M. Bianco

Excitatory deep repetitive transcranial magnetic stimulation with H-coil as add-on treatment of motor symptoms in Parkinson's disease: an open label, pilot study.

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a potential treatment for Parkinsons disease (PD). H-coils, inducing deeper and wider magnetic fields compared to traditional coils, may be potentially useful in PD, characterized by widespread, bilateral involvement of cortico-subcortical circuits. OBJECTIVE To evaluate the safety of repetitive deep TMS (rDTMS) with H-coil as add-on treatment of motor symptoms in PD. METHODS Twenty-seven PD patients (aged 60.1 ± 6.8 y; PD-duration: 6.3 ± 2.8 y; motor-UPDRS: 39.6 ± 10.1) underwent 12 rDTMS sessions over 4 weeks at excitatory (10 Hz) frequency over primary motor (M1) and bilateral prefrontal (PF) regions. Motor UPDRS off therapy was assessed before and after the last rDTMS session, together with safety records at each treatment session. RESULTS No drop-outs or adverse events were recorded. Motor UPDRS significantly improved after rDTMS (10.8 points average reduction; P < 0.0001). CONCLUSIONS High-frequency rDTMS might be a safe treatment for PD motor symptoms. Further placebo-controlled, randomized studies are warranted.

Optical coherence tomography and visual evoked potentials: which is more sensitive in multiple sclerosis?:

Objective: To assess the sensitivity of optic coherence tomography (OCT) and visual evoked potentials (VEPs) to visual pathway abnormalities in multiple sclerosis (MS). Methods: A total of 40 MS subjects, 28 with optic neuritis (ON) at least 3 months before (bilateral in 5), underwent assessment of visual acuity, Expanded Disability Status Scale (EDSS), OCT and VEPs, the latter quantified with a 0–4 conventional score. Results: OCT and VEPs were abnormal in 36% and 56% respectively in all eyes (p=0.11), 68% and 86% in eyes with previous ON (p=0.12), and in 19% versus 40% in eyes without ON history (p=0.007). Combining VEP and OCT increased sensitivity to 89% in ON and 44% in non-ON eyes. Considering all eyes, global retinal nerve fibre layer (RNFL) thickness and VEP score were significantly correlated between them (ρ=−0.63, p<0.001) and with EDSS (RNFL: ρ=0.40, p<0.001; VEP score: ρ=0.47, p<0.001). Disease duration correlated with VEP score (ρ=0.25, p=0.025) and RNFL thickness (ρ=−0.71, p<0.001). Conclusions: In eyes without ON, VEPs were more frequently abnormal than OCT, while the two techniques showed similar sensitivity in eyes previously affected by ON. The correlation of VEPs and OCT measures with disability prompts further exploration of the two techniques as potential markers of disease burden.

Computational classifiers for predicting the short-term course of Multiple sclerosis

BackgroundThe aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS).MethodsWe obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center.ResultsWe found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later.ConclusionsThe usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability.

P19.19 Effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied with H-coil for chronic migraine prophylaxis

Introduction: We investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on corticomotor excitability (CE), motor behavior, and mood in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Repetitive TMS has not been investigated systematically in PSP or CBD patients. PSP and CBD share bradykinetic-rigid features of Parkinson’s disease. PSP and CBD show a high incidence of frontal dysfunction and depression; CBD is dominated by asymmetric limb apraxia and dystonia. Objectives: We hypothesized that rTMS over primary motor cortex (M1rTMS) would affect CE and motor behavior while rTMS over dorsolateral prefrontal cortex (DLPFC-rTMS) would affect mood. Patients were randomized to receive M1-rTMS, DLPFC-rTMS, or sham-rTMS at 90% motor threshold in 3 sessions with assessments before vs. after stimulation. 5 CBD patients received 1 Hz-rTMS (for dystonia) and 10 PSP patients received 5 Hz-rTMS (for akinesia-rigidity) over M1 contralateral to the more symptomatic limb. All patients received 5 Hz-rTMS over left DLPFC. Methods: CE was assessed with resting motor thresholds (rMT) and motor evoked potential amplitudes (MEP); motor behavior assessed with maximal (MAX) and comfortable (COM) tapping speed; mood assessed with visual analog scales. Results: (1) In PSP, 5 Hz rTMS over M1 did not improve tapping speeds, (2) rTMS over left DLPFC showed a trend towards improvement of overall wellness (p = 0.07, 2-tailed), a protocol comparable with rTMS use for depression, (3) rTMS over M1 in PSP did not significantly modify MEP amplitude. We found no significant differences in rMT in PSP patients vs healthy controls; CBD patients may have higher motor thresholds compared to healthy controls (p = 0.028), but was limited in CBD patients due to high rMT. Conclusions: These preliminary results provide support to further explore high-frequency left DLPFC rTMS for affective symptoms. Higher frequency rTMS over M1 or higher intensity stimulation may be needed to demonstrate changes in CE. Alternative strategies for addressing high rMT in CBD patients may be needed for applying rTMS.

Thrombolysis with rt-PA for an ischemic stroke in boy treated with Fontan operation

We first report the case of a 14-year-old boy, previously treated with a modified Fontan operation at the age of 2, who underwent an intra-arterial thrombolysis for an ischemic stroke with a favorable outcome. No controlled randomized trials on thrombolysis among childhood stroke have been conducted yet. This and other similar cases suggest that thrombolysis may also be safe and beneficial in pediatric patients and those cases may benefit from a prompt access to specialized stroke centers.

P568: Multimodal evoked potentials in predicting response to immunomodulating treatment in multiple sclerosis

S.-M. Kim1, S.-Y. Park2, J.Y. Kim3, J.-J. Sung1, K.S. Park3, O. Kwon4, S.H. Kim5, J. Park5, K.-W. Lee1 1Seoul Nationl University Hospital, Neurology, Seoul, Republic of Korea; 2National cancer center, Neurology, Seoul, Republic of Korea; 3Seoul National University, Bundang Hospital, Neurology, Gyeonggi, Republic of Korea; 4Eulji General Hospital, Neurology, Seoul, Republic of Korea; 5Seoul National University Hospital, Medical Research Collaborating Center, Seoul, Republic of Korea

P18.5 Visual and sensorimotor pathways in primary and secondary progressive multiple sclerosis: neurophysiological differences?

Methods: A correlation between CSF levels of IL4, IL5, IL10, IL13 and markers of neurodegeneration such as the amyloid-b1 42 CSF content and the retinal nerve fibre layer (RNFL) thickness, an imaging index of neuronal integrity measured at the optical coherence tomography (OCT) was evaluated in 52 relapsing-remitting MS patients. To provide insights into the potential mechanisms of TH2 cytokine-induced neuroprotection in MS, we also explored whether their CSF levels correlate with measures of cortical inhibition and facilitation by means of paired pulse transcranial magnetic stimulation (ppTMS). Results: IL13, but not IL4, IL5 and IL10 correlated with amyloid-b1 42 CSF levels, suggesting that IL13 may prevent amyloid-b oligomerization and deposition and neuronal damage. In line with this, IL13 also directly correlated with the RNFL thickness and macular volume. Furthermore, higher levels of IL13 were related to a higher performance in the low-contrast visual acuity test and MS Functional Composite scoring, suggesting beneficial effects also on functional outcomes. Finally, ppTMS showed that GABAA-mediated cortical inhibition is increased in patients with high IL13 levels in the CSF. Conclusion: The present study provides evidences for an active role of IL13 in the modulation of neuronal integrity and synaptic function in MS patients.

P22.14 Selective modulation of the motor cortex excitability during listening to known melodic sequences in pianists

Methods: 20 subjects executed a learning task with an engineered glove with the right hand. We measured reaction time (RT), Touch Duration (TD) and Inter Tapping Interval (ITI), thus providing a description of the motor behaviour. In 11 subjects we measured motor evoked potentials recruitment curve with transcranial magnetic stimulation (TMS) in right M1 while in the remaining 9 we studied connectivity between rPP area and right M1 by means of a paired pulse TMS paradigm. All TMS procedures were performed before and after the learning task. Results: Sequence learning induced a significant decrease of RT and a change of motor strategy (increased TD and decreased ITI). Subjects showed, at the end of the task, a significant increase of cortical excitability in the ipsilateral M1 and stronger facilitatory interaction between rPP area and right M1. Conclusions: Changes in motor behaviour observed in the explicit group suggest that motor optimization is a general aspect of the sequence learning process. Cortical excitability results support the hypothesis that explicit sequence learning accompanies changes in ispilateral hemisphere, likely due to the engagement of rPP cortex in learning process.

P20.7 Safety and efficacy of deep repetitive transcranial magnetic stimulation (rTMS) with H-coil in Alzheimer disease

Introduction: Although converging evidence suggests that neuromodulation with rTMS may be useful as additional treatment of Alzheimer’s disease (AD), the rationale for focal rTMS may be somewhat limited by a relatively low extension of the stimulated cortex. Objectives: To evaluate the efficacy and tolerability of deep repetitive transcranial magnetic stimulation (rTMS) applied with H-coil in patients with Alzheimer disease (AD). Methods: Inclusion criteria: age 18 80 years, diagnosis of AD for at least 1 year, Mini Mental State Examination (MMSE) lower than 24, stable therapy for AD for at least 5 weeks, no history of epilepsy or other contraindications to TMS. This is a double blind study: a group of patients receives a treatment with real rTMS and the control group receives a treatment with a sham rTMS. rTMS is applied to the prefrontal and temporal areas at an intensity of 120% of motor threshold and a frequency of 10 Hz. Treatment consists of 42 series of 2-second trains, separated by 22-second intervals, per session; the stimulation period lasts two months: the first one includes 3 rTMS sessions per week and the second one only a session per week. Patients underwent neurological and neuropsychological assessment (MMSE, ADAS-Cog, BDI) before treatment, at the end of the first month and at the end of the second month; a followup visit is also provided 8 weeks after the end of stimulation period. An interim analysis will be performed when 20 patients will be recruited. Results: To date treatment has been well tolerated and no side effects have been reported. Results of interim analysis will be presented. Conclusion: To date rTMS has been applied in AD patients only in few studies using a surface coil, with improvement of cognitive performance. rTMS with H-coil aims at stimulating deep brain regions involved in cognitive functions to enhance neuronal viability and synaptic activity. Results of this study will give information on the possibility of providing patients a new treatment for a disease that so far poorly benefits from available therapies.

P21.9 Evoked potential abnormalities predict disability progression at 5 years in patients with CIS

Introduction and Objective: Previous studies in relapsing remitting Multiple Sclerosis patients found evoked potentials to be reliable predictors of long term disability. Induction strategy is becoming increasingly used in MS and it is particularly valid as therapeutic strategy if applied in the early phases of the disease. The aim of this study was to assess the role of EPs in predicting future disability and the risk of conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS). Methods: We retrospectively analyzed 91 patients with CIS. Medical files were reviewed for clinical presentation. All patients underwent multimodal EPs after a mean time of 2±1.9 months from onset: visual (VEP), somatosensory (SEP) and motor (MEP) evoked potentials were obtained in all patients, brainstem auditory evoked potentials (BAEP) in 86. Each EP received an abnormality score from 0 to 3 (normal to absent; maximum possible multimodal total sum score = 36). Results: Average global score of abnormal EPs was 5±4. Basal global EPs score significantly correlated with EDSS5 (ø = 0.27 p = 0.008) and disability progression (EDSS5 EDSS2; ø = 0.30 p = 0.004). EP global score >5 predicted a higher risk of disability at 5 years, defined as an EDSS 3 (PPV = 24% p = 0.001). Lower limb SEP and MEP sum score were better able to predict the development of disability at 5 years (46% p = 0.0001). Subclinical EP abnormalities predicted the development of involvement of the corresponding FS at 5 years. This predictive value was found for VEP (PPV = 15.8% p = 0.04) BAEP (PPV = 55.6% p = 0.04), SEP (PPV = 30.6% p = 0.03), MEP (PPV = 90% p = 0.03). When excluding, in monofocal patients, EPs related to the symptomatic pathway, patients with 2 or 3 abnormal EPs at onset had a higher risk of conversion to CDMS (PPV = 40.4% p = 0.05). Conclusions: The present findings suggest that multimodal EPs at onset in patients with CIS have a predictive value regarding the evolution of disability. Moreover, a subclinical wide involvement of multiple sensorimotor pathways, detected as abnormalities in at least 2 EPs, increases the risk of conversion to CDMS.