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Botulinum toxin (BT) is an effective and safe treatment for spasticity, with limited evidence in multiple sclerosis (MS). We aim to describe the use of BT for the management of MS spasticity in the clinical practice, its combination with other anti-spastic treatments in MS and possible MS clinical correlates. This is a multicentre cross-sectional observational study including 386 MS patients, receiving BT for spasticity in 19 Italian centres (age 53.6 ± 10.9 years; female 228 (59.1%); disease duration 18.7 ± 9.2 years; baseline Expanded Disability Status Scale (EDSS) 6.5 (2.0–9.0)). BT was used for improving mobility (n = 170), functioning in activities of daily living (n = 56), pain (n = 56), posturing-hygiene (n = 63) and daily assistance (n = 41). BT formulations were AbobotulinumtoxinA (n = 138), OnabotulinumtoxinA (n = 133) and IncobotulinumtoxinA (n = 115). After conversion to unified dose units, higher BT dose was associated with higher EDSS (Coeff = 0.591; p

Safinamide (SF) is a third-generation monoamine-oxidase-B inhibitor that proved efficacy as add-on to levodopa in fluctuating Parkinson’s disease (PD) patients. Despite the high prevalence of complicated PD in older population, the data on the tolerability, safety and efficacy of SF in elderly patients are rather poor. Here we studied retrospectively the consequences of add-on with SF in PD patients older than 65 years. Fifty-three fluctuating PD patients were included (30 subjects aged between 65 and 75 years, the remaining 23 subjects aged > 75 years). Patients were treated with either 50 (n = 27) or 100 mg (n = 26) SF for at least 6 months. In all patients, fluctuations were identified by the report of a Wearing-Off-Questionnaire-19 (WOQ-19) score ≥ 3 at baseline. Add-on with SF was well tolerated and safe. Adverse events occurred in 30% of patients and led to drug discontinuation in 11% of cases. At follow-up visits, 60% of patients reported lowering of the WOQ-19 score to ≤ 2. There were no significant differences related to age or daily drug dose in tolerability, safety or efficacy. The results of this study provide evidence of the efficacy, tolerability and safety of SF in elderly PD patients.

Objective: To determine if segmental muscle vibration and botulinum toxin-A injection, either alone or in combination, reduces spasticity in a sample of patients with multiple sclerosis. Design: Single-blind, randomized controlled trial. Setting: Physical medicine and rehabilitation outpatients service. Subjects: Forty-two patients affected by the secondary progressive form of multiple sclerosis randomized to group A (30 minutes of 120 Hz segmental muscle vibration over the rectus femoris and gastrocnemius medial and lateral, three per week, over a period of four weeks), group B (botulinum toxin in the rectus femoris, gastrocnemius medial and lateral and soleus, and segmental muscle vibration) and group C (botulinum toxin). Main measures: Modified Ashworth Scale at knee and ankle, and Fatigue Severity Scale. All the measurements were performed at baseline (T0), 10 weeks (T1) and 22 weeks (T2) postallocation. Results: Modified Ashworth Scale at knee and ankle significantly decreased over time ( p < 0.001) in all groups. Patients in group C displayed a significant increase of knee and ankle spasticity at T2 when compared with T1 ( p < 0.05). Fatigue Severity Scale values in groups A and C were significantly higher at T0 [A: 53.6 (2.31); C: 48.5 (2.77)] than at either T1 [A: 48.6 (2.21); p = 0.03; C: 43.5 (3.22); p = 0.03] or T2 [A: 46.7 (2.75); p = 0.02; 42.5 (2.17); p = 0.02], while no differences were detected in group B [T0: 43.4 (3.10); T1: 37.3 (3.15); T2: 39.7 (2.97)]. Conclusion: Segmental muscle vibration and botulinum toxin-A reduces spasticity and improves fatigue in the medium-term follow-up in patients with multiple sclerosis.

The purpose of the present study was to investigate the long-term persistence to treatment with botulinum toxin type A (BoNT-A) for multiple sclerosis (MS)-related spasticity and the determinants of BoNT-A discontinuation in daily clinical setting. We retrospectively collected data of patients who started BoNT-A injections and underwent regular follow-up visits. Determinants of BoNT-A discontinuation were explored in a time-to-event Cox regression analysis which included as independent variables a large set of demographic and clinical characteristics. A total of 185 patients started BoNT-A injections from 2002 to 2014 and were followed up to September 2016. Of them, data on 121 were considered in our analysis. At follow-up, 53 (44%) patients were still on treatment and 68 (56%) patients discontinued BoNT-A after a median time of 1.2 years [interval 6 months to 7.4 years]. The reasons for discontinuation were loss of efficacy (n = 45), logistic problems or barriers to reach the structure (n = 16), and adverse events (n = 7). The absence of caregiver (hazard ratio = 1.69, p = 0.03) and lack of regular rehabilitation (hazard ratio = 1.78, p = 0.02) were two independent predictors for BoNT-A discontinuation. Our study confirms the beneficial effect of combining BoNT-A injections with rehabilitation and highlights the crucial role of caregivers for achieving better long-term outcomes in people with MS suffering from spasticity.

Cognitive impairment is a frequent non-motorsymptom of Parkinson’s disease (PD). In early disease stage, this takes the features of dysexecutive syndrome, and is mostly dependent on derangement of frontostriatal circuitries. In advanced stages, worsening of dysexecutive symptoms is accompanied by disorientation and memory deficit leading to dementia in 30% of cases, due to multiple neurotransmitter derangement. Dysexecutive symptoms in the early stages of PD may benefit from dopamine replacement therapy (DRT). Conversely, severe cognitive symptoms in more advanced stages are frequently aggravated by DRT. In particular, pulsatile stimulation of dopaminergic receptors by orally administered levodopa (LD) plays a significant negative role on cognitive and neuropsychiatric symptoms in advanced PD. The introduction of a gel of LD-carbidopa for continuous intestinal administration (LCIG) allows marked stabilization of plasma LD concentrations and provides benefit on motor fluctuations and dyskinesia of significantly greater magnitude than conventional oral administration in advanced PD patients. The results from several preliminary studies suggest that efficacy of LCGI on motor symptoms may be accompanied by good tolerability and potential benefit on several non-motor symptoms, including cognitive impairment. Future studies with longer observation period and larger cohorts are advised to confirm these preliminary observations.

Previous reports showed the reduction of dopamine transporter immunoreactivity in peripheral blood lymphocytes in Parkinson's disease. In this work, we sought to investigate the possible correlation between central and peripheral dopamine transporter immunoreactivity values in a group of 11 drug-naive patients with Parkinson's disease.Densitometric measurements of dopamine transporter immunoreactivity in peripheral blood lymphocytes was accomplished as described recently, using a monoclonal antidopamine transporter antibody. Dopamine transporter binding in the caudate and putamen nuclei was measured by means of (123)I-fluopane single-photon emission computed tomography in the same patients.The results failed to show any significant correlation between dopamine transporter immunoreactivity in peripheral blood lymphocytes and the caudate or putamen dopamine transporter binding. Moreover, dopamine transporter immunoreactivity in peripheral blood lymphocytes was reduced also in the single patient with normal striatal dopamine transporter binding.These results indicate the lack of correlation between central and peripheral dopamine transporter reduction in Parkinson's disease, using the methodologies applied herein. They therefore suggest that the two phenomena are unlikely to share a common pathogenetic mechanism.

The motor symptoms of Parkinson's disease (PD), bradykinesia, muscular rigidity, and tremor depend upon degeneration of the dopaminergic neurons in the substantia nigra pars compacta. Recent neuropathological studies show that the Lewy bodies, the intraneuronal landmark of PD, accumulate in several neuronal cell types in the brain. An ascending gradient of pathological involvement, from the medulla oblongata to neocortical areas has been reported. Thus the original view of PD as a disease characterized by selective damage of the dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder. Additionally, the neuropathological alterations outside the substantia nigra are soundly correlated with the non-motor symptoms of PD. As a result of these findings, interest is growing in the identification of prodromal non-motor symptoms of PD. Indeed, data from the literature suggest that autonomic disturbances, olfactory dysfunctions, depression and sleep disorders (in particular REM-sleep behavior disorder) may represent prodromal non-motor symptoms of PD. Several tests are available to detect most of these symptoms. Thus, the identification of prodromal non-motor symptoms may contribute to the precocious diagnosis of PD, and might be useful in the future to test the efficacy of neuroprotective agents.

Peripheral blood lymphocytes (PBL) provide a model to study the changes of neurotransmitter-receptor systems in neurodegenerative disorders, including Parkinson's disease (PD). In this study, densitometric analysis was applied to measure dopamine transporter (DAT) immunoreactivity in PBL from dopaminergic drug-free patients suffering PD or essential tremor (ET) with respect to healthy subjects. The results showed a significant reduction of DAT immunoreactivity in PBL in PD but not in ET. These finding suggests that DAT immunoreactivity in PBL may discriminate between PD and ET in the early clinical stages.

By analyzing the kinematics of repetitive, constant-amplitude, finger oppositions, we compared the impairment of individual and nonindividual finger movements in patients with Parkinson's disease. In one task, subjects tapped only the index finger against the thumb (individual oppositions); in the other task, they tapped all four fingers together against the thumb pad (nonindividual oppositions). We used an optoelectronic motion analysis system to record movements in three-dimensional space and recorded three 5-second trials for each task. We counted how many finger oppositions subjects performed during each trial and measured the duration and amplitude of the flexions and extensions. We also calculated the duration of the pauses after flexion and extension. We assessed the deterioration of motor performance in patients by investigating the changes in speed and amplitude with task completion. During both tasks, normal subjects and patients performed finger flexions faster than extensions, and they invariably paused longer after flexion than after extension. Patients performed individual and nonindividual finger movements slowly and with reduced amplitude. Patients were disproportionately slow during flexion and in switching from flexion to extension. Movement slowness increased as finger oppositions progressed but predominantly when patients had to move fingers individually. In conclusion, in patients with Parkinson's disease, the motor performance deteriorated with task completion more during individual than during nonindividual finger movements. Parkinson's disease, therefore, impairs individual finger movements more than gross hand movements. This distinction reflects the finer cortical control needed to promote and sustain this highly fractionated type of motor output.

Levodopa (LD) provides the most effective symptomatic treatment for Parkinson's disease (PD). Long-term treatment with LD, however, is often associated with the development of response fluctuations. Previous evidence suggests that the short half-life of LD is a major contributor to the development of response fluctuations and the wearing-off phenomenon in particular. Entacapone, a peripheral catechol-O-methyltransferase inhibitor has been shown to reduce OFF time and increase ON time in several therapeutic trials on PD patients treated with LD experiencing motor fluctuations. However, data are missing on the tolerability and efficacy of entacapone in elderly PD patients. This is of particular relevance, as most PD patients develop LD-related motor fluctuations after several years of disease duration. Here we report that addition of entacapone in a group of 45 elderly PD patients with LD-related motor fluctuations is well tolerated and efficacious in reducing the time, frequency and severity of the OFF periods. These data suggest that the drug can be used safely and efficaciously in elderly PD patients.

Background Dopamine agonists (DA) are the first-choice drug for treatment of the early stage of Parkinson’s disease (PD) in subjects younger than 70 years. Recently, a number of third generation DA have been marketed, including transdermal patch of rotigotine and extended release oral formulation of ropinirole and pramipexole. We investigated the impact of third generation DA on management of the early stage of PD in an outpatient service for Movement Disorders in Italy. Methods Two 12-month observation periods were selected (January - December, 2007, and January - December, 2011) as representative for prescription of immediate and extended release formulations of DA respectively. Within each period, PD patients were divided into subgroups according to age (75 years) or functional requirement (high; moderate; low). For each period, the number of subjects receiving monotherapy with DA, monotherapy with levodopa (LD), or combined DA/LD therapy and the relative doses were calculated. The severity of parkinsonian motor symptoms was calculated by means of the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) score. The frequency and severity of side-effects leading to discontinuation or reduction of DA drugs at each time point were also calculated. Results We found a significant reduction of daily LD dose (both as mono- and combined therapy) between the second and the first observation period. There was also a significant increase of monotherapy with DA and corresponding reduction of monotherapy with LD in patients aged 65–75 years, as well as in PD patients with moderate functional requirements. A significant reduction of frequency of side-effects was measured with extended release DA as compared to immediate release formulations. There were no significant differences of the UPDRS-III scores between the 2 observation periods in any subgroup. Conclusions Our results suggest that extended release DA might optimize therapeutic management of the early stages of PD even in patients older than 70 years of age.

Fahr’s disease is a rare neurological disorder characterized by diffuse intracranial calcification with a prevalent involvement of the basal ganglia and dentate nucleus of the cerebellum. It has been reported to be an autosomal dominant inheritance in familial cases, although the causal gene is still unknown, and sporadic types have been described. Most cases initially present with a deterioration of motor function. Later in the development of the disease, other symptoms and signs occur, especially extrapyramidal symptoms. We report a case with an unusual presentation and no extrapyramidal signs: An 58-year-old woman was brought to the Emergency Department (ED) because of a sudden loss of consciousness with seizure and urinary incontinence. She denied chest or abdominal pain, nausea vomiting or diarrhea. Upon falling from the seizure, she sustained cranial trauma (frontal skull). She denied any past medication history, allergies to medications, chest or abdominal pain, nausea, vomiting or diarrhea. There was no family history of mental illness, dementia, or major physical illness. Prior to the present illness, she had been living independently. On physical examination, the patient was a healthy appearing woman who was 155 cm tall, and weighed 49 kg. The vital signs were: blood pressure 140/85 mmHg, pulse 70 beats/min, respirations 12 breaths/min, temperature 37 C. The general physical examination other than the skull contusion was unremarkable. Neurological examination revealed cerebellar ataxia (antagonist hypotonia, asynergy, dismetria and dysdiadochokinesia); there were no extrapyramidal signs, athetosis or dementia; normal cranial nerve functions, and no motor or sensory focal findings. A laboratory screening panel was normal including calcium (8.9 mg/dL) and phosphate (3.1 mg/dL). Because of the new onset seizure activity, a non-contrast head computed tomography (CT scan) was obtained, and revealed extensive and symmetrical hyper-dense lesions over the caudate, dentate nuclei and periventricular white substance (Figs. 1, 2). The patient was admitted to the medicine ward, where other examinations were performed. Routine laboratory investigation confirmed that calcium and phosphate ions were in normal range; also normal were other tests including inflammation indices and coagulation tests. An electroencephalogram (EEG) revealed a normal pattern. Imaging diagnostic procedures gave no evidence of radiographic cardiopulmonary lesions, and there were no tumors of bone or other organs. Magnetic resonance imaging of the head revealed multiple areas of modified intensity signal, hyper-intense in T2, softly hyper-intense in T1 calibrated images and hypointense using the echo gradient technique, localized into peri-ventricular area, semi-oval centers, basal nuclei and cerebellum dentate nucleus. A. Sentimentale (&) M. Matteoli M. Corsino E. Ferri S. Di Somma Department of Emergency Medicine, II Medical School University La Sapienza, Sant’Andrea Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy e-mail: alberto.sentimentale@ospedalesantandrea.it

Previous studies showed the reduction of dopamine transporter immunoreactivity (DAT-IR) in peripheral blood lymphocytes (PBL) in Parkinson's disease. Here we report the reduction of DAT-IR in PBL in the extrapyramidal variant of multiple system atrophy. These results suggest the reduction of DAT-IR in PBL in a variety of neurodegenerative disorders, provided the presence of damage of the central dopaminergic systems. The reduction of DAT-IR in PBL in these disorders may represent a compensatory phenomenon aimed at reducing intracellular dopamine influx and, consequently, dopamine-mediated aggravation of oxidative stress in these cells.

Objective : To determine whether additional physiotherapy increases botulinum toxin type A effects in reducing spasticity in patients with multiple sclerosis. Design : A single-blind, randomized, controlled pilot trial with a 12-week study period. Subjects : Thirty-eight patients with progressive multiple sclerosis affected by focal spasticity and who were observed at the Multiple Sclerosis Centre operating in the S. Andrea Hospital in Rome. Interventions : For intervention all patients received botulinum toxin type A; the treatment group also received additional physiotherapy to optimize management through passive or active exercise and stretching regimens. Main measures : To measure objective and subjective level of spasticity, patients were assessed at baseline, 2, 4 and 12 weeks post treatment by Modified Ashworth Scale and visual analogue scale. Results : When compared with the control group, we found a significant decrease of spasticity by Modified Ashworth Scale (P < 0.01 by t-test) in the treatment group at week 2 (2.73 versus 3.22), week 4 (2.64 versus 3.33) and week 12 (2.68 versus 3.33). The mean (%) difference in Modified Ashworth Scale score between baseline and the end of follow-up was —0.95 (26.1) in the treatment group and —0.28 (7.7) in the control group (P < 0.01). The combined treatment proved also to be more effective by visual analogue scale (P < 0.01) at week 4 (6.95 versus 5.50) and at week 12 (7.86 versus 6.56) but not at week 2 (5.18 versus 5.50; P = 0.41). Conclusions : Our data suggest that physiotherapy in combination with botulinum toxin type A injection can improve overall response to botulinum toxin.

By analyzing the kinematics of repetitive, constant-amplitude, finger oppositions, we compared the impairment of individual and nonindividual finger movements in patients with Parkinson's disease. In one task, subjects tapped only the index finger against the thumb (individual oppositions); in the other task, they tapped all four fingers together against the thumb pad (nonindividual oppositions). We used an optoelectronic motion analysis system to record movements in three-dimensional space and recorded three 5-second trials for each task. We counted how many finger oppositions subjects performed during each trial and measured the duration and amplitude of the flexions and extensions. We also calculated the duration of the pauses after flexion and extension. We assessed the deterioration of motor performance in patients by investigating the changes in speed and amplitude with task completion. During both tasks, normal subjects and patients performed finger flexions faster than extensions, and they invariably paused longer after flexion than after extension. Patients performed individual and nonindividual finger movements slowly and with reduced amplitude. Patients were disproportionately slow during flexion and in switching from flexion to extension. Movement slowness increased as finger oppositions progressed but predominantly when patients had to move fingers individually. In conclusion, in patients with Parkinson's disease, the motor performance deteriorated with task completion more during individual than during nonindividual finger movements. Parkinson's disease, therefore, impairs individual finger movements more than gross hand movements. This distinction reflects the finer cortical control needed to promote and sustain this highly fractionated type of motor output.

To investigate whether the type of movement cueing influences motor performance in patients with dystonia, we studied externally triggered (ET) and self-initiated (SI) sequential rapid arm movements in patients with generalized or focal dystonia and healthy control subjects. The ET task required subjects to initiate movements in response to consecutive visual cues; the SI task allowed them to start at will. To determine whether patients found sequential motor tasks more difficult than single tasks, we also analyzed single ET movements. Control subjects performed the SI task significantly faster than the ET task. Their single ET movements and first ET sequential submovements had similar speeds. Patients with generalized dystonia were slow in performing the single movement, the ET and the SI sequential tasks, and they executed the SI sequence more slowly than the ET. They made long pauses between SI sequential submovements, had longer reaction times during the ET sequences, and performed the first ET submovement more slowly than the single ET movement. Patients with focal dystonia had normal reaction times but they performed single and sequential tasks slowly, made long pauses during SI tasks, and also executed the first ET submovement more slowly than the single ET movement. Our findings indicate that patients with dystonia have a general impairment of sequential movements. The more marked slowness in executing SI than ET movements observed in patients with generalized dystonia shows that dystonia impairs internal cueing more than external cueing mechanisms. Overall, these findings imply abnormal activation of primary and nonprimary motor areas during movement in dystonia. The greater impairment of SI tasks as well as the delayed motor responses during ET task suggest predominant underactivity of the supplementary motor area.

We used transcranial magnetic stimulation in 10 patients with essential tremor and 8 matched healthy subjects. A round stimulating coil was placed over the vertex and electromyographic activity was recorded from the first dorsal interosseous muscle. Paired transcranial stimuli were delivered at interstimulus intervals of 3, 5, 20, 100, 150, and 200 ms. The intensity of the conditioning stimulus was 80% of motor threshold at short and 150% at long interstimulus intervals (ISIs). We also measured the silent period obtained after a single magnetic pulse delivered at 150% of motor threshold during a submaximal muscle contraction. Patients and controls had similar motor threshold and similar latencies. Paired magnetic stimuli given at short and long ISIs at rest, and during a voluntary muscle contraction, elicited similar responses in both groups. The silent period evoked by transcranial magnetic stimulation had a similar duration in patients with ET and controls. In conclusion, these findings suggest that patients with essential tremor have normal cortical motor area excitability. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1304–1308, 1998.