Early effect of onabotulinumtoxinA on EEG-based functional connectivity in patients with chronic migraine: A pilot study.

OBJECTIVE: In this pilot prospective cohort study, we aimed to evaluate, using high-density electroencephalography (HD-EEG), the longitudinal changes in functional connectivity (FC) in patients with chronic migraine (CM) treated with onabotulinumtoxinA (OBTA). BACKGROUND: OBTA is a treatment for CM. Several studies have shown the modulatory action of OBTA on the central nervous system; however, research on migraine is limited. METHODS: This study was conducted at the Neurology Unit of "Policlinico Tor Vergata," Rome, Italy, and included 12 adult patients with CM treated with OBTA and 15 healthy controls (HC). Patients underwent clinical scales at enrollment (T0) and 3 months (T1) from the start of treatment. HD-EEG was recorded using a 64-channel system in patients with CM at T0 and T1. A source reconstruction method was used to identify brain activity. FC in δ-θ-α-ß-low-γ bands was analyzed using the weighted phase-lag index. FC changes between HCs and CM at T0 and T1 were assessed using cross-validation methods to estimate the results' reliability. RESULTS: Compared to HCs at T0, patients with CM showed hyperconnected networks in δ (p = 0.046, area under the receiver operating characteristic curve [AUC: 0.76-0.98], Cohen's κ [0.65-0.93]) and ß (p = 0.031, AUC [0.68-0.95], Cohen's κ [0.51-0.84]), mainly involving orbitofrontal, occipital, temporal pole and orbitofrontal, superior temporal, occipital, cingulate areas, and hypoconnected networks in α band (p = 0.029, AUC [0.80-0.99], Cohen's κ [0.42-0.77]), predominantly involving cingulate, temporal pole, and precuneus. Patients with CM at T1, compared to T0, showed hypoconnected networks in δ band (p = 0.032, AUC [0.73-0.99], Cohen's κ [0.53-0.90]) and hyperconnected networks in α band (p = 0.048, AUC [0.58-0.93], Cohen's κ [0.37-0.78]), involving the sensorimotor, orbitofrontal, cingulate, and temporal cortex. CONCLUSION: These preliminary results showed that patients with CM presented disrupted EEG-FC compared to controls restored by a single session of OBTA treatment, suggesting a primary central modulatory action of OBTA.

Pisa Syndrome in Parkinson's Disease: Evidence for Bilateral Vestibulospinal Dysfunction.

INTRODUCTION: Pisa syndrome (PS) is a postural complication of Parkinson's disease (PD). Yet, its pathophysiology remains unclear, although a multifactorial component is probable. Cervical vestibular evoked myogenic potentials (cVEMPs) explore vestibulospinal pathway, but they have not been measured yet in PD patients with PS (PDPS) to assess a potential vestibular impairment. MATERIALS AND METHODS: We enrolled 15 PD patients, 15 PDPS patients, and 30 healthy controls (HCs). They underwent neurological examination and were examined with Unified Parkinson's Disease Rating Scale II-III (UPDRSII-III), audiovestibular workup, and cVEMP recordings. Data were analysed with Chi-square, one-way ANOVA, multinomial regression, nonparametric, and Spearman's tests. RESULTS: cVEMPs were significantly impaired in both PD and PDPS compared with HCs. PDPS exhibited more severe cVEMP abnormalities with prevalent bilateral loss of potentials, compared with the PD group, in which a prevalent unilateral loss was instead observed. No clinical-neurophysiological correlations emerged. CONCLUSIONS: Differently from HC, cVEMPs are altered in PD. Severity of cVEMPs alterations increases from PD without PS to PDPS, suggesting an involvement of vestibulospinal pathway in the pathophysiology of PS. Our results provide evidence for a significant impairment of cVEMPs in PDPS patients and encourage further studies to test validity of cVEMPs as diagnostic and prognostic biomarkers of PD progression.

Continuous Positive Airway Pressure Treatment May Improve Optic Nerve Function in Obstructive Sleep Apnea: An Electrophysiological Study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a sleep disorder frequently associated with optic nerve diseases. Moreover, untreated patients with severe OSA may show optic nerve dysfunction as documented by electrophysiological studies using visual evoked potentials (VEP). Because continuous positive airway pressure (CPAP) treatment has proved to restore the physiologic nocturnal breathing, thus preventing nocturnal hypoxemia and reducing inflammation, in this study we tested whether 1-year CPAP treatment may modify VEP responses in patients with severe OSA. METHODS: VEP were recorded at baseline and after 1 year of CPAP treatment in 20 patients with severe OSA, divided in two groups on the basis of CPAP adherence, and compared to a healthy control group. RESULTS: Patients with good adherence to CPAP therapy (CPAP+; n = 10) showed VEP P100 amplitude significantly higher than patients with poor adherence to CPAP therapy (CPAP-; n = 10). Moreover, the CPAP+ group showed VEP responses similar to those in the control group (n = 26). Considering the mean difference of VEP responses between baseline and follow-up, the CPAP+ group showed a significant increase in VEP P100 amplitude and a significant decrease in VEP P100 latency compared to the CPAP- group. CONCLUSIONS: This study documented that CPAP therapy significantly improves VEP in patients with OSA who are adherent to the treatment. We hypothesize that CPAP treatment, minimizing the metabolic, inflammatory and ischemic consequences of OSA, may normalize the altered VEP responses in patients with OSA by restoring and preserving optic nerve function.

Executive functioning in relapsing-remitting multiple sclerosis patients without cognitive impairment: A task-switching protocol.

BACKGROUND: Cognitive dysfunction affects 40%-65% of multiple sclerosis (MS) patients, most often affecting information processing speed and working memory, mediated by the pre-frontal cortex (PFC). OBJECTIVE: Our study aimed to investigate PFC functioning through a task-switching protocol in relapsing-remitting multiple sclerosis (RRMS) patients without cognitive impairment. METHODS: A total of 24 RRMS patients and 25 controls were enrolled. Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called switch cost (SC). RESULTS: Patients had worse performance than controls only in the switch trials, as indicated by increased SC and reaction times. Moreover, patients showed a reduced ability to reconfigure the task-set for the execution of a new task and to disengage from the previous one. CONCLUSION: Our results showed a primary deficit in executive control processes involved in the task-switching performance in RRMS patients without cognitive impairment. This deficit may depend on the functional impairment of the PFC, which is essential to adjust behaviour rapidly and flexibly in response to environmental changes, representing one of the most sophisticated human abilities.

Posterior Reversible Encephalopathy Syndrome after Hematopoietic Cell Transplantation in Children with Hemoglobinopathies.

Posterior reversible encephalopathy syndrome (PRES) is a serious adverse event associated with calcineurin inhibitors used for graft-versus-host disease (GVHD) prophylaxis. We compared the incidence of PRES in children with thalassemia (n = 222, 1.4 to 17.8 years old) versus sickle cell disease (SCD; n = 59, 2 to 17 years old) who underwent hematopoietic cell transplantation from HLA-matched siblings or alternative donors and analyzed the risk factors for PRES. Overall, 31 children developed calcineurin inhibitor-related PRES (11%), including 30 patients with seizures and 1 patient without seizures. PRES incidence was significantly higher in SCD patients (22%; 95% confidence interval [CI], 10% to 32%) than in thalassemia patients (8%; 95% CI, 5% to 12%;P = .002). In multivariate analysis, factors associated with PRES were hypertension (hazard ratio [HR], 5.87; 95% CI, 2.57 to 13.43; P = .0001), SCD (HR, 2.49; 95% CI, 1.25 to 4.99; P = .009), and acute GVHD (HR 2.27; 95% CI, 1.06 to 4.85; P= .031). In the entire cohort overall survival (OS) was significantly higher in patients without versus with PRES (90% versus 77%; P = .02). In a subgroup analysis that including matched sibling transplants, OS and disease-free survival (DFS) were similar in thalassemia patients without PRES (92% and 88%, respectively) and with PRES (82% and 73%, respectively), whereas SCD patients with PRES had significantly lower OS (67%) and DFS (67%) than patients without PRES (94% and 94%, respectively; P = .008). Thus, SCD patients had a significantly higher incidence of PRES than thalassemia patients, and hypertension and GVHD were the 2 main risk factors for PRES in patients with hemoglobinopathies. Although PRES did not significantly influence survival in patients with thalassemia, patients with SCD had significantly lower survival after PRES.

Mild cerebello-thalamo-cortical impairment in patients with normal dopaminergic scans (SWEDD).

INTRODUCTION: Patients with Scans-Without-Evidence-of-Dopaminergic-Deficit (SWEDD) often present asymmetric rest tremor not responsive to levodopa. Although a dystonic origin of this tremor has been proposed, the underlying pathophysiology of such condition is still unclear. An abnormal activity in the Cerebello-Thalamo-Cortical circuit is involved in the pathogenesis of tremor and other movement disorders. Here we used different paradigms of cerebellar transcranial magnetic stimulation to evaluate the Cerebello-Thalamo-Cortical functioning in patients with normal scans. METHODS: Cerebello-Thalamo-Cortical circuit was investigated in 12 patients with normal scans, 8 patients with Parkinson's Disease (PD), 8 patients with adult-onset isolated dystonia and 9 healthy controls. We studied the effects of a single cerebellar magnetic pulse over the excitability of the contralateral primary motor cortex tested with Motor-Evoked-Potentials (Cerebellar-Inhibition) both at rest and during arm extension. Furthermore, we also tested the effects of cerebellar continuous-Theta-Burst-Stimulation on Motor-Evoked-Potentials amplitude. RESULTS: patients with normal scans compared to controls show a deficient Cerebellar-Inhibition at rest but not in arm extension; in both conditions they differ from PD but not from dystonic patients. Cerebellar Continuous-Theta-Burst-Stimulation induced the expected long-lasting cortical inhibition of Motor-Evoked-Potentials amplitude in patients with normal scans differently from PD and dystonic patients. CONCLUSIONS: patients with normal scans show a mild impairment in Cerebello-Thalamo-Cortical circuit that emerges only at rest. Such neurophysiological phenotype differs from the one observed in PD and dystonic patients, suggesting a distinct involvement of this pathway in the pathophysiology of these disorders.

Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS) in the Italian population.

Cognitive dysfunction involves 40-65 % of multiple sclerosis (MS) patients. It can be detected in all MS phenotypes from the early stages of the disease, and it tends to progress over time. Minimal Assessment of Cognitive Function in MS (MACFIMS) has been proved to be the most sensitive and comprehensive battery available for MS cognitive assessment in the English population. In Italy, MACFIMS applicability is limited in everyday clinical practice since the overall validity of this battery in the Italian MS population has never been demonstrated. The aim of this study was to translate/cross-culturally adapt and validate an Italian version of the MACFIMS. A total of 130 MS patients and 60 healthy controls (HCs) were enrolled and evaluated with an Italian version of the MACFIMS. All tests discriminated MS patients from HCs; according to the literature, approximately more than half of MS patients (70.8 %) exhibit cognitive impairment. Principal component analysis showed four distinct components: visual-spatial memory/processing speed, working memory, executive functions and verbal memory. Our study is the first to validate an Italian version of the MACFIMS. Several aspects of validity have been demonstrated: criterion and, partially, construct. Future work will investigate the longitudinal course of neuropsychological dysfunction in Italian MS patients using these measures.

Optic Nerve Dysfunction in Obstructive Sleep Apnea: An Electrophysiological Study.

STUDY OBJECTIVES: The aim of this study was to evaluate the integrity of the visual system in patients affected by obstructive sleep apnea (OSA) by means of electroretinogram (ERG) and visual evoked potential (VEP). METHODS: We performed electrophysiological study of the visual system in a population of severe OSA (apnea-hypopnea events/time in bed ≥ 30/h) patients without medical comorbidities compared to a group of healthy controls similar for age, sex, and body mass index. Patients and controls did not have visual impairment or systemic disorders with known influence on the visual system. ERG and VEP were elicited by a reversal pattern generated on a television monitor at low (55') and high (15') spatial frequencies stimulation. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) in both patients and controls. RESULTS: In comparison with healthy controls (n = 27), patients with OSA (n = 27) showed a significant latency delay coupled with a significant amplitude reduction of P100 wave of VEP at all spatial frequencies in both eyes. No significant differences between groups were detected as concerning ERG components. No correlations were found between polygraphic parameters, ESS scores, or VEP and ERG components in OSA patients. CONCLUSIONS: This study documented that patients with OSA, without medical comorbidities, present VEP alteration as documented by lower amplitude and longer latency of the P100 component than healthy controls. These altered electrophysiological findings may be the expression of optic nerve dysfunction provoked by hypoxia, acidosis, hypercarbia and airway obstruction, frequently observed in patients with OSA. Hence, we hypothesize that OSA per se may impair optic nerve function.

Neurophysiological and functional MRI evidence of reorganization of cortical motor areas in cerebral arteriovenous malformation.

Functional magnetic resonance imaging (fMRI) research has shown that brain arteriovenous malformations (AVMs) lead to reorganization of cortical motor areas. Since it is known that blood oxygenation level-dependent signal in fMRI may be influenced by the hemodynamic perturbation associated with the presence of the AVM, in the present study, a combined exploration with fMRI and transcranial magnetic stimulation was performed in a patient with a right rolandic AVM in order to explore the relationship between neuronal and hemodynamic activity. The combined protocol of investigation adopted in this study was able to provide significant information regarding neuronal activity of the different cortical areas that partake to post-lesional reorganization.

L-dopa modulates motor cortex excitability in Alzheimer's disease patients.

In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have shown abnormalities of motor cortical excitability, such as a decreased intra-cortical inhibition (ICI) and changes in resting motor threshold (rMT). We studied the effects of L-dopa on rMT and ICI in a cohort of moderate AD patients after paired-pulse TMS. Results were compared with a control group of healthy subjects. As expected, AD patients showed a significant reduction in ICI and a lower rMT. L-dopa administration (soluble form, melevodopa 200 mg) promptly reversed the ICI impairment up to normalization. This effect was specific, since it was not mimicked in control subjects. These results indicate a possible role of dopamine in modulating AD cortical excitability, thus suggesting an interaction between dopaminergic ascending pathways and endogenous intracortical transmitters. In addition, considering that L-dopa showed a pharmacological profile similar to the one of cholinomimetics, L-dopa might represent a reliable tool to study new therapeutic perspective and strategies for AD.

Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study.

STUDY OBJECTIVES: To verify the existence of a symptomatic form of restless legs syndrome (RLS) secondary to multiple sclerosis (MS) and to identify possible associated risk factors. DESIGN: Prospective, multicenter, case-control epidemiologic survey. SETTINGS: Twenty sleep centers certified by the Italian Association of Sleep Medicine. PATIENTS: Eight hundred and sixty-one patients affected by MS and 649 control subjects. INTERVENTIONS: N/A. MEASURES AND RESULTS: Data regarding demographic and clinical factors, presence and severity of RLS, the results of hematologic tests, and visual analysis of cerebrospinal magnetic resonance imaging studies were collected. The prevalence of RLS was 19% in MS and 4.2% in control subjects, with a risk to be affected by RLS of 5.4 (95%confidence interval: 3.56-8.26) times greater for patients with MS than for control subjects. In patients with MS, the following risk factors for RLS were significant: older age; longer MS duration; the primary progressive MS form; higher global, pyramidal, and sensory disability; and the presence of leg jerks before sleep onset. Patients with MS and RLS more often had sleep complaints and a higher intake of hypnotic medications than patients with MS without RLS. RLS associated with MS was more severe than that of control subjects. CONCLUSIONS: RLS is significantly associated with MS, especially in patients with severe pyramidal and sensory disability. These results strengthen the idea that the inflammatory damage correlated with MS may induce a secondary form of RLS. As it does in idiopathic cases, RLS has a significant impact on sleep quality in patients with MS; therefore, it should be always searched for, particularly in the presence of insomnia unresponsive to treatment with common hypnotic drugs.

Pedunculopontine nucleus deep brain stimulation changes spinal cord excitability in Parkinson's disease patients.

Bilateral peduncolopontine nucleus (PPN) and subthalamic nucleus (STN) deep brain stimulation (DBS) was performed in six-advanced Parkinson's disease (PD) patients. We report the effect of both PPN-DBS (25 Hz) and STN-DBS (185 Hz) on patient spinal reflex excitability by utilizing the soleus-Hoffman reflex (HR) threshold. Compared to controls (n = 9), patients showed an increase of HR-threshold, which was scarcely affected by levodopa, but significantly reduced by DBS. In particular, we found that PPN-DBS alone, or plus STN-DBS induced a complete recovery of HR-threshold up to control values. The HR-threshold changes, although do not allow to investigate the contribution of specific intraspinal pathways, suggest that PPN may play a key-role in modulating spinal excitability in PD possibly by improving the basal ganglia-brainstem descending system activity.

Effect of Vigabatrin on motor responses to transcranial magnetic stimulation: an effective tool to investigate in vivo GABAergic cortical inhibition in humans.

In this study, transcranial magnetic stimulation (TMS) of the hand primary motor area was used to test possible excitability changes induced by the administration of Vigabatrin (Gamma-Vinyl-gamma-aminobutryic acid;4-amino-hex-5-enoic acid; GVG), a selective GABAergic drug, on cortical inhibitory mechanisms in healthy subjects. In a group of 15 healthy volunteers, the level of motor cortical excitability was studied by means of paired-pulse TMS (p-TMS) protocols exploring the early (1-6 ms of interstimulus intervals, ISI) and the late cortical inhibition (20-250 ms ISI), and by evaluating the cortical silent period (CSP) duration obtained in response to single pulse stimulation of cortical motor area. In all participants TMS procedures were carried out before and after administering GVG for three consecutive days at a daily dosage of 50 mg/kg. Three months later, a third TMS recording session was repeated to investigate possible long-lasting GVG effects on cortical excitability. GVG induces relevant changes of cortical excitability consisting in an increase of late cortical inhibition in response to the long ISI p-TMS and in a prolonged duration of the CSP. No significant change in the early cortical inhibition was observed in response to the short ISI p-TMS. The analysis of peripheral motor excitability was also assessed, with no effects. The present electrophysiological data show that GVG is able to induce a significant increase of the late cortical inhibition, whereas it does not affect the early cortical inhibition. These data suggest that the great availability of synaptic GABA differently acts on the inhibitory circuitries controlled by different GABA-receptor subtypes.