 years after EM onset (age at EM onset 17.4 +/- 9.1 vs. age at CM onset 35.3 +/- 12.5 [mean +/- SD]). CM prophylaxis, used by 430/866 (49.6%) of the patients, was often ineffective, not tolerated, and prematurely discontinued. Medications and diagnostic workup, frequently inappropriate, were mostly subsidized by the Italian national health service. CM patients with >= 25 headache days/month revealed substantial clinical differences and heavier disability and economic burden compared with those with

Objective To evaluate whether increased cerebrospinal fluid (CSF) pressure causes alteration of periventricular white matter (WM) microstructure in patients with idiopathic intracranial hypertension (IIH). Methods In a prospective study, patients with refractory chronic headache with and without IIH performed a neuroimaging study including 3T MRI, 3D Phase Contrast MR venography, and diffusion tensor imaging (DTI) of the brain. Whole‐brain voxel‐wise comparisons of DTI abnormalities of WM were performed using tract‐based spatial statistics. A correlation analysis between DTI indices and CSF opening pressure, highest peak, and mean pressure was also performed in patients with IIH. Results We enrolled 62 consecutive patients with refractory chronic headaches. Thirty‐five patients with IIH, and 27 patients without increased intracranial pressure. DTI analysis revealed no fractional anisotropy changes, but decreased mean, axial, and radial diffusivity in body (IIHMD = 0.80 ± 0.04, non‐IIHMD = 0.84 ± 0.4, IIHAD = 1.67 ± 0.07, non‐IIHAD = 1.74 ± 0.05, IIHRD = 0.38 ± 0.04, non‐IIHRD = 0.42 ± 0.05 [mm2/sec × 10−3]) of corpus callosum, and in right superior corona radiata (IIHMD = 0.75 ± 0.04, non‐IIHMD = 0.79 ± 0.05, IIHAD = 1.19 ± 0.07, non‐IIHAD = 1.28 ± 0.09, IIHRD = 0.59 ± 0.03, non‐IIHRD = 0.53 ± 0.03 [mm2/sec × 10−3]) of 35 patients with IIH compared with 27 patients without increased intracranial pressure. DTI indices were negatively correlated with high CSF pressures (P

Background The clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting. Methods This multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation. Results One hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both p p p = .018) and had failed a lower number of preventive treatments (p = .013) than non-responders. At V6, 77.2% of CM patients converted to EM, and 82.0% ceased MO. Adverse events, none serious, were reported in up to 10.3% of patients during evaluation times. Conclusions Galcanezumab in real life was safe, well tolerated and seemed more effective than in RCTs. Normal weight and a low number of failed preventives were positively associated with galcanezumab effectiveness in CM patients. Trial registration ClinicalTrials.govNCT04803513.

Background Adult-onset focal dystonia can spread to involve one, or less frequently, two additional body regions. Spread of focal dystonia to a third body site is not fully characterized. Materials and methods We retrospectively analyzed data from the Italian Dystonia Registry, enrolling patients with segmental/multifocal dystonia involving at least two parts of the body or more. Survival analysis estimated the relationship between dystonia features and spread to a third body part. Results We identified 340 patients with segmental/multifocal dystonia involving at least two body parts. Spread of dystonia to a third body site occurred in 42/241 patients (17.4%) with focal onset and 10/99 patients (10.1%) with segmental/multifocal dystonia at onset. The former had a greater tendency to spread than patients with segmental/multifocal dystonia at onset. Gender, years of schooling, comorbidity, family history of dystonia/tremor, age at dystonia onset, and disease duration could not predict spread to a third body site. Among patients with focal onset in different body parts (cranial, cervical, and upper limb regions), there was no association between site of focal dystonia onset and risk of spread to a third body site. Discussion and conclusion Spread to a third body site occurs in a relative low percentage of patients with idiopathic adult-onset dystonia affecting two body parts. Regardless of the site of dystonia onset and of other demographic/clinical variables, focal onset seems to confer a greater risk of spread to a third body site in comparison to patients with segmental/multifocal dystonia at onset.

Introduction Functional motor disorders (FMDs) are usually categorized according to the predominant phenomenology; however, it is unclear whether this phenotypic classification mirrors the underlying pathophysiologic mechanisms. Objective To compare the characteristics of patients with different FMDs phenotypes and without co-morbid neurological disorders, aiming to answer the question of whether they represent different expressions of the same disorder or reflect distinct entities. Methods Consecutive outpatients with a clinically definite diagnosis of FMDs were included in the Italian registry of functional motor disorders (IRFMD), a multicenter data collection platform gathering several clinical and demographic variables. To the aim of the current work, data of patients with isolated FMDs were extracted. Results A total of 176 patients were included: 58 with weakness, 40 with tremor, 38 with dystonia, 23 with jerks/facial FMDs, and 17 with gait disorders. Patients with tremor and gait disorders were older than the others. Patients with functional weakness had more commonly an acute onset (87.9%) than patients with tremor and gait disorders, a shorter time lag from symptoms onset and FMDs diagnosis (2.9 ± 3.5 years) than patients with dystonia, and had more frequently associated functional sensory symptoms (51.7%) than patients with tremor, dystonia and gait disorders. Patients with dystonia complained more often of associated pain (47.4%) than patients with tremor. No other differences were noted between groups in terms of other variables including associated functional neurological symptoms, psychiatric comorbidities, and predisposing or precipitating factors. Conclusions Our data support the evidence of a large overlap between FMD phenotypes.

Background and purpose\ud The aims of this study were to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases (“comorbid FMDs”), and to compare comorbid FMDs with FMDs not overlapping with other neurological diseases (“pure FMDs”).\ud \ud Methods\ud For this multicenter observational study, we enrolled outpatients with a definite FMD diagnosis attending 25 tertiary movement disorder centers in Italy. Each patient with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Group comparisons (comorbid FMDs vs. pure FMDs) were performed in order to compare demographic and clinical variables. Logistic regression models were created to estimate the adjusted odds ratios (95% confidence intervals) of comorbid FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables).\ud \ud Results\ud Out of 410 FMDs, 21.7% of patients (n = 89) had comorbid FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%), FMDs appeared after the diagnosis of a neurological disease. Patients with comorbid FMDs were older, and more frequently had tremor, non‐neurological comorbidities, paroxysmal non‐epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid FMDs was more likely associated with longer time lag until the final diagnosis of FMD, presence of tremor and non‐neurological comorbidities.\ud \ud Conclusions\ud Our findings highlight the need for prompt diagnosis of FMDs, given the relatively high frequency of associated neurological and non‐neurological diseases.

Cervical dystonia is associated with neck pain in a significant proportion of cases, but the mechanisms underlying pain are largely unknown. In this exploratory study, we compared demographic and clinical variables in cervical dystonia patients with and without neck pain from the Italian Dystonia Registry. Univariable and multivariable logistic regression analysis indicated a higher frequency of sensory trick and a lower educational level among patients with pain.

Background Acute peripheral trauma is a controversial risk factor for idiopathic dystonia. Materials and methods We retrospectively analyzed data from the Italian Dystonia Registry regarding the occurrence of acute peripheral trauma severe enough to require medical attention in 1382 patients with adult-onset idiopathic dystonia and 200 patients with acquired adult-onset dystonia. Results Patients with idiopathic and acquired dystonia showed a similar burden of peripheral trauma in terms of the number of patients who experienced trauma (115/1382 vs. 12/200, p = 0.3) and the overall number of injuries (145 for the 1382 idiopathic patients and 14 for the 200 patients with secondary dystonia, p = 0.2). Most traumas occurred before the onset of idiopathic or secondary dystonia but only a minority of such injuries (14 in the idiopathic group, 2 in the acquired group, p = 0.6) affected the same body part as that affected by dystonia. In the idiopathic group, the elapsed time between trauma and dystonia onset was 8.1 ± 9.2 years; only six of the 145 traumas (4.1%) experienced by 5/1382 idiopathic patients (0.36%) occurred one year or less before dystonia onset; in the acquired dystonia group, the two patients experienced prior trauma to the dystonic body part 5 and 6 years before dystonia development. Discussion and conclusion Our data suggest that the contribution of peripheral acute trauma to idiopathic dystonia is negligible, if anything, and likely involves only a small subset of patients.

Background: Diagnosis of focal dystonia is based on clinical grounds and is therefore open to bias. To date, diagnostic guidelines have been only proposed for blepharospasm and laryngeal dystonia. To provide practical guidance for clinicians with less expertise in dystonia, a group of Italian Movement Disorder experts formulated clinical diagnostic recommendations for cervical, oromandibular, and limb dystonia. Methods: A panel of four neurologists generated a list of clinical items related to the motor phenomenology of the examined focal dystonias and a list of clinical features characterizing neurological/non-neurological conditions mimicking dystonia. Thereafter, ten additional expert neurologists assessed the diagnostic relevance of the selected features and the content validity ratio was calculated. The clinical features reaching a content validity ratio > 0.5 contributed to the final recommendations. Results: The recommendations retained patterned and repetitive movements/postures as the core feature of dystonia in different body parts. If present, a sensory trick confirmed diagnosis of dystonia. In the patients who did not manifest sensory trick, active exclusion of clinical features related to conditions mimicking dystonia (features that would be expected to be absent in dystonia) would be necessary for dystonia to be diagnosed. Discussion: Although reliability, sensitivity, and specificity of the recommendations are yet to be demonstrated, information from the present study would hopefully facilitate diagnostic approach to focal dystonias in the clinical practice and would be the basis for future validated diagnostic guidelines.

Isolated cerebrospinal fluid hypertension (ICH) is a condition of increased cerebrospinal fluid (CSF) pressure in the cranial-spinal compartment without an identifiable cause. Isolated headache is the most common symptom of ICH, while missing may be signs such as papilledema or sixth nerve palsy. This fact makes difficult the clinical diagnosis of headache attributable to ICH in headache sufferers. Another source of confusion stems from the CSF pressure measurement. It has been observed that a single-spot CSF opening pressure measurement may be insufficient to identify elevated CSF pressure in headache sufferers. A new method of CSF pressure measurement has been able to identify pressure-related features of isolated CSF hypertension (ICH). In fact, nocturnal or postural headache and abnormal pressure pulsations are the more common pressure-related features of ICH in patients with chronic headache. The compressive action of these abnormal pressure pulsations causes the periventricular white matter microstructure alterations leading to the focal diffusion tensor imaging findings in patients with ICH. Abnormal pressure pulsations are a marker of ICH in chronic headache. The identification of the CSF pressure-related features may be useful for differentiating headache sufferers with ICH from those with primary headache disorder in clinical practice. The therapeutic strategy in these headache sufferers with ICH includes the CSF removal and a medical treatment.

Introduction We tested whether a change in head/neck position initiates head deviation in drug-naive patients with cervical dystonia and to identify the electrophysiological and neuroanatomical correlates of dystonic head rotation. Methods Twenty-five consecutive drug-naive patients with cervical dystonia and 25 healthy controls underwent the simultaneous surface electromyographic (EMG) recording of sternocleidomastoid (SCM) muscle contractions during head/neck position changes, blink reflex recovery cycle (BRrc), DAT-SPECT, and advanced structural neuroimaging analysis using voxel-based morphometry (VBM). Results Surface EMG recordings of SCM muscle activity during changes in head/neck position demonstrated an insignificant asymmetric low amplitude of the SCM muscle contractions in the horizontal position in both patients and controls, but an asymmetric high amplitude in SCM muscle contractions leading to abnormal head movements in vertical positions in patients with cervical dystonia. All controls had a symmetric low increase in amplitude of SCM muscle contractions in response to changes in head/neck position. VBM analysis in 19 patients showed abnormal decreases of gray matter (GM) volume in the bilateral motor (localized in the homunculus of the head) and premotor cortices when compared to controls. In addition, the side of these neuroanatomical changes was asymmetrically related to abnormal head deviations in these patients. All subjects had normal results during BRrc and DAT-SPECT. Conclusions The passage from inactive horizontal position to active vertical head/neck posture initiates head deviation in drug-naive patients with cervical dystonia, and the anatomical correlates of this dystonic head rotation is a restricted abnormal pattern of GM changes in the motor cortices.

Background The degree to which work-related difficulties are recognized in headache research is poor and often carried out with inadequate information such as “reduced ability to work as usual”, which do not capture at all the variety of difficulties and the factors that impact over them. The aim of this paper is to present the validation of the HEADWORK questionnaire, which addresses the amount and severity of difficulties in work-related tasks and the factors that impact over them. Methods We developed a set of items based on a previous literature review and patients’ focus groups and tested it on a wide set of patients with episodic and chronic migraine attending eight different Italian headache centers. HEADWORK factor structure was assessed with exploratory and confirmatory factor analysis; internal consistency and construct validity were addressed as well. Results The validation sample (N = 373) was mostly composed of patients with episodic migraine without aura (64.3%) and of females (81%). Factor analysis retrieved two different scales: “Work-related difficulties”, composed of eleven items which explain 67.1% of the total variance, and “Factors contributing to work difficulties”, composed of six items which explain 52.1% of the total variance. Both HEADWORK subscales have good measurement properties, with higher scores being associated to higher disability, lower quality of life, lower productivity, higher headache frequency and pain intensity. Conclusions HEADWORK is a 17-item, two-scale questionnaire addressing the impact of migraine on work-related difficulties in terms of difficulties in general or specific skills, and the factors contributing to these difficulties, defined as negative impact on work tasks. It can be used to address disability weights for the purpose of calculating the burden of migraine, and to assess the balance between therapeutic and side effects of medication on productivity.

Objective To evaluate circadian fluctuations and night/day ratio of Heart Rate Variability (HRV) spectral components in patients with obstructive sleep apnea (OSA) in comparison with controls. Participants and methods This is a simultaneous HRV-polysomnographic (PSG) study including 29 patients with OSA and 18 age-sex-matched controls. Four patients with OSA dropped out. All participants underwent PSG and HRV analysis. We measured the 24-hour fluctuations and the night/ day ratio of low frequency (LF) and high frequency (HF) spectral components of HRV in all subjects and controls. The LF night/day ratio was termed the cardiac sympathetic index while the HF night/day ratio was termed the cardiac parasympathetic index. Results All twenty-five OSA patients were PSG positive (presence of OSA) while 18 controls were PSG negative (absence of OSA). There was no significant difference in LF and HF 24-hour fluctuation values between OSA patients and controls. In OSA patients, LF and HF values were significantly higher during night-time than day time recordings (p

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Hereditary motor and sensory neuropathy with focally folded myelin sheaths, or Charcot-Marie-Tooth neuropathy type 4B (CMT4B), is a distinct clinical and genetic entity belonging to the heterogeneous group of autosomal recessive demyelinating neuropathies. We first described a large inbred pedigree with 10 patients affected by CMT4B, which enabled us to uncover the genetic findings, clinical spectrum, and natural history of such a disorder. The clinical picture was characterized by infantile onset with progressive symmetric distal and proximal muscular weakness. Using homozygosity mapping and haplotype sharing analysis, we found evidence of linkage of chromosome 11q23. We then identified a second unrelated family in which two individuals were affected with CMT4B. Although the clinical findings were similar to those previously reported, we excluded the disease locus segregating in this smaller pedigree from the 11q23 region. We thus provided evidence for a second locus causing the CMT4B phenotype. All these findings indicate that CMT4B seems to be phenotypically quite homogeneous, but is genetically heterogeneous.

The Italian Dystonia Registry is a multicenter data collection system that will prospectively assess the phenomenology and natural history of adult-onset dystonia and will serve as a basis for future etiological, pathophysiological and therapeutic studies. In the first 6 months of activity, 20 movement disorders Italian centres have adhered to the registry and 664 patients have been recruited. Baseline historical information from this cohort provides the first general overview of adult-onset dystonia in Italy. The cohort was characterized by a lower education level than the Italian population, and most patients were employed as artisans, builders, farmers, or unskilled workers. The clinical features of our sample confirmed the peculiar characteristics of adult-onset dystonia, i.e. gender preference, peak age at onset in the sixth decade, predominance of cervical dystonia and blepharospasm over the other focal dystonias, and a tendency to spread to adjacent body parts, The sample also confirmed the association between eye symptoms and blepharospasm, whereas no clear association emerged between extracranial injury and dystonia in a body site. Adult-onset dystonia patients and the Italian population shared similar burden of arterial hypertension, type 2 diabetes, coronary heart disease, dyslipidemia, and hypothyroidism, while hyperthyroidism was more frequent in the dystonia population. Geographic stratification of the study population yielded no major difference in the most clinical and phenomenological features of dystonia. Analysis of baseline information from recruited patients indicates that the Italian Dystonia Registry may be a useful tool to capture the real world clinical practice of physicians that visit dystonia patients.

In this study, we used an automated segmentation of regions of interest and co-registration to diffusion tensor imaging (DTI) images to investigate whether microstructural abnormalities occur in gray structures of the frontal-subcortical circuits in patients with amyotrophic lateral sclerosis (ALS). Twenty-four patients with probable or definite sporadic ALS and 22 healthy controls were enrolled in the study. Thirteen out of 24 ALS patients and all of the control subjects underwent a detailed neuropsychological evaluation. DTI was performed to measure mean diffusivity (MD) and fractional anisotropy in the frontal cortex, caudate, putamen, globus pallidus, thalamus, amygdala and hippocampus. MD values of ALS patients were significantly higher in the frontal cortex (P = 0.023), caudate (P = 0.01), thalamus (P = 0.019), amygdala (P = 0.012) and hippocampus (P = 0.002) compared to controls. MD of these structures significantly correlated to a variable degree with neurological disability and neuropsychological dysfunctions. The increased MD values in several cortical and subcortical gray structures and their correlations with neuropsychological variables substantiate a multisystemic degeneration in ALS and suggest that dysfunctions of frontal-subcortical circuits could play a pivotal role in frontal impairment and behavioral symptoms in ALS patients.

Previous MR studies have established that bilateral transverse sinus stenosis (BTSS) predicts idiopathic intracranial hypertension without papilledema (IIHWOP) in migraine. However, it is uncertain whether BTSS identifies IIHWOP in patients with chronic tension-type headache (CTTH): using cerebral MR venography this study aimed to address this question.In a prospective study from February 2002 to December 2006, 198 consecutive patients with CTTH underwent MR venography. Of these patients, 58 underwent lumbar puncture to measure cerebrospinal fluid (CSF) pressure. MR venography and lumbar puncture were also performed in 45 age-matched control subjects. BTSS was considered present when the signal flow was poor or lacking (flow gap) in the mid-lateral portion of both transverse sinuses. IIHWOP was diagnosed if the patient met the diagnostic criteria for idiopathic intracranial hypertension and did not have papilledema. Among the 198 patients with CTTH who underwent MR venography, 18 (9%) had BTSS. Thirteen of these 18 patients with BTSS underwent lumbar puncture, and nine (69.2%) had IIHWOP. CSF opening pressure was normal in all 45 patients as well as in all 45 controls with normal MR venography.These data suggest that BTSS on MR venography is associated with increased intracranial pressure in the absence of papilledema in patients with headache mimicking CTTH.

Mutations in the SPG4 gene are the most common causes of hereditary spastic paraplegia (HSP) accounting for up to 40% of autosomal dominant (AD) forms and 12-18% of sporadic cases. The phenotype associated with HSP due to mutations in the SPG4 gene tends to be pure. There is increasing evidence, however, of patients with complicated forms of spastic paraplegia in which SPG4 mutations were identified. A cohort of 38 unrelated Italian patients with spastic paraplegia, of which 24 had a clear dominant inheritance and 14 were apparently sporadic, were screened for mutations in the SPG4 gene.We identified 11 different mutations, six of which were novel (p.Glu143GlyfsX8, p.Tyr415X, p.Asp548Asn, c.1656_1664delinsTGACCT, c.1688-3C>G and c.*2G>T) and two exon deletions previously reported. The overall rate of SPG4 gene mutation in our patients was 36.8% (14/38); in AD-HSP we observed a mutation frequency of 45.8% (11/24), in sporadic cases the frequency was 21.4% (3/14). Furthermore, we found a mutational rate of 22.2% (2/9) and 41.4% (12/29) in the complicated and pure forms, respectively. The results underlie the importance of genetic testing in all affected individuals.

Objective The objective of this article is to determine whether cutaneous allodynia (CA) influences the response to treatment with occipital transcutaneous electrical stimulation (OTES) in chronic migraine (CM) and chronic tension-type headache (CTTH). Methods One hundred and sixty consecutive patients with CM or CTTH were randomized to be treated with real or sham OTES stimulation three times a day for two consecutive weeks. All patients completed the validated 12-item allodynia symptom checklist for assessing the presence and the severity of CA during headache attack. Primary end-point was change (≥50%) in number of monthly headache-free days. Results There was a significant difference in the percentage of responders in the real OTES compared with sham OTES group ( p Conclusions Severe CA is associated with decreased response to treatment with OTES in patients with CM and CTTH.

A 70-year-old woman presented with a 2-year history of progressive difficulty in walking with frequent falls. Neurologic examination showed postural instability with backward falls, vertical supranuclear gaze palsy with normal vestibular-ocular reflex, rigidity, and pyramidal signs in the right limbs. There was no clinical response to levodopa. Laboratory serologic tests had normal results. MRI displayed midbrain compression and dislocation caused by a large tumor in the left lateral ventricle (figure). Dopamine transporter SPECT showed normal striatal binding. The patient died before neurosurgery could be performed; there was no autopsy. Brain tumors should be considered in the diagnostic workup(1) of progressive supranuclear palsy-like phenotypes.

Hereditary motor and sensory neuropathy (HMSN) with focally folded myelin sheaths, or Charcot-Marie-Tooth type 4B (CMT4B), is a distinct clinical entity belonging to the heterogeneous group of autosomal recessive demyelinating neuropathies. We first described a large pedigree with CMT4B, which showed a high consanguinity level and an autosomal recessive pattern of inheritance. Through conventional linkage analysis, we excluded linkage of the locus segregating in this pedigree to any of the known genes responsible for other HMSNs. Using homozygosity mapping and haplotype sharing analysis, we were able to localize the disease gene in a 4 cM interval on chromosome 11q23, between the D11S1332 and D11S917 loci. On the basis of the clinical characteristics of the disease, we propose that this locus corresponds to the CMT4B gene.

A 65-year-old woman presented with chronic lingering headache and REM sleep behavior disorder (RBD). Head MRI (figure) showed spontaneous intracranial hypotension (SIH) with deep brain swelling (DBS),1 and CSF opening pressure was low. She was treated with lumbar epidural blood patch. Within 3 months, she became asymptomatic with improvement of brain sagging. Since SIH with DBS is related to brain sagging with deformity of the diencephalon and midbrain and since focal brain lesions may cause RBD,2 distortion and dysfunction of REM sleep circuits in this patient may be caused by DBS. RBD expands the clinical spectrum of SIH.

Fused in sarcoma (FUS) or translocation in liposarcoma (TLS), a DNA/RNA-binding protein, causes a dominant autosomal inherited form of amyotrophic lateral sclerosis (ALS), ALS 6. Its main role in neurodegeneration is highlighted by the presence of cytoplasmic accumulation of its mutant protein form in ALS patients. To further define the frequency and spectrum of FUS gene mutations, we have performed a molecular screening of a cohort of 327 Italian patients from Southern Italy with sporadic ALS (SALS). We identified 4 patients carrying 3 different missense mutations and several polymorphisms. Two different substitutions occurring in the same amino acidic position have been observed in 2 patients: R521G and R521C respectively; P525L mutation has been found in 2 additional cases. Most of the patients with FUS mutations showed early symptom onset and had short disease survival. We also detected 4 different polymorphic variants (3=-untranslated region [UTR] variant, c.*41G.A; c.52313ins[GAGGTG]; c.335-15del[TTTT]; and rs13331793) in 9 patients from within our cohort. This study underlines the importance of population-based mutation screening of newly identified genes. © 2011 Elsevier Inc. All rights reserved.

Objective: Recent evidence suggests that intermediate-length polyglutamine (PolyQ) expansions in the ataxin-2 ( ATXN-2 ) gene are a risk factor for amyotrophic lateral sclerosis (ALS). This work was undertaken with the aim to investigate the frequency of ataxin-1 ( ATXN-1 ) and ATXN-2 PolyQ expansions in a cohort of patients with sporadic ALS (sALS) and patients with familial ALS (fALS) from southern Italy. Methods: We assessed the PolyQ lengths of ATXN-1 and ATXN-2 in 405 patients with sALS, 13 patients with fALS, and 296 unrelated controls without history of neurodegenerative disorders. Results: We found significantly higher intermediate PolyQ expansions ≥32 for ATXN-1 alleles and ≥28 for ATXN-2 alleles in the sALS cohort ( ATXN-1 : ALS, 7.07% vs controls, 2.38%; p = 0.0001; ATXN-2 : ALS, 2.72% vs controls, 0.5%; p = 0.001). ATXN-1 CAT and ATXN-2 CAA interruptions were detected in patients with ALS only. Age at onset, site of onset, and sex were not significantly related to the ATXN-1 or ATXN-2 PolyQ repeat length expansions. Conclusions: Both ATXN-1 and ATXN-2 PolyQ intermediate expansions are independently associated with an increased risk for ALS.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies. The underlying mutations in demyelinating forms tend to affect genes expressed in Schwann cells (CMT types 1, 3, and 4), while axonal forms of the disease usually have their origins in genes expressed in the affected neurons (CMT type 2). Repeated rounds of nerve degeneration and regeneration characterize CMT2, but evidence for regeneration has not been demonstrated at a molecular level. Subtractive hybridization was performed on sural nerve biopsies from a patient presenting an axonal form of CMT and an unaffected sibling, which revealed an overexpression of genes associated with the regeneration of axons, including PMP22, SPARC/osteonectin, CD9, CD44, EEF1A1, and gamma-actin. These results suggest that axonal degeneration elicits a regeneration transcriptional response in the surrounding Schwann cells. This response contrasts with other neurodegenerative diseases, in which programmed cell death or an inappropriate immune response are activated. Additionally, Lamin A/C, which is mutated in CMT2B1, was overexpressed in the patient, suggesting that CMT-causing genes may interact in a regulatory network.

Mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have been reported to cause adult-onset autosomal dominant amyotrophic lateral sclerosis (FALS). In sporadic cases (SALS), de novo mutations in the SOD1 gene have occasionally been observed. All the SOD1 mutations are autosomal dominantly inherited with the exception of D90A. To date, in Italy, only two sporadic ALS cases carrying the D90A mutation have been reported in a homozygous state. We investigated for the presence of this mutation in 169 unrelated ALS patients from southern Italy. The genetic analysis revealed three ALS patients (1.8%) with mild phenotype carrying the homozygous D90A mutation.

For proteomic analysis, sample preparation plays a crucial role in two-dimensional gel electrophoresis (2DE), since, very often, each tissue or cell culture requires specific treatments. In the present paper, we report a sample preparation procedure suitable for 2DE that was done on peripheral nerve using bovine sciatic nerves and human sural nerve biopsies. We obtained an appreciable reduction of tissue heterogeneity using protein extracts obtained from nerve-fiber bundles instead of the entire nerve. In addition, we optimized 2DE protein separation using a combination of CHAPS, Triton X-100, and SB3-10 detergents in an isoelectric-focusing (IEF) buffer. The reported experimental procedures appear to be essential for 2DE separation of peripheral nerve proteins for the establishment of a reference map.

Cerebral venous outflow abnormalities, as transverse sinuses (TSs) stenosis,may underlie a picture of idiopathic intracranial hypertension (IIH). To identify the best non–invasive MR venography (MRV) technique for exploring the disturbance of flow of TSs in IIH patients, we compared threedimensional phase contrast (3–DPC) MRV images, acquired with different velocity encodings (15 and 40 cm/s) with two–dimensional time–of–flight (2D–TOF) MR images in 6 subjects with IIH and 12 age–matched normal controls. In both groups, we also measured flow velocity in TSs by using single slice 2D–CINE PC acquisitions. In all subjects with IIH, 3D-PC showed marked flow disturbance in the mid–lateral portion of both TSs when velocity encoding (VENC) was set to 15 cm/s while only a slightly irregular flow in TSs was detected when VENC was set to 40 cm/s or when 2D–TOF was used. By contrast, 3D–PC (VENC 15 and 40) and 2D–TOF techniques were comparable in detecting TS signal flow in normal controls. Measures of flow velocity, by using 2D-CINE PC, revealed a three–fold increase of velocity at the level of the flow disturbance in IIH patients compared to normal controls (p < 0.0001), suggesting a marked stenosis of mid–lateral portion of TSs in these patients. Setting the VENC to 15 cm/s on 3D–PC MRV may represent the best technical approach for visualizing disturbances of flow in TSs in subjects with symptoms suggestive of IIH.

Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying the most common haplogroup, H (odds ratio 0.08, 95% confidence interval 0.04-0.4, p < 0.01). Further stratification of the dataset by sex, age and site of onset of disease and survival failed to reach significance for association. Our study provides evidence of the contribution of mitochondrial variation to the risk of ALS development in Caucasians. Further it may help elucidate the mechanism of the mitochondrial dysfunction detectable in ALS, and may be of relevance in development of strategies for the treatment of this disease.

Objectives - The APOE gene polymorphism and the -491 A/T polymorphism in its regulatory region have been associated with an increased risk for developing Alzheimer's disease. We examined these polymorphisms in multiple sclerosis (MS) patients, to determine if a genetic predisposition may explain the risk for developing cognitive decline in MS. Material and methods - Eighty-nine relapsing-remitting and secondary progressive MS patients underwent to a full neuropsychological battery as well as to determination of APOE and -491 A/T polymorphisms. Genetic analysis was also performed in 107 population controls. Results - The APOE polymorphism was not associated with the risk of cognitive impairment in MS patients. The AA genotype of the -491 A/T polymorphism in the APOE regulatory region was more frequent in cognitively impaired than in cognitively preserved MS subjects. Conclusion - The AA homozygous state of the -491 A/T polymorphism of the APOE regulatory region is associated with cognitive impairment in patients with MS.