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Background and purpose : Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus-based diagnostic criteria (AE-DC) allow clinic-serological subgrouping of AE, with unclear prognostic implications. The impact of AE-DC on patients’ management was studied, focusing on the subgroupofAb-negative-AE. Methods: This was a retrospective multicenter study on patients fulfilling AE-DC. All patients underwent Ab testing with commercial cell-based assays (CBAs) and, when available, in-house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab-positive-AE [N-methyl-d-aspartate-receptor encephalitis (NMDAR-E), Ab-positive limbic encephalitis (LE), definite-AE] or Ab-negative-AE (Ab-negative-LE, probable-AE, possible-AE). Results: Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab-negative cases, in-house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE-DC, 81 (68.6%) with Ab-positive-AE (Ab-positive-LE, 40; NMDAR-E, 32; definite-AE, nine) and 37 (31.4%) with Ab-negative-AE (Ab-negative-LE, 17; probable/possible-AE, 20). Clinical phenotypes were similar in Ab-positive-LE versus Ab-negative-LE. Twenty-four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab-positive or Ab-negative. Ab-positive-AE patients were treated earlier than Ab-negative-AE patients (P=0.045), responded more frequently to treatments (92.3% vs. 65.6%, P&nbsp

Objective: To investigate the mechanism subtending the analgesic effect of high frequency non-painful somatosensory stimulation. Methods: Laser evoked potentials (LEPs) and laser-pain rating were obtained from healthy subjects to stimulation of different parts of the body. LEPs were recorded at baseline and during non-painful electrical stimulation of the superficial branch of the right radial nerve (RRES). Results: RRES reduced N2/P2 LEP amplitude to right radial (F(8,10) = 82.4, p < 0.001), left radial (F(8,10) = 22.2, p < 0.001), and right ulnar (F(8,10) = 7.2, p = 0.008) stimulation, while the N2/P2 amplitude to left ulnar territory stimulation remained unchanged (F(8,10) = 3.6, p = 0.07). The laser-pain rating was reduced by RRES to bilateral radial territory stimulation (p < 0.05). In a control experiment, laser-pain rating and LEPs to left foot stimulation were not modified by RRES (p > 0.05). Conclusions: Our study confirms that the non-nociceptive afferents dampen the nociceptive input. The spatial pattern of this interaction suggests that, when conditioning higher frequency non-painful stimulation is used, the inhibition takes place at the spinal cord. Significance: Our experimental design reproduces what happens when non-painful somatosensory stimuli are used to reduce pain, such as rubbing a wound or during transcutaneous electrical nerve stimulation. Therefore, in these situations the analgesia is likely to occur at the spinal cord level.

Autoimmune encephalitis (AIE) can produce a very wide range of neuropsychiatric symptoms. A major challenge in diagnosis is that different symptoms may appear at different times and different levels of intensity, so the disease may mimic many other disorders. Pathogenesis is likely to be mediated by antibodies (Abs) to CNS proteins. This article focuses on recent clinical advances, newly characterized Abs, and treatment approaches to these disorders.

Background Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) have been recently reevaluated as a biomarker of acquired demyelinating syndromes (ADS) of the central nervous system (CNS). Here, we describe the clinical and neuroimaging features, and the long-term outcome of children with ADS of the CNS associated with MOG-IgG. Methods All patients underwent brain and spinal cord magnetic resonance imaging (MRI), lumbar puncture for cerebrospinal fluid (CSF) analysis and MOG-IgG and aquaporin-4 IgG (AQP4-IgG) testing. Results Forty-eight pediatric patients were recruited. MOG-IgG were detected in 11/48 (25%) patients with the following clinical presentations: encephalomyelitis (EM), 8/11 (73%); optic neuritis (ON), 2/11 (18%); transverse myelitis (TM), 1/11 (9%). Patients negative for MOG-IgG were diagnosed with Multiple Sclerosis (MS) (n=15), EM (n=7), ON (n=7), neuromyelitis optica spectrum disorders (NMOSD) (n=5), TM (n=2) and encephalitis (n=1). MOG-IgG positive patients were younger at disease onset and they more frequently experienced encephalopathy and epileptic seizures compared with negative patients. EM and inflammatory lesions involving optic nerves on MRI imaging were more frequent in MOG-IgG positive patients. None of the patients with MOG-IgG became persistently seronegative during the follow-up, although a decrease in MOG-IgG titer was observed. Patients with MOG-IgG showed a good response to therapy and only two patients presented relapses during follow-up. Conclusion This study supports the distinction of MOG autoimmune oligodendrocytopathy as a unique disease entity, with clinical features different from those of MS and AQP4-IgG-positive NMOSD.

The link between migraine and nutrition can be explored from several points of view. Lifestyle and, in particular, aspects of nutrition can have a significant impact on the course of pediatric migraine. In addition, some dietary treatments, such as the ketogenic diet, and some active ingredients present in foods (nutraceuticals) may have a therapeutic effect on migraine. A diet that can control weight gain and obesity has beneficial effects on migraine severity. On the other hand, when we talk about the link between nutrition and headaches, it is also necessary to point out that some public information is actually fake news that has no scientific basis. The purpose of this review is to provide an update on the salient points linking pediatric migraine to nutritional principles, focusing on the relationship between weight and headaches, the therapeutic effect of food for medical purposes, the ketogenic diet as a migraine treatment, and the relationship between migraine and dietary habits.

Background Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA). Methods We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy. Results De novo missense mutations of CACNA1A were found in four patients (4/48, ∼8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases. Conclusion Our results expand the clinical and mutational spectrum of CACNA1A -related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias.

Restless legs syndrome (RLS) is characterized by unpleasant sensations generally localized to legs, associated with an urge to move. A likely pathogenetic mechanism is a central dopaminergic dysfunction. The exact role of pain system is unclear. The purpose of the study was to investigate the nociceptive pathways in idiopathic RLS patients. We enrolled 11 patients (mean age 53.2 ± 19.7 years; 7 men) suffering from severe, primary RLS. We recorded scalp laser-evoked potentials (LEPs) to stimulation of different sites (hands and feet) and during two different time conditions (daytime and nighttime). Finally, we compared the results with a matched control group of healthy subjects. The Aδ responses obtained from patients did not differ from those recorded from control subjects. However, the N1 and the N2-P2 amplitudes’ night/day ratios after foot stimulation were increased in patients, as compared to controls (N1: patients: 133.91 ± 50.42%; controls: 83.74 ± 34.45%; p=0.016; Aδ-N2-P2: patients: 119.15 ± 15.56%; controls: 88.42 ± 23.41%; p=0.003). These results suggest that RLS patients present circadian modifications in the pain system, which are not present in healthy controls. Both sensory-discriminative and affective-emotional components of pain experience show parallel changes. This study confirms the structural integrity of Aδ nociceptive system in idiopathic RLS, but it also suggests that RLS patients present circadian modifications in the pain system. These findings could potentially help clinicians and contribute to identify new therapeutic approaches.

Background and aim Episodic syndromes that may be associated with migraine are a group of disorders affecting patients with migraine or with an increased risk of presenting it, and likely represent an early life expression of migraine. Cyclic vomiting syndrome and benign paroxysmal torticollis are well characterized and represent a frequent cause of request for specialist consultations. The aim of this study is to longitudinally assess the rate of headache in patients presenting with cyclic vomiting syndrome and benign paroxysmal torticollis during infancy, and to define the main clinical features of the disorder. Methods We administered a questionnaire to the parents of all our pediatric patients with previous diagnosis of cyclic vomiting syndrome and/or benign paroxysmal torticollis according to ICHD-3; questions were focused on the main clinical features of the disorder as well as the prognosis, with particular emphasis on the development of headache. Results For the final analysis we considered 82 patients with cyclic vomiting syndrome and 33 with benign paroxysmal torticollis. Seventy-nine percent of patients with cyclic vomiting syndrome presented with headache during the follow-up, with a mean age at onset of 6 years; 67% of patients with benign paroxysmal torticollis suffered from headache during the follow-up, with a mean age at onset of 5 years. Discussion Cyclic vomiting syndrome and benign paroxysmal torticollis are associated with a very high risk of developing headache, mostly migraine, later in life. In both groups of patients, the vast majority presented with different episodic syndromes that may be associated with migraine at different ages, thus suggesting an age-dependent evolution of migraine-like symptoms before the onset of clear migrainous headache.

Phantom limb pain (PLP) is a disabling and intractable sensation arising in about 80% of patients after amputation. The aim of this study was to evaluate the possibility to modulate nociceptive processing and pain perception with cerebellar transcranial direct current stimulation (ctDCS) in patients suffering from painful and non-painful phantom limb sensations. Fourteen upper limb amputees underwent ctDCS (anodal or sham, 2.0 mA, 20 min per day, 5 days a week). Clinical scores and electrophysiological parameters were assessed before tDCS, at the end of the 5-day treatment, 2 and 4 weeks later. Laser-evoked potentials (LEPs) were obtained from the stump using a Nd:YAP laser by pulses with short duration (5 ms) and small diameter spots (5 mm). Changes in visual analogue scores (VAS) were evaluated (chronic pain, paroxysmal pain, stump pain, phantom movements, phantom sensations). Anodal polarization significantly dampened LEP amplitudes (N1, p = 0.021 and N2/P2, p = 0.0034), whereas sham intervention left them unchanged. Anodal ctDCS significantly reduced paroxysmal pain (p

Introduction Several observations would suggest that dystonic pain is not simply muscular in origin. While ascending nociceptive pathways are normal in cervical dystonia, it is unknown whether descending inhibitory pain pathways are also normal. Methods We applied a conditioned pain modulation protocol and concomitantly recorded laser evoked potentials in patients with cervical dystonia (n = 15), blepharospasm (n = 15) and healthy volunteers (n = 15). Results During the application of a heterotopic noxious conditioning stimulation, patients with cervical dystonia, but not with blepharospasm, lacked the physiological reduction of the perceived intensity of a painful test stimulus as well as of the related evoked potential. This was observed in cervical dystonia patients regardless of the presence of clinical pain. Conclusions Our results suggest that pain in CD is not simply muscular in origin but it also possibly reflects a dysfunction of the descending pain inhibitory control, thus providing a novel venue to explore the pathophysiology of pain in CD.

Background: Data on clinical presentation of Hemiplegic Migraine (HM) are quite limited in the literature, particularly in the pediatric age. The aim of the present study is to describe in detail the phenotypic features at onset and during the first years of disease of sporadic (SHM) and familial (FHM) pediatric hemiplegic migraine and to review the pertinent literature. Results: Retrospective study of a cohort of children and adolescents diagnosed with hemiplegic migraine, recruited from 11 Italian specialized Juvenile Headache Centers. Forty-six cases (24 females) were collected and divided in two subgroups: 32 SHM (16 females), 14 FHM (8 females). Mean age at onset was 10.5 ± 3.8 y (range: 2–16 y). Mean duration of motor aura was 3.5 h (range: 5 min−48 h). SHM cases experienced more prolonged attacks than FHM cases, with significantly longer duration of both motor aura and of total HM attack. Sensory (65%) and basilar-type auras (63%) were frequently associated to the motor aura, without significant differences between SHM and FHM. At follow-up (mean duration 4.4 years) the mean frequency of attacks was 2.2 per year in the first year after disease onset, higher in FHM than in SHM cases (3.9 vs. 1.5 per year, respectively). A literature review retrieved seven studies, all but one were based on mixed adults and children cohorts. Conclusions: This study represents the first Italian pediatric series of HM ever reported, including both FHM and SHM patients. Our cohort highlights that in the pediatric HM has an heterogeneous clinical onset. Children present fewer non-motor auras as compared to adults and in some cases the first attack is preceded by transient neurological signs and symptoms in early childhood. In SHM cases, attacks were less frequent but more severe and prolonged, while FHM patients had less intense but more frequent attacks and a longer phase of active disease. Differently from previous studies, the majority of our cases, even with early onset and severe attacks, had a favorable clinical evolution.

To improve patient care and help clinical research, the Neuropathic Pain Special Interest Group of the Italian Neurological Society appointed a task force to elaborate a consensus statement on pharmacoresistant neuropathic pain. The task force included 19 experts in neuropathic pain. These experts participated in a Delphi survey consisting of three consecutive rounds of questions and a face-to-face meeting, designed to achieve a consensus definition of pharmacoresistant neuropathic pain. In the three rounds of questions, the participants identified and described the main distinguishing features of pharmacoresistance. In the face-to-face meeting the participants discussed the clinical features determining pharmacoresistance. They finally agreed that neuropathic pain is pharmacoresistant when "the patient does not reach the 50% reduction of pain or an improvement of at least 2 points in the Patient Global Impression of Change, having used all drug classes indicated as first, second, or third line in the most recent and widely agreed international guidelines, for at least 1 month after titration to the highest tolerable dose." Our consensus statement might be useful for identifying eligible patients for invasive treatments, and selecting patients in pharmacological trials, thus improving patient care and helping clinical research.

Background/Objective: The aim of the study was to estimate the rate of evolution or for multiple sclerosis (MS), after a first acute demyelinating event (ADE) in pediatric patients, and to investigate the variables that predict this evolution. Methods: We retrospectively evaluated the clinical and neuroradiological features of children who presented a first ADE between January 2005 and April 2017. All patients included underwent a baseline MRI, a cerebrospinal fluid and blood analysis, including virological examinations. The evolution into MS was determined by the 2013 International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria. Clinical and radiological features predictive of MS were determined using multivariate analyses. Results: Ninety-one patients were selected (mean age at onset: 10.11 ± 4.6). After a mean follow-up of 5.6 ± 2.3 years, 35% of patients' conditions evolved to MS. In the logistic multivariate analysis of clinical and laboratory data, the best predictors of evolution into MS were: the presence of oligoclonal bands in CSF (p < 0.001), past infection with EBV (p < 0.001), periventricular lesions (p < 0.001), hypointense lesions on T1 (p < 0.001), and lesions of the corpus callosum (p < 0.001) including Dawson fingers (p < 0.001). Conclusion: Our findings suggest that a pattern of neuroimaging and laboratory findings may help to distinguish between, at clinical onset, children with a monophasic syndrome (clinically isolated syndrome or acute disseminated encephalomyelitis) from those who will develop MS.

Introduction: Neurodegenerative diseases are increasing in parallel to the lengthening of survival. The management of Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, and motor neuron diseases (MND), is mainly targeted to motor and cognitive impairment, with special care for vital functions such as breathing and feeding.Areas covered: The present review focuses on chronic pain in main neurodegenerative diseases, addressing current evidence on pain therapeutic management, pain frequency and clinical features, and possible pathophysiological mechanisms. The search on PubMed had no time limits and was performed by searching for the following key issues: pain, dementia, Alzheimer disease, Parkinson's disease, extrapyramidal disorders, motoneuronal disease, Amyotrophic lateral sclerosis, FXTAS, frequency, pathophysiology, treatments, therapy, efficacy, opioids, side effects. No controlled therapeutic trials and guidelines are currently available. The effects of current therapies such as L-Dopa or riluzole on pain symptoms are not clear. Emerging evidences on the possible anti-nociceptive effects of cannabis or botulinum toxin might be available soon.Expert commentary: Pain needs to be better evaluated and fully considered in the global management of neurodegenerative disease because a more focused treatment may have a positive impact on the global burden of these devastating disorders.

INTRODUCTION Cold-induced sweating syndrome type 1 (CISS1), is a rare, severe, autosomal recessive disease. It is characterized by morphological alterations and profuse sweating when ambient temperature is

Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; HE Gd, gadolinium.

Introduction: Chronic headaches are not a rare condition in children and adolescents with negative effects on their quality of life. Our aims were to investigate the clinical features of chronic headache and usefulness of the International Classification of Headache Disorders 3rd edition (ICHD 3) criteria for the diagnosis in a cohort of pediatric patients. Methods: We retrospectively reviewed the charts of patients attending the Headache Center of Bambino Gesù Children and Insubria University Hospital during the 2010-2016 time interval. Statistical analysis was conducted to study possible correlations between: (a) chronic primary headache (CPH) and demographic data (age and sex), (b) CPH and headache qualitative features, (c) CPH and risk of medication overuse headache (MOH), and (d) CPH and response to prophylactic therapies. Moreover, we compared the diagnosis obtained by ICHD 3 vs. ICHD 2 criteria Results: We included 377 patients with CPH (66.4% females, 33.6% males, under 18 years of age). CPH was less frequent under 6 years of age (0.8%; p < 0.05) and there was no correlation between age/sex and different CPH types. The risk to develop MOH was higher after 15 years of age (p < 0.05). When we compared the diagnosis obtained by ICHD 2 and ICHD 3 criteria we found a significant difference for the undefined diagnosis (2.6% vs. 7.9%; p < 0.05), while the diagnosis of probable chronic migraine was only possible by using the ICHD2 criteria (11.9% of patients; p < 0.05). The main criterion which was not satisfied for a definitive diagnosis was the duration of the attacks less than 2 h (70% of patients younger than 6 years; p < 0.005). Amitriptyline and topiramate were the most effective drugs (p < 0.05), although no significant difference was found between them (p > 0.05). Conclusion: The ICHD 3 criteria show limitations when applied to children under 6 years of age. The risk of developing MOH increases with age. Although our "real word" study shows that amitriptyline and topiramate are the most effective drugs regardless of the CPH type, the lack of placebo-controlled data and the limited follow-up results did not allow us to conclude about the drug efficacy.

Background In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported. Aim The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population. Results We included 164 patients who experienced aura associated with headache (mean age 9.92 ± 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks). Conclusion Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents.

Stiff person syndrome (SPS) is an autoimmune disorder with multiple clinical presentations, all characterized by generalized or focal muscular stiffness leading to abnormal postures and movements. To date, no standardized treatments are available; also, the outcome measures are mainly clinical based and unstandardized, limiting the reliability of clinical trials. In this case study, we used the eight-camera motion capture system for gait analysis (GA) to outline the gait features and track the clinical evolution of a young patient with SPS receiving a personalized multimodal therapy. GA was accurate in reflecting clinical changes over a 7-week-long period, thus representing a potential source for objective biomarkers in SPS. Therefore, future studies focusing on either the natural history or the treatment of SPS could adopt GA for reliable outocome measures, confirming this preliminary observation.

Rationale: Spinal cord stimulation (SCS) is an effective option for neuropathic pain treatment. New technological developments, as high-frequency (HF) and theta burst stimulation (TBS), have shown promising results, although putative mechanisms of action still remain debated. Methods: thirty patients with lower back pain were enrolled and underwent LF, HF, and TBS. Laser evoked potentials (LEPs) were recorded by using a Nd:YAG laser. Amplitudes and latencies of the main two components (N1, N2/P2) were compared among different experimental sessions. Changes in resting motor threshold (RMT), cortical silent period (cSP), short intracortical inhibition (SICI), and intracortical facilitation (ICF) were also evaluated. Results: TBS dampened LEP amplitudes compared with LF (N1: p = 0.032; N2/P2: p < 0.0001) and HF stimulation (N1: p = 0.029; N2/P2: p < 0.0001, Holm-Sidak post-hoc test). Concurrently, TBS increased N1 latency, when compared with baseline and LF stimulation (p = 0.009 and 0.0033). Whereas RMT and SICI did not change among experimental conditions, TBS significantly prolonged cSP duration compared with baseline (p = 0.002), LF (p = 0.048), and HF-SCS (p = 0.016); finally, both HF (p = 0.004) and TBS (p = 0.0039) increased ICF. Conclusion: TBS modulates medial and lateral pain pathways through distinct mechanisms, possibly involving both GABA(a)ergic and Glutamatergic networks at an intracortical level. These results may have implications for therapy and for the choice of best stimulation protocol.

ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.

Introduction: A growing body of literature has shown an association between somatic symptoms and insecure "attachment style." In a recent study, we found a relationship between migraine severity, ambivalent attachment style, and psychological symptoms in children/adolescents. There is evidence that caregivers' attachment styles and their way of management/expression of emotions can influence children's psychological profile and pain expression. To date, data dealing with headache are scarce. Our aim was to study the role of maternal alexithymia and attachment style on their children's migraine severity, attachment style, and psychological profile. Materials and methods: We enrolled 84 consecutive patients suffering from migraine without aura (female: 45, male: 39; mean age 11.8 ± 2.4 years). According to headache frequency, children/adolescents were divided into two groups: (1) high frequency (patients reporting from weekly to daily attacks), and (2) low frequency (patients having =3 episodes per month). We divided headache attacks intensity into two groups (mild and severe pain). SAFA "Anxiety," "Depression," and "Somatization" scales were used to explore children's psychological profile. To evaluate attachment style, the semi-projective test SAT for patients and ASQ Questionnaire for mothers were employed. Maternal alexithymia traits were assessed by TAS-20. Results: We found a significant higher score in maternal alexithymia levels in children classified as "ambivalent," compared to those classified as "avoiding" (Total scale: p = 0.011). A positive correlation has been identified between mother's TAS-20 Total score and the children's SAFA-A Total score (p = 0.026). In particular, positive correlations were found between maternal alexithymia and children's "Separation anxiety" (p = 0.009) and "School anxiety" (p = 0.015) subscales. Maternal "Externally-oriented thinking" subscale correlated with children's school anxiety (p = 0.050). Moreover, we found a correlation between TAS-20 Total score and SAFA-D "Feeling of guilt" subscale (p = 0.014). Our data showed no relationship between TAS-20 and ASQ questionnaires and children's migraine intensity and frequency. Conclusion: Maternal alexithymia and attachment style have no impact on children's migraine severity. However, our results suggest that, although maternal alexithymic traits have no causative roles on children's migraine severity, they show a relationship with patients' attachment style and psychological symptoms, which in turn may impact on migraine severity.

Background: Transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is benign and self-limited, with neurologic deficits including sensory disturbance of one body side, aphasia, nausea/vomiting, weakness, decreased vision, homonymous hemianopsia, photophobia. Acute confusional state can rarely occur. Papilledema and intracranial hypertension have also been described. It is a rare entity mainly affecting adults; however, it has been sporadically described in children and adolescents. Main findings: In this clinical observational study, we describe a clinical series of three consecutive pediatric patients being diagnosed with HaNDL after presenting with altered consciousness, papilledema, and increased intracranial pressure. They all recovered without relapses. Conclusion: Presentation during childhood and adolescence is rare; the majority of pediatric cases presented with altered consciousness, which is infrequent in HaNDL. This may suggest that in childhood this symptom might be more common than in adults. All three patients presented with increased intracranial pressure and papilledema, thus suggesting that these aspects should be investigated in all patients presenting with this clinical pattern. Finally, all our patients began to suffer from migraine. This feature, together with the benign course of the disease, could favor the hypothesis of a migrainous pathophysiology of this syndrome, although this remains a speculative.

Aims The cortical response to nociceptive thermal stimuli recorded as contact heat evoked potentials (CHEPs) may be altered by morphine. However, previous studies have averaged CHEPs over multiple stimuli, which are confounded by jitter between sweeps. Thus, the aim was to assess single-sweep characteristics to identify alterations induced by morphine. Methods In a crossover study 15 single-sweep CHEPs were analyzed from 62 electroencephalography electrodes in 26 healthy volunteers before and after administration of morphine or placebo. Each sweep was decomposed by a continuous wavelet transform to obtain normalized spectral indices in the delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–32 Hz) and gamma (32–80 Hz) bands. The average distribution over all sweeps and channels was calculated for the four recordings for each volunteer, and the two recordings before treatments were assessed for reproducibility. Baseline corrected spectral indices after morphine and placebo treatments were compared to identify alterations induced by morphine. Results Reproducibility between baseline CHEPs was demonstrated. As compared with placebo, morphine decreased the spectral indices in the delta and theta bands by 13% (P = 0.04) and 9% (P = 0.007), while the beta and gamma bands were increased by 10% (P = 0.006) and 24% (P = 0.04). Conclusion The decreases in the delta and theta band are suggested to represent a decrease in the pain specific morphology of the CHEPs, which indicates a diminished pain response after morphine administration. Hence, assessment of spectral indices in single-sweep CHEPs can be used to study cortical mechanisms induced by morphine treatment.

Background: The 2013 International Classification of Headache Disorders-3 was published in a beta version to allow clinicians to confirm the validity of the criteria or suggest improvements based on field studies. The aim of this work was to review the Secondary Headache Disorders and Cranial Neuralgias and Other Headache Disorders sections of ICHD-3 beta data on children and adolescents (age 0–18 years) and to suggest changes, additions, and amendments. Methods: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the available literature on pediatric headache, they made observations and proposed suggestions for the mentioned headache disorders on children and adolescents. Results: Some headache disorders in children have specific features, which are different from adults that should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psychosocial basis in children and adolescents making primary headache disorders in children distinct from those in adults. Conclusions: Several recommendations are presented in order to make ICHD-3 more appropriate for use in children.

Background: The 2013 International Classification of Headache Disorders-3 (ICHD-3) was published in a beta version to allow the clinicians to confirm the validity of the criteria or to suggest improvements based on field studies. The aim of this work was to review the Primary Headache Disorders Section of ICHD-3 beta data on children and adolescents (age 0-18 years), and to suggest changes, additions, and amendments. Methods: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the literature available on pediatric headache, they made observations and proposed suggestions for the primary headache disorders section of ICHD-3 beta data on children and adolescents. Results: Some headache disorders in children have specific features which are different from those seen in adults and which should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psycho-social basis in children and adolescents making primary headache disorders in children distinct from those in adults. Conclusions: Several recommendations are presented in order to make ICHD-3 more appropriate for use with children.

Background Criteria defined by the International headache Society are commonly used for the diagnosis of the different headache types in both adults and children. However, some authors have stressed some limits of these criteria when applied to preschool age. Objective Our study aimed to describe the characteristics of primary headaches in children younger than 6 years and investigate how often the International Classification of Headache Disorders (ICHD) criteria allow a definitive diagnosis. Methods This retrospective study analysed the clinical feature of 368 children younger than 6 years with primary headache. Results We found that in our patients the percentage of undefined diagnosis was high when either the ICHD-II or the ICHD-III criteria were used. More than 70% of our children showed a duration of their attacks shorter than 1 hour. The absence of photophobia/phonophobia and nausea/vomiting significantly correlate with tension-type headache (TTH) and probable TTH. The number of first-degree relatives with migraine was positively correlated to the diagnosis of migraine in the patients ( p Conclusions Our study showed that the ICHD-III criteria are difficult to use in children younger than 6 years. The problem is not solved by the reduction of the lowest duration limit for the diagnosis of migraine to 1 hour, as was done in the ICHD-II.

Background In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE-PREPs) is still debated. Methods In this neurophysiological study we aimed at verifying the nociceptive specificity of SE-PREPs. We recorded LEPs, CHEPs and SE-PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin-induced nociceptive nerve fibre loss in the epidermis. Results We found that whereas LEPs and CHEPs were suppressed after capsaicin-induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE-PREPs. Conclusion The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE-PREP changes suggests that SE-PREPs do not provide selective information on nociceptive system function. Significance Capsaicin-induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain-related evoked potentials by surface concentric electrode (SE-PREPs). These findings suggest that unlike LEPs and CHEPs, SE-PREPs are not selectively mediated by nociceptive system.

Although the most widely agreed neurophysiological tool for investigating small fiber damage is laser-evoked potential (LEP) recording, no study has documented its diagnostic accuracy. In this clinical, neurophysiological, and skin biopsy study, we collected age-corrected LEP normative ranges, verified the association of LEPs with pinprick sensory disturbances in the typical diabetic mixed fiber polyneuropathy, and assessed the sensitivity and specificity of LEPs in diabetic small fiber neuropathy. From 288 LEP recordings from the face, hand, and foot in 73 healthy subjects, we collected age-corrected normative ranges for LEPs. We then selected 100 patients with mixed-fiber diabetic neuropathy and 25 patients with possible small-fiber diabetic neuropathy. In the 100 patients with mixed fiber neuropathy, we verified how LEP abnormalities were associated with clinically evident pinprick sensory disturbances. In the 25 patients with possible pure small fiber neuropathy, using the skin biopsy for assessing the intraepidermal nerve fiber density as a reference standard, we calculated LEP sensitivity and specificity. In healthy participants, age strongly influenced normative ranges for all LEP variables. By applying age-corrected normative ranges for LEPs, we found that LEPs were strongly associated with pinprick sensory disturbances. In relation to the skin biopsy findings, LEPs yielded 78% sensitivity and 81% specificity in the diagnosis of diabetic small fiber neuropathy. Our study, providing age-corrected normative ranges for the main LEP data and their diagnostic accuracy, helps to make LEPs more reliable as a clinical diagnostic tool, and proposes this technique as a less invasive alternative to skin biopsy for diagnosing diabetic small fiber neuropathy.

Frequent headache and juvenile fibromyalgia (JFM) are common conditions observed in childhood and adolescents. They can present in isolation or as comorbid conditions. There is no scientific literature investigating this association in adolescents or childhood. There is evidence in adults that headache, particularly migraine, can be a potential risk factor for developing fibromyalgia (FMS) and that migraine can be also a comorbid and perpetuating factor of FMS. Comorbidity between these two conditions can lead to increased levels of sensitization of the central nervous system and limit therapeutic approaches. Additionally, the presence of comorbid FMS and migraine is associated with worse clinical presentation and higher psychological disturbances. Early identification of risk factors for development of this comorbid association seems to be a challenge for pediatric clinicians.

OBJECTIVES: Many patients with painful chronic pancreatitis (CP) have insufficient effect of treatment, and the prevalence of adverse effects is high. Consequently, alternatives to conventional management are needed. We aimed to study the effect of acupuncture in painful CP.METHODS: This was a prospective, single-blinded, randomized crossover trial. Fifteen patients with CP were assigned to a session of acupuncture followed by sham stimulation or vice versa. Patients rated clinical pain scores daily on a 0 to 10 visual analogue scale (VAS) and completed the Patient Global Impression of Change. For mechanistic linkage, resting state electroencephalograms were recorded and quantified by spectral power analysis to explore effects on central pain processing.RESULTS: Acupuncture, compared with sham stimulation, caused more pain relief (2.0 ± 1.5 VAS vs 0.7 ± 0.8 VAS; P = 0.009). The effect, however, was short, and after 1-week follow-up, there was no difference in clinical pain scores between groups (P = 1.0) or the rating of Patient Global Impression of Change (P = 0.8). Electroencephalogram spectral power distributions between sham and acupuncture were comparable between groups (all P > 0.6).CONCLUSIONS: The study presents proof-of-concept for the analgesic effect of acupuncture in pancreatic pain. Although the effect was short lasting, the framework may be used to conceptualize future trials of acupuncture in visceral pain.

Aim The purpose of this retrospective multicenter study was to evaluate the use and the self-perceived efficacy and tolerability of pharmacological and non-pharmacological treatments in children and adolescents with primary headaches. Methods Study of a cohort of children and adolescents diagnosed with primary headache, consecutively referred to 13 juvenile Italian Headache Centers. An ad hoc questionnaire was used for clinical data collection. Results Among 706 patients with primary headaches included in the study, 637 cases with a single type of headache (migraine 76% – with and without aura in 10% and 67% respectively; tension-type headache 24%) were selected (mean age at clinical interview: 12 years). Acetaminophen and non-steroidal anti-inflammatory drugs (in particular ibuprofen) were commonly used to treat attacks, by 76% and 46% of cases respectively. Triptans were used overall by 6% of migraineurs and by 13% of adolescents with migraine, with better efficacy than acetaminophen and non-steroidal anti-inflammatory drugs. Preventive drugs were used by 19% of migraineurs and by 3% of subjects with tension-type headache. In migraineurs, flunarizine was the most frequently used drug (18%), followed by antiepileptic drugs (7%) and pizotifen (6%), while cyproheptadine, propanolol and amitriptyline were rarely used. Pizotifen showed the best perceived efficacy and tolerability. Melatonin and nutraceuticals were used by 10% and 32% of subjects, respectively, both for migraine and tension-type headache, with good results in terms of perceived efficacy and tolerability. Non-pharmacological preventive treatments (i.e. relaxation techniques, biofeedback, cognitive-behavioral therapy, acupuncture) were used only by 10% of cases (migraine 9%, tension-type headache 15%). Discussion Non-steroidal anti-inflammatory drugs, especially ibuprofen, should be preferred to acetaminophen for acute attacks of migraine or tension-type headache, because they were usually more effective and well tolerated. Triptans could be used more frequently as first or almost second choice for treating migraine attack in adolescents. Non-pharmacological preventive treatments are recommended by some pediatric guidelines as first-line interventions for primary headaches and their use should be implemented in clinical practice. Prospective multicenter studies based on larger series are warranted to better understand the best treatment strategies for young people with primary headaches.

Objective We aimed to study the role of attachment style on headache severity and psychological symptoms in migraineurs children/adolescents. Moreover, we investigated the association between attachment style, migraine severity, and psychological symptoms. Background Attachment theory suggests that early interpersonal relationships may be important determinants of psychopathology and pain management. In particular, individuals with insecure attachment styles have been shown to experience more pain than people with secure attachment style. Few studies focused on headache and data on attachment style in pediatric headache are scarce. Methods We studied 90 migraineurs (mean age 12.2 ± 2.6 years; female: 54, male: 36). Patients were divided in two groups according to headache attack frequency: (1) high frequency (HF) patients, having from weekly to daily episodes and (2) low frequency (LF) patients, showing ≤3 episodes per month. According to headache attack intensity, patients were classified in two groups: (1) mild pain (MP), allowing the patient to continue his/her daily activities and (2) severe pain (SP), leading to interruption of patient activities or forcing the child to go to bed. The psychological screening was assessed by SAFA Anxiety, Depression, and Somatization questionnaires. Attachment style was measured by the semi-projective test Separation Anxiety Test. Patients were divided into “secure,” “avoidant,” “ambivalent,” and “disorganized/confused” attachment patterns. Results We found a significant relationship between the attachment style and migraine features. The ambivalent attachment was the most common style among patients reporting high attack frequency (51%) and severe pain intensity (50%). Anxiety (SAFA-A Tot: F = 23.3, P

Aims Opioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat severe and moderate pain, but their mechanisms of action in humans remain unclear. The present study aimed to explore how oxycodone (an opioid) and venlafaxine (an SNRI) modulate spinal and supraspinal sensory processing. Methods Twenty volunteers were included in a randomized, double-blinded, three-way (placebo, oxycodone, venlafaxine), crossover study. Spinal and full scalp cortical evoked potentials (EPs) to median nerve stimulation were recorded before and after 5 days of treatment. Assessment of the central effects of the three treatments involved: (i) amplitudes and latencies of spinal EPs (spinal level); (ii) amplitudes and latencies of the P14 potential (subcortical level); (iii) amplitudes and latencies of early and late cortical EPs (cortical level); (iv) brain sources underlying early cortical Eps; and (v) brain networks underlying the late cortical EPs. Results In the venlafaxine arm, the spinal P11 and the late cortical N60-80 latencies were reduced by 1.8% [95% confidence interval (CI) 1.7%, 1.9%) and 5.7% (95% CI 5.3%, 6.1%), whereas the early cortical P25 amplitude was decreased by 7.1% (95%CI 6.1%, 8.7%). Oxycodone increased the subcortical P14 [+25% (95% CI 22.2%, 28.6%)], early cortical N30 [+12.9% (95% CI 12.5%, 13.2%)] amplitudes and the late cortical N60-80 latency [+2.9% (95% CI 1.9%, 4.0%)]. The brainstem and primary somatosensory cortex source strengths were increased by 66.7% (95% CI 62.5%, 75.0%) and 28.8% (95% CI 27.5%, 29.6%) in the oxycodone arm, whereas the primary somatosensory cortex strength was decreased in the venlafaxine arm by 18.3% (95% CI 12.0%, 28.1%). Conclusions Opioids and SNRI drugs exert different central effects. The present study contributed to the much-needed human models of the mechanisms of action of drugs with effects on the central nervous system.

Objective To investigate the generators of the somatosensory evoked potential (SEP) components recorded from the Pedunculopontine Tegmental nucleus (PPTg). Methods Twenty-two patients, suffering from Parkinson’s disease (PD), underwent electrode implantation in the PPTg area for deep brain stimulation (DBS). SEPs were recorded from the DBS electrode contacts to median nerve stimulation. Results SEPs recorded from the PPTg electrode contacts could be classified in 3 types, according to their waveforms. (1) The biphasic potential showed a positive peak (P16) whose latency (16.05 ± 0.61 ms) shifted of 0.18 ± 0.07 ms from the lower to the upper contact of the electrode. (2) The triphasic potential showed an initial positive peak (P15) whose latency (15.4 ± 0.2 ms) did not change across the DBS electrode contacts. (3) In the last SEP configuration (mixed biphasic and triphasic waveform), the positive peak was bifid including both the P15 and P16 potentials. Conclusion While the P16 potential is probably generated by the somatosensory volley travelling along the medial lemniscus, the P15 response represents a far-field potential probably generated at the cuneate nucleus level. Significance Our results show the physiological meaning of the somatosensory responses recorded from the PPTg nucleus area.

Background The aim of this study was to explore the nociceptive system of patients affected by trigeminal neuralgia (TN) secondary to documented vascular contact who underwent microvascular decompression. For that purpose, we used the classical trigeminal reflexes and the trigeminal laser-evoked potentials (tLEPs) before and after surgery, in order to verify any possible change after decompression and determine if there was any correlation between the neurophysiological parameters and the clinical outcome. Methods Eleven patients affected by TN caused by trigeminovascular contact and 10 age-matched controls underwent conventional trigeminal reflexes (bilateral Blink Reflex/BR and Masseter Inhibitory Reflex stimulating infraorbital and mental nerves/MIR V2 and V3) and tLEPs. Patients repeated neurophysiological tests one week after surgery. Results Short-latency BR and MIR were normal in all patients before surgery and there was no statistical difference before and after surgery. Conversely, in patients before surgery, tLEPs' amplitudes were significantly lower in the affected than in the healthy side (p = 0.017 for V2 and 0.037 for V3 branches). After surgery, on the affected side, tLEP amplitude increased and the pre/post-operative difference was significant (p = 0.017 for V2 and 0.028 for V3 divisions). Nine patients referred satisfactory pain relief and the favourable clinical outcome correlated with the neurophysiological recovery. Conclusions This study demonstrates that TN caused by trigeminovascular compression may be related to Aδ fibres impairment, and tLEPs are more sensitive than conventional trigeminal reflexes to reveal small fibre dysfunction and to monitor the post-surgical outcome in these patients.

Background The underlying pain mechanisms of chronic pancreatitis (CP) are incompletely understood, but recent research points to involvement of pathological central nervous system processing involving pain-relevant brain areas. We investigated the organization and connectivity of brain networks involved in nociceptive processing in patients with painful CP. Methods Contact heat-evoked potentials (CHEPs) were recorded in 15 patients with CP and in 15 healthy volunteers. The upper abdominal area (sharing spinal innervation with the pancreatic gland) was used as a proxy of ‘pancreatic stimulation’, while stimulation of a heterologous region remote to the pancreas (right forearm) was used as a control. Subjective pain scores were assessed by visual analogue scale. The brain source organization and connectivity of CHEPs components were analysed. Results After pancreatic area stimulation, brain source analysis revealed abnormalities in the cingulate/operculo-insular network. A posterior shift of the operculo-insular source (p = 0.004) and an anterior shift of the cingulate source (p

Background Although somatosensory evoked potentials (SEPs) represent a largely diffused neurophysiological technique, the pathways generating the short-latency scalp components are not fully known. We aimed to investigate the SEPs recorded from the scalp and deep brain stimulation (DBS) leads to selective electrical stimulation of either muscular or cutaneous afferents. Material and methods SEPs were recorded in 6 patients suffering from advanced Parkinson’s disease who underwent electrode implantation in the pedunculopontine (PPTg) nucleus area. We compared SEPs recorded from the scalp and DBS electrode contacts to electrical stimulation of: (a) the median nerve at the wrist (mixed stimulation), (b) the abductor pollicis brevis motor point (pure stimulation of the muscle afferents), and (c) the distal phalanx of the thumb (pure cutaneous stimulation). High-frequency oscillations (HFOs) subtending the low-frequency SEPs were also analysed. Results The macroelectrode contacts recorded a triphasic (P1-N1-P2) potential and the scalp electrodes recorded all the classical SEP components, including the widespread N18 response, after both median nerve and pure cutaneous stimulation. After motor point stimulation, the scalp N18 component and the PPTg N1 response were not recorded. No difference in the HFOs between the stimulation modalities was found. The scalp N20 component was recorded to stimulation of any modality, even if with different latency and amplitude. Conclusions Considering that both the scalp N18 response and PPTg N1component reflect the activity of a pre-postsynaptic neural network in the cuneatus nucleus, our data suggest that the cuneate response is specifically evoked by cutaneous inputs, while muscle afferents are processed elsewhere.

Background Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs acting as regulators of gene expression, through interaction with histones or through interaction with complementary DNA sequences, implicated in various human diseases such as cancer, cardiovascular diseases, autoimmune and neurodegenerative disorders and have been reported to be involved in the modulation of neuropathic pain. We recorded Laser Evoked Potentials (LEPs) in order to study: (1) lncRNAs modifications in experimental pain model; (2) correlation between the lncRNA changes and objective measure of pain perception. Material and methods LEPs were recorded in 11 healthy subjects after hand and perioral region stimulation. Three consecutive series were recorded for each stimulation site in order to investigate the habituation. Blood samples were collected immediately before LEP recording (baseline) and after 30-min (post-pain). We screened 84 lncRNAs, involved in autoimmunity and inflammatory response. Results We identified 2 lncRNAs up-regulated at the post-pain time: RP11-819C21.1 (fold change = 8.2; p = 0.038) and ZNRD1 antisense RNA 1 non-protein coding (ZNRD1-AS) (fold change = 6.3; p = 0.037). The up-regulation of both lncRNAs showed a significant positive correlation with the LEP habituation to perioral region stimulation (p = 0.04 and p = 0.01, respectively). Conclusions This is the first study showing lncRNA changes in a pain experimental model. RP11-819C21.1 and ZNRD1-AS shows as direct target miR-19a and miR19b, a class of microRNAs involved in modulation of multiple potassium channel α-subunits. lncRNAs could be involved in the pathophysiology of painful diseases characterized by reduced habituation to pain.

Long non-coding RNAs (lncRNAs) are a group of 200 nucleotides acting as regulators of gene expression implicated in various diseases such as cancer, cardiovascular diseases, autoimmune and neurodegenerative disorders. Moreover, lncRNAs are involved in pain modulation. We recorded LEPs in order to study: (1) lncRNAs modifications in experimental pain model; (2) correlation between the lncRNA changes and objective measure of pain perception. LEPs were recorded in 12 healthy subjects after hand and perioral region stimulation. Three consecutive series were recorded for each stimulation site in order to investigate the habituation. Blood samples were obtained immediately before LEP recording (baseline) and after 30-min (post-pain). We screened 84 lncRNAs, involved in autoimmunity and inflammatory response. Two lncRNAs were up-regulated after pain: RP11-819C21.1 (fold change = 8.2; p = 0.038) and ZNRD1 antisense-RNA1 non-protein coding (ZNRD1-AS) (fold change = 6.3; p = 0.037). lncRNAs up-regulated showed a significant positive correlation with perioral LEP habituation (p = 0.04 and p = 0.01, respectively). This is the first study showing lncRNA changes in a pain experimental model. RP11-819C21.1 and ZNRD1-AS shows as direct target miR-19a andmiR19b, a class of microRNAs involved in modulation of multiple potassium channel α -subunits. lncRNAs could be involved in the pathophysiology of painful diseases characterized by reduced habituation to pain.

Childhood-onset cluster headache is an excruciatingly painful and distressing condition. A retrospective study was conducted on charts of patients referring to our Headache Center. Those diagnosed as cluster headache were selected. We identified 11 children (6 males and 5 females). The mean age of cluster headache onset was 10 years (range: 5-16). All children had episodic cluster headache. All children had unilateral orbital pain; 7 patients had throbbing pain, whereas 4 children complained stabbing pain. The mean duration of the attack was 86 minutes (ranging from 30 to 180 minutes). The frequency of episodes was between 1 and 4 per day. All children had the typical cluster headache autonomic features, such as lacrimation, conjunctival injection, ptosis, and nostril rhinorrhea. Steroids showed a good clinical efficacy in interrupting cluster headache recurrence. As symptomatic drugs, acetaminophen as well as ibuprofen were ineffective; indomethacin was effective in 1 case.

Background & Aims Long-term diabetes mellitus (DM) has been associated with neuronal changes in the enteric, peripheral and/or central nervous system. Moreover, abnormal visceral sensation and gastrointestinal (GI) symptoms are seen in up to 75% of patients. To explore the role of diabetic autonomic neuropathy (DAN) in patients with long-standing DM, we investigated psychophysical responses and neuronal activity recorded as evoked brain potentials and dipolar source modelling. Methods Fifteen healthy volunteers and 14 type-1 DM patients with DAN were assessed with a symptom score index characterizing upper GI abnormalities. Multichannel (62) electroencephalography was recorded during painful electrical stimulation of the lower oesophagus. Brain activity to painful stimulations was modelled using Brain Electrical Source Analysis (besa). Results Diabetic patients had higher stimulus intensities to evoke painful sensation (p ≤ 0.001), longer latencies of N2 and P2 components (both p ≤ 0.001), and lower amplitudes of P1-N2 and N2-P2 complexes (p ≤ 0.001; p = 0.02). Inverse modelling of brain sources showed deeper bilateral insular dipolar source localization (p = 0.002). Symptom score index was negatively correlated with the depth of insular activity (p = 0.004) and positively correlated with insular dipole strength (p = 0.03). Conclusion DM patients show peripheral and central neuroplastic changes. Moreover, the role of abnormal insular processing may explain the appearance and persistence of GI symptoms related to DAN. This enhanced understanding of DAN may have future clinical and therapeutical implications.

Background Headache is a common disorder affecting a growing number of children and adolescents. In recent years, there has been an increase in scientific interest in exploring the relationship between migraine and emotional regulation, and in particular, the impact of emotional dysregulation on mental and physical health. The present study aims to explore the relationship between migraine and alexithymia among adolescents and their mothers as well as the impact of this association on mental health. An additional aim is to verify whether alexithymia may be a predictor of psychopathological symptoms in adolescents and mothers with migraines. Methods A total of 212 subjects were involved in this study. The sample was divided into (a) Experimental Group (EG) consisting of 106 subjects (53 adolescents and 53 mothers) with a diagnosis of migraine according to International Classification of Headache Disorders (ICHD-3) and (b) Control Group (CG) including 106 subjects (53 adolescents and 53 mothers) without a diagnosis of migraine. All participants completed the Toronto Alexithymia Scale to assess alexithymia and the Symptom Checklist-90-R to assess psychopathological symptoms. Results Higher rates of alexithymia were found in the adolescents and mothers of the EG in comparison to the adolescents and mothers of the CG. Furthermore, adolescents and mothers experiencing both migraine and alexithymia, demonstrated a higher risk of psychopathology. Conclusions Findings from this study provide evidence that the co-occurrence of migraine and alexithymia increases the risk of psychopathology for both adolescents and their mothers.

Neurodegenerative diseases are going to increase as the life expectancy is getting longer. The management of neurodegenerative diseases such as Alzheimer’s disease (AD) and other dementias, Parkinson’s disease (PD) and PD related disorders, motor neuron diseases (MND), Huntington’s disease (HD), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA), is mainly addressed to motor and cognitive impairment, with special care to vital functions as breathing and feeding. Many of these patients complain of painful symptoms though their origin is variable, and their presence is frequently not considered in the treatment guidelines, leaving their management to the decision of the clinicians alone. However, studies focusing on pain frequency in such disorders suggest a high prevalence of pain in selected populations from 38 to 75% in AD, 40% to 86% in PD, and 19 to 85% in MND. The methods of pain assessment vary between studies so the type of pain has been rarely reported. However, a prevalent nonneuropathic origin of pain emerged for MND and PD. In AD, no data on pain features are available. No controlled therapeutic trials and guidelines are currently available. Given the relevance of pain in neurodegenerative disorders, the comprehensive understanding of mechanisms and predisposing factors, the application and validation of specific scales, and new specific therapeutic trials are needed.

Increased pain perception due to the expectation to feel more pain is called nocebo effect. The present study aimed at investigating whether: (1) the mere expectation to feel more pain after the administration of an inert drug can affect the laser-pain rating and the laser-evoked potential (LEP) amplitude, and (2) the learning potentiates the nocebo effect. Eighteen healthy volunteers were told that an inert cream, applied on the right hand, would increase the laser pain and LEP amplitude to right hand stimulation. They were randomly assigned to either “verbal session” or “conditioning session”. In the “verbal session”, LEPs to both right and left hand stimulation were recorded at the same intensity before (baseline) and after cream application. In the “conditioning session”, after an initial cream application the laser stimulus intensity was increased surreptitiously to make the subjects believe that the treatment really increased the pain sensation. Then, the cream was reapplied, and LEPs were recorded at the same stimulus intensity as at the baseline. It was found that the verbal suggestion to feel more pain disrupted the physiological habituation of the laser-pain rating and LEP amplitude to treated (right) hand stimulation. Unlike previously demonstrated for the placebo effect, the learning did not potentiate the nocebo effect.

Background Nonpainful tactile and electrical stimulation of the large myelinated fibers reduces spontaneous pain and the amplitude of laser-evoked potentials (LEPs), which represent the most reliable technique to assess the nociceptive pathway function. Focal mechanical vibration stimulates the Aβ afferents selectively; thus, it is conceivable its action on nociceptive pathways. Aim The aim of this study was to investigate the effect of vibratory stimuli, activating either both muscle and skin receptors or cutaneous afferents only on the LEPs and subjective laser-pain rating. Methods Ten healthy volunteers were studied. The subjects were evaluated in two different sessions to test muscle and skin receptors or cutaneous afferents only. In each session, LEPs were recorded to stimulation of the dorsal hand skin in radial and ulnar territory bilaterally, while the vibratory stimulus was delivered on the radial territory of the right forearm. Results The results showed a substantial stability of the potential N1 and N2/P2 after the two protocols, with a declining trend from the initial to the last test of the same session, probably due to habituation. Accordingly, the laser-pain perception did not change during the experimental setting. Conclusions We conclude that a vibratory stimulus is ineffective in reducing the laser-evoked potentials and laser-pain perception.