Giovanni Abbruzzese

Background: Safinamide modulates both dopaminergic and glutamatergic systems with positive effects on motor and non-motor symptoms of Parkinson’s disease (PD). The drug utilization study SYNAPSES was designed to investigate the use of safinamide in routine clinical practice, as recommended by the European Medicines Agency. Objective: To describe the occurrence of adverse events in PD patients treated with safinamide in real-life conditions. Methods: The SYNAPSES trial is an observational, European, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months with analyses performed in the overall population and in patients aged >75 years, with relevant comorbidities and with psychiatric conditions. Results: Of the 1610 patients included, 82.4% were evaluable after 12 months with 25.1% of patients >75 years, 70.8% with relevant comorbidities and 42.4% with psychiatric conditions. During observation 45.8% patients experienced adverse events, 27.7% patients had adverse drug reactions and 9.2% patients had serious adverse events. The adverse events were those already described in the patients’ information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroup of patients. Clinically significant improvements were seen in the UPDRS motor score and in the UPDRS total score in ≥40% of patients, according to the criteria developed by Shulman et al. Conclusion: The SYNAPSES study confirms the good safety profile of safinamide even in special groups of patients. Motor complications and motor scores improved with clinically significant results in the UPDRS scale maintained in the long-term.

Spinocerebellar ataxia 17 (SCA17) is one of the most heterogeneous forms of autosomal dominant cerebellar ataxias with a large clinical spectrum which can mimic other movement disorders such as Huntington disease (HD), dystonia and parkinsonism. SCA17 is caused by an expansion of CAG/CAA repeat in the Tata binding protein (TBP) gene. Normal alleles contain 25 to 40 CAG/CAA repeats, alleles with 50 or greater CAG/CAA repeats are pathological with full penetrance. Alleles with 43 to 49 CAG/CAA repeats were also reported and their penetrance is estimated between 50 and 80%. Recently few symptomatic individuals having 41 and 42 repeats were reported but it is still unclear whether CAG/CAA repeats of 41 or 42 are low penetrance disease-causing alleles. Thus, phenotypic variability like the disease course in subject with SCA17 locus restricted expansions remains to be fully understood. The patients was a 63-year-old woman who, at 54 years, showed personality changes and increased frequency of falls. At 55 years of age neuropsychological tests showed executive attention and visuospatial deficit. At the age of 59 the patient developed dysarthria and a progressive cognitive deficit. The neurological examination showed moderate gait ataxia, dysdiadochokinesia and dysmetria, dysphagia, dysarthria and abnormal saccadic pursuit, severe axial asynergy during postural changes, choreiform dyskinesias. Molecular analysis of the TBP gene demonstrated an allele with 41 repeat suggesting that 41 CAG/CCG TBP repeats could be an allele associated with the full clinical spectrum of SCA17. The described case with the other similar cases described in the literature suggests that 41 CAG/CAA trinucleotides should be considered as critical threshold in SCA17. We suggest that SCA17 diagnosis should be suspected in patients presenting with movement disorders associated with other neurodegenerative signs and symptoms.

Levodopa is still recognised to be the “gold standard” symptomatic treatment for Parkinson’s disease. After 4–5 years however, its clinical efficacy declines and patients may experience the so-called “long-term levodopa syndrome”, which represents the clinical counterpart of the changes of pharmacodynamic response to the drug. Long duration response (LDR) is substituted by the short duration response (SDR), which is responsible for the fluctuations of the clinical response. Strategies aimed at maintaining the clinical benefits for as long as possible and postponing the occurrence of motor complications as late as possible have been at the centre of scientific debates in recent years. We are still far from optimal use of the drug in the different stages or the disease, both regarding mode of administration and dose adjustment to individual needs.

Background: Primary late-onset focal dystonias may spread over time to adjacent body regions, but differences in the risk of spread over time among the various focal forms and the influence of age at dystonia onset on the risk of spread are not well established. Methods: Patients presenting with primary late-onset focal blepharospasm (BSP, n = 124), cervical dystonia (CD, n = 73) and focal hand dystonia (FHD, n = 24) with 10 years or more of disease duration (mean ± SD, 15.3 (SD 4.9) years) were included in the study. The relationship between demographic/clinical variables and spread of dystonia was assessed by Kaplan–Meier survival curves and Cox proportional hazard regression models. Results: Patients starting with BSP, CD and FHD had similar age, sex and disease duration. Age at dystonia onset, age at initial spread and the risk of initial spread were significantly higher, whereas time elapsing from onset to initial spread was significantly lower in the BSP group than in those with onset in the neck or in the upper extremities. Conversely, these parameters were similar in the CD and FHD groups. The greater risk of spread in the BSP group was mainly evident in the first 5 years of history; thereafter, it declined and became similar to that of patients with CD/FHD. The difference in the risk of initial spread by site of onset was partly confounded by age at dystonia onset. Site of and age at dystonia onset, and age at first spread, were not significant predictors of the risk of a second spread. Conclusion: This study adds new insights into the phenomenon of spread of primary late-onset focal dystonia and provides the framework for future studies aimed at an indepth investigation of the mechanism(s) of spread.

We tested the hypothesis that transcranial magnetic stimulation (TMS), in addition to its inhibitory action on the corticospinal output, can also exert some inhibitory effect on the transcallosal system connecting the two motor cortices. In seven normal subjects, instructed to keep their right opponens pollicis (OP) muscle fully relaxed and their left OP muscle voluntarily contracted, we used a paired-pulse TMS protocol, to stimulate the left motor cortex. We evaluated the effect of low-intensity conditioning stimulation on the ipsilateral silent period (iSP) elicited by the subsequent test stimulus. Compelling evidence exists to support that this iSP is mediated by the activation of transcallosal motor fibres. Simultaneously, the inhibition of the motor evoked potential (MEP) in the right OP muscle was also investigated. At the interstimulus interval (ISI) of 3 ms, the iSP was significantly (P P<0.05, repeated-measures ANOVA). Several findings suggest that the suppression of iSP is brought about by the activation of inhibitory mechanisms operating in the stimulated (left) motor cortex. We propose that the assessment of iSP suppression could be a method to study the excitability of intracortical inhibitory circuits in the affected hemisphere of patients with unilateral damage of the corticospinal tract.

A simple visual reaction time (RT) paradigm was used to investigate whether the velocity of relaxation is impaired in dystonia. In 16 subjects with a clinical diagnosis of adult‐onset focal, segmental or multifocal dystonia and in 15 age‐matched normal controls, the relaxation reaction time (R‐RT) and the contraction reaction time (C‐RT) were compared across different tasks involving the flexor carpi radialis (FCR), biceps brachii (BB) and triceps brachii (TR) arm muscles. In normal controls, the latency of EMG termination (R‐RT) was significantly shorter than the latency of electromyographic (EMG) onset (C‐RT) in the BB and TR muscles, but not in the FCR muscle. In dystonic patients, the latency of EMG termination (R‐RT) was significantly longer than the latency of EMG onset (C‐RT) in the FCR and BB muscles. No significant difference of the C‐RT was observed between patients and controls whereas the R‐RT was prolonged significantly in the BB and TR muscles of patients with dystonia and almost significantly in the FCR muscle. This study indicates that muscle relaxation is abnormal in patients with focal (multifocal or segmental) dystonia. The impaired muscle relaxation may contribute to the longer overlap of agonist–antagonist activities (co‐contraction) typically observed in dystonia and to the slowness of voluntary movement sequencing. © 2004 Movement Disorder Society

To analyse the effect of concomitant cognitive or motor task performance on balance control in Parkinson's disease (PD), we performed a posturographic study in 24 PD patients and in 20 sex‐ and age‐matched control subjects. Postural sway was measured with eyes open (EO) and eyes closed (EC) during quiet stance and during performance of calculation or motor sequence of thumb opposition to the other fingers. No difference of centre of foot pressure (COP) parameters was observed during quiet standing (either EO or EC) between patients and controls, but visual deprivation induced in both groups a worsening of postural stability. COP area was significantly increased in PD patients during dual task performance, whereas no difference of COP path and x–y axes was observed. The effects induced by the performance of cognitive or motor task were significantly more evident in PD patients with clinical evidence of postural instability (presence of prior falls in the history). This study demonstrates that dual task interference on postural control can be observed in PD patients during performance of cognitive as well as motor tasks. The balance deterioration during dual task performance was significantly enhanced in patients with history of prior falls. These findings have some implications for the strategies to be used in reducing the risk of fall in PD. © 2003 Movement Disorder Society

Although current knowledge attributes movement disorders to a dysfunction of the basal ganglia–motor cortex circuits, abnormalities in the peripheral afferent inputs or in their central processing may interfere with motor program execution. We review the abnormalities of sensorimotor integration described in the various types of movement disorders. Several observations, including those of parkinsonian patients' excessive reliance on ongoing visual information during movement tasks, suggest that proprioception is defective in Parkinson's disease (PD). The disturbance of proprioceptive regulation, possibly related to the occurrence of abnormal muscle‐stretch reflexes, might be important for generating hypometric or bradykinetic movements. Studies with somatosensory evoked potentials (SEPs), prepulse inhibition, and event‐related potentials support the hypothesis of central abnormalities of sensorimotor integration in PD. In Huntington's disease (HD), changes in SEPs and long‐latency stretch reflexes suggest that a defective gating of peripheral afferent input to the brain might impair sensorimotor integration in cortical motor areas, thus interfering with the processing of motor programs. Defective motor programming might contribute to some features of motor impairment in HD. Sensory symptoms are frequent in focal dystonia and sensory manipulation can modify the dystonic movements. In addition, specific sensory functions (kinaesthesia, spatial–temporal discrimination) can be impaired in patients with focal hand dystonia, thus leading to a “sensory overflow.” Sensory input may be abnormal and trigger focal dystonia, or defective “gating” may cause an input–output mismatch in specific motor programs. Altogether, several observations strongly support the idea that sensorimotor integration is impaired in focal dystonia. Although elemental sensation is normal in patients with tics, tics can be associated with sensory phenomena. Some neurophysiological studies suggest that an altered “gating” mechanism also underlies the development of tics. This review underlines the importance of abnormal sensorimotor integration in the pathophysiology of movement disorders. Although the physiological mechanism remains unclear, the defect is of special clinical relevance in determining the development of focal dystonia.

The evaluation of motor cortical output after transcranial magnetic stimulation (TMS) is a means of investigating how the motor cortex reacts to external stimuli (i.e., a method to assess the excitability of the motor cortex). The recording of the descending volleys at the surface of the spinal cord provides a direct measure of the motor cortical output. However, this approach is highly invasive and can be used only during particular conditions. On the other hand, electromyographic recordings of the motor phenomena induced by TMS provide a completely painless, noninvasive, indirect measure of the cortical output, with these phenomena obviously reflecting the excitability of the spinal motoneurons as well as that of the muscle itself. The authors review how the electromyographic activity induced by TMS can provide valuable information about motor cortical excitability for use in clinical practice and research.

When spasticity produces a clinical disability by interfering with posture, motor capacity, nursing or daily living activities, medical treatment is recommended. It is mainly indicated when the muscle overactivity is diffusely distributed and should be implemented early, to prevent permanent musculoskeletal deformities or contractures. A pharmacological approach relies on the use of drugs which modulate neurotransmitters acting at the cortico‐spinal level (GABA, glycine, glutamate, noradrenaline, serotonin). The aim of this treatment is to decrease spinal reflex excitability by reducing the release of excitatory neurotransmitters, or by potentiating the activity of inhibitory inputs. Evaluation of the efficacy of these drugs is determined by the therapeutic objectives which may be biomechanical, or functional. Diazepam increases presynaptic inhibition by stimulating GABA_A receptors in the brainstem and spinal cord. In double‐blind studies of patients with spinal cord lesions, antispastic efficacy has been shown, but side‐effects are common. Baclofen stimulates GABA_B receptors inducing a suppression of excitatory neurotransmitter release. Antispastic efficacy is sufficiently documented, but no definite effects on ambulation or activities of daily living have been proved. Tizanidine has an α₂‐agonist activity (at spinal and supraspinal level) and decreases the presynaptic activity of excitatory interneurones. The main clinical effects are a reduction in tonic stretch, polysynaptic reflexes, and co‐contraction, with fewer side‐effects but no definite functional change. The efficacy of several other antispastic drugs is documented in a few controlled studies, but the majority of information arises from open trials or anecdotal observations.