Francesca Spagnolo

Predictors of punding in Parkinson's disease: Results from a questionnaire survey

Dopamine replacement therapy (DRT) for Parkinsons disease (PD) has recently been linked to the development of a number of nonmotor behavioral control problems. Punding, one of these nonmotor problems, is a term used to describe complex, purposeless stereotyped behaviors such as the repetitive handling or sorting of objects. A self‐report questionnaire was adapted to assess punding in the context of dysfunctional hobby‐related activities. We report the results of a survey of PD outpatients from a PD research clinic (n = 141) and non‐PD controls (n = 103); conducted to identify clinical and psychological factors predictive of punding behaviors. The PD group reported hobbies and activities, which scored significantly higher on the Punding Scale than controls. Higher impulsivity, poorer disease‐related quality of life, younger age of disease onset, and concomitant daily medication dosage from dopamine receptor agonists were independently predictive of higher Punding Scale scores in the PD group. These findings are similar to those seen in dopamine dysregulation syndrome, and provide further evidence for the role of impulsivity and age at disease onset in DRT‐related nonmotor behavioral problems in PD.

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.

Mapping early changes of cortical motor output after subcortical stroke: A transcranial magnetic stimulation study

After acute stroke several changes in cortical excitability occur involving affected (AH) and unaffected hemisphere (UH) but whether they contribute to motor recovery is still controversial. We performed transcranial magnetic stimulation mapping of several upper limb muscles over the two hemispheres in thirteen patients at 4-12 days from subcortical stroke and after 1 month. The occurrence of mirror movements (MMs) on the healthy side during contraction of paretic muscles was measured. At baseline, cortical excitability parameters over the AH decreased in comparison with controls, while excitability over the UH increased correlating with severity of motor deficits of the affected arm at baseline as well as with poor recovery. At follow-up, map parameters of the UH became closer to those of controls independently from recovery, while for the AH the number of responsive sites increased significantly. Ipsilateral motor evoked responses (iMEPs) in the affected arm were never elicited. We observed an early impairment in dexterity of the ipsilesional hand that recovered over-time but persistently differed in comparison with controls. MMs occurrence increased at baseline correlating with reduced cortical excitability of the AH as well as with increased map density over the UH. The acute increased excitability of the UH after stroke has a negative prognostic value on recovery and negatively affects motor performance of the ipsilesional hand. Moreover, the absence of iMEPs and the normalization of motor cortical excitability at follow-up indicate that the UH primary motor area does not contribute to recovery.

Age-related changes in motor cortical representation and interhemispheric interactions: a transcranial magnetic stimulation study

To better understand the physiological mechanisms responsible for the differential motor cortex functioning in aging, we used transcranial magnetic stimulation to investigate interhemispheric interactions and cortical representation of hand muscles in the early phase of physiological aging, correlating these data with participants’ motor abilities. Right-handed healthy subjects were divided into a younger group (n = 15, mean age 25.4 ± 1.9 years old) and an older group (n = 16, mean age 61.1 ± 5.1 years old). Activity of the bilateral abductor pollicis brevis (APB) and abductor digiti minimi (ADM) was recorded. Ipsilateral silent period (ISP) was measured in both APBs. Cortical maps of APB and ADM were measured bilaterally. Mirror movements (MM) were recorded during thumb abductions. Motor abilities were tested using Nine Hole Peg Test, finger tapping, and grip strength. ISP was reduced in the older group on both sides, in terms of duration (p = 0.025), onset (p = 0.029), and area (p = 0.008). Resting motor threshold did not differ between groups. APB and ADM maps were symmetrical in the younger group, but were reduced on the right compared to the left hemisphere in the older group (p = 0.008). The APB map of the right hemisphere was reduced in the older group compared to the younger (p = 0.021). Older subjects showed higher frequency of MM and worse motor abilities (p < 0.001). The reduction of right ISP area correlated significantly with the worsening of motor performances. Our results showed decreased interhemispheric interactions in the early processes of physiological aging and decreased cortical muscles representation over the non-dominant hemisphere. The decreased ISP and increased frequency of MM suggest a reduction of transcallosal inhibition. These data demonstrate that early processes of normal aging are marked by a dissociation of motor cortices, characterized, at least, by a decline of the non-dominant hemisphere, reinforcing the hypothesis of the right hemi-aging model.

Deep Repetitive Transcranial Magnetic Stimulation With H-coil on Lower Limb Motor Function in Chronic Stroke: A Pilot Study

OBJECTIVES To assess the efficacy of high-frequency (20 Hz) brain stimulation on lower limb motor function in subjects with chronic (> 6 mo) subcortical stroke. DESIGN Double-blind, placebo-controlled crossover study. SETTING University hospital. PARTICIPANTS Right-handed subjects (N=10) affected by a first-ever subcortical stroke in the territory of the middle cerebral artery were included in this study. INTERVENTIONS Repetitive transcranial magnetic stimulation (rTMS) was delivered with the H-coil, specifically designed to target deeper and larger brains regions. Each subject received both real and sham rTMS in a random sequence. The 2 rTMS cycles (real or sham) were composed of 11 sessions each, administered over 3 weeks and separated by a 4-week washout period. MAIN OUTCOME MEASURES Lower limb functions were assessed by the lower limb Fugl-Meyer scale, the 10-m walk test, and the 6-minute walk test before and 1 day after the end of each treatment period, as well as at a 4-week follow-up. RESULTS Real rTMS treatment was associated with a significant improvement in lower limb motor function. This effect persisted over time (follow-up) and was significantly greater than that observed with sham stimulation. A significant increase in walking speed was also found after real rTMS, but this effect did not reach statistical significance in comparison with the sham stimulation. CONCLUSIONS These data demonstrated that 3 weeks of high-frequency deep rTMS could induce long-term improvements in lower limb functions in the chronic poststroke period, lasting at least 1 month after the end of the treatment.

Deep magnetic stimulation in a progressive supranuclear palsy patient with speech involvement

In the last few years, several dementia conditions have been recognized as responsible for speech disorders [1]. The underlying pathology is variable and encompasses Alzheimer’s disease (AD) [2] and frontotemporal lobar degeneration, including its variants such as corticobasal degeneration and progressive supranuclear palsy (PSP) [3]. Particularly, beside the classical symmetric parkinsonism and gaze supranuclear palsy, PSP patients may present apraxia of speech (AOS) and progressive nonfluent aphasia (PNFA) [4]. AOS represents a motor speech disorder showing slow speech rate, prolonged intervals between words, decreased articulatory accuracy and sound distortions [4]. PNFA is a language disorder with dysfluent, effortful and agrammatic speech, often accompanied by similar difficulty with writing and comprehension [1]. Regardless of aetiology, AOS and PNFA usually co-occur, eventually leading to a complete mutism. Cortical atrophy predominantly shows a perisylvian distribution [1]. Unfortunately despite the recent advantages in diagnostic accuracy, the therapeutic options for these patients are disappointing. Repetitive TMS (rTMS) is based on the application of transient electromagnetic fields to induce electric currents in the brain and consequently transynaptic depolarization of neurons located in superficial cortical layers. Increased cortical excitability has been reported after high-frequency rTMS (5 Hz or higher), while the opposite after low-frequency (\1 Hz) [5]. Evidence is accumulating about a possible beneficial role of high-frequency left prefrontal rTMS on cognitive performances in subjects with dementia [7]. For example, improved naming was observed after stimulation of the dorsolateral prefrontal cortex (DLPF) [6]. This non-invasive technique has also been applied to improve both motor and non-motor symptoms in Parkinson’s disease (PD) [8]. However, one main feature of rTMS applied with traditional focal coils is its relatively narrow and superficial magnetic field, which can be a limiting factor when aiming to target deep or widespread brain regions, as could be the case in neurodegenerative disorders. Deep transcranial magnetic stimulation (DTMS) can be obtained with the H-coil, capable of generating broader and deeper magnetic field than the figure-of-8 coil, without significantly increasing superficial stimulation intensities [9]. The broader and deeper stimulation of H-coils may increase the risk for side effects, [10] however no significant safety concerns have been reported so far with the H2-coil, used in this study [11]. Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6772-3) contains supplementary material, which is available to authorized users.

Migralepsy: a new case confirming the existence of this migraine complication and proposing therapy

We describe the case of a 43-years-old, right handed woman, who suffered from migraine with aura and epilepsy. Co-morbidity of migraine and epilepsy is a well known condition since more than 100 years ago [1]. Although it is a rare phenomenon, migraine attack may trigger an epileptic seizure. ICHD II (International Classification of Headache Disorders) [2] classified migralepsy (migraine triggered seizures) as a complication of migraine (coded 1.5.5) if two diagnostic criteria are fulfilled: (1) migraine fulfilling diagnostic criteria for coded 1.2 migraine with aura and (2) a seizure fulfilling diagnostic criteria for one type of epileptic attack developing during or within 1 hour of a migraine aura. Despite the fact that the term migralepsy (attributed to Lennox and Lennox) [3] was coined in 1960 both to define an ‘‘ophtalmic migraine with perhaps nausea and vomiting followed by symptoms characteristics of epilepsy’’ and to describe three specific cases, the migraine-epilepsy sequence (migralepsy) seems to be less common than epilepsymigraine (hemicrania epileptica coded 7.6.1) and post-ictal headache (coded 7.6.2). A review of the literature suggested that migralepsy as coded by ICHD II is quite infrequent but not indeed inexistent [4]. A 43-years-old woman referred to the ER Department of San Raffaele Hospital, Milano, because of a generalized tonic seizure. She was born full term with a normal delivery and had normal developmental milestones. She has a family history positive for migraine with aura (mother) but no family member suffered from epilepsy. At age 9 years she developed migraine with visual and sensitive aura. Aura consisted of flickering flashing lights, developing gradually in 15 min with a global duration of 45 min, followed by sensitive symptoms (paresthesia of hand and face) and finally by headache with migraine features (frequency of 1 attack/month in the past; in the last months they rapidly increased to 8 attacks/month). In 21 September 2011, at 10:30 a.m. she experienced her typical visual aura (photopsia) for 15 minutes. After few minutes she noted the appearance of clonic palpebral movements in her right eye. She eventually lost consciousness, felt to the ground and had a generalized seizure (lasting 5 min). She was rapidly admitted at the Hospital, being unresponsive and confused during the transport. At Neurological examination (11:30 a.m.), patient was responsive to pain stimulus with no other signs. At general examination, blood pressure was 140/80, Heart rate 98 and O2 saturation 96 %. A slight metabolic acidosis was detected at blood gas analysis. Brain CT scan (12:00) was normal. She was treated with Diazepam i.v. (10 mg). A second neurological examination (1:30 p.m.) was normal, but patient reported the onset of a severe migraine attack (9/10 VAS) localized on the left parietal and temporal side with nausea, vomiting and photo-phonophobia. EEG (2:30 p.m.) revealed epileptiform discharges in right temporal hemisphere. Brain MRI was normal and when she performed EEG again, a normalization of the previously described epileptiform features was noted, with only residual theta slowing over the left hemisphere. A therapy with topiramate was started at the initial dose of 50 mg (after one week the dose was increased to 100 mg). At follow-up (3 and 6 months), she reported only three migraine attacks without aura in the first month of therapy (VAS 5/10) and no more migraine with aura attacks or epileptic seizures. EEG was normal. B. Colombo D. Dalla Libera (&) M. A. Volontè F. Spagnolo G. Dalla Costa V. Martinelli G. Comi Department of Neurology, San Raffaele Hospital, Vita-Salute University, Via Olgettina 48, Milan, Italy e-mail: dallalibera.dacia@hsr.it

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.

A complex case of anti-GAD antibody-related syndrome treated with Rituximab

Glutamic acid decarboxylase (GAD) is involved in the metabolism of gamma aminobutyric acid (GABA). AntiGAD antibodies (Ab) have been found in many neurological disorders [1], but also in autoimmune diseases such as type 1 diabetes mellitus, autoimmune thyroiditis and several other disorders associated under the autoimmune polyglandular syndrome-type 3 (APS-3) [1, 2]. We describe a patient suffering from a complex antiGAD Ab-related syndrome who was consecutively treated with intravenous immunoglobulins and plasma exchange without lasting benefit. Therapy with Rituximab brought instead some sustained improvement.

Motor Cortical Plasticity to Training Started in Childhood: The Example of Piano Players

Converging evidence suggest that motor training is associated with early and late changes of the cortical motor system. Transcranial magnetic stimulation (TMS) offers the possibility to study plastic rearrangements of the motor system in physiological and pathological conditions. We used TMS to characterize long-term changes in upper limb motor cortical representation and interhemispheric inhibition associated with bimanual skill training in pianists who started playing in an early age. Ipsilateral silent period (iSP) and cortical TMS mapping of hand muscles were obtained from 30 strictly right-handed subjects (16 pianists, 14 naïve controls), together with electromyographic recording of mirror movements (MMs) to voluntary hand movements. In controls, motor cortical representation of hand muscles was larger on the dominant (DH) than on the non-dominant hemisphere (NDH). On the contrary, pianists showed symmetric cortical output maps, being their DH less represented than in controls. In naïve subjects, the iSP was smaller on the right vs left abductor pollicis brevis (APB) indicating a weaker inhibition from the NDH to the DH. In pianists, interhemispheric inhibition was more symmetric as their DH was better inhibited than in controls. Electromyographic MMs were observed only in naïve subjects (7/14) and only to voluntary movement of the non-dominant hand. Subjects with MM had a lower iSP area on the right APB compared with all the others. Our findings suggest a more symmetrical motor cortex organization in pianists, both in terms of muscle cortical representation and interhemispheric inhibition. Although we cannot disentangle training-related from preexisting conditions, it is possible that long-term bimanual practice may reshape motor cortical representation and rebalance interhemispheric interactions, which in naïve right-handed subjects would both tend to favour the dominant hemisphere.