Paolo Manganotti

Patient-Specific Detection of Cerebral Blood Flow Alterations as Assessed by Arterial Spin Labeling in Drug-Resistant Epileptic Patients

Electrophysiological and hemodynamic data can be integrated to accurately and precisely identify the generators of abnormal electrical activity in drug-resistant focal epilepsy. Arterial Spin Labeling (ASL), a magnetic resonance imaging (MRI) technique for quantitative noninvasive measurement of cerebral blood flow (CBF), can provide a direct measure of variations in cerebral perfusion associated with the epileptic focus. In this study, we aimed to confirm the ASL diagnostic value in the identification of the epileptogenic zone, as compared to electrical source imaging (ESI) results, and to apply a template-based approach to depict statistically significant CBF alterations. Standard video-electroencephalography (EEG), high-density EEG, and ASL were performed to identify clinical seizure semiology and noninvasively localize the epileptic focus in 12 drug-resistant focal epilepsy patients. The same ASL protocol was applied to a control group of 17 healthy volunteers from which a normal perfusion template was constructed using a mixed-effect approach. CBF maps of each patient were then statistically compared to the reference template to identify perfusion alterations. Significant hypo- and hyperperfused areas were identified in all cases, showing good agreement between ASL and ESI results. Interictal hypoperfusion was observed at the site of the seizure in 10/12 patients and early postictal hyperperfusion in 2/12. The epileptic focus was correctly identified within the surgical resection margins in the 5 patients who underwent lobectomy, all of which had good postsurgical outcomes. The combined use of ESI and ASL can aid in the noninvasive evaluation of drug-resistant epileptic patients.

Cerebrospinal Fluid Cytokine Expression Profile in Multiple Sclerosis and Chronic Inflammatory Demyelinating Polyneuropathy

ABSTRACT Background: Cerebrospinal fluid (CSF) analysis in patients with particular neurologic disorders is a powerful tool to evaluate specific central nervous system inflammatory markers for diagnostic needs, because CSF represents the specific immune micro-environment to the central nervous system. Methods: CSF samples from 49 patients with multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and non-inflammatory neurologic disorders (NIND) as controls were submitted to protein expression profiles of 47 inflammatory biomarkers by multiplex Luminex bead assay to investigate possible differences in the inflammatory process for MS and CIDP. Results: Our results showed differences in CSF cytokine levels in MS and CIDP; in particular, IL12 (p40) was significantly highly expressed in MS in comparison with CIDP and NIND, while SDF-1α and SCGF-β were significantly highly expressed in CIDP cohort when compared to MS and NIND. IL-9, IL-13, and IL-17 had higher expression levels in NIND if compared with the other groups. Conclusions: Our study showed that, despite some common pathogenic mechanisms, central and peripheral nervous system demyelinating diseases, such as MS and CIDP, differ in some specific inflammatory soluble proteins in CSF, underlining differences in the immune response involved in those autoimmune diseases.

Complex neurological symptoms in bilateral thalamic stroke due to Percheron artery occlusion.

The artery of Percheron is a rare anatomical variant where a single thalamic perforating artery arises from the proximal posterior cerebral artery (P1 segment) between the basilar artery and the posterior communicating artery and supplies the rostral mesencephalon and both paramedian territories of the thalami. Almost one-third of human brains present this variant. Occlusion of the artery of Percheron mostly results in a bilateral medial thalamic infarction, which usually manifests with altered consciousness (including coma), vertical gaze paresis, and cognitive disturbance. The presentation is similar to the “top of the basilar syndrome”, and early recognition should be prompted. We describe the case of a young female with this vessel variant who experienced a bilateral thalamic stroke. Magnetic resonance angiography demonstrated bilateral thalamic infarcts and a truncated artery of Percheron. Occlusion of the vessel was presumably due to embolism from a patent foramen ovale. Thrombolysis was performed, with incomplete symptom remission, cognitive impairment, and persistence of speech disorders. Early recognition and treatment of posterior circulation strokes is mandatory, and further investigation for underlying stroke etiologies is needed.

Altered Modulation of Silent Period in Tongue Motor Cortex of Persistent Developmental Stuttering in Relation to Stuttering Severity.

Motor balance in developmental stuttering (DS) was investigated with Transcranial Magnetic Stimulation (TMS), with the aim to define novel neural markers of persistent DS in adulthood. Eleven DS adult males were evaluated with TMS on tongue primary motor cortex, compared to 15 matched fluent speakers, in a “state” condition (i.e. stutterers vs. fluent speakers, no overt stuttering). Motor and silent period thresholds (SPT), recruitment curves, and silent period durations were acquired by recording tongue motor evoked potentials. Tongue silent period duration was increased in DS, especially in the left hemisphere (P<0.05; Hedge’s g or Cohen’s dunbiased = 1.054, i.e. large effect size), suggesting a “state” condition of higher intracortical inhibition in left motor cortex networks. Differences in motor thresholds (different excitatory/inhibitory ratios in DS) were evident, as well as significant differences in SPT. In fluent speakers, the left hemisphere may be marginally more excitable than the right one in motor thresholds at lower muscular activation, while active motor thresholds and SPT were higher in the left hemisphere of DS with respect to the right one, resulting also in a positive correlation with stuttering severity. Pre-TMS electromyography data gave overlapping evidence. Findings suggest the existence of a complex intracortical balance in DS tongue primary motor cortex, with a particular interplay between excitatory and inhibitory mechanisms, also in neural substrates related to silent periods. Findings are discussed with respect to functional and structural impairments in stuttering, and are also proposed as novel neural markers of a stuttering “state” in persistent DS, helping to define more focused treatments (e.g. neuro-modulation).

Action Observation Plus Sonification. A Novel Therapeutic Protocol for Parkinson’s Patient with Freezing of Gait

Freezing of gait (FoG) is a disabling symptom associated with falls, with little or no responsiveness to pharmacological treatment. Current protocols used for rehabilitation are based on the use of external sensory cues. However, cued strategies might generate an important dependence on the environment. Teaching motor strategies without cues [i.e., action observation (AO) plus Sonification] could represent an alternative/innovative approach to rehabilitation that matters most on appropriate allocation of attention and lightening cognitive load. We aimed to test the effects of a novel experimental protocol to treat patients with Parkinson’s disease (PD) and FoG, using functional, and clinical scales. The experimental protocol was based on AO plus Sonification. 12 patients were treated with 8 motor gestures. They watched eight videos showing an actor performing the same eight gestures, and then tried to repeat each gesture. Each video was composed by images and sounds of the gestures. By means of the Sonification technique, the sounds of gestures were obtained by transforming kinematic data (velocity) recorded during gesture execution, into pitch variations. The same 8 motor gestures were also used in a second group of 10 patients; which were treated with a standard protocol based on a common sensory stimulation method. All patients were tested with functional and clinical scales before, after, at 1 month, and 3 months after the treatment. Data showed that the experimental protocol have positive effects on functional and clinical tests. In comparison with the baseline evaluations, significant performance improvements were seen in the NFOG questionnaire, and the UPDRS (parts II and III). Importantly, all these improvements were consistently observed at the end, 1 month, and 3 months after treatment. No improvement effects were found in the group of patients treated with the standard protocol. These data suggest that a multisensory approach based on AO plus Sonification, with the two stimuli semantically related, could help PD patients with FoG to relearn gait movements, to reduce freezing episodes, and that these effects could be prolonged over time.

How far away from having an effective treatment option for progressive multiple sclerosis are we

The availability of numerous disease-modifying drugs for relapsing-remitting (RR) multiple sclerosis (MS) is one of the greatest successes of the last 30 years of neurology history. Unfortunately, this story has a dark side, represented by progressive forms of the disease, still without an effective treatment. A total of 15% of MS patients show a progression form onset, while secondary progression is developed by about 80–90% of RR patients after long-standing disease. Clinical differences between primary progressive (PP) and secondary progressive (SP) forms are well known; nevertheless, these two entities share so many pathological mechanisms and characteristics [1] that seem warranted considering them as part of the same spectrum. The prominence of neurodegeneration over inflammation, with microglial activation, chronic axonal demyelination mediated by oxidative injury, and axonal mitochondrial dysfunction, translates in high disability levels that have deep consequences on patients’ quality of life and give rise to significant familiar, social, and economic burden. It is easy to understand why finding an answer to such a disabling disease represents a priority for scientific community.

Can We Speak of Lack of Habituation in Visual Snow

We read with interest the article by Unal-Cevik et al reporting a case of visual snow (VS) in a patient with a pre-existing migraine with aura (MWA). The authors recorded a subjective improvement of the patient’s VS symptoms after treatment with lamotrigine (LTG) and the effect was objectively assessed by the evaluation of repetitive pattern reversal visual evoked potentials (rVEPs). At baseline, the patient showed a potentiation response, defined as an increase in amplitude of rVEPs between the first and the last block of 100 stimuli, which partially recovered after treatment with LTG. In our opinion, the authors proposed a valid and feasible approach to explore the pathophysiology and therapeutic responsiveness of VS, but we feel that there are some methodological concerns that need to be discussed. First, as the authors correctly stated, “the consequences of cortical hyperexcitability due to comorbid migraine cannot be eliminated,” and this is a crucial point. Indeed the lack of habituation, or even potentiation, is recognized as a characteristic feature of interictal migraine, especially with aura and in VS a high prevalence migraine (30-60%) has already been reported. Therefore, we believe that the potentiation effect on rVEPs that the authors described cannot be unequivocally attributed to VS but rather seems to be related to the underlying MWA. We suggest that this finding should be more prudently confirmed on a larger number of patients, possibly trying to make a distinction between the subgroups of VS with or without comorbid migraine. If we were able to unveil some differences between those two groups we could ascertain whether a state of cortical hyperexcitability is truly VS related or just migraine related. Second, taking in to account the ongoing controversy about the validity of rVEPs habituation paradigms in migraine, we suggest that in a single subject study design the reduction of the potentiation effect after LTG treatment should be interpreted with caution. Changes of few millivolts (mV) between blocks could be explained, for example, by an intrinsic sampling variability, fluctuations in subject’s attention, or concomitant treatments. Perhaps if we were able to demonstrate the restoration of a physiologic habituation response – at a group level – we could have a more solid clue to affirm that a normalization of cortical excitability levels has occurred. Third, LTG has been proven to be effective in the prophylaxis of MWA. Its mechanism of action is still only partially understood and presumably involves the modulation of the glutamatergic transmission, which may be altered in VS as well as in MWA. Some patients with VS reported some improvement of VS after receiving LTG but it is still unclear whether LTG ameliorates VS acting on both VS and migraine pathophysiology or if it has a specific effect on VS. In this specific case, a concomitant effect on MWA should be hypothesized and this observation is supported by the patient’s objective reduction of headache attacks and by the evidence of an increased likelihood of having additional visual symptoms and tinnitus in VS with comorbid migraine. We reaffirm that VS should be considered as a distinct clinical entity although the overlaps with migraine pathophysiology are relevant. Neurophysiological investigations are safe, non-invasive, Abbreviations: LTG, lamotrigine; mV, millivolts; MWA, migraine with aura; rVEPs, repetitive visual evoked potentials; VS, visual snow. Conflict of Interest: The authors declare that there is no conflict of interest.

Quantification of Upper Limb Motor Recovery and EEG Power Changes after Robot-Assisted Bilateral Arm Training in Chronic Stroke Patients: A Prospective Pilot Study

Background Bilateral arm training (BAT) has shown promise in expediting progress toward upper limb recovery in chronic stroke patients, but its neural correlates are poorly understood. Objective To evaluate changes in upper limb function and EEG power after a robot-assisted BAT in chronic stroke patients. Methods In a within-subject design, seven right-handed chronic stroke patients with upper limb paresis received 21 sessions (3 days/week) of the robot-assisted BAT. The outcomes were changes in score on the upper limb section of the Fugl-Meyer assessment (FM), Motricity Index (MI), and Modified Ashworth Scale (MAS) evaluated at the baseline (T0), posttraining (T1), and 1-month follow-up (T2). Event-related desynchronization/synchronization were calculated in the upper alpha and the beta frequency ranges. Results Significant improvement in all outcomes was measured over the course of the study. Changes in FM were significant at T2, and in MAS at T1 and T2. After training, desynchronization on the ipsilesional sensorimotor areas increased during passive and active movement, as compared with T0. Conclusions A repetitive robotic-assisted BAT program may improve upper limb motor function and reduce spasticity in the chronically impaired paretic arm. Effects on spasticity were associated with EEG changes over the ipsilesional sensorimotor network.

Neurophysiological and BOLD signal uncoupling of giant somatosensory evoked potentials in progressive myoclonic epilepsy: a case-series study

In progressive myoclonic epilepsy (PME), a rare epileptic syndrome caused by a variety of genetic disorders, the combination of peripheral stimulation and functional magnetic resonance imaging (fMRI) can shed light on the mechanisms underlying cortical dysfunction. The aim of the study is to investigate sensorimotor network modifications in PME by assessing the relationship between neurophysiological findings and blood oxygen level dependent (BOLD) activation. Somatosensory-evoked potential (SSEP) obtained briefly before fMRI and BOLD activation during median-nerve electrical stimulation were recorded in four subjects with typical PME phenotype and compared with normative data. Giant scalp SSEPs with enlarger N20-P25 complex compared to normal data (mean amplitude of 26.2 ± 8.2 μV after right stimulation and 27.9 ± 3.7 μV after left stimulation) were detected. Statistical group analysis showed a reduced BOLD activation in response to median nerve stimulation in PMEs compared to controls over the sensorimotor (SM) areas and an increased response over subcortical regions (p < 0.01, Z > 2.3, corrected). PMEs show dissociation between neurophysiological and BOLD findings of SSEPs (giant SSEP with reduced BOLD activation over SM). A direct pathway connecting a highly restricted area of the somatosensory cortex with the thalamus can be hypothesized to support the higher excitability of these areas.

Case Report: Coexistence of SUNCT and Hypnic Headache in the Same Patient

Short‐lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and hypnic headache (HH) are two exceedingly rare and distinctly classified primary headaches. The hypothalamus seems to be a crucial region involved in the pathophysiology of both conditions, but no cases of SUNCT and HH co‐occurrence have been described so far.