Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activity, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA’s neuroprotective action derives from animal models of Alzheimer’s disease, Parkinson’s disease, Huntington’s diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

BACKGROUND: Patient journey maps are increasingly used as a tool that enables healthcare providers to refine their service provision to best meet patient needs. We developed a cervical dystonia patient journey map (CDPJM) that describes the holistic patient experience from pre-diagnosis through to long-term treatment. METHODS: The CDPJM was developed in 2 stages; a patient survey (open questions and multichoice) of 15 patients with CD was conducted to inform the design of the CDPJM, which was then refined and validated by an expert-patient focus group. RESULTS: Qualitative analysis of the patient survey supported five key stages of the patient journey: symptom onset, diagnosis and therapeutic relationship with healthcare professionals, initiation of care for CD, start of CD treatment, and living with treated CD. Following symptom onset, survey respondents described having multiple visits to their family doctor who prescribed strong pain killers and muscle relaxants and referred their patient to up to 10 different specialists for diagnosis. Over half (53.3%) of respondents had received >/= 1 misdiagnosis. Respondents reported relief at having a diagnosis but a lack of understanding of the prognosis and treatment options; 46.7% said their neurologist did not spend enough time addressing their concerns. Survey respondents reported using a variety of alternative sources of information, including the internet (86.7%), self-help groups (66.7%) and information leaflets provided by health care professionals (60.0%). While botulinum toxin (BoNT) was consistently discussed as the main treatment option, some neurologists also mentioned physiotherapy, counselling, and other complementary approaches. However, patients were often left to seek complementary services themselves. Patients reported a ‘rollercoaster’ of relief with BoNT treatment with symptoms (and subsequent impact on daily life) returning towards the end of an injection cycle. “When BoNT works well I can return to an almost normal life … when the injections stop working so well, I have to rest more and avoid going to work and experience life restrictions.” CONCLUSIONS: We present the first patient journey map for CD that can be used to guide local service mapping and to compare current provision with what patients say they want and need.

We analysed clinical trials of pharmacological interventions on patients with amyotrophic lateral sclerosis (ALS), and compared study quality and design features. The systematic review included articles published in PubMed and trials registered in ClinicalTrials.gov. Included studies were randomised double-blind placebo-controlled clinical trials assessing a disease-modifying pharmacological intervention. Studies were excluded if primary end points were safety or dose finding. A total of 28 735 articles and 721 current trials were identified. 76 published articles and 23 ongoing trials met inclusion criteria; they referred to distinct populations comprising 22 817 participants with ALS. Most articles and all current trials had parallel group design; few articles had cross-over design. A run-in observation period was included in about 20% of published studies and ongoing trials. Primary end points included functional assessment, survival, muscle strength, respiratory function, biomarkers and composite measures. Most recent trials had only functional assessment and survival. Risk of bias was high in 23 articles, moderate in 35, low in 18. A disease modification effect was observed for 10 interventions in phase II studies, two of which were confirmed in phase III. Three confirmatory phase III studies are currently underway. The present review provides cues for the design of future trials. Functional decline and survival, as single or composite measures, stand as the reference end points. Post hoc analyses should not be performed, particularly in studies using composite end points. There is a general agreement on diagnostic criteria; but eligibility criteria must be improved. Run-in observations may be used for censoring patients but are discouraged for refining participants’ eligibility. The ALS Functional Rating Scale-Revised needs improvement for use as an ordinal measure of functional decline.

OBJECTIVE: We aimed to describe the prevalence and clinical-demographical features of patients with functional gait disorders (FGDs) and to compare them to patients with functional motor disorders (FMDs) without FGDs (No-FGDs). METHODS: In this multicenter observational study, we enrolled patients with a clinically definite diagnosis of FMDs in 25 tertiary movement disorders centers in Italy. Each subject with FMDs underwent a comprehensive clinical assessment, including screening for different subtypes of functional gait disorders. Multivariate regression models were implemented in order to estimate the adjusted odds ratio (OR; 95% confidence interval) of having FGDs in relation to sociodemographic and clinical characteristics. RESULTS: Out of 410 FMDs, 26.6% (n = 109) of patients exhibited FGDs. The most frequent FGDs were slow gait (n = 43, 39.4%), astasia-abasia (n = 26, 23.8%), and knee buckling (n = 24, 22%). They exhibited single FGDs in 51.4% (n = 56) or complex FGDs (more than one type of FGDs) in 48.6% (n = 53) of cases. On multivariate regression analysis, the presence of FGDs was more likely associated with older age (OR 1.03, 95% CI 1.01-1.04), functional visual symptoms (OR 2.19, 95% CI 1.08-4.45), and the diagnosis of somatic symptoms disorder (OR 2.97, 95% CI 1.08-8.17). FGDs were also more likely to undergo physiotherapy (OR 1.81, 95% CI 1.08-3.03). CONCLUSIONS: People with FMDs may present with different and overlapping types of FGDs, which may occur in older age. The association of FGDs with functional visual symptoms and somatic symptoms disorder opens up to new avenues to the understanding of the neural mechanisms of these disorders.

INTRODUCTION: Functional motor disorders (FMDs) are usually categorized according to the predominant phenomenology; however, it is unclear whether this phenotypic classification mirrors the underlying pathophysiologic mechanisms. OBJECTIVE: To compare the characteristics of patients with different FMDs phenotypes and without co-morbid neurological disorders, aiming to answer the question of whether they represent different expressions of the same disorder or reflect distinct entities. METHODS: Consecutive outpatients with a clinically definite diagnosis of FMDs were included in the Italian registry of functional motor disorders (IRFMD), a multicenter data collection platform gathering several clinical and demographic variables. To the aim of the current work, data of patients with isolated FMDs were extracted. RESULTS: A total of 176 patients were included: 58 with weakness, 40 with tremor, 38 with dystonia, 23 with jerks/facial FMDs, and 17 with gait disorders. Patients with tremor and gait disorders were older than the others. Patients with functional weakness had more commonly an acute onset (87.9%) than patients with tremor and gait disorders, a shorter time lag from symptoms onset and FMDs diagnosis (2.9 +/- 3.5 years) than patients with dystonia, and had more frequently associated functional sensory symptoms (51.7%) than patients with tremor, dystonia and gait disorders. Patients with dystonia complained more often of associated pain (47.4%) than patients with tremor. No other differences were noted between groups in terms of other variables including associated functional neurological symptoms, psychiatric comorbidities, and predisposing or precipitating factors. CONCLUSIONS: Our data support the evidence of a large overlap between FMD phenotypes.

BACKGROUND AND PURPOSE: The aims of this study were to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases (“comorbid FMDs”), and to compare comorbid FMDs with FMDs not overlapping with other neurological diseases (“pure FMDs”). METHODS: For this multicenter observational study, we enrolled outpatients with a definite FMD diagnosis attending 25 tertiary movement disorder centers in Italy. Each patient with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Group comparisons (comorbid FMDs vs. pure FMDs) were performed in order to compare demographic and clinical variables. Logistic regression models were created to estimate the adjusted odds ratios (95% confidence intervals) of comorbid FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables). RESULTS: Out of 410 FMDs, 21.7% of patients (n = 89) had comorbid FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%), FMDs appeared after the diagnosis of a neurological disease. Patients with comorbid FMDs were older, and more frequently had tremor, non-neurological comorbidities, paroxysmal non-epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid FMDs was more likely associated with longer time lag until the final diagnosis of FMD, presence of tremor and non-neurological comorbidities. CONCLUSIONS: Our findings highlight the need for prompt diagnosis of FMDs, given the relatively high frequency of associated neurological and non-neurological diseases.

Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.

We aimed to study the attitude of Italian neurologists in the use of conventional MRI in patients with idiopathic adult-onset focal dystonia. Patients were included in the Italian Dystonia Registry by experts working in different Italian centers. MRI was available for 1045 of the 1471 (71%) patients included in the analysis. Using logistic regression analysis, we found that MRI was more likely to be performed in patients with cervical dystonia, spasmodic dysphonia, or non-task-specific upper limb dystonia, whereas it was less likely to be performed in patients with blepharospasm or task-specific upper limb dystonia. We did not find differences in the number of MRIs performed between neurological centers in Northern, Central, and Southern Italy. We conclude that although the diagnosis of idiopathic adult-onset dystonia is mainly based on clinical grounds, many movement disorder experts rely on MRI to confirm a diagnosis of idiopathic dystonia. We suggest that neuroimaging should be used in patients with adult-onset focal dystonia to rule out secondary forms.

Improved care for people with dystonia presents a number of challenges. Major gaps in knowledge exist with regard to how to optimize the diagnostic process, how to leverage discoveries in pathophysiology into biomarkers, and how to develop an evidence base for current and novel treatments. These challenges are made greater by the realization of the wide spectrum of symptoms and difficulties faced by people with dystonia, which go well-beyond motor symptoms. A network of clinicians, scientists, and patients could provide resources to facilitate information exchange at different levels, share mutual experiences, and support each other’s innovative projects. In the past, collaborative initiatives have been launched, including the American Dystonia Coalition, the European Cooperation in Science and Technology (COST-which however only existed for a limited time), and the Dutch DystonieNet project. The European Reference Network on Rare Neurological Diseases includes dystonia among other rare conditions affecting the central nervous system in a dedicated stream. Currently, we aim to broaden the scope of these initiatives to a comprehensive European level by further expanding the DystoniaNet network, in close collaboration with the ERN-RND. In line with the ERN-RND, the mission of DystoniaNet Europe is to improve care and quality of life for people with dystonia by, among other endeavors, facilitating access to specialized care, overcoming the disparity in education of medical professionals, and serving as a solid platform to foster international clinical and research collaborations. In this review, both professionals within the dystonia field and patients and caregivers representing Dystonia Europe highlight important unsolved issues and promising new strategies and the role that a European network can play in activating them.

OBJECTIVE: To assess the prevalence and phenomenology of Impulse control behavior (ICB) in Parkinson’s disease (PD) patients carrying mutations in the beta-glucocerebrosidase (GBA) gene. BACKGROUND: GBA mutations are a common genetic factor predisposing to PD. ICB is among the most disabling non-motor complications of PD. The occurrence of ICB in PD patients carrying GBA gene mutations (GBA-PD) has not been yet established. METHODS: Forty-six patients with clinically definite PD (23 GBA-PD and 23 non-mutated patients, NM-PD) were screened for ICB. Diagnosis was clinically and rating based on a specific questionnaire (QUIP-RS). Other demographic and clinical variables did not differ between groups. RESULTS: ICB occurred more frequently in GBA-PD patients (52.2%) compared to NM-PD (13%) and the total QUIP-RS score was higher in the GBA-PD group. Hypersexuality and compulsive shopping were the most prevalent ICB types occurring in GBA patients. ICB occurred only in one GBA-PD patient on levodopa monotherapy and in 11 patients taking dopamine agonists, either monotherapy or combined with levodopa (the corresponding figures in NM-PD patients were 0 and 3). Most GBA-PD patients were heterozygous for two common genetic variants, without appreciable difference in their ICB profile. CONCLUSION: ICB is more common in GBA-PD patients compared to NM-PD. Dopamine agonist therapy may be synergic to GBA carrier status for ICB occurrence.

BACKGROUND: Functional motor disorders (FMDs) are abnormal movements that are significantly altered by distractive maneuvers and are incongruent with movement disorders seen in typical neurological diseases. OBJECTIVE: The objectives of this article are to (1) describe the clinical manifestations of FMDs, including nonmotor symptoms and occurrence of other functional neurological disorders (FND); and (2) to report the frequency of isolated and combined FMDs and their relationship with demographic and clinical variables. METHODS: For this multicenter, observational study, we enrolled consecutive outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each patient underwent a detailed clinical evaluation with a definition of the phenotype and number of FMDs (isolated, combined) and an assessment of associated neurological and psychiatric symptoms. RESULTS: Of 410 FMDs (71% females; mean age, 47 +/- 16.1 years) the most common phenotypes were weakness and tremor. People with FMDs had higher educational levels than the general population and frequent nonmotor symptoms, especially anxiety, fatigue, and pain. Almost half of the patients with FMDs had other FNDs, such as sensory symptoms, nonepileptic seizures, and visual symptoms. Patients with combined FMDs showed a higher burden of nonmotor symptoms and more frequent FNDs. Multivariate regression analysis showed that a diagnosis of combined FMDs was more likely to be delivered by a movement disorders neurologist. Also, FMD duration, pain, insomnia, diagnosis of somatoform disease, and treatment with antipsychotics were all significantly associated with combined FMDs. CONCLUSIONS: Our findings highlight the need for multidimensional assessments in patients with FMDs given the high frequency of nonmotor symptoms and other FNDs, especially in patients with combined FMDs.

Cervical dystonia is associated with neck pain in a significant proportion of cases, but the mechanisms underlying pain are largely unknown. In this exploratory study, we compared demographic and clinical variables in cervical dystonia patients with and without neck pain from the Italian Dystonia Registry. Univariable and multivariable logistic regression analysis indicated a higher frequency of sensory trick and a lower educational level among patients with pain.

Introduction: Cervical dystonia (CD) is one of the most common forms of adult-onset isolated dystonia. Recently, CD has been classified according to the site of onset and spread, in different clinical subgroups, that may represent different clinical entities or pathophysiologic subtypes. In order to support this hypothesis, in this study we have evaluated whether different subgroups of CD, that clinically differ for site of onset and spread, also imply different sensorimotor features. Methods: Clinical and demographic data from 842 patients with CD from the Italian Dystonia Registry were examined. Motor features (head tremor and tremor elsewhere) and sensory features (sensory trick and neck pain) were investigated. We analyzed possible associations between motor and sensory features in CD subgroups [focal neck onset, no spread (FNO-NS); focal neck onset, segmental spread (FNO-SS); focal onset elsewhere with segmental spread to neck (FOE-SS); segmental neck involvement without spread (SNI)]. Results: In FNO-NS, FOE-SS, and SNI subgroups, head tremor was associated with the presence of tremor elsewhere. Sensory trick was associated with pain in patients with FNO-NS and with head tremor in patients with FNO-SS. Conclusion: The frequent association between head tremor and tremor elsewhere may suggest a common pathophysiological mechanism. Two mechanisms may be hypothesized for sensory trick: a gating mechanism attempting to reduce pain and a sensorimotor mechanism attempting to control tremor.

OBJECTIVE: The objective of this study was to describe the clinical and demographic features of idiopathic non-task-specific upper limb dystonia compared with the task-specific form. METHODS: In this retrospective study, adult patients with idiopathic upper limb dystonia, either focal or as part of a segmental/multifocal dystonia, from the Italian Dystonia Registry were enrolled. In patients with focal upper limb dystonia, dystonia spread was estimated by survival analysis. RESULTS: Of the 1522 patients with idiopathic adult-onset dystonia included in the Italian Dystonia Registry, we identified 182 patients with upper limb dystonia. Non-task-specific dystonia was present in 61.5% of enrolled cases. Women predominated among non-task-specific patients, whereas men predominated in the task-specific group. Peak age of upper limb dystonia onset was in the sixth decade in the non-task-specific group and in the fourth decade in the task-specific group. In both groups, upper limb dystonia started as focal dystonia or as part of a segmental dystonia. Segmental onset was more frequent among non-task-specific patients, whereas focal onset predominated among task-specific patients. Dystonic action tremor was more frequent among non-task-specific patients. No significant differences between groups emerged in terms of sensory trick frequency, rest tremor, or family history of dystonia. In patients with focal upper limb dystonia, dystonia spread was greater in the non-task-specific group. CONCLUSION: Novel information on upper limb dystonia patients suggests that non-task-specific and task-specific upper limb dystonia have different demographic and clinical features. However, it remains to be determined whether these differences also reflect pathophysiological differences. (c) 2020 International Parkinson and Movement Disorder Society.

BACKGROUND: Variants in GBA are the most common genetic risk factor for Parkinson’s disease (PD). The impact of different variants on the PD clinical spectrum is still unclear. OBJECTIVES: We determined the frequency of GBA-related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time. METHODS: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. beta-glucocerebrosidase activity was measured. The Kaplan-Meier method and Cox proportional hazard regression models were performed. RESULTS: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA-PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA-PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA-PD had the lowest beta-glucocerebrosidase activity. CONCLUSIONS: GBA-PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles. (c) 2020 International Parkinson and Movement Disorder Society.

Background: Parkinson’s disease (PD) is one of the most common chronic neurological conditions leading to disability and social burden. According to the 2016 Italian National Plan on Chronic Diseases, regional health authorities are implementing dedicated networks to manage neurological diseases, including PD. Methods: A panel of experts representing health-care providers in Lombardy reached consensus on the organization of a patient-centered regional PD healthcare network. Results: The panel proposed a structure and organization implementing a hub-and-spoke PD network model. Three levels of neurological services were identified: General Neurologist, PD Clinic, PD Center. This model was applied to health service providers currently accredited in Lombardy, yielding 12 candidate PD Centers, each serving an area of ~1,000-2,000 km(2), and not less than 27 PD Clinics. The panel agreed on uniform diagnostic and staging criteria for PD, and on a minimum common clinical data set, on PD patient management by the network at initial and follow-up assessments, on the cadence of follow-up visits, on patient referrals, and on outcome measures for the assessment of network activities. Conclusions: The implementation of disease-centered networks for chronic neurological diseases provides an innovative opportunity to improve patient management, facilitate research and education.

BACKGROUND: Acute peripheral trauma is a controversial risk factor for idiopathic dystonia. MATERIALS AND METHODS: We retrospectively analyzed data from the Italian Dystonia Registry regarding the occurrence of acute peripheral trauma severe enough to require medical attention in 1382 patients with adult-onset idiopathic dystonia and 200 patients with acquired adult-onset dystonia. RESULTS: Patients with idiopathic and acquired dystonia showed a similar burden of peripheral trauma in terms of the number of patients who experienced trauma (115/1382 vs. 12/200, p=0.3) and the overall number of injuries (145 for the 1382 idiopathic patients and 14 for the 200 patients with secondary dystonia, p=0.2). Most traumas occurred before the onset of idiopathic or secondary dystonia but only a minority of such injuries (14 in the idiopathic group, 2 in the acquired group, p=0.6) affected the same body part as that affected by dystonia. In the idiopathic group, the elapsed time between trauma and dystonia onset was 8.1+/-9.2 years; only six of the 145 traumas (4.1%) experienced by 5/1382 idiopathic patients (0.36%) occurred one year or less before dystonia onset; in the acquired dystonia group, the two patients experienced prior trauma to the dystonic body part 5 and 6 years before dystonia development. DISCUSSION AND CONCLUSION: Our data suggest that the contribution of peripheral acute trauma to idiopathic dystonia is negligible, if anything, and likely involves only a small subset of patients.

BACKGROUND: There is a discrepancy in the way dystonia is classified in the literature, as articles continue to reference the old criteria or fail to use the 2013 criteria correctly. METHODS: We performed a systematic review of the dystonia literature and distinguished between studies that use the new classification correctly, made errors in implementing the new classification, or continued to use the old classification methods. RESULTS: Of the 990 articles included in the study, 59.8% used the classification correctly, 31.3% used mixed terminology, and 8.9% continued to use the old classification. Articles relating to surgery were significantly less likely to use the new classification correctly. There is an upward trend in the annual rate of articles properly referencing the new classification. CONCLUSIONS: The 2013 classification has been well received in scientific literature, and more studies are adapting to its use.

OBJECTIVE: The current study aimed to assess the effects of five cycles of automated mechanical somatosensory stimulation (AMSS) of the fore-feet on blood pressure (BP) and cardiovascular autonomic control in Parkinson’s Disease patients. METHODS: Out of 23 patients, 16 underwent an AMSS session every 72 h, for a total of five sessions per patient. Electrocardiogram, noninvasive beat-to-beat blood pressure and respiratory activity were recorded for 20 min in supine position at baseline and after the AMSS sessions. Main outcomes were the changes in SBP and DBP, in the spectral indices of cardiac sympathetic (LFRRn.u.) and vagal (HFRR) modulatory activities, cardiac sympathovagal relationship (LF/HF), vascular sympathetic modulation (LFSAP) and arterial baroreflex sensitivity (sequence technique). Symbolic analysis of heart rate variability provided additional indices of cardiac sympathetic (0V%) and vagal (2UV%) modulation to the sinoatrial node. RESULTS: After five AMSS trials a reduction in SBP (baseline: 131.2 +/- 15.5 mmHg; post-AMSS: 122.4 +/- 16.2 mmHg; P = 0.0004) and DBP (baseline: 73.2 +/- 6.1 mmHg; post-AMSS: 68.9 +/- 6.2 mmHg; P = 0.008) was observed. Post-AMSS, spectral and symbolic indices of cardiovascular sympathetic control decreased and arterial baroreflex sensitivity increased (baseline: 5.7 +/- 1.3 ms/mmHg; post-AMSS: 11.27 +/- 2.7 ms/mmHg). CONCLUSION: AMSS sessions were effective in reducing BP, increasing baroreflex sensitivity and decreasing cardiovascular sympathetic modulation in Parkinson’s disease patients. AMSS might be useful to control supine hypertension in Parkinson’s disease.

Several symptomatic treatments for Parkinson’s disease (PD) are currently available. Still, the challenge today is to find a therapy that might reduce degeneration and slow down disease progression. The identification of pathogenic mutations in familial Parkinsonism (fPD) associated to the monogenic forms of PD provided pathophysiological insights and highlighted novel targets for therapeutic intervention. Mutations in the VPS35 gene have been associated with autosomal dominant fPD and a clinical phenotype indistinguishable from idiopathic PD. Although VPS35 mutations are relatively rare causes of PD, their study may help understanding specific cellular and molecular alterations that lead to accumulation alpha-synuclein in neurons of PD patients. Interacting with such mechanisms may provide innovative therapeutic approaches. We review here the evidence on the physiological role of VPS35 as a key intracellular trafficking protein controlling relevant neuronal functions. We further analyze VPS35 activity on alpha-synuclein degradation pathways that control the equilibrium between alpha-synuclein clearance and accumulation. Finally, we highlight the strategies for increasing VPS35 levels as a potential tool to treat PD.

BACKGROUND: Diagnosis of focal dystonia is based on clinical grounds and is therefore open to bias. To date, diagnostic guidelines have been only proposed for blepharospasm and laryngeal dystonia. To provide practical guidance for clinicians with less expertise in dystonia, a group of Italian Movement Disorder experts formulated clinical diagnostic recommendations for cervical, oromandibular, and limb dystonia. METHODS: A panel of four neurologists generated a list of clinical items related to the motor phenomenology of the examined focal dystonias and a list of clinical features characterizing neurological/non-neurological conditions mimicking dystonia. Thereafter, ten additional expert neurologists assessed the diagnostic relevance of the selected features and the content validity ratio was calculated. The clinical features reaching a content validity ratio > 0.5 contributed to the final recommendations. RESULTS: The recommendations retained patterned and repetitive movements/postures as the core feature of dystonia in different body parts. If present, a sensory trick confirmed diagnosis of dystonia. In the patients who did not manifest sensory trick, active exclusion of clinical features related to conditions mimicking dystonia (features that would be expected to be absent in dystonia) would be necessary for dystonia to be diagnosed. DISCUSSION: Although reliability, sensitivity, and specificity of the recommendations are yet to be demonstrated, information from the present study would hopefully facilitate diagnostic approach to focal dystonias in the clinical practice and would be the basis for future validated diagnostic guidelines.

PURPOSE OF REVIEW: We provide a practical guide on the use of electromyography (EMG) and ultrasound (US) to assist botulinum neurotoxin (BoNT) treatment in patients with cervical dystonia (CD). RECENT FINDINGS: US and EMG guidance improve BoNT treatment in CD. Their use is particularly valuable for targeting deep neck muscles and managing complex cases. There is also evidence that adverse events are reduced when superficial or intermediate layer muscles are injected with assisted guidance. SUMMARY: A structured clinical approach, based on functional neck anatomy, guides CD assessment and BoNT treatment. Muscles are selected according to clinical, EMG and US findings. US provides anatomical visualization, while EMG complements by detecting muscle activity. We review here the current practice for assisted treatment of CD through BoNT cycles. We also describe how to recognize and manage the main adverse events.

Clinical practice in dystonia has greatly evolved in recent years; a synthetic review on patient management is provided here. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures or both. A recent classification has innovated clinical practice and serves as guidance for clinical assessment: Axis I describes clinical features, whereas Axis II indicates etiology. Dystonia presents with different syndromic aggregations with varied somatic involvement and some common features. There are five recognizable physical signs of dystonia: two main signs (dystonic postures and movements) and three additional signs (gestes antagonistes or tricks, mirror dystonia and overflow dystonia). There is still no validation of diagnostic criteria for the different dystonia syndromes, and many cases with mild phenomenology remain undiagnosed. Patients with dystonia also present non-motor features that are variably combined with the movement disorder. The features of the most common inherited and acquired dystonia syndromes are reviewed here. There is clear evidence of genetic-environmental interaction in the determinism of dystonia. The diagnostic process is guided by clinical examination and based on specific laboratory examinations. Symptomatic treatments are available for dystonia: botulinum neurotoxin injections are the primary choice for most focal dystonia syndromes; deep brain stimulation is useful in some generalized and non-generalized syndromes. Additional treatment strategies are currently being assessed.

BACKGROUND: The benefits of neurosurgery in Tourette Syndrome (TS) are still incompletely understood. Prefrontal cortical electrical stimulation offers a less invasive alternative to deep brain stimulation. OBJECTIVE: To perform a pilot assessment on safety and efficacy of prefrontal cortical bilateral electrical stimulation in TS using clinical and brain metabolic assessments. METHODS: Four adult TS patients underwent tic assessment using the Yale Global Tic Severity Scale and the Rush Video Rating Scale at baseline and 1, 3, 6, and 12-months after implant; whereas FDG-PET scans were acquired at baseline and after 6 and 12 months. RESULTS: Tic clinical scores were improved at 6 months after implant, meanwhile they showed a tendency to re-emerge at the 12-month follow-up. There was a correlation between FDG-PET and tics, mainly consisting in a reduction of baseline brain hypermetabolism, which paralleled tic score reduction. CONCLUSION: Epidural stimulation in TS is safe and yields a modulation of tics, paralleled by FDG-PET metabolic modulation.

Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts’ primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning. Fibroblasts’ analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p<0.05), and a reduction of complex II steady-state level (p<0.01); a reduction of Coenzyme Q10 level (p<0.001) and an up-regulation of some CoQ10 biosynthesis enzymes, namely COQ5 and COQ7; an impairment of mitophagy, demonstrated by a decreased reduction of mitochondrial markers after mitochondrial inner membrane depolarization (p<0.05); a reduced basal autophagic activity, shown by a decreased level of LC3 II (p<0.05); an increased mitochondrial mass in MSA-C, demonstrated by higher TOMM20 levels (p<0.05) and suggested by a wide analysis of mitochondrial DNA content in blood of large cohorts of patients. The present study contributes to understand the causative mechanisms of Multiple System Atrophy. In particular, the observed impairment of respiratory chain activity, mitophagy and Coenzyme Q10 biosynthesis suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of the disease. Furthermore, these findings will hopefully contribute to identify novel therapeutic targets for this still incurable disorder.

BACKGROUND AND PURPOSE: The quality of clinical practice guidelines on dystonia has not yet been assessed. Our aim was to appraise the methodological quality of guidelines worldwide and to analyze the consistency of their recommendations. METHODS: We searched for clinical practice guidelines on dystonia diagnosis/treatment in the National Guideline Clearinghouse, PubMed, National Institute for Health and Care Excellence, Guidelines International Network and Web of Science databases. We also searched for guidelines on homepages of international neurological societies. We asked for guidelines from every Management Committee member of the BM1101 Action of the Cooperation between Science and Technology European framework and every member of the International Parkinson and Movement Disorders Society with special interest in dystonia. RESULTS: Fifteen guidelines were evaluated. Among guidelines on treatment, only one from the American Academy of Neurology could be considered as high quality. Among guidelines on diagnosis and therapy, the guideline from the European Federation of Neurological Societies was recommended by the appraisers. Clinical applicability and reports of editorial independence were the greatest shortcomings. The rigor of development was poor and stakeholder involvement was also incomplete in most guidelines. Discrepancies among recommendations may result from the weight given to consensus statements and expert opinions due to the lack of evidence, as well as inaccuracy of disease classification. CONCLUSIONS: The quality of appraised guidelines was low. It is necessary to improve the quality of guidelines on dystonia, and the applied terminology of dystonia also needs to be standardized.

There are many rare movement disorders, and new ones are described every year. Because they are not well recognized, they often go undiagnosed for long periods of time. However, early diagnosis is becoming increasingly important. Rapid advances in our understanding of the biological mechanisms responsible for many rare disorders have enabled the development of specific treatments for some of them. Well-known historical examples include Wilson disease and dopa-responsive dystonia, for which specific and highly effective treatments have life-altering effects. In recent years, similarly specific and effective treatments have been developed for more than 30 rare inherited movement disorders. These treatments include specific medications, dietary changes, avoidance or management of certain triggers, enzyme replacement therapy, and others. This list of treatable rare movement disorders is likely to grow during the next few years because a number of additional promising treatments are actively being developed or evaluated in clinical trials. (c) 2017 International Parkinson and Movement Disorder Society.

Botulinum neurotoxins (BoNTs) are increasingly used in clinical practice for several indications. Following the pioneering years of discoveries, the recent years have witnessed an increase of new indications and new toxin brands. We review here the clinical trials on BoNTs performed since 2014 and put them into perspective. We also review the ongoing trials listed by the National Institutes of Health registry (Clinicaltrials.gov). The following indications are reviewed here: blepharospasm, cervical dystonia, spasticity, cerebral palsy, urinary incontinence, headache, topical formulations, postoperative cardiac arrhythmia, keloids and scars. For each of these indications the latest trials are reviewed and commented.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

The aim of this review was to provide strong clinical evidence of the efficacy of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in isolated inherited or idiopathic dystonia. Eligible studies were identified after a systematic literature review of the effects of bilateral GPi-DBS in isolated dystonia. Absolute and percentage changes from baseline in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor and disability scores were pooled, and associations between treatment effect and patient characteristics were explored using meta-regression. In total, 24 studies were included in the meta-analysis, comprising 523 patients. The mean absolute and percentage improvements in BFMDRS motor score at the last follow-up (mean 32.5 months; 24 studies) were 26.6 points [95% confidence interval (CI), 22.4-30.8] and 65.2% (95% CI, 59.6-70.7), respectively. The corresponding changes in disability score at the last follow-up (mean 32.9 months; 14 studies) were 6.4 points (95% CI, 5.0-7.8) and 58.6% (95% CI, 50.3-66.9). Multivariate meta-regression of absolute scores indicated that higher BFMDRS motor and disability scores before surgery, together with younger age at time of surgery, were the main factors associated with significantly better DBS outcomes at the latest follow-up. Reporting of safety data was frequently inconsistent and could not be included in the meta-analysis. In conclusion, patients with isolated inherited or idiopathic dystonia significantly improved after GPi-DBS. Better outcomes were associated with greater dystonia severity at baseline. These findings should be taken into consideration for improving patient selection for DBS.

The Italian Dystonia Registry is a multicenter data collection system that will prospectively assess the phenomenology and natural history of adult-onset dystonia and will serve as a basis for future etiological, pathophysiological and therapeutic studies. In the first 6 months of activity, 20 movement disorders Italian centres have adhered to the registry and 664 patients have been recruited. Baseline historical information from this cohort provides the first general overview of adult-onset dystonia in Italy. The cohort was characterized by a lower education level than the Italian population, and most patients were employed as artisans, builders, farmers, or unskilled workers. The clinical features of our sample confirmed the peculiar characteristics of adult-onset dystonia, i.e. gender preference, peak age at onset in the sixth decade, predominance of cervical dystonia and blepharospasm over the other focal dystonias, and a tendency to spread to adjacent body parts, The sample also confirmed the association between eye symptoms and blepharospasm, whereas no clear association emerged between extracranial injury and dystonia in a body site. Adult-onset dystonia patients and the Italian population shared similar burden of arterial hypertension, type 2 diabetes, coronary heart disease, dyslipidemia, and hypothyroidism, while hyperthyroidism was more frequent in the dystonia population. Geographic stratification of the study population yielded no major difference in the most clinical and phenomenological features of dystonia. Analysis of baseline information from recruited patients indicates that the Italian Dystonia Registry may be a useful tool to capture the real world clinical practice of physicians that visit dystonia patients.

The study aimed to evaluate safety and efficacy of shifting stimulation settings from constant-voltage (CV) to constant-current (CC) programming in patients with Parkinson’s disease (PD) and chronic subthalamic nucleus deep brain stimulation (STN DBS). Twenty PD patients with chronic STN DBS set in CV programming were shifted to CC and followed for 3 months; the other stimulation settings and the medication regimen remained unchanged. Side effects, motor, non-motor, executive functions, and impedance were assessed at baseline and during follow-up. No adverse events were observed at time of shifting or during CC stimulation. Motor and non-motor measures remained unchanged at follow-up despite impedance decreased. Compared to baseline, inhibition processes improved at follow-up. The shifting strategy was well tolerated and the clinical outcome was maintained with no need to adjust stimulation settings or medications notwithstanding a decrease of impedance. Improvement of inhibition processes is a finding which needed further investigation.

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

Literary reports on dystonia date back to post-Medieval times. Medical reports are instead more recent. We review here the early descriptions and the historical establishment of a consensus on the clinical phenomenology and the diagnostic features of dystonia syndromes. Lumping and splitting exercises have characterized this area of knowledge, and it remains largely unclear how many dystonia types we are to count. This review describes the history leading to recognize that focal dystonia syndromes are a coherent clinical set encompassing cranial dystonia (including blepharospasm), oromandibular dystonia, spasmodic torticollis, truncal dystonia, writer’s cramp, and other occupational dystonias. Papers describing features of dystonia and diagnostic criteria are critically analyzed and put into historical perspective. Issues and inconsistencies in this lumping effort are discussed, and the currently unmet needs are critically reviewed.

INTRODUCTION: Deep brain stimulation (DBS) is effective for some neurological and psychiatric conditions. Idiopathic delayed-onset edema (IDE) surrounding the leads has been anecdotally reported. The etiology, predisposing factors and prognosis of this complication are unknown. We present a multicenter case series of patients with IDE, and a systematic literature review, aimed at defining the pathophysiology and identifying appropriate treatment strategies. METHODS: IDE was defined as edema along the DBS lead, occurring >/=72 h postoperatively, in absence of trauma, vascular events or infection. Information on patients with IDE was collected in a standardized way. A systematic search was performed in Pubmed. RESULTS: Twelve new patients presenting with 14 episodes of IDE are described. From the literature, 38 patients were identified. No common surgical aspects or patient-related factors were identified as risk predictors for the onset of IDE. Symptoms included deterioration of the stimulation effect, seizures and focal neurological signs. Although the condition is self-limiting, with symptoms resolution in 28.5 days on average, three patients underwent surgical revision and seven received antibiotics. CONCLUSIONS: IDE is a rare complication of DBS procedures, presenting from few days to months after surgery. Symptoms can be mild and not-specific, and the condition is self-limiting. The diagnosis of IDE is made after exclusion of vascular events or infections. The pathophysiology is still unexplained. The recognition of this complication can help avoiding unnecessary surgical procedures (system explantation) and antibiotic treatment.

OBJECTIVE: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). METHODS: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. RESULTS: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 x 10(-6), including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. CONCLUSIONS: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.

INTRODUCTION: Parkin disease (PARK2, OMIM 602544) is an autosomal-recessive early-onset parkinsonism characterized by an early occurrence of lower limb dystonia. The aim of this study was to analyze spatiotemporal, kinematic, and kinetic gait parameters in patients with parkin disease in the OFF and ON conditions compared to healthy age-matched controls. METHODS: Fifteen patients with parkin disease and 15 healthy age-matched controls were studied in a gait analysis laboratory with an integrated optoelectronic system. Spatiotemporal, kinematic, and kinetic gait parameters at a self-selected speed were recorded in the OFF and ON conditions. A jerk index was computed to quantify the possible reduction of smoothness of joint movements. RESULTS: Compared to controls, parkin patients had, either in the OFF or in the ON conditions, significant reduction of walking velocity, increased step width, and decreased percentage of double support. Kinematic analysis in both conditions showed: increased ankle dorsiflexion and knee flexion at the initial contact; maximal flexion and increased range of motion in mid stance; increased hip flexion and max extension in stance at pelvis; and increased mean tilt antiversion. Kinetics showed increased hip and knee power generation in stance in either condition. The jerk index was increased at all joints both in OFF and ON. There were no correlations between individual gait parameters and clinical ratings. CONCLUSION: Parkin patients have an abnormal gait pattern that does not vary between the OFF and the ON conditions. Variations recorded with instrumented analysis are more evident for kinematic than kinetic parameters at lower limbs. Severity of dystonia does not correlate with any individual kinematic parameter. (c) 2016 International Parkinson and Movement Disorder Society.

The American Academy of Neurology (AAN) has updated its guidelines on the use of botulinum neurotoxins in neurological disorders. The new guidelines provide individual recommendations for the four products that are commercially available in the USA; however, the clinical differences between the products are still not clear.

BACKGROUND: Dystonia and tremor share many commonalities. Isolated tremor is part of the phenomenological spectrum of isolated dystonia and of essential tremor. The occurrence of subtle features of dystonia may allow one to differentiate dystonic tremor from essential tremor. Diagnostic uncertainty is enhanced when no features of dystonia are found in patients with a tremor syndrome, raising the question whether the observed phenomenology is an incomplete form of dystonia. METHODS: Known forms of syndromes with isolated tremor are reviewed. Diagnostic uncertainties between tremor and dystonia are put into perspective. RESULTS: The following isolated tremor syndromes are reviewed: essential tremor, head tremor, voice tremor, jaw tremor, and upper-limb tremor. Their varied phenomenology is analyzed and appraised in the light of a possible relationship with dystonia. DISCUSSION: Clinicians making a diagnosis of isolated tremor should remain vigilant for the detection of features of dystonia. This is in keeping with the recent view that isolated tremor may be an incomplete phenomenology of dystonia.

BACKGROUND AND PURPOSE: Dystonia is difficult to recognize due to its large phenomenological complexity. Thus, the use of experts in dystonia is essential for better recognition and management of dystonia syndromes (DS). Our aim was to document managing strategies, facilities and expertise available in various European countries in order to identify which measures should be implemented to improve the management of DS. METHODS: A survey was conducted, funded by the Cooperation in Science and Technology, via the management committee of the European network for the study of DS, which is formed from representatives of the 24 countries involved. RESULTS: Lack of specific training in dystonia by general neurologists, general practitioners as well as other allied health professionals was universal in all countries surveyed. Genetic testing for rare dystonia mutations is not readily available in a significant number of countries and neurophysiological studies are difficult to perform due to a lack of experts in this field of movement disorders. Tetrabenazine is only readily available for treatment of dystonia in half of the surveyed countries. Deep brain stimulation is available in three-quarters of the countries, but other surgical procedures are only available in one-quarter of countries. CONCLUSIONS: Internationally, collaboration in training, advanced diagnosis, treatment and research of DS and, locally, in each country the creation of multidisciplinary teams for the management of dystonia patients could provide the basis for improving all aspects of dystonia management across Europe.

Botulinum neurotoxins (BoNTs) are used to achieve therapeutic benefit in focal dystonia. An expert panel recently reviewed published evidence on the efficacy of BoNTs for the treatment of focal dystonias and produced recommendations for clinical practice. Another panel reviewed the clinimetric properties of rating scales for dystonia and produced recommendations for current usage and future directions. Considering that the strength of evidence derives not only from the quality of the study design, but also from usage of validated outcome measures, we combined the information provided by these two recent reviews and assessed the appropriateness of the rating instruments used in clinical trials on BoNT treatment in focal dystonia. Data sources included all the publications on BoNT treatment for focal dystonias reviewed by the recent evidence-based analysis. We reviewed all rating instruments used to assess primary and secondary outcome following BoNT treatment. The publications were allocated into five topics according to the focal dystonia type reviewed in the meta-analysis: blepharospasm, oromandibular dystonia, cervical dystonia, upper limb dystonia, and laryngeal dystonia. For each topic, papers were divided, according to the terminology used in the meta-analysis, into placebo-controlled, active comparator and methodological or uncontrolled. For each topic we identified the rating tools used in each study class and annotated which were the mostly used in each focal dystonia type. Outcome measures included tools related to motor and non-motor features, such as pain and depression, and functional as well as health-related quality of life features. Patient- and investigator-reported outcomes were also included. Rating instruments were classified as recommended, suggested, listed or not included, based on recommendations produced by the rating scale task force. Both primary and secondary outcome measures were assessed. As a final step we compared current practice, as summarized by the meta-analysis, with the recommendations of the rating scales panel. For blepharospasm, three placebo-controlled trials used suggested scales, one active-comparator study used a recommended scale and three active-comparator studies used suggested scales. For oromandibular dystonia, one placebo-controlled study used a suggested scale. For cervical dystonia, six placebo-controlled trials used a recommended scale, four active-comparator trials used a recommended scale and one active-comparator study used a suggested scale. For upper limb and laryngeal dystonia, no trial used validated instruments. Appropriately designed studies should be based on recommended rating instruments. Therapeutic trials not using clinimetrically tested rating measures do not provide sufficient information on efficacy of BoNT treatment, even if the study design is robust. Further research is needed to develop and validate new tools to assess all types of focal dystonia and to apply them in prospective placebo-controlled clinical trials.

1. Albanese A, Abbruzzese G, Dressler D, Duzynski W, Khatkova S, Marti MJ, Mir P, Montecucco C, Moro E, Pinter M, Relja M, Roze E, Skogseid IM, Timerbaeva S, Tzoulis C. Practical guidance for CD management involving treatment of botulinum toxin: a consensus statement. Journal of Neurology, 262: 2201-2213, 2015.

Knowledge on dystonia has greatly improved recently, because of a renewed effort in understanding its cause, pathophysiology, and clinical characterization. Different drug classes traditionally have been used for the symptomatic treatment of dystonia, more recently surpassed by the introduction of botulinum neurotoxins and deep brain stimulation. No curative or disease-modifying treatments are available. Recent knowledge regarding the pathophysiology of inherited dystonias is highlighting new potential treatment strategies. We review therapeutic advances in dystonia that have been published over the last 3 years, particularly regarding oral medications, local injections of botulinum neurotoxins, deep brain stimulation, and transcranial or epidural brain stimulations. We discuss evidence of efficacy, highlight recent advances, and focus on key areas under development.

OBJECTIVE: We performed a real-life observation of patients with Parkinson disease (PD) who received duodenal levodopa infusion (DLI) to determine which adverse events caused treatment discontinuation and when such events occurred. METHODS: All consecutive patients with PD treated at the Carlo Besta Neurological Institute were included. The patients were evaluated at baseline and after DLI at regular intervals. Their motor condition was assessed and adverse events were recorded. RESULTS: Thirty-five patients with PD (15 men and 20 women) were included. They received DLI implants between October 2007 and September 2013. Four patients died of causes unrelated to the procedure. At the end of the study, 21 patients (60%) were still on treatment. DLI provided efficacious motor control in all patients. Discontinuation was most frequently caused by device- or infusion-related adverse events. Ten patients of the remaining 31 discontinued DLI. There were 2 main causes of withdrawal: stoma infection (4 patients), and worsening of dyskinesias not manageable with infusion reduction (3 patients). In most patients, discontinuations occurred during the first year after implant. Risk of discontinuation was related to age at implant, but no other demographic or clinical variables. CONCLUSIONS: We identified 2 main causes leading to DLI withdrawal during the first year postimplant and suggest adopting measures to prevent such occurrences. Elderly patients are at higher risk of treatment discontinuation.

Mutations in PARK2, encoding Parkin, cause an autosomal recessive form of juvenile Parkinson Disease (JPD). The aim of the present study was to investigate the impact of PARK2 mutations on mitochondrial function and morphology in human skin fibroblasts. We analyzed cells obtained from four patients clinically characterized by JPD, harboring recessive mutations in PARK2. By quantitative PCR we found a reduction (<50%) of PARK2 transcript in all patients but one; however Western Blot analysis demonstrated the virtual absence of Parkin protein in all mutant fibroblasts. Respiration assays showed an increment of oxygen consumption, which was uncoupled to ATP cellular levels. This finding was probably due to presence of altered mitochondrial membrane potential (DeltaPsim), confirmed by JC-1 analysis. The mitochondrial network was comparable between mutant and control cells but, interestingly, a “chain-like” network was found only in mutant fibroblasts. Dissipation of DeltaPsim usually leads to mitochondrial fragmentation in healthy cells and eventually to mitophagy; however, this behavior was not observed in patients’ fibroblasts. The absence of mitochondrial fragmentation in mutant Parkin fibroblasts could results in accumulation of damaged mitochondria not targeted to mitophagy. This condition should increase the oxidative stress and lead to cellular dysfunction and death. Our results suggest that PARK2 mutations cause mitochondrial impairment, in particular reduction in ATP cellular levels and alteration of DeltaPsim, even in non-neuronal cells and confirm the hypothesis that Parkin holds a pivotal role in pro-fission events.

BACKGROUND AND PURPOSE: There is increasing evidence that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is effective in patients with idiopathic or inherited generalized dystonia. There is comparatively less experience about the effects of GPi DBS on acquired dystonia, particularly dystonia due to cerebral palsy (DCP). Clinical and demographic outcome predictors for DBS in dystonia syndromes are also poorly defined. Our aim was to examine the efficacy and safety of GPi DBS for the treatment of generalized DCP. METHODS: Fifteen patients with DCP up to 6.2 years after DBS surgery were studied. Only mild limb spasticity or mild static brain magnetic resonance imaging abnormalities were acceptable for inclusion. Dystonia severity and disability were assessed by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS), and health-related quality of life was assessed by the Short Form General Health Survey (SF-36) scale. The amount of energy delivered was calculated, and adverse events and side effects were collected. RESULTS: At last follow-up, BFMDRS motor score improved on average by 49.5%, and the disability score improved by 30%. Health-related quality of life improved in most patients. Age at implant, age at onset and disease duration did not correlate to outcome, whilst higher pre-operative dystonia severity and occurrence of spasticity were associated with poorer outcome. The patients received a stable amount of energy after the first 2 years post-implant and throughout all the observation period. There were few serious adverse events or side effects. CONCLUSIONS: The outcome was encouraging in the majority of DCP patients, with a stable outlook and a good safety profile.

OBJECTIVE: Sustained abnormal postures (i.e., fixed dystonia) are the most frequently reported motor abnormalities in complex regional pain syndrome (CRPS), but these symptoms may also develop after peripheral trauma without CRPS. Currently, there is no valid and reliable measurement instrument available to measure the severity and distribution of these postures. The range of motion scale (ROMS) was therefore developed to assess the severity based on the possible active range of motion of all joints (arms, legs, trunk, and neck), and the present study evaluates its reliability and validity. METHODS: Inter- and intra-rater reliability of the ROMS was determined in 16 patients with abnormal sustained postures, who were videotaped following a standard video protocol in a university hospital. The recordings were rated by a panel of international experts. In addition, 30 patients were clinically tested with both the Burke-Fahn-Marsden (BFM) scale as well as the ROMS to assess construct validity. RESULTS: Inter-rater reliability for total ROMS scores showed an intra-class correlation coefficient (ICC) of 0.85. The majority of the scores for the separate joints (13 out of 18) demonstrated an almost perfect agreement with ICCs ranging from 0.81 to 0.94; of the other items, one showed fair, one moderate, and three substantial agreement. The ICCs for the intra-rater reliability ranged from moderate to almost perfect (0.68-0.98). Spearman’s correlation coefficients between corresponding body areas as measured with the ROMS or BFM were all above 0.82. CONCLUSION: The ROMS is a reliable and valid instrument to evaluate the severity and distribution of sustained abnormal postures.

A recent consensus update classifies dystonia according to two main axes describing the motor features and the different etiologies. Dystonia with no other neurological signs is called “isolated”, whereas dystonia associated with other neurological signs is called “combined”. Since its first description by Oppenheim, dystonia has been considered a pure motor disorder, but recently non-motor features have been recognized as part of clinical phenotype. In isolated dystonias psychiatric disturbances including depression, anxiety disorders and obsessive-compulsive disorder have been frequently reported. Also cognitive deficits, mainly of executive and visuospatial domains, have been observed, but no major cognitive impairment or dementia were reported. Also in combined dystonia syndrome psychiatric and cognitive dysfunction are described, with differences among specific syndromes. The topic of neuropsychiatric features in dystonia is evolving and further studies are needed to elucidate the observed phenomenological diversities.

OBJECTIVE: To document the occurrence of impulse control behaviours (ICBs) in patients with Parkinson’s disease after 3 years of continuous deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: Detailed neurological and ICB assessments were performed before STN DBS and up to 3 years after implant. RESULTS: 13 out of 56 patients (23.2%) had ICBs at baseline; they took higher doses of dopamine agonists (DAA). Three years after implant 11 had fully remitted with a 60.8% reduction of DAA medication; the remaining two, who had a similar medication reduction, had only compulsive eating, having recovered from hypersexuality. Six of the 43 patients without ICBs at baseline (14%) developed transient de novo ICBs after implant; none of them had ICBs at the 3-year observation. CONCLUSIONS: ICBs were abolished in patients 3 years after STN DBS and DAA dosages were lowered. New ICBs may occur after implant and are transient in most cases. Compulsive eating may be specifically related to STN stimulation.

BACKGROUND: Deep Brain Stimulation of the Subthalamic Nucleus (STN-DBS) is an effective treatment for Parkinson’s disease (PD), but only few studies investigated its long-term efficacy. Furthermore, little is known about the role of PD-subtype on STN-DBS long-term outcome. OBJECTIVE: To report the results of a long-term follow-up (mean 11 years, range 10-13) on 26 patients bilaterally implanted in two centres. METHODS: Patients were assessed preoperatively and 1, 5 and 11 years after the implant by the Unified Parkinson’s Disease Rating Scale (UPDRS) and a battery of neuropsychological tests. Stimulation parameters, drugs dosages, non-motor symptoms and adverse events were also recorded. RESULTS: At 11 years, stimulation significantly improved the motor symptoms by 35.8%, as compared to the preoperative off-state. Motor complications were well controlled, with a 84.6% improvement of dyskinesias and a 65.8% improvement of motor fluctuations. Despite this, the UPDRS-II-on score worsened by 88.5%, mainly for the worsening of poorly levodopa-responsive symptoms. More than 70% of the patients performed in the normal range in most of the neuropsychological tests, despite the development of dementia in 22.7%. Age at disease onset, axial subscore in off-condition and presence of REM behaviour disorder at baseline were found to be associated with a higher risk of developing disability over time. CONCLUSIONS: Our study confirms the long-term safety and efficacy of STN-DBS in PD. Nevertheless, the functionality of patients worsens over time, mainly for the onset and progression of levodopa-resistant and non-motor symptoms. The role of PD-subtype seems to be relevant in the long-term outcome.

This study focused on the substantia nigra (SN) in Parkinson’s disease (PD). We measured its area and volume, mean diffusivity (MD), fractional anisotropy (FA) and iron concentration in early and late PD and correlated the values with clinical scores. Twenty-two early PD (EPD), 20 late PD (LPD) and 20 healthy subjects (age 64.7 +/- 4.9, 60.5 +/- 6.1, and 61 +/- 7.2 years, respectively) underwent 1.5 T MR imaging with double-TI-IR T1-weighted, T2*-weighted and diffusion tensor imaging scans. Relative SN area, MD, FA and R2* were measured in ROIs traced on SN. Correlation with Unified Parkinson Disease Rating Scale (UPDRS) scores was assessed. In LPD, the SN area was significantly reduced with respect to EPD (p = 0.04) and control subjects (p < 0.001). In EPD, the SN area was also significantly smaller than in controls (p = 0.006). Similarly, the SN volume significantly differed between LPD and controls (p = 0.001) and between EPD and LPD (p = 0.049), while no significant differences were found between controls and EPD. Both SN area (r = 0.47, p = 0.004) and volume (r = 0.46, p = 0.005) correlated with UPDRS scores. At 1.5 T, SN morphological measurements were sensitive to early PD changes and able to track the disease progression, while MD and FA measures and relaxometry did not provide significant results.

The original clinical application of botulinum neurotoxin was in the treatment of strabismus by local chemical denervation of the neuromuscular junction and relaxation of the muscle with a duration of several months. This initial application has been followed by use of the neurotoxin to treat a wide range of disorders of muscle hyper-contraction. Botulinum neurotoxin is now a major clinical product for the treatment of spasticity and muscle hyperactivity. Muscle relaxation also underpins the cosmetic use of the neurotoxin. This chapter will review and assess the clinical utility of the various botulinum products in neuromuscular disorders.

Musician’s dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer’s dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 x 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 x 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 x 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (lambda = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

OBJECTIVE: Assessing the frequency of Wearing-Off (WO) in Parkinson’s disease (PD) patients, and its impact on Quality of Life (QoL). METHODS: Consecutive ambulatory patients, who were on dopaminergic treatment for >/= 1 year, were included in this multicentre, observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as using the validated Italian version of a patient self-rated 19-question Wearing-Off Questionnaire (WOQ-19); WO was defined for scores >/= 2. QoL was evaluated by the 8-item Parkinson’s Disease Questionnaire (PDQ-8). RESULTS: 617 subjects were included, with a mean anti-Parkinson treatment duration of 6.6 +/- 4.6 years, 87.2% were on levodopa treatment. Neurologists identified presence of WO in 351 subjects (56.9%), whereas 415 subjects (67.3%) were identified by the self-administered WOQ-19. In patients with a <2.5 years disease duration, WO was diagnosed in 12 subjects (21.8%) by neurologists and in 23 subjects (41.8%) by the WOQ-19. The most frequent WO symptoms, as identified by WOQ-19, were “slowness of movements” (55.8%) and “reduced dexterity” (48.8%). Younger age, female gender, Unified Parkinson’s Disease Rating Scale (UPDRS) part II score and duration of anti-Parkinson treatment were found significantly associated with WO. The number of motor (p < 0.0001) and non-motor (p < 0.0001) WO symptoms correlated with PDQ-8 total score. CONCLUSIONS: WO is common already at the early stages of PD and is underestimated by routine neurological clinical evaluation. The number of WO symptoms, both motor and non motor, increases along with disease duration and has a negative impact on patients QoL.

With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.

We tested the efficiency of three attentional systems (spatial orienting, phasic alerting and executive control) in patients with Parkinson’s disease (PD), by using a modified version of the Attention Network Test, which employs acoustic tones to modulate phasic alertness. PD patients were generally slower than age-matched controls, but they showed a similar pattern of effects and interactions. Responses were faster with congruent than with incongruent stimuli (executive control), with valid visual cues than with invalid or no cues (orienting), and when acoustic tones preceded the target (alerting). This last effect was significantly larger in PD patients than in controls. We concluded that, for the present group of patients, the activity of attentional networks was relatively normal, if slowed. Slowed responses in PD may be improved by the use of acoustic stimuli, with potential clinical implications.

Pathological gambling develops in up to 8% of patients with Parkinson’s disease. Although the pathophysiology of gambling remains unclear, several findings argue for a dysfunction in the basal ganglia circuits. To clarify the role of the subthalamic nucleus in pathological gambling, we studied its activity during economics decisions. We analyzed local field potentials recorded from deep brain stimulation electrodes in the subthalamic nucleus while parkinsonian patients with (n = 8) and without (n = 9) pathological gambling engaged in an economics decision-making task comprising conflictual trials (involving possible risk-taking) and non conflictual trials. In all parkinsonian patients, subthalamic low frequencies (2-12 Hz) increased during economics decisions. Whereas, in patients without gambling, low-frequency oscillations exhibited a similar pattern during conflictual and non conflictual stimuli, in those with gambling, low-frequency activity increased significantly more during conflictual than during non conflictual stimuli. The specific low-frequency oscillatory pattern recorded in patients with Parkinson’s disease who gamble could reflect a subthalamic dysfunction that makes their decisional threshold highly sensitive to risky options. When parkinsonian patients process stimuli related to an economics task, low-frequency subthalamic activity increases. This task-related change suggests that the cognitive-affective system that drives economics decisional processes includes the subthalamic nucleus. The specific subthalamic neuronal activity during conflictual decisions in patients with pathological gambling supports the idea that the subthalamic nucleus is involved in behavioral strategies and in the pathophysiology of gambling.

Patients affected by Parkinson’s disease (PD) can provide crucial information about the involvement of the motor system and prefrontal cortex in processing idioms including action verbs, since dopamine modulates the activity of these structures, and, consequently, different levels of this neurotransmitter can induce different cognitive impairments. In order to investigate the ability to process ambiguous idioms containing an action verb in patients, we asked 15 PD patients, in both OFF- and ON-phases, and 15 healthy matched participants to judge the plausibility of literal and idiomatic sentences, each presented at a self-paced rate. Patients in OFF-phase were faster in reading idiomatic than literal sentences, supporting the view that the motor system is not involved in online idiom processing. However, patients during OFF-phase were impaired in judging the plausibility of idiomatic ambiguous sentences, possibly due to the reduction of dopamine in prefrontal regions. The involvement of the motor system was evident in the ON-phase for literal sentences, suggesting that motor activation is strictly dependent on the context.

BACKGROUND: Multiplications of the SNCA gene that encodes alpha-synuclein are a rare cause of autosomal dominant Parkinson’s disease (PD). METHODS: Here, we describe 2 novel families in which there is autosomal dominant PD associated with SNCA duplication, and we compare the clinical features of all known patients carrying 3 or 4 SNCA copies. RESULTS: Affected members in family A presented with early onset PD that was variably associated with nonmotor features, such as dysautonomia, cognitive deficits, and psychiatric disturbances. In family B, the clinical presentation ranged from early onset PD-dementia with psychiatric disturbances to late onset PD with mild cognitive impairment. CONCLUSIONS: The presence of 4 SNCA copies is associated with a rich phenotype, characterized by earlier onset of motor and nonmotor features compared with patients who bear 3 SNCA copies. The clinical spectrum associated with SNCA duplications is wide, even within a single family, suggesting a role for as yet unidentified genetic or environmental modifiers.

Many rating scales have been applied to the evaluation of dystonia, but only few have been assessed for clinimetric properties. The Movement Disorders Society commissioned this task force to critique existing dystonia rating scales and place them in the clinical and clinimetric context. A systematic literature review was conducted to identify rating scales that have either been validated or used in dystonia. Thirty-six potential scales were identified. Eight were excluded because they did not meet review criteria, leaving 28 scales that were critiqued and rated by the task force. Seven scales were found to meet criteria to be “recommended”: the Blepharospasm Disability Index is recommended for rating blepharospasm; the Cervical Dystonia Impact Scale and the Toronto Western Spasmodic Torticollis Rating Scale for rating cervical dystonia; the Craniocervical Dystonia Questionnaire for blepharospasm and cervical dystonia; the Voice Handicap Index (VHI) and the Vocal Performance Questionnaire (VPQ) for laryngeal dystonia; and the Fahn-Marsden Dystonia Rating Scale for rating generalized dystonia. Two “recommended” scales (VHI and VPQ) are generic scales validated on few patients with laryngeal dystonia, whereas the others are disease-specific scales. Twelve scales met criteria for “suggested” and 7 scales met criteria for “listed.” All the scales are individually reviewed in the online information. The task force recommends 5 specific dystonia scales and suggests to further validate 2 recommended generic voice-disorder scales in dystonia. Existing scales for oromandibular, arm, and task-specific dystonia should be refined and fully assessed. Scales should be developed for body regions for which no scales are available, such as lower limbs and trunk.

This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in-person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia. (c) 2013 Movement Disorder Society.

BACKGROUND: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. METHODS: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. FINDINGS: 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56.2 (SD 8.4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9.8 years (95% CI 8.1-11.4). The parkinsonian variant of MSA (hazard ratio [HR] 2.08, 95% CI 1.09-3.97; p=0.026) and incomplete bladder emptying (HR 2.10, 1.02-4.30; p=0.044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9.4 [SD 5.9]), 74% (12.9 [8.5]), and 57% (21.9 [11.9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0.68, 0.5-0.9; p=0.006) and absent levodopa response (OR 3.4, 1.1-10.2; p=0.03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. INTERPRETATION: Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of certain movement disorders, including blepharospasm, hemifacial spasm, oromandibular dystonia, cervical dystonia, focal limb dystonias, laryngeal dystonia, tics, and essential tremor, an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for movement disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, the serotypes BoNT-A and BoNT-B, as well as the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations for each therapeutic indication, based upon the strength of clinical evidence and following the AAN classification scale. For the treatment of blepharospasm, the evidence supported a Level A recommendation for BoNT-A, A/Inco, and A/Ona; a Level B recommendation for A/Abo; and a Level U recommendation for B/Rima. For hemifacial spasm, the evidence supported a Level B recommendation for BoNT-A and A/Ona, a Level C recommendation for A/Abo, and a Level U recommendation for A/Inco and B/Rima. For the treatment of oromandibular dystonia, the evidence supported a Level C recommendation for BoNT-A, A/Abo, and A/Ona, and a Level U recommendation for A/Inco and B/Rima. For the treatment of cervical dystonia, the published evidence supported a Level A recommendation for all four BoNT formulations. For limb dystonia, the available evidence supported a Level B recommendation for both A/Abo and A/Ona, but no published studies were identified for A/Inco or B/Rima, resulting in a Level U recommendation for these two formulations. For adductor laryngeal dystonia, evidence supported a Level C recommendation for the use of A/Ona, but a Level U recommendation was warranted for B/Rima, A/Abo, and A/Inco. For the treatment of focal tics, a Level U recommendation was warranted at this time for all four formulations. For the treatment of tremor, the published evidence supported a level B recommendation for A/Ona, but no published studies were identified for A/Abo, A/Inco, or B/Rima, warranting a Level U recommendation for these three formulations. Further research is needed to address evidence gaps and to evaluate BoNT formulations where currently there is insufficient or conflicting clinical data.

Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of spasticity associated with the upper motor neuron syndrome (UMNS), an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for autonomic disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, the serotypes BoNT-A and BoNT-B, as well as the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations on the effectiveness of BoNT for the management of spasticity, based upon the strength of clinical evidence and following the AAN classification scale. While the prior report by the AAN provided recommendations for the use of BoNT as a class of drug, this report provides more detail and includes recommendations for the individual formulations. For the treatment of upper limb spasticity, the evidence supported a Level A recommendation for BoNT-A, A/Abo, and A/Ona, with a Level B recommendation for A/Inco; there was insufficient evidence to support a recommendation for B/Rima. For lower limb spasticity, there was sufficient clinical evidence to support a Level A recommendation for A/Ona individually and BoNT-A in aggregate; the clinical evidence for A/Abo supported a Level C recommendation; and there was insufficient information to recommend A/Inco and B/Rima (Level U). There is a need for further comparative effectiveness studies of the available BoNT formulations for the management of spasticity.

Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. It often causes embarrassment and more rarely serious disability, requiring treatment. To assess the current state of knowledge on ET therapy and produce recommendations based on the analysis of evidence the authors reviewed the literature regarding pharmacologic and surgical therapies, providing a quality assessment of the studies and the strength of recommendations for each treatment. A committee of experts selected clinical-based questions to guide the search. A systematic literature review was performed to identify all the studies conducted on patients with ET published until September 2010. Articles were classified according to GRADE evidence profile, a system for grading the quality of evidence and the strength of recommendation based on the quality of the studies. The quality of evidence was often rated as “low” or “very low” for the studies analyzed. Propranolol, long-acting propranolol, primidone, and topiramate are recommended as first-line therapy, with restrictions for their side effects. Arotinolol, sotalol, ICI 118.551 and LI 32.468 (experimental drugs), zonisamide, gabapentin, alprazolam, clozapine, and olanzapine are recommended as a second-line treatment. Botulinum toxin type A and thalamic deep-brain stimulation are recommended for refractory ET. The results highlight the need of well-designed direct comparison trials aimed at evaluating relative effectiveness and safety of the drugs currently used in clinical practice. Furthermore, additional controlled clinical trials are required to define other possible treatment strategies for ameliorating the management of ET.

The Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an ‘Official MDS translation,’ the Comparative Fit Index (CFI) had to be >/=0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was >/=0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Deep brain stimulation (DBS) extends the treatment of some severe neurological diseases beyond pharmacological and conservative therapy. Our experience extends the field of DBS beyond the treatment of Parkinson disease and dystonia, including several other diseases such as cluster headache and disruptive behavior. Since 1993, at the Istituto Nazionale Neurologico “Carlo Besta” in Milan, 580 deep brain electrodes were implanted in 332 patients. The DBS targets include Stn, GPi, Voa, Vop, Vim, CM-pf, pHyp, cZi, Nacc, IC, PPN, and Brodmann areas 24 and 25. Three hundred patients are still available for follow-up and therapeutic considerations. DBS gave a new therapeutic chance to these patients affected by severe neurological diseases and in some cases controlled life-threatening pathological conditions, which would otherwise result in the death of the patient such as in status dystonicus, status epilepticus and post-stroke hemiballismus. The balance of DBS in severe neurological disease is strongly positive even if further investigations and studies are needed to search for new applications and refine the selection criteria for the actual indications.

OBJECTIVE: Huntington’s disease (HD) appearing before the age of 20 years gives rise to a distinct phenotype with respect to the classical adult-onset disease. Here we describe three patients with childhood or juvenile HD onset presenting with action myoclonus. METHODS: We performed jerk-locked back-averaging (JLBA), EEG-EMG coherence and phase analysis, long-loop reflexes (LLRs) and somatosensory evoked potentials (SSEPs). In one patient, we also performed transcranial magnetic stimulation (TMS) using single and paired pulses. RESULTS: In all patients, the EMG features revealed movement activated quasi-rhythmic repetitive jerks; the JLBA and EEG-EMG spectral and coherence profiles indicated a cortical generator of the myoclonus. All patients had enhanced LLRs during muscle contraction, while none showed giant SSEPs. The evaluation of intracortical inhibition by means of TMS revealed reduced inhibition at short and long interstimulus intervals. CONCLUSIONS: The rhythmic course of the action myoclonus and the characteristics of the LLRs suggest that myoclonus is due to a reverberant circuit involving the motor cortex, possibly because of an imbalance between excitatory and inhibitory cortical neuronal systems. SIGNIFICANCE: Our findings suggest a similar cortical dysfunction in childhood and juvenile onset HD, which probably results from a specific circuitry impairment.

The aim of this study was to test the concordance between disease severity, prevalence of nonmotor symptoms, age, health-related quality of life (HRQoL), disability and medication use in patients with Parkinson’s disease (PD). Severity was classified with the Hoehn and Yahr (HY) scale and Levodopa Equivalent Daily Dose (LEDD) calculated. HRQoL was evaluated with the SF-36, disability with the WHO-DAS II and nonmotor symptoms with the NMSQuest. Patients were clustered using SF-36 and WHO-DAS II into three groups covering the continuum from low disability and HRQoL, to severe disability and HRQoL decrement. Contingency Coefficient were used to verify the relationships between clusters and HY stage; ANOVA to evaluate differences in NMS, age and LEDD between clusters; odds ratio to test the likelihood of taking levodopa or dopamine agonist and being member of the three clusters; t test to evaluate differences in LEDD between patients with HY >/=3 or </=2. Eighty-six patients were clustered: 48 had low disability and HRQoL decrement, 18 intermediate disability and HRQoL decrement and 20 high disability and HRQoL decrement. A significant relationship was found between PD severity groups, HRQoL and disability profiles. No differences for age and LEDD were observed in the three groups, and those with more disability and lower HRQoL reported a higher number of nonmotor symptoms; patients in HY >/=3 were prescribed higher doses of drugs. In conclusion, we found a substantial concordance between PD staging, prevalence of nonmotor symptoms and patient-reported HRQoL and disability measures. In our opinion, the SF-36 and the WHO-DAS II can be used for profiling patients.

UNLABELLED: An impairment for verbs has been described in patients with Parkinson’s disease (PD), suggesting that a disruption of frontal-subcortical circuits may result in dysfunction of the neural systems involved in action-verb processing. A previous study suggested that deep brain stimulation (DBS) of the subthalamic nucleus (STN) during verb generation may affect the ability to select from many competing lexical alternatives. In this study, 12 PD patients who had undergone bilateral STN DBS and completed an 8-year follow-up and 14 matched normal controls were administered action and object naming tasks and verb and noun reading tasks. Their responses were recorded using a microphone, resulting in a signal that marked the onset of the verbal response and allowed to measure response times (RTs). Accuracy was scored manually. RESULTS: Overall performance in naming (independently of stimulation): In naming task controls were faster and more accurate than PD patients. In both groups, performance (accuracy and RTs) was worse on action naming than object naming. PD patients were significantly slower than controls in naming actions. Effect of stimulation: Compared with the OFF stimulation condition, in ON stimulation condition PD patients showed improved performance on object and action naming tasks (increased accuracy, faster RTs), with a decreased number of semantic errors. Some evidence also emerged that action naming in the ON stimulation condition improved more than object naming. On noun and verb reading tasks, although accuracy was at ceiling in both groups and no significant difference was observed in RTs for nouns and verbs, PD patients were slower than controls. CONCLUSIONS: Our findings suggest that STN DBS may improve lexical search in PD patients. We hypothesize that STN stimulation may facilitate the motor components involved in naming and reading tasks (increased speed of speech onset), resulting in shorter RTs in both naming and reading and, to some extent, in increased accuracy in naming due to fewer omissions (no response within the 7500 ms time limit). However, to account for greater accuracy in naming due to decreased number of semantic errors in the ON stimulation condition, we hypothesize that STN stimulation restores the activity of the corticostriatal circuits involved in selection processes of a target word among different alternatives.

PURPOSE OF REVIEW: This review considers the recent literature pertaining to the clinical features, genetics, neuropathology and treatment of dystonia syndromes. RECENT FINDINGS: The term dystonia indicates at the same time a clinical phenotype and a collection of neurological syndromes mainly of genetic origin. The physical signs contributing to the phenomenology of dystonia have been recently assembled into a coherent set. The molecular genetics of primary dystonia syndromes (DYT1 and DYT6) have been the object of extensive analysis, providing converging views on their causative mechanisms. The relationship between genotype, phenotype, and endophenotypes has been explored for hereditary and sporadic dystonia syndromes. Neurophysiological studies on DYT1 and DYT6 patients, as well as on nonmanifesting carriers, have demonstrated the presence of altered synaptic plasticity. Several recent data indicate a role of dopamine and acetylcholine (ACh) transmission in the pathophysiology of primary dystonia. SUMMARY: Recent findings have led to novel, testable hypotheses on cellular mechanisms and physiopathological abnormalities underlying dystonia. Neurophysiological studies, imaging data and animal models support the view that corticostriatal, cerebellar, and dopaminergic dysfunctions converge to produce the pathophysiological abnormalities of dystonia.

The aim of this study was to evaluate the efficacy and safety of epidural premotor stimulation in patients with primary focal dystonia. Seven patients were selected: 6 had cervical dystonia and 1 had right upper limb dystonia. In 2 patients, sustained muscle contractions led to a prevalently fixed head posture. Patients with cervical dystonia received a bilateral implant, whereas the patient with hand dystonia received a unilateral implant. Neurological and neuropsychological evaluations were performed before surgery (baseline), and 1, 3, 6, and 12 months afterward. The Burke-Fahn-Marsden scale (BFMS) and the Toronto Western spasmodic torticollis rating scale (TWSTRS) were administered at the same time points. Patients underwent resting (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans, before and 12 months after surgery. No adverse events occurred. An overall improvement was observed on the BFMS and TWSTRS after surgery. Patients with prevalently fixed cervical dystonia had a reduced benefit. Presurgical neuroimaging revealed a significant bilateral metabolic increase in the sensorimotor areas, which was reduced after surgery.

Deep brain stimulation (DBS) is an established procedure for the symptomatic treatment of Parkinson’s disease. Several deep brain nuclei have been stimulated, producing a wide range of effects on the motor and non-motor symptoms of Parkinson’s disease. Long-term, high-quality evidence is available for stimulation of the subthalamic nucleus and globus pallidus internus, both of which uniformly improve motor features, and for stimulation of the thalamic ventralis intermedius, which improves tremor. Short-term data are available for stimulation of other deep brain targets, such as the pedunculopontine nucleus and the centremedian/parafascicular thalamic complex. Some non-motor symptoms improve after DBS, partly because of motor benefit or reduction of drug treatment, and partly as a direct effect of stimulation. More evidence on the effects of DBS on non-motor symptoms is needed and specifically designed studies are warranted.

Pain and fatigue are part of the phenomenological spectrum of Parkinson’s disease (PD). These non-motor symptoms can be as troublesome as motor symptoms, impact activities of daily living, and are often underdiagnosed. The recognition of pain and fatigue requires a high degree of clinical suspicion and is facilitated by the use of specific questionnaires and ancillary tests. This workup is highly valuable particularly considering that pain and fatigue in PD may be treatable. We review here the clinical manifestations and management of these non-motor symptoms. Their resolution can be challenging, as there is insufficient evidence concerning effective treatment options.

Patients with Parkinson’s disease suffer from a variety of motor and nonmotor symptoms (NMS), report reduced quality of life and increased disability. Aims of this study are to assess the impact of Parkinson’s disease on disability and quality of life, to evaluate the relationships between them and NMS prevalence. In this cross-sectional study, adult patients were consecutively enrolled and administered the World Health Organization Disability Assessment Schedule (WHO-DAS II), the 36-Item Short-Form Health Survey (SF-36) and the Non Motor Symptoms Questionnaire (NMSQuest). One-sample t-test was used to compare WHO-DAS II and SF-36 scores with normative value. Pearson’s correlation was performed between NMSQuest, WHO-DAS II and SF-36 summary scales. Independent-sample t-test was used to compare NMSQuest, WHO-DAS II and SF-36 scores in patients with Hoehn & Yahr stage <3 and >/= 3. In total, 96 patients were enrolled. SF-36 and WHO-DAS II scores were significantly worse than the normative values. Correlation coefficients between NMSQuest, WHO-DAS II and SF-36’s mental score were moderate, and were high between WHO-DAS II and and SF-36’s physical score. Patients with Hoehn & Yahr stage >/= 3 reported reduced quality of life, higher disability and more NMS. Parkinson’s disease severity is strongly associated with reduced quality of life, increased disability and NMS prevalence. Disability and quality of life assessment tools measure psychosocial facets that are similar specifically with regard to physical health component of health-related quality of life, are sensitive enough to capture differences related to disease’s progression and increased prevalence of NMS.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) and continuous dopaminergic infusions (jejunal levodopa or subcutaneous apomorphine) are indicated in complicated Parkinson’s disease (PD), although it remains unsettled how they compare to each other. METHODS: We investigated the daytime motor condition in patients with advanced PD under monotherapy with jejunal levodopa, subcutaneous apomorphine, or STN DBS and also measured the motor changes produced by an additional standard morning dose of levodopa. Motor performance was assessed with the UPDRS-III, hand taps, the AIMS dyskinesia score and patients’ diaries. Outcome measures were time to best motor ‘on’ after start of morning treatment, daytime variability of motor condition, motor scores. RESULTS: The time to ‘on’ was longest in the jejunal levodopa group. DBS and jejunal levodopa treatments produced stable motor conditions without appreciable ‘off’ episodes. Continuous apomorphine infusion was associated with the worst motor scores (UPDRS-III and taps) and the most frequent off-states. Jejunal levodopa infusion was associated with the highest AIMS scores. Addition of a levodopa dose produced shortening of time to ‘on’ and a transient motor improvement in the jejunal levodopa group without increase in dyskinesias; in the DBS and apomorphine groups, there was an increase in dyskinesias without changes in UPDRS-III or taps. CONCLUSIONS: STN DBS provided adequate trade-off between motor improvement and dyskinesia control, although dyskinesias could be elicited by adding oral levodopa. Jejunal levodopa infusion produced adequate motor improvement with slow time to ‘on’ and moderate dyskinesias. Apomorphine infusion produced insufficient motor control and negligible dyskinesias.

BACKGROUND: Primary focal hyperhidrosis (PFH) is a disabling disorder. A first locus has been mapped in families with only palmar involvement, raising the question whether other unknown genes are responsible for more diffuse phenotypes. OBJECTIVE: We investigated a PFH family with a new phenotype, providing evidence that PFH is a clinically and genetically heterogeneous condition. METHODS: Family members were examined by autonomic tests, skin biopsy and genetic analysis, and followed up for 4 years. RESULTS: Age at onset was early, involving the axillae, palms and soles. Affected members had dysautonomic features also at onset. Cardiovascular dysautonomia was present in affected and unaffected members. Skin biopsy revealed impairment of intraepidermal nerve fibers and reduced innervation of sweat glands. There was no linkage to PFH and aquaporin-5 loci. CONCLUSION: This pedigree may serve as a basis for identifying a novel unmapped gene. Skin biopsy and cardiovascular autonomic tests provide important additions to the characterization of PFH.

The links between Stn DBS and advanced Parkinson disease, and between GPi DBS and dystonia are nearly universally accepted by the neurologists and neurosurgeons. Nevertheless, in some conditions, targets such as the ventral thalamus and the Zona Incerta may be considered to optimize the results and avoid the side effects. Positive and negative aspects of current DBS treatments justify the research of new targets, new stimulation programs and new hardware. Since 1993, at the Istituto Nazionale Neurologico “Carlo Besta” in Milan, 580 deep brain electrodes were implanted in 332 patients. 276 patients were affected by movement disorders. The DBS targets included Stn, GPi, Voa, Vop, Vim, CM-pf, cZi, IC. The long-term follow-up is reported and related to the chosen target. DBS gave a new therapeutic option to patients affected by severe movement disorders, and in some cases resolved life-threatening pathological conditions that would otherwise result in the death of the patient, such as in status dystonicus, and post-stroke hemiballismus. Nevertheless, the potential occurrence of severe complications still limit a wider use of DBS. At today, the use of DBS in severe movement disorders is strongly positive even if further investigations and studies are needed to unveil potential new applications, and to refine the selection criteria for the actual indications and targets. The experience of different targets may be useful to guide and tailor the target choice to the individual clinical condition.

The dystonias are a heterogeneous group of hyperkinetic movement disorders characterised by involuntary sustained muscle contractions that lead to abnormal postures and repetitive movements. Dystonia syndromes represent common movement disorders and yet are often misdiagnosed or unrecognised. In recent years, there have been substantial advances in the understanding of the spectrum of clinical features that encompass dystonia syndromes, from severe generalised childhood dystonia that is often genetic in origin, to adult-onset focal dystonias and rarer forms of secondary dystonias, to dystonia as a feature of other types of CNS dysfunction. There has also been a rationalisation of the classification of dystonia and a greater understanding of the causes of dystonic movements from the study of genetics, neurophysiology, and functional imaging in the most prevalent form of dystonia syndrome, primary dystonia.

Patients with Parkinson’s disease have nonmotor symptoms (NMS) that, although poorly considered, have an impact on their quality of life. In contrast, the effect on disability is not systematically evaluated. Adult patients were consecutively enrolled and administered the Non-Motor Symptoms Questionnaire and the WHO Disability Assessment Schedule. Student’s t-test was used to assess the difference in the disability score between patients declaring and not declaring NMS. In total, 86 patients were enrolled and reported a median of nine NMS. Patients reporting symptoms in cognitive, emotional, cardiovascular, and sleep functions, as well as those reporting more than nine symptoms as a whole, also reported higher disability levels. The presence of NMS, including little evaluated areas connected to cardiovascular and sleep functions, negatively impacts disability in patients with Parkinson’s disease.

BACKGROUND: Preclinical and clinical evidence suggests that impaired gamma-aminobutyric (GABA) control, leading to disinhibition within the sensorimotor system, might play a role in dystonia. Aim of this study is the in vivo assessment of the GABAergic system in dystonia using positron emission tomography (PET) and (11) C-flumazenil, a selective GABA(A) receptor ligand. METHODS: Fourteen subjects with primary dystonia (9 carriers of the DYT1 mutation and 5 sporadic cases) were compared to 11 controls, using a simplified reference tissue model to measure binding potential. RESULTS: Voxel-based analyses showed a reduction in GABA(A) receptor expression/affinity both in DYT1 carriers and sporadic patients in primary motor and premotor cortex, primary and secondary somatosensory cortex, and in the motor component of the cingulate gyrus. CONCLUSIONS: Dysfunction of GABA(A) receptors in sensorimotor systems in primary (genetic and sporadic) dystonia supports the view that lack of GABAergic control may be associated with the generation of dystonic movements.

BACKGROUND: Sleep disorders are common in multiple system atrophy (MSA), but the prevalence of excessive daytime sleepiness (EDS) is not well known. OBJECTIVE: To assess the frequency and associations of EDS in MSA. DESIGN: Survey of EDS in consecutive patients with MSA and comparison with patients with Parkinson disease (PD) and individuals without known neurologic disease. SETTING: Twelve tertiary referral centers. PARTICIPANTS: Eighty-six consecutive patients with MSA; 86 patients with PD matched for age, sex, and Hoehn and Yahr stage; and 86 healthy subject individuals matched for age and sex. MAIN OUTCOME MEASURES: Epworth Sleepiness Scale (ESS), modified ESS, Sudden Onset of Sleep Scale, Tandberg Sleepiness Scale, Pittsburgh Sleep Quality Index, disease severity, dopaminergic treatment amount, and presence of restless legs syndrome. RESULTS: Mean (SD) ESS scores were comparable in MSA (7.72 [5.05]) and PD (8.23 [4.62]) but were higher than in healthy subjects (4.52 [2.98]) (P < .001). Excessive daytime sleepiness (ESS score >10) was present in 28% of patients with MSA, 29% of patients with PD, and 2% of healthy subjects (P < .001). In MSA, in contrast to PD, the amount of dopaminergic treatment was not correlated with EDS. Disease severity was weakly correlated with EDS in MSA and PD. Restless legs syndrome occurred in 28% of patients with MSA, 14% of patients with PD, and 7% of healthy subjects (P < .001). Multiple regression analysis (with 95% confidence intervals obtained using nonparametric bootstrapping) showed that sleep-disordered breathing and sleep efficiency predicted EDS in MSA and amount of dopaminergic treatment and presence of restless legs syndrome in PD. CONCLUSIONS: More than one-quarter of patients with MSA experience EDS, a frequency similar to that encountered in PD. In these 2 conditions, EDS seems to be associated with different causes.

The objective of this study was to describe the functional profiles of patients with Parkinson’s disease (PD), and the relationships between impairment in body functions, limitations in activities, and environmental factors, using the World Health Organization’s International Classification of Functioning, Disability, and Health (ICF). Patients were consecutively enrolled, and the ICF checklist was administered. Two count-based indices were developed: ‘extension’, containing ICF categories rated with qualifiers 1-4 and ‘severity’, containing ICF categories rated with qualifiers 3-4. Categories rated with qualifiers 1-4 in at least 50% of patients are described separately. Spearman’s correlation analysis was carried out to identify the relationships between impairments in body functions (BF) and body structures, activities and participation, and environmental factors (EF); linear regressions were performed to identify the best predictors of performance indices in activities and participation. A total of 96 patients were enrolled; 34 categories rated with qualifiers 1-4 in at least 50% of patients are reported, and most of them describe impairment in movement-related functions and limitations in mobility and self-care. Performance indices are significantly lower than capacity and significant relationships with both BF impairments and EF are observed. High difficulties in activities and participation performance are connected with both presence of severe BF symptoms and relevant barriers in EF. Both BF and EF play a relevant role in improving functioning of the patients with PD. The connection between EF barriers and severe problems in activities and participation performance suggests the need of fostering participation of patients with PD by promoting facilitators among EFs. Methodologies and tools are needed to couple information on symptoms, on the difficulties in executing activities, and on environmental features.

OBJECTIVE: Neurophysiologic studies demonstrated that patients with primary torsion dystonia (PTD) and with psychogenic dystonia (Psy-D) share similar abnormalities in the motor system. In this study, we evaluated somatosensory function in Psy-D by testing temporal discrimination threshold (TDT), and compared the results with those obtained in patients with PTD. METHODS: TDT of tactile stimuli was assessed in 10 patients with Psy-D, 10 patients with PTD, and 16 control subjects. The 2 groups of patients were matched for age, gender, disease duration, and distribution of dystonia. Tactile stimuli consisted of pairs of non-noxious electrical shocks delivered to the right or left hand at interstimulus interval increasing from 0 to 400 msec, in 10-msec steps. TDT was defined as the value at which subjects recognized the 2 stimuli as asynchronous. RESULTS: TDT was higher in Psy-D and PTD compared to control subjects, for both the right and the left hand. In a subgroup of patients with unilateral dystonia (Psy-D = 4, PTD = 5), TDT did not differ between the affected and the unaffected side in both groups of patients. Disease duration was not correlated to the increased TDT value. CONCLUSIONS: Our study suggests an impaired processing of somatosensory inputs in both Psy-D and PTD. These abnormalities might represent a neurophysiological trait predisposing to develop a dystonic posture triggered by psychiatric and psychological factors.

The ability to choose effectively when faced with potential risks and rewards is fundamental for adaptive survival. The striatum has a well-established role supporting learning from the outcomes of decisions, but it remains unclear whether this structure is also necessary for computing expected value (i.e., advantageousness of potential decisions) when all information is explicitly given. We addressed this question presenting simple monetary gambles, where all decisional parameters were given and outcome feedback was absent, to patients with early Huntington’s and Parkinson’s disease, taken as complementary models of striatal dysfunction. Behavioural responses and associated times were found to be unaltered. This negative finding suggests that striatal activity may not be essential for decision-making in situations where all information is provided and learning from outcomes is unnecessary.

BACKGROUND: The preoperative evaluation in dystonia aims at characterizing the severity and topography of motor symptoms in patients, who have previously been selected for deep brain stimulation (DBS). METHODS: The literature search was performed using PubMed, CINAHL, and the Cochrane Collaborative databases. RESULTS: Commonly used scales for clinical assessment are the Burke-Fahn-Marsden dystonia rating scale for generalized dystonia and the Toronto Western Spasmodic Torticollis Scale for cervical dystonia. Motor assessment is completed by quality of life and functional scales, such as the Short-Form Health Survey (SF-36) or the Parkinson’s Disease Questionnaire 39. Validated rating scales for cranial or upper limb dystonia are lacking. DISCUSSION: In common clinical practice, these outcome measures can be administered in an open-label fashion because double blind assessment is only required for ascertaining new treatment indications or research purposes. The same measures are to be used postoperatively to revaluate outcome after DBS. Brain MRI is required to confirm diagnosis and assess structural abnormalities. Other imaging techniques, particularly functional imaging, are used for research purposes.

When considering a patient with dystonia for deep brain stimulation (DBS) surgery several factors need to be considered. Level B evidence has shown that all motor features and associated pain in primary generalized and segmental dystonia are potentially responsive to globus pallidus internus (GPi) DBS. However, improvements in clinical series of >/= 90% may reflect methods that need improvement, and larger prospective studies are needed to address these factors. Nevertheless, to date the selection criteria for DBS-specifically in terms of patient features (severity and nature of symptoms, age, time of evolution, or any other demographic or disease aspects)–have not been assessed in a systematic fashion. In general, dystonia patients are not considered for DBS unless medical therapies have been previously and extensively tested. The vast majority of reported patients have had DBS surgery when the disease was provoking important disability, with loss of independence and impaired quality of life. There does not appear to be an upper age limit or a minimum age limit, although there are no published data regarding the outcome of GPi DBS for dystonia in children younger than 7 years of age. There is currently no enough evidence to prove that subjects with primary–generalized dystonia who undergo DBS at an early age and sooner rather than later after disease onset may gain more benefit from DBS than those undergoing DBS after the development of fixed skeletal deformities. There is no enough evidence to refuse or support consideration of DBS in patients with previous ablative procedures.

INTRODUCTION: There is a general agreement among movement disorder specialists that the recognition of dystonia may be underestimated. In parallel, the growing interest and the improving knowledge of genetic and physiopathological aspects of dystonias require systematization. AREAS COVERED: This review focuses on the phenomenology and etiology of pediatric and adult dystonias. It is designed to provide practical help for neurologists and neuropediatricians to make appropriate diagnoses and plan the therapeutical management of these disorders. The reader will get a systematization of the main etiological and diagnostic aspects that differentiate child-onset from adult-onset dystonias. The reader will also gain insights into specific treatments or cures. EXPERT OPINION: Because dystonia can vary in clinical presentation and etiology, proper diagnosis and classification of these disorders are important in making therapeutic decisions.

BACKGROUND: Dopamine neurotransmission plays a key role in several brain activities, including motor, cognitive, and behavioral functions. Parkinson’s disease (PD) typically begins with asymmetrical motor features related to asymmetrical dopamine denervation. This study was designed to examine whether distinct cognitive, behavioral, and personality features are related to this asymmetry. METHODS: Fifty-six patients with mild PD and lateralized motor features were grouped according to dominant side of motor features and evaluated using a neuropsychological assessment focused on attention and executive functions, impulse control disorders, and personality inventory. RESULTS: There were no differences in neuropsychological functions between patients with right and left lateralized PD, but differences occurred in personality features. Patients with motor impairment predominant on the left-hand side had prevalence of hypomania and conversion profile. CONCLUSIONS: This study suggests that side dominance of dopaminergic denervation may be related to personality features in patients with PD that could influence behavioral aspects.

Although lesional, neuroimaging, and brain stimulation studies have provided an insight into the neural mechanisms of judgement and decision-making, all these works focused on the cerebral cortex, without investigating the role of subcortical structures such as the basal ganglia. Besides being an effective therapeutic tool, deep brain stimulation (DBS) allows local field potential (LFP) recordings through the stimulation electrodes thus providing a physiological “window” on human subcortical structures. In this study we assessed whether subthalamic nucleus LFP oscillations are modulated by processing of moral conflictual, moral nonconflictual, and neutral statements. To do so, in 16 patients with Parkinson’s disease (8 men) bilaterally implanted with subthalamic nucleus (STN) electrodes for DBS, we recorded STN LFPs 4 days after surgery during a moral decision task. During the task, recordings from the STN showed changes in LFP oscillations. Whereas the 14–30 Hz band (beta) changed during the movement executed to perform the task, the 5–13 Hz band (low-frequency) changed when subjects evaluated the content of statements. Low-frequency band power increased significantly more during conflictual than during nonconflictual or neutral sentences. We conclude that STN responds specifically to conflictual moral stimuli, and could be involved in conflictual decisions of all kinds, not only those for moral judgment. LFP oscillations provide novel direct evidence that the neural processing of conflictual decision-making spreads beyond the cortex to the basal ganglia and encompasses a specific subcortical conflict-dependent component.

OBJECTIVES: to provide a revised version of earlier guidelines published in 2006. BACKGROUND: primary dystonias are chronic and often disabling conditions with a widespread spectrum mainly in young people. DIAGNOSIS: primary dystonias are classified as pure dystonia, dystonia plus or paroxysmal dystonia syndromes. Assessment should be performed using a validated rating scale for dystonia. Genetic testing may be performed after establishing the clinical diagnosis. DYT1 testing is recommended for patients with primary dystonia with limb onset before age 30, and in those with an affected relative with early-onset dystonia. DYT6 testing is recommended in early-onset or familial cases with cranio-cervical dystonia or after exclusion of DYT1. Individuals with early-onset myoclonus should be tested for mutations in the DYT11 gene. If direct sequencing of the DYT11 gene is negative, additional gene dosage is required to improve the proportion of mutations detected. A levodopa trial is warranted in every patient with early-onset primary dystonia without an alternative diagnosis. In patients with idiopathic dystonia, neurophysiological tests can help with describing the pathophysiological mechanisms underlying the disorder. TREATMENT: botulinum toxin (BoNT) type A is the first-line treatment for primary cranial (excluding oromandibular) or cervical dystonia; it is also effective on writing dystonia. BoNT/B is not inferior to BoNT/A in cervical dystonia. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for primary generalized or cervical dystonia, after medication or BoNT have failed. DBS is less effective in secondary dystonia. This treatment requires a specialized expertise and a multidisciplinary team.

Knowledge about the genetics of primary torsion dystonia (PTD) has been progressing at a very slow pace compared with other movement disorders. For many years, only one causative gene was known, DYT1/TOR1A, yet the recent identification of a second PTD causative gene (DYT6/THAP1), the detection of subclinical alterations caused by mutations in PTD genes in some healthy non-penetrant individuals, and functional studies on TOR1A and THAP1 protein products have significantly improved mutation detection, genotype-phenotype correlates, and our understanding of the cellular mechanisms underlying the development of dystonia.

There is no unique way to define Parkinson’s disease (PD) clinically. “Classical parkinsonian features” can be found not only in sporadic idiopathic PD patients, but also in other parkinsonian disorders, such as genetic forms associated with mutations in PARK or in other genes. The present review will describe the parkinsonian phenotypes emerging from the new Mendelian genes which have been linked to PD (such as PARK9 and PARK14), the associated dystonia-parkinsonism disorders (such as the syndromes of neurodegeneration with brain iron accumulation) and the emerging data on heterozygous variants of genes which could influence the risk to develop PD and the PD phenotypes (like PD associated with glucose cerebrosidase mutations).

BACKGROUND AND IMPORTANCE: Meige syndrome (MS) is an adult-onset segmental dystonia characterized by the combination of upper and lower cranial involvement. Its treatment is challenging and the use of oral medication or of botulinum neurotoxin treatment is not decisive. Deep brain stimulation of the globus pallidus internum (GPi DBS) has been used occasionally in severe cases. CLINICAL PRESENTATION: We report the long-term efficacy of low-voltage chronic bilateral GPi DBS in a patient with segmental dystonia featuring severe MS and cervical brachial involvement. The patient received a bilateral ventroposterolateral GPi implant. Postoperative 3-dimensional reconstruction allowed checking of the definitive position of the electrode and contacts within the targeted nucleus. Following implant, the patient received bilateral low-voltage stimulation, consisting in amplitude of 1.3 V with a pulse width of 90 microseconds and a frequency of 130 Hz, yielding a current of 23 microA. Clinical follow-up for 38 months showed a progressive and sustained improvement of dystonia with unchanged electrical settings throughout the observation period. The patient again undertook normal life activities. CONCLUSION: Bilateral low-voltage GPi stimulation allowed efficient control of MS symptoms and the associated brachial cervical dystonia.

The long-term efficacy and safety of deep brain stimulation (DBS) implant for Parkinson’s disease (PD) is described in several recent papers. This procedure has been reported to permit a stable reduction of dopaminergic therapy requirements for up to 5 years, although some expectation of deterioration in non-dopaminergic signs has been recently stated. Our aim is to perform a literature-based review of papers available describing long-term post-operative follow-up after a bilateral implant for subthalamic DBS (STN-DBS). Only peer-reviewed published papers with a post-operative follow-up of at least 5 years were considered. Clinical outcome, disease progression and side effects were assessed at baseline and 2 (or 3 years) and 5 years after surgery. Seven papers were included in the review. A total of 238 patients were analyzed. STN-DBS was confirmed to be an effective treatment for selected patients with PD. In all studies, off-related motor symptoms improved dramatically, compared with pre-implant, at 2 (or 3, according to the study) years and this result persisted at 5-year evaluations. Antiparkinsonian drug reductions, improvements in motor fluctuations and dyskinesias, functional measures and the progression of underlying PD were also reported in all series. Some axial scores, in particular postural stability and speech, improved transiently. Persisting adverse effects included eyelid opening apraxia, weight gain, psychiatric disorders, depression, dysarthria, dyskinesias, and apathy. The present review of the 5-year observations confirms that STN-DBS is a powerful method in the management of PD, but its long-term effects must be thoroughly assessed.

OBJECTIVE: To describe functioning and disability of patients with Parkinson’s Disease (PD) according to the model endorsed by the International Classification of Functioning Disability and Health (ICF). DESIGN: Adult PD patients were consecutively enrolled. The ICF checklist and the WHO Disability Assessment Schedule II (WHO-DAS II) were administered in individual sessions. Hoehn and Yahr Staging (HY) was used to define PD severity. Descriptive analyses have been performed to report on HY and WHO-DAS II scores. ICF categories reported as a problem by more than 20% of patients are described in detail. RESULTS: Ninety-six patients with PD (mean age 64.1, 33.3% females) were enrolled, 48.4% of them were in HY class 2. WHO-DAS II mean score was 18.1 and the most severe limitations are reported in getting around and in participation to social situations. A total of 71 ICF categories reached the threshold of 20%, mostly derived from Activities and Participation domain. CONCLUSIONS: We reported information on a broad set of domains, expanding those PD-specific, such as reduced mobility. Our results are useful to define what dimensions have to be considered to expand disability assessment in patients with PD, considering both symptoms, activities and the role of environmental factors.

Deep brain stimulation of the subthalamic nucleus represents the most important innovation for treatment of advanced Parkinson’s disease. Prospective studies have shown that although the beneficial effects of this procedure are maintained at 5 years, axial motor features and cognitive decline may occur in the long term after the implants. In order to address some unsolved questions raised by previous studies, we evaluated a series of 20 consecutive patients who received continuous stimulation for 8 years. The overall motor improvement reported at 5 years (55.5% at Unified Parkinson’s Disease Rating Scale-motor part, P < 0.001 compared with baseline) was only partly retained 3 years later (39%, P < 0.001, compared with baseline; -16.5%, P < 0.01, compared with 5 years), with differential effects on motor features: speech did not improve and postural stability worsened (P < 0.05). The preoperative levodopa equivalent daily dose was reduced by 58.2% at 5 years and by 60.3% at 8 years. In spite of subtle worsening of motor features, a dramatic impairment in functional state (-56.6% at Unified Parkinson’s Disease Rating Scale-Activities of Daily Living, P < 0.01) emerged after the fifth year of stimulation. The present study did not reveal a predictive value of preoperative levodopa response, whereas few single features at baseline (such as gait and postural stability motor scores and the preoperative levodopa equivalent daily dose) could predict long-term motor outcome. A decline in verbal fluency (slightly more pronounced than after 5 years) was detected after 8 years. A significant but slight decline in tasks of abstract reasoning, episodic memory and executive function was also found. One patient had developed dementia at 5 years with further progression at 8 years. Executive dysfunction correlated significantly with postural stability, suggesting interplay between axial motor deterioration and cognition. Eight years after surgery, no significant change was observed on scales assessing depression or anxiety when compared with baseline. At 8 years, there was no significant increase of side-effects when compared with 5-year follow-up. In conclusion, deep brain stimulation of the subthalamic nucleus is a safe procedure with regard to cognitive and behavioural morbidity over long-term follow-up. However, the global benefit partly decreases later in the course of the disease, due to progression of Parkinson’s disease and the appearance of medication- and stimulation-resistant symptoms.

Dystonia is a movement disorder characterized by sustained muscle contractions causing twisting and repetitive movements and abnormal postures. Diagnosing dystonia may be difficult, because of variability of dystonia presentation, uncertain recognition of the specific clinical signs, wide etiological spectrum, and coexistence of other movement disorders. The major difficulties in the diagnostic assessment of primary and non-primary dystonia derive from its confusion with other movement disorders or with a psychogenic disorder. The clinical heterogeneity of dystonia and some examples of misdiagnosis are reviewed here. The movement disorders that can be most commonly taken for dystonia are tremor, Parkinson’s disease, myoclonus, chorea, and tics. Given the occurrence of confounding factors, along with specific genetic and laboratory test, it is of great importance to apply a specific algorithm to recognize the clinical signs of dystonia.

Although the understanding of dystonia has improved in recent years, primary dystonia is still insufficiently recognized and patients may not receive the correct diagnosis, leading to transient or permanent misclassification of their symptoms. We reviewed cases of primary dystonia who were at first misdiagnosed and analyzed the reasons why the correct diagnosis was first missed and later retained. Primary dystonia is misdiagnosed mainly, but not exclusively, in favor of other movement disorders: Parkinson’s disease (PD), essential tremor, myoclonus, tics, psychogenic movement disorder (PMD), and even headache or scoliosis. Accounts are more numerous for PD and PMD, where diagnostic tests, such as DAT scan and psychological assessment, support clinical orientation. The correct diagnosis was achieved in all cases following the recognition of inconsistencies in the first judgment and of distinctive clinical features of dystonia. These clues have been collected here and assembled into a diagnostic epitome.

INTRODUCTION: Subthalamic nucleus deep brain stimulation has become a useful tool in effectively treating severe Parkinson’s disease. METHOD: While most reports in literature describe the immediate and short-term post-operative brain lead implant-related adverse events, we present the case of a 65-year-old man who developed herpes zoster (HZ) upon the subcutaneous placement of the pulse generator two years after the procedure. CONCLUSION: He had excellent recovery of HZ lesions and related pain after specific antiviral therapy. The importance of a correct diagnosis of this unusual complication is outlined in order to minimize the risk of debilitating chronic HZ-associated pain.

Multiple system atrophy (MSA) is a Parkinson’s Disease (PD)-like alpha-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas.

Little is known about the gender-related long-term efficacy and safety after subthalamic nucleus deep brain stimulation (STN DBS) implant for Parkinson’s disease (PD), although some differences could be expected as recently stated in a short-term report. We assessed the possible gender-related differences in clinical outcome and disease progression along a 5-year period after STN DBS for PD. A prospective cohort of PD patients who underwent STN DBS and reached the 5-year follow-up (FU) was considered. Clinical outcome, disease progression and side effects were assessed at baseline and 1, 3, and 5 years after surgery. Eleven men and nine women were included in the study. At baseline, no inter-gender difference of age at implant, disease duration and severity or levodopa responsiveness was detected. A higher motor responsiveness in men compared to women was detected only at 1-year FU: this difference was mainly related to worse lower limb akinesia and gait score in women. The difference was not confirmed at 3 and 5 years. Antiparkinsonian drugs reduction, improvement in motor fluctuations and dyskinesias, functional measures and progression of underlying PD, were comparable in both groups. Women had persistent adverse events comparable to men. The present long-term observation confirms the occurrence of slight gender-related differences in PD patients treated with STN DBS, indicating a transient poorer outcome in women. Further observational time and a wider number of patients are needed to better analyze the dimension of long-term gender-related differences.

We report the 5 to 6 year follow-up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson’s disease (PD) patients. Thirty-five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson’s Disease Rating Scale (UPDRS) assessed with a prospective cross-over double-blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off- and on-medication states with and without stimulation, activities of daily living (ADL), anti-PD medications, and dyskinesias. In double-blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off-stimulation, regardless of the sequence of stimulation. In open assessment, both STN- and GPi-DBS significantly improved the off-medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti-PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long-term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN-DBS patients and fewer adverse events in the GPi-DBS group.

Mutations in the THAP1 gene on chromosome 8p21-p22 (DYT6 locus) have been recently reported as causative of autosomal dominant primary torsion dystonia (PTD) in four Amish-Mennonite families and in 12 additional probands of different ancestry. We sequenced the THAP1 gene in 158 patients with DYT1-negative PTD who had onset of symptoms below 30 years and/or positive family history. One sporadic Greek male patient, aged 57 years, was found to carry a novel heterozygous missense variant in THAP1 exon 3 (p.Cys170Arg), of likely pathogenic significance. This subject first presented with right writer’s cramp at age of 10 years and, subsequently, developed left arm dystonia and an extremely severe left laterocollis, without further spreading to other body districts. Our findings expand the genotypic spectrum of THAP1 and strengthen the association with upper body involvement, including the cranial and cervical districts that are usually spared in DYT1-PTD.

Hyposmia is a common nonmotor feature of Parkinson’s disease (PD) and has been variably detected in monogenic Parkinsonisms. To assess olfactory dysfunction in PINK1-related Parkinsonism, we evaluated olfactory detection threshold, odor discrimination, and odor identification in five groups of subjects: sporadic PD (n = 19), PINK1 homozygous (n = 7), and heterozygous (n = 6) parkinsonian patients, asymptomatic PINK1 heterozygous carriers (n = 12), and Italian healthy subjects (n = 67). All affected subjects and all healthy heterozygotes but one resulted hyposmic, with most patients in the range of functional anosmia or severe hyposmia. Detection threshold was more preserved and discrimination more impaired in patients with PINK1 mutations than in PD cases. Alterations of detection and discrimination were observed also in PINK1 asymptomatic heterozygotes. On the contrary, odor identification appeared to be mostly related to the disease status, as it was impaired in nearly all patients (including PD and PINK1 cases) and preserved in healthy heterozygotes. Our data indicate that olfactory dysfunction is common in PINK1 Parkinsonism and consists typically in defective odor identification and discrimination. A milder olfactory deficit, mostly involving discrimination, can be found in asymptomatic heterozygotes, possibly indicating an underlying preclinical neurodegenerative process.

We assessed the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) or internal pallidum (GPi-DBS) on health-related quality of life (HrQoL) in patients with advanced Parkinson’s disease participating in a previously reported multicenter trial. Sickness Impact Profile (SIP) questionnaires were available for analysis in a subgroup of n = 20/20 patients with GPi-DBS and n = 45/49 patients with STN-DBS at baseline, 6 and 36 months. The SIP provides a physical dimension and a psychosocial dimension sum score and 12 category scores: Alertness/Intellectual Behavior (AIB), Ambulation (A), Body Care and Movement (BCM), Communication (C), Eating (E), Emotional Behavior (EB), Home Management (HM), Mobility (M), Recreation and Pastimes (RP), Sleep and Rest (SR), Social Interaction (SI), and Work (W). Motor functioning was assessed by means of the Unified Parkinson’s Disease Rating Scale and diaries. At 6 months significant improvements in off-period motor symptoms and activities of daily living were paralleled by significant reductions in the total, physical, and psychosocial SIP score in both treatment groups. At 3 years, sustained improvements were observed in the physical dimension score, BCM, E, M, RP after STN-DBS and M, SI after GPi-DBS. All other SIP subscores approached baseline values, but were still the same or better (except C) whereas motor functioning remained stable after 36 months. STN-DBS and GPi-DBS led to significant early improvements in HrQoL. Despite sustained motor improvements many of these initial benefits were lost after 3 years. This may reflect either progression of the disease or adaptive changes in the subjective perception of health-related wellbeing over time.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) offers a unique window on the connectivity changes, extending beyond the basal ganglia, which accompany the cognitive symptoms of Parkinson disease (PD). The primary purpose of this study was to assess the microstructural damage to cerebral white matter occurring in idiopathic PD. MATERIALS AND METHODS: Our sample included patients with PD without dementia (n = 10; Hoehn and Yahr stages I and II; Unified Parkinson Disease Rating Scale, 20.5 +/- 8.3; and Mini-Mental State Examination, 28.3 +/- 1.5) and age-matched healthy control subjects (n = 10). DTI was performed on a 1.5T scanner, and mean diffusivity (MD) and fractional anisotropy (FA) maps were obtained. Regions of interest (ROIs) were drawn on the major fiber bundles as well as on gray matter nuclei. RESULTS: In patients, the MD was increased at borderline significance in the substantia nigra but was unaltered in the thalamus, globus pallidus, putamen, and in the head of the caudate nucleus. The FA and MD were unaltered in the corticospinal tract in the midbrain and at the level of the internal capsule, and in the splenium of the corpus callosum. By contrast, the MD was increased and the FA was decreased in the genu of the corpus callosum and in the superior longitudinal fasciculus; in the cingulum, only the MD was altered. The observed changes were not significantly lateralized. CONCLUSIONS: Widespread microstructural damage to frontal and parietal white matter occurs already in the early stages of PD.

Torsion dystonia is characterized by sustained muscle contractions causing twisting and repetitive movements and abnormal postures. The diagnosis can be made difficult, delayed, and often misled by several factors: variability of dystonia presentation, uncertain recognition of the specific physical signs, lack of diagnostic tests, wide etiological spectrum, and coexistence of other movement disorders. Diagnostic tools are of limited assistance for the diagnosis of dystonia, which remains based on clinical diagnostic skills. We propose here, a new diagnostic algorithm to systematize the clinical diagnostic workout. A correct recognition of the physical signs that constitute the hallmark of most dystonia syndromes provides the grounds to perform a structured diagnostic sequence and share a consistent methodology. This clinical algorithm may be enhanced by adding diagnostic tools for dystonia, once their diagnostic value is assessed.

The upper motor neuron (UMN) syndrome is a collection of interactive positive signs (associated with spastic hypertonia) and negative signs, such as muscle weakness and loss of voluntary control. In clinical practice, the distinction between active and passive functions allows identifying appropriate treatment objectives. During the last decades, many studies have evaluated the possibility to treat UMN syndromes with botulinum neurotoxin (BoNT). They have shown that BoNT is effective in controlling upper limb spasticity in adults. The clinical improvement is more consistent in the distal joints and the reduction of muscle hypertonia is dose-dependent. The functional efficacy of BoNT for lower limb spasticity has not been documented as well, as some series report efficacy in reducing muscle tone in the lower limb, but not in improving walking. The functional benefit arising from the reduction of spasticity is often difficult to judge in the context of the complex phenomenology of the UMN syndrome. Certain data indicate that some disabilities related to passive and active function in the upper limb can improve with treatment. However, to date, the functional improvement after BoNT treatment in patients with UMN symptoms remains a point of ambiguity in the literature. BoNT is overall well tolerated and must be regarded as a safe treatment intervention. Safety data are abundant in the literature for type-A toxin and scant for type-B toxin. There is no clear evidence to suggest the best time to introduce BoNT injections in the management of UMN syndromes. A common sense approach would be to introduce BoNT treatment as early as possible, in order to prevent further complications including contractures.

The aim of this systematic review was to determine whether botulinum neurotoxin (BoNT) reduce spasticity or improve function in adult patients after stroke. Eleven double-blind randomized placebo-controlled trials met inclusion criteria. They encompassed 782 patients, 767 (98%) of whom received BoNT/A, and 15 (2%) BoNT/B. Most studies used the Ashworth scale as primary outcome measure. Differences between treated and control groups were assessed as categorical or continuous comparisons. The overall effect on upper limb spasticity was in favor of BoNT/A. A significantly higher number of patients had a reduction of upper limb spasticity at 4-week and 8-week evaluations in the treatment group compared with placebo. Mean changes in joint spasticity revealed improvement 3 to 6 weeks and 9 to 12 weeks after treatment. There were insufficient data to establish BoNT/A efficacy on lower limb spasticity or the effect of BoNT/B on the upper and lower limbs. Because of inconsistency and heterogeneity of the available data, it was not possible to perform a meta-analysis on disability and patients’ reported outcomes. There was an overlapping safety profile between the treatment and the placebo groups. BoNT/A reduces upper limb spasticity in patients post-stroke, but the improvement in functional ability remains to be established. This gap needs to be filled by new studies to assess the effect of BoNT in the context of multidisciplinary patient management.

Stimulation of the subthalamic nucleus (STN) is an effective treatment for advanced Parkinson’s disease (PD), but the medication requirements after implant are poorly known. We performed a long-term prospective evaluation of 20 patients maintained at stable dopaminergic therapy for 5 years after bilateral STN implants, who were evaluated 6 months, 1 year, 3 years, and 5 years after surgery. We measured, during the entire observation period, the effect of deep brain stimulation on motor and functional outcome measures, the levodopa equivalent daily dose and the total electrical energy delivered. At 5 years, the UPDRS motor score had improved by 54.2% and levodopa equivalent dose was reduced by 61.9%, compared with preimplant. Dopaminergic medication remained stable during the observation period, but energy was progressively increased over time. Rest tremor, rigidity, gait, lower and upper limb akinesia, and total axial score were improved in decreasing order. Postural stability and speech improved transiently, whereas on-period freezing of gait, motor fluctuations and dyskinesias recovered durably. Functional measures did not show improvement in autonomy and daily living activities after STN implant. Chronic STN stimulation allows to replace for dopaminergic medications in the long-term at the expense of an increase of the total energy delivered. This is associated with marked improvement of motor features without a matching benefit in functional measures.

OBJECTIVES: To compare the clinical characteristics and the long-term outcome of a large series of patients with blepharospasm (BS) treated with the two most used brands of BoNT-A over the last 15 years. METHODS: We have reviewed the clinical charts of 128 patients with BS who received botulinum neurotoxin (BoNT) in 1341 treatments (Botox in 1009, Dysport in 332) over the last 15 years. RESULTS: Mean dose per session was 34U +/- 15 for Botox and 152U +/- 54 for Dysport. Mean latency of clinical effect was 4.5 +/- 4.6 days for Botox and 5.0 +/- 5.7 days for Dysport (P > 0.05). Mean duration of clinical improvement was higher for Dysport than Botox: 80.1 +/- 36.3 and 66.2 +/- 39.8 days, respectively (P < 0.01). In a six-point scale (0: no efficacy, 6: remission of BS), the mean efficacy of both treatments was 3.60 +/- 1.3; 3.51 +/- 1.4 (Botox) and 3.85 +/- 1.2 (Dysport), P < 0.01. The doses of Botox (beta = 0.40) and Dysport (beta = 0.16) were significantly increased over time. Side effects occurred in 325 out of 1341 treatments (24.2%): 21.8% of the patients who had received Botox, and in 31.6% of those who had received Dysport (P < 0.01). CONCLUSIONS: Both brands are effective and safe in treating blepharospasm; efficacy is long lasting. The differences in outcome and side effects suggest that, albeit the active drug is the same, Botox and Dysport should be considered as two different drugs.

BACKGROUND AND PURPOSE: To review the clinical characteristics and the long-term outcome of patients with hemifacial spasm (HFS) who received botulinum neurotoxin (BoNT) over the past 10 years. RESULTS: A total of 108 patients received 665 treatments. Mean latency of clinical effect was 5.4 +/- 5.3 days for Botox and 4.9 +/- 4.6 days for Dysport (P > 0.05). Mean duration of clinical improvement was higher after the injection of Dysport than Botox: 105.9 +/- 54.2 and 85.4 +/- 41.6 days respectively (P < 0.01). The percentage of treatment failures was 6.5% for Botox and 4.6% for Dysport (P > 0.05). The doses of Botox significantly increased over time (beta = 0.35, P < 0. 001) whilst Dysport dose remained unchanged (beta = 0.16, n.s.). The duration of clinical benefit slightly increased with Botox (beta = 0.12; P < 0.01), but remained constant for Dysport. Side effects occurred in 17.4% of treatments: 16.7% of patients who had received Botox, and in 19.7% who had received Dysport (P > 0.05). The most common side effects were palpebral ptosis and lacrimation; ptosis and lagophtalmos was more common in Dysport treatments (P < 0.005). CONCLUSIONS: Both brands are effective and safe in treating HFS; efficacy is long-lasting. The differences in outcome and side effects confirm that, albeit the active drug is the same, Botox and Dysport should be considered as two different drugs.

Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.

This paper reviews the epidemiology, pathophysiology, clinical features and rationale for managing dyskinesias associated with Parkinson’s disease. These are a common clinical problem occurring in up to 90% of patients and more frequently affect those with early-onset. Dyskinesias have a negative impact on quality of life and are an important cause of disability. Their precise etiology is still poorly understood, although it is recognized that dopaminergic pre-synaptic and post-synaptic mechanisms are involved together with extra-dopaminergic factors. The phenomenology of dyskinesias encompasses a variable mixture of two prevalent features: dystonia and chorea. We have studied their time course following a single acute levodopa challenge and have found that dystonia occurs throughout the duration of the on period, whereas choreiform movements occur only at the peak of therapeutic dopaminergic motor responses. This allows a schematic relationship to be drawn between a short duration motor response and the occurrence of dystonia and chorea. There is currently no satisfactory treatment for dyskinesias. Managing the therapeutic window does not provide an adequate solution due to the appearance of a dyskinesia threshold dose that narrows the therapeutic margin. High frequency stimulation of the subthalamic nucleus probably has some specific anti-dyskinetic action, but is limited by the small number of patients who are candidates for this treatment. Research efforts are currently focused on the development of specific anti-dyskinetic medications. Their availability will certainly change the current clinical practice and will widen again the therapeutic window of dopaminergic medications that has now become too narrow.

Extradural motor cortex stimulation has been employed in cases of Parkinson’s disease (PD), fixed dystonia (FD) and spastic hemiparesis (SH) following cerebral stroke. Symptoms of PD are improved by EMCS: results were evaluated on the basis of the UPDRS and statistically analysed. In PD EMCS is less efficacious than bilateral subthalamic nucleus (STN) stimulation, but it may be safely employed in patients not eligible for deep brain stimulation (DBS). The most rewarding effect is the improvement, in severely affected patients, of posture and gait. FD, unresponsive to bilateral pallidal stimulation, has been relieved by EDMS. In SH reduction of spasticiy by EMCS allows improvement of the motor function.

Dementia associated with Parkinson’s disease (PD) ultimately develops in approximately 70% of patients with PD older than 80 years of age. The neuropathology of PD dementia (PDD) is likely multifactorial and affects several neuronal populations. There is evidence that PDD is associated with a cholinergic deficit, supporting the therapeutic role of cholinesterase inhibitors, which are already first-line agents in the treatment of Alzheimer’s disease. Open-label and small controlled studies suggested a clinical efficacy of cholinesterase inhibitors in PDD. One large randomized placebo-controlled trial of 541 patients demonstrated that oral rivastigmine improved cognition, attention and executive functions, activities of daily living and behavioral symptoms after 6 months of treatment. Rivastigmine is a dual cholinesterase inhibitor, being effective on both acetylcholinesterase and butyrylcholinesterase. This paper reviews the pharmacokinetic and pharmacodynamic properties of rivastigmine (oral and transdermal administration). It also reviews evidence on clinical efficacy, safety and tolerability of the oral administration in PDD patients at doses of 3-12 mg/day.

The clinical diagnosis of multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson’s disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as “red flags” or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/-7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P.

OBJECTIVE: To determine whether pain is more frequent among people with Parkinson disease (PD) than among age-matched controls. DESIGN: Case-control study. Patients and METHODS: Logistic regression models taking into account type of pain, time between pain and PD onset, and possible confounders were used to compare 402 PD patients with 317 age-matched healthy control subjects. RESULTS: The overall frequency of pain was significantly greater in PD patients than in controls (281 [69.9%] vs 199 [62.8%]; P = .04), mainly because the healthy control group lacked dystonic pain. Conversely, the frequency of nondystonic pain was similar among PD patients and controls (267 [66.4%] vs 199 [62.8%]; P = .28). Nevertheless, we observed a significant association between PD and nondystonic pain, beginning after the onset of parkinsonian symptoms (odds ratio, 2.1; 95% confidence interval, 1.4-2.9). Cramping and central neuropathic pain were more frequent among PD patients than controls. About one-quarter of patients who experienced pain reported pain onset before starting antiparkinsonian therapy. CONCLUSION: These data support the hypothesis that pain begins at clinical onset of PD or thereafter as a nonmotor feature of PD.

OBJECTIVE: The only known genetic cause of early-onset primary torsion dystonia is the GAG deletion in the DYT1 gene. Due to the reduced penetrance, many mutation carriers remain clinically asymptomatic, despite the presence of subclinical abnormalities, mainly in the motor control circuitry. Our aim was to investigate whether the DYT1 mutation impairs the inner simulation of movements, a fundamental function for motor planning and execution, which relies upon cortical and subcortical systems, dysfunctional in dystonia. METHODS: DYT1 manifesting patients, DYT1 non-manifesting carriers and control subjects were asked to fixate body (hand, foot, face) or non-body (car) stimuli on a computer screen. Stimuli were presented at different degrees of orientations and subjects had to mentally rotate them, in order to give a laterality judgement. Reaction times and accuracy were collected. RESULTS: DYT1 carriers, manifesting and non-manifesting dystonic symptoms, were slower in mentally rotating body parts (but not cars) than control subjects. CONCLUSIONS: The DYT1 gene mutation is associated with a slowness in mental simulation of movements, independently from the presence of motor symptoms. SIGNIFICANCE: These findings suggest that the cognitive representation of body movements may be altered subclinically in dystonia, thus contributing to the endophenotypic trait of disease.

Mutations in the epsilon-sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus-dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11-MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 +/- 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo-rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a “startle-like” muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long-loop reflexes were normal, as was silent period and long-term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short-term intracortical inhibition revealed subtle impairment, and event-related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11-MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11-MDS may justify the involvement of different brain areas.

Continuous high-frequency stimulation of the globus pallidum internum (GPi) is an accepted treatment for patients with primary dystonia. In a series of 18 consecutive dystonia cases that were successfully treated by bilateral GPi stimulation, 1 patient had an adverse event involving the downward migration of the electrodes. He developed remarkable behavioral complications and was found to have dislodgement of the left electrode to a position close to the left amygdala. The patient developed behavioral changes consisting of depression, psychotic symptoms, and heightened pain perception. This syndrome reverted when the left electrode was removed and a new one inserted in the correct position. We describe in detail the clinical features associated with left amygdala dysregulation induced by high-frequency stimulation through the displaced electrode.

Dystonia refers to sustained and vigorous contractions forcing a body region into an abnormal position that is consistently present. Dystonic postures and movements can variably combine to produce a wide spectrum of clinical presentations. The movement can affect one, two or more body regions, as in focal, segmental or generalized dystonia. Dystonic movements display specific features that can be recognised by clinical observation, such as speed, consistency, predictability, variability and relationship with voluntary movement. Sensory tricks and gestes antagonistes are manoeuvres that specifically alleviate dystonic movements and postures, thereby providing diagnostic clues. The diagnosis of primary dystonia can be established by applying a simple diagnostic flow chart during neurological examination to guide further laboratory testing.

Microrecordings of three neurons were obtained at the target site in three patients with trigeminal autonomic cephalalgias who were implanted with deep brain stimulators in the posterior hypothalamus. Two patients had chronic cluster headache, one short unilateral neuralgiform headache with conjunctival injection and tearing. Average firing rate was around 24 spikes/s. All neurons were firing randomly, and for most of the recordings in tonic fashion. In one patient, tactile stimulation of the ophthalmic branch, contralateral to the recording site, decreased the firing rate. Neuronal activity in these patients was similar to that reported in animal studies of the posterior hypothalamus. Positioning deep brain stimulators in the posterior hypothalamus may offer a tool to better characterise the activity of this part of the brain in humans.

The objective of this study was to investigate cardiovascular autonomic function in patients with parkin disease. Ten patients with a genetically confirmed diagnosis were compared to 11 healthy controls. Symptoms related to autonomic dysfunction were collected by structured interviews. Cardiovascular autonomic reflex function was evaluated using a standard battery of eight tests. Autonomic tests included the study of sympathetic function through the analysis of blood pressure responses to head-up tilt, standing, isometric hand grip, cold pressor, mental arithmetic, Valsalva maneuver (Valsalva overshoot), and the study of parasympathetic function through the analysis of heart rate responses to deep breathing, hyperventilation, and Valsalva ratio. Seven out of 10 patients reported symptoms involving different aspects of autonomic function, while 5 out of 11 controls reported symptoms related exclusively to orthostatic dizziness and constipation. Symptoms related to bladder dysfunction were the most frequent autonomic abnormality occurring in six patients, followed by orthostatic dizziness and dry mouth (in four patients each). Constipation occurred in three patients, sialorrhea in two, and erectile dysfunction, dry eye, and warm intolerance in one each. Cardiovascular reflex testing revealed no difference between patients and controls in quantitative assessment of both sympathetic and parasympathetic functions, except for diastolic blood pressure after isometric hand grip that did not increase normally in parkin patients compared to controls (P = 0.007). These data show that cardiovascular dysautonomia is not associated to the parkin phenotype, whereas urinary complaints are more frequently reported by parkin patients than by controls. Urinary dysautonomia warrants further investigation in patients with parkin disease.

AIM: To assess the long-term cognitive and behavioural outcome after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients affected by Parkinson’s disease, with a 5-year follow-up after surgery. METHODS: 11 patients with Parkinson’s disease treated by bilateral DBS of STN underwent cognitive and behavioural assessments before implantation, and 1 and 5 years after surgery. Postoperative cognitive assessments were carried out with stimulators turned on. RESULTS: A year after surgery, there was a marginally significant decline on a letter verbal fluency task (p = 0.045) and a significant improvement on Mini-Mental State Examination (p = 0.009). 5 years after surgery, a significant decline was observed on a letter verbal fluency task (p = 0.007) and an abstract reasoning task (p = 0.009), namely Raven’s Progressive Matrices 1947. No significant postoperative change was observed on other cognitive variables. No patient developed dementia 5 years after surgery. A few days after the implantation, two patients developed transient manic symptoms with hypersexuality and one patient developed persistent apathy. CONCLUSION: The decline of verbal fluency observed 5 years after implantation for DBS in STN did not have a clinically meaningful effect on daily living activities in our patients with Parkinson’s disease. As no patient developed global cognitive deterioration in our sample, these findings suggest that DBS of STN is associated with a low cognitive and behavioural morbidity over a 5-year follow-up, when selection criteria for neurosurgery are strict.

To assess severity and progression of self-perceived dysautonomia and their impact on health-related quality of life (Hr-QoL) in multiple system atrophy (MSA), twenty-seven patients were recruited by the European MSA Study Group (EMSA-SG). At baseline, all patients completed the Composite Autonomic Symptom Scale (COMPASS) and the 36 item Short Form Health Survey (SF-36), and they were assessed using the 3-point global disease severity scale (SS-3) and the Unified MSA Rating Scale (UMSARS). After 6 months follow-up, the self completed COMPASS Change Scale (CCS), the SF-36, SS-3, and UMSARS were obtained. MSA patients showed marked self-perceived dysautonomia at baseline visit and pronounced worsening of dysautonomia severity on the CCS at follow-up. Severity and progression of dysautonomia did not correlate with age, disease duration, motor impairment and overall disease severity at baseline. There were no significant differences between genders and motor subtypes. Baseline COMPASS scores were, however, inversely correlated with SF-36 scores. Progression of self-perceived dysautonomia did not correlate with global disease progression. Hr-QoL scores were stable during follow-up. This is the first study to investigate self-perceived dysautonomia severity in MSA and its evolution over time. Our data suggest that dysautonomia should be recognized as a key target for therapeutic intervention in MSA.

OBJECTIVES To review the literature on primary dystonia and dystonia plus and to provide evidence-based recommendations. BACKGROUND Primary dystonia and dystonia plus are chronic and often disabling conditions with a widespread spectrum mainly in young people. SEARCH STRATEGY Computerised MEDLINE and EMBASE literature reviews (1966–1967 February 2005) were conducted. The Cochrane Library was searched for relevant citations. RESULTS ON DIAGNOSIS Diagnosis and classification of dystonia are highly relevant for providing appropriate management and prognostic information, and genetic counselling. Expert observation is suggested. DYT-1 gene testing in conjunction with genetic counselling is recommended for patients with primary dystonia with onset before the age of 30 and in those with an affected relative with early onset. Positive genetic testing for dystonia (e.g. DYT-1) is not sufficient to diagnose dystonia. Individuals with myoclonus should be tested for the epsilon-sarcoglycan gene (DYT-11). A levodopa trial is warranted in every patient with early onset dystonia without an alternative diagnosis. Brain imaging is not routinely required when there is a confident diagnosis of primary dystonia in adult patients, whereas it is necessary in the paediatric population. RESULTS ON TREATMENT Botulinum toxin (BoNT) type A (or type B if there is resistance to type A) can be regarded as first line treatment for primary cranial (excluding oromandibular) or cervical dystonia and can be effective in writing dystonia. Actual evidence is lacking on direct comparison of the clinical efficacy and safety of BoNT-A vs. BoNT-B. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for generalised or cervical dystonia, after medication or BoNT has failed to provide adequate improvement. Selective peripheral denervation is a safe procedure that is indicated exclusively in cervical dystonia. Intrathecal baclofen can be indicated in patients where secondary dystonia is combined with spasticity. The absolute and comparative efficacy and tolerability of drugs in dystonia, including anticholinergic and antidopaminergic drugs, is poorly documented and no evidence-based recommendations can be made to guide prescribing.

Botulinum toxin serotype A (BoNT-A) has long heritage of use leading to confidence in its safety and efficacy. The application of BoNT-A does not lead to persistent histological changes in the nerve terminal or the target muscle. Clinical trials defined the safety and tolerability profile of BoNT-A across common therapeutic indications and showed an incidence of adverse events of approximately 25% in the BoNT-A-treated group compared with 15% in the control group. Focal weakness was the only adverse event to occur more often following BoNT-A treatment. Long-term BoNT-A administration has been assessed in various treatment settings, with the level and duration of BoNT-A efficacy response being maintained over repeated rounds of injection with no major safety concerns. The treatment of children with cerebral palsy often require long-term, repeated, multimuscle BoNT-A injections that lead to the administration of comparably higher toxin doses. Despite the high total body doses used, their distribution over multiple muscles and injection sites means that systemic side effects are rare. Recent formulation changes have reduced the incidence of antibody development following treatment with BOTOX. These findings show long-term BoNT-A treatment to be both safe and efficacious for a wide variety of indications.

To investigate the clinical features of early-onset primary torsion dystonia (EO-PTD), 57 consecutive genetically characterized patients with onset before 21 years were studied. Sex, ethnic origin, family history of dystonia, age at onset, disease duration, site of dystonia onset and distribution at latest examination, dystonia progression, time to generalization, and motor disability were noted. The 14 patients (25%) with GAG deletion (904_906/907_909delGAG) in the DYT1 gene were compared with the remaining non-DYT1 patients. Cranial involvement was present in 49% of non-DYT1 cases, but only 14% of DYT1 cases; non-DYT1 patients were younger at time of generalization. DYT1 cases had features similar to sporadic non-DYT1 cases but differed markedly from familial non-DYT1 cases, the latter having later age at onset, less common limb onset, more frequent cervical involvement, and slower progression than DYT1 PTD. These findings indicate that non-DYT1 forms of EO-PTD differ clinically from those of DYT1 forms. Cranial involvement before 21 years of age is the strongest predictor of non-DYT1 status. Positive family history and cervical involvement are associated with less severe progression in non-DYT1 forms.

To evaluate the frequency of the LRRK2 G2019S mutation in Italy, we tested 1,072 probands with Parkinson’s disease (PD; 822 sporadic and 250 familial): 20 patients (1.9%) carried the G2019S mutation, 11 patients (1.3%) were sporadic, and 9 (4.3%) had a positive family history. Considering only probands with autosomal dominant inheritance, the G2019S frequency raises to 5.2%. All presented a typical phenotype with variable onset and shared the common ancestral haplotype. Mutation frequency raised from 1.2% in early onset PD to 4.0% in late onset PD.

Four hundred and sixty records of patients with primary torsion dystonia (296 women and 164 men) were evaluated. The mean age at disease onset was 48.3 +/- 17.7 years; 13 patients carried the DYT1 CAG deletion. The distribution of age at onset was represented by a bi-modal curve, with a nadir at 21 year separating early onset from late onset cases. In 15.9% of cases there was a positive family history of dystonia. Cranial, cervical or lower limb onset was more common amongst women (M:F ratios were 1:2.7, 1:1.9, and 1:3); by contrast, onset in the upper limb was more common in men (M:F ratio 2.2:1). As expected, disease progression was more pronounced in cases with early onset; it was reckoned that onset at or above 32 years was associated with a negligible likelihood to progress to a generalized form. The mean age at onset of familial cases was 44.8 +/- 11.2 years, significantly lower than the mean age at onset of sporadic cases (53.5 +/- 13.4 years). Familial cases were characterized by more sites involved throughout disease course. Familial cases had a higher tendency to progress to a segmental or generalized form than sporadic cases.

The blink rate (BR) during rest, conversation, and reading was assessed in 50 patients with blepharospasm (BS) and in 150 healthy subjects. BR at rest and during conversation was higher in patients with BS. Moreover, 76% of patients had BR higher at rest than during conversation, whereas in 74% of controls, BR was higher during conversation than at rest. The sensitivity and specificity of two parameters (value of BR at rest and pattern rest-BR higher than conversation-BR) in discriminating patients and controls were computed. The best fit was obtained with a rest-BR above 27 blinks per minute. When the two parameters were combined (rest-BR above 27 blinks per minute together with the pattern rest-BR higher than conversation-BR), we obtained a 92.3% sensitivity and a 82.0% specificity in discriminating between BS patients and controls. These findings indicate that specific features of BR can be associated with BS, suggesting that the analysis of BR might be helpful for the diagnosis of BS in early stages.

Since its introduction in the late 1970s for the treatment of strabismus and blepharospasm, botulinum toxin (BoNT) has been increasingly used in the interventional treatment of several other disorders characterized by excessive or inappropriate muscle contractions. Over the years, the number of primary clinical publications has grown exponentially, and still continues to increase. It has been shown that BoNT blocks cholinergic nerve endings in the autonomic nervous system but does not block non-adrenergic non-cholinergic responses mediated by nitric oxide (NO). The present paper reviews a number of recent clinical indications for urological and pelvic floor dysfunctions, such as overactive and neurogenic bladder, non-bacterial prostatitis, benign prostatic hyperplasia, chronic anal fissure, or conditions associated to hyperactivity of the puborectalis muscle during straining. These indications provide a new promising palette of indications for future usage of BoNT in clinical practice.

Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients’ own evaluation of their illness and factors associated with poor health-related quality of life (Hr-QoL). We, therefore, assessed Hr-QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA-Study Group (EMSA-SG) Natural History Study: Medical Outcome Study Short Form (SF-36), EQ-5D, Beck Depression Inventory (BDI), Mini-Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), Hoehn & Yahr (H&Y) Parkinson’s disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson’s Disease Sleep Scale (PDSS). Forty-six percent of patients had moderate to severe depression (BDI > or = 17); Hr-QoL scores on the SF-36 and EQ-5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA-P (predominantly parkinsonian motor subtype) than MSA-C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr-QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate-to-strong predictors for the SF-36 physical summary score and the BDI and UMSARS motor scores for the SF-36 mental summary score. This report is the first study to show that Hr-QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr-QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr-QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease.

To review the literature on primary dystonia and dystonia plus and to provide evidence-based recommendations. Primary dystonia and dystonia plus are chronic and often disabling conditions with a widespread spectrum mainly in young people. Computerized MEDLINE and EMBASE literature reviews (1966-1967 February 2005) were conducted. The Cochrane Library was searched for relevant citations. Diagnosis and classification of dystonia are highly relevant for providing appropriate management and prognostic information, and genetic counselling. Expert observation is suggested. DYT-1 gene testing in conjunction with genetic counselling is recommended for patients with primary dystonia with onset before age 30 years and in those with an affected relative with early onset. Positive genetic testing for dystonia (e.g. DYT-1) is not sufficient to make diagnosis of dystonia. Individuals with myoclonus should be tested for the epsilon-sarcoglycan gene (DYT-11). A levodopa trial is warranted in every patient with early onset dystonia without an alternative diagnosis. Brain imaging is not routinely required when there is a confident diagnosis of primary dystonia in adult patients, whereas it is necessary in the paediatric population. Botulinum toxin (BoNT) type A (or type B if there is resistance to type A) can be regarded as first line treatment for primary cranial (excluding oromandibular) or cervical dystonia and can be effective in writing dystonia. Actual evidence is lacking on direct comparison of the clinical efficacy and safety of BoNT-A vs. BoNT-B. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for generalized or cervical dystonia, after medication or BoNT have failed to provide adequate improvement. Selective peripheral denervation is a safe procedure that is indicated exclusively in cervical dystonia. Intrathecal baclofen can be indicated in patients where secondary dystonia is combined with spasticity. The absolute and comparative efficacy and tolerability of drugs in dystonia, including anticholinergic and antidopaminergic drugs, is poorly documented and no evidence-based recommendations can be made to guide prescribing.

Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson’s Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and – to a lesser degree – of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson’s disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson’s disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the ‘off’ medication score of the Unified Parkinson’s Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the ‘off’ medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the ‘on’ time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the ‘on’ medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson’s disease.

It has been proposed that European mitochondrial DNA (mtDNA) haplogroups J and K, and their shared 10398G single-nucleotide polymorphism (SNP) in the ND3 gene, are protective from Parkinson’s disease (PD). We evaluated the distribution of the different mtDNA haplogroups in a large cohort of 620 Italian patients with adult-onset (>50, <65 years of age) idiopathic PD vs two groups of ethnic-matched controls. Neither the frequencies of haplogroup J nor that of 10398G were significantly different. However, the frequency of haplogroup K was significantly lower in PD. Stratification by sex and age indicated that the difference in the distribution of haplogroup K was more prominent in >50 year old males. In spite of the common 10398G SNP, haplogroups J and K belong to widely diverging mitochondrial clades, a consideration that may explain the different results obtained for the two haplogroups in our cohorts. Our study suggests that haplogroup K might confer a lower risk for PD in Italians, corroborating the idea that the mitochondrial oxidative phosphorylation pathway is involved in the susceptibility to idiopathic PD.

Mutations in the PINK1 gene cause autosomal recessive parkinsonism characterized by early onset and a variable phenotypic presentation. A patient homozygous for the Ala168Pro mutation has been fully characterized clinically. Apart from onset at age 39 years and the excellent and sustained response to levodopa, all clinical and laboratory features, including SPECT and assessment of autonomic function, were indistinguishable from typical idiopathic Parkinson disease.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is an efficacious symptomatic treatment for Parkinson’s disease. We have analysed the genetic status of a series of consecutive parkinsonian patients implanted for STN HFS and compared the outcome of five carrying mutations in the parkin gene with that of the non-parkin group. All patients obtained sustained control of PD symptoms and achieved functional improvement; in the parkin group the UPDRS motor score improved by 56.4%, the levodopa equivalent daily dosage was reduced by 75.5%. Postoperative medications were reduced more in parkin than in non-parkin patients. We confirm that the current inclusion criteria for STN HFS do not exclude patients carrying mutations in the parkin gene; their clinical outcome is comparable to that of the non-parkin group.

Adult-onset focal dystonia was the presenting sign of pantothenate kinase-associated neurodegeneration (PKAN) in a patient with a novel homozygous missense mutation (C856T). His brother shared the same mutation and showed similar, albeit minor, motor signs, but a different behavioral profile. Both brothers had an atypical form of PKAN. The neuropsychological assessment showed that, despite a normal Mini-Mental State Examination, both patients presented a deficit of executive functions and of attention. The profile of cognitive impairment in these cases was typically that of a subcortical dementia. Both patients fulfilled Diagnostic and Statistical Manual for Mental Disorders criteria for obsessive-compulsive disorder; however, paranoia was associated with depression and aggressive behavior in Patient 1, whereas Patient 2 had hyperactivity, disinhibition, and euphoria. Our findings suggest that these two brothers had a different pattern of involvement of motor and nonmotor basal ganglia-thalamocortical circuits.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson’s disease (PD) and the “gold standard” against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson’s disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. METHODS: Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson’s disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer’s Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. RESULTS: A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer’s disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). CONCLUSIONS: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson’s disease but also with higher rates of nausea, vomiting, and tremor.

We have recently reported homozygous mutations in the PINK1 gene in three consanguineous families with early-onset parkinsonism (EOP) linked to the PARK6 locus. To further evaluate the pathogenic role of PINK1 in EOP and to draw genotype-phenotype correlates, we performed PINK1 mutation analysis in a cohort of Italian EOP patients, mostly sporadic, with onset younger than 50 years of age. Seven of 100 patients carried missense mutations in PINK1. Two patients had two PINK1 mutations, whereas in five patients only one mutation was identified. Age at onset was in the fourth-fifth decade (range, 37-47 years). The clinical picture was characterized by a typical parkinsonian phenotype with asymmetric onset and rare occurrence of atypical features. Slow progression and excellent response to levodopa were observed in all subject. Two of 200 healthy control individuals also carried one heterozygous missense mutation. The identification of a higher number of patients (5%) than controls (1%) carrying a single heterozygous mutation, along with previous positron emission tomography studies demonstrating a preclinical nigrostriatal dysfunction in PARK6 carriers, supports the hypothesis that haploinsufficiency of PINK1, as well as of other EOP genes, may represent a susceptibility factor toward parkinsonism. However, the pathogenetic significance of heterozygous PINK1 mutations still remains to be clarified.

BACKGROUND: Botulinum neurotoxin induces healing in patients with idiopathic fissure. The optimal dosage is not well established. AIM: To compare the efficacy and tolerability of two different formulations of type A botulinum neurotoxin, and to provide more evidence with regard to the choice of dosage regimens. METHODS: Symptomatic adults with chronic anal fissure were enrolled in a randomized study. The outcome of each group was evaluated clinically, and by comparing the pressure of the anal sphincters before and after treatment. RESULTS: Fifty patients received injections of 50 units of Botox formulation (group I), and 50 patients received injections of 150 units of Dysport toxin (group II). One month after injection, 11 patients in group I and eight in group II had mild incontinence of flatus. At the 2-month evaluation point, 46 patients in group I and 47 patients in group II had a healing scar. In group I patients, the mean resting anal pressure was 41.8% lower, and the maximum voluntary squeeze pressure was 20.2% lower, than the baseline value. In group II patients, the resting anal pressure and maximum voluntary squeeze pressure were 60.0 +/- 12.0 mmHg and 71.0 +/- 30.0 mmHg, respectively. There were no relapses during an average of about 21 months of follow-up. CONCLUSIONS: Botulinum neurotoxin may be considered an effective treatment in patients with chronic anal fissure. The efficacy and tolerability of the two different formulations of botulinum neurotoxin were indistinguishable.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.

Local injections of botulinum neurotoxin are now considered an efficacious treatment for neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum neurotoxin provides benefit in diseases of the gastrointestinal tract. Botulinum neurotoxin inhibits contraction of gastrointestinal smooth muscles and sphincters; it has also been shown that the neurotoxin blocks cholinergic nerve endings in the autonomic nervous system, but it does not block nonadrenergic responses mediated by nitric oxide. This aspect has further promoted the interest to use botulinum neurotoxin as a treatment for overactive smooth muscles, such as the anal sphincters to treat anal fissure and outlet-type constipation, or the lower esophageal sphincter to treat esophageal achalasia. Knowledge of the anatomical and functional organization of innervation of the gastrointestinal tract is a prerequisite to understanding many features of botulinum neurotoxin action on the gut and the effects of injections placed into specific sphincters. This review presents current data on the use of botulinum neurotoxin to treat diseases of the gastrointestinal tract and summarizes recent knowledge on the pathogenesis of disorders of the gut due to a dysfunction of the enteric nervous system.

We describe the phenotype of DYT13 primary torsion dystonia (PTD) in a family first examined in 1994. A complete neurological evaluation was performed on all available family members: 8 individuals were definitely affected by dystonia. The family was re-evaluated in March 2000: at that time, 3 more individuals had developed symptoms of dystonia. Inheritance of PTD was autosomal dominant, with affected individuals spanning three consecutive generations and male-to-male transmission. Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred only in 2 cases. We did not find anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13-PTD is an autosomal dominant disease, with incomplete penetrance (58%). Clinical presentation and age at onset were more variable than in DYT1-PTD, and the neck was involved in most of those affected. Moreover, the individuals with generalised dystonia were not severely disabled and were able to lead independent lives. To date, this is the only family with DYT13-PTD.

Cervical dystonia (CD) is one of the most common forms of primary dystonia. The pathogenesis of the disease is still unknown, although evidence suggests a role for genetic factors. Recently, a polymorphism in the dopamine D5 receptor (DRD5) gene has been associated with the disease in a British population, suggesting that DRD5 is a susceptibility gene for CD. To confirm these data, we performed a case-control study of the microsatellite (CT/GT/GA)(n) at the DRD5 locus in 104 Italian CD patients and 104 healthy controls. The frequency of allele 4 was higher in the CD patients compared to the controls. This resulted in a twofold increased risk of developing the disease. These results provide further evidence of an association between DRD5 and cervical dystonia, supporting the involvement of the dopamine pathway in the pathogenesis of CD.

Dystonia (from the Greek, “altered muscle tone”) refers to sustained and vigorous contractions forcing a body region into an abnormal position that is consistently present. Dystonic postures and movements can variably combine to produce a wide spectrum of clinical presentations. The movement can affect one, two or more body regions, as in focal, segmental or generalised dystonia. Dystonia arising in childhood tends to progress to a generalised form; adult-onset dystonia, instead, is often focal or segmental. Dystonic movements have specific features that can be recognised by clinical observation, such as speed, consistency, predictability, variability and relationship with voluntary movement. Sensory tricks and gestes antagonistes are manoeuvres that specifically alleviate dystonic movements and postures thereby providing diagnostic clues. The diagnosis of primary dystonia requires the observation of a consistent clinical picture.

BACKGROUND: Few cases of frontotemporal dementia parkinsonism (FTDP-17) have been described in the literature. To our knowledge, this is the first Italian case. OBJECTIVE: To report a case of FTDP linked to chromosome 17, exhibiting progressive supranuclear palsy on initial examination. PATIENT: A 50-year-old woman had a 4-year history of behavior changes associated with slowly progressive mental decay and parkinsonism, with poor balance, supranuclear vertical gaze palsy, and bradykinesia. The symptoms were not responsive to dopaminergic therapy. Her father had died at age 46 years after a 7-year history of parkinsonism, and her brother, diagnosed as having progressive supranuclear palsy, died at age 45 years. RESULTS: Magnetic resonance imaging showed mild midbrain atrophy, results of an electroencephalogram were normal, and cognitive evaluation showed moderate cognitive impairment, especially evident in the executive and attentional functions. Genetic testing revealed a tau gene mutation at codon 279 (AAT–>AAG) of exon 10. CONCLUSION: Exon 10 mutations (including the N279K mutation) that result in overproduction of the tau isoform with 4 microtubule binding motifs seem to be associated with a mainly parkinsonian phenotype at disease onset.

OBJECTIVES: To evaluate the therapeutic role of botulinum toxin injection in men with benign prostatic hyperplasia. METHODS: Men with benign prostatic hyperplasia were enrolled in a randomized, placebo-controlled study. After a baseline evaluation, each participant received 4 mL of solution injected into the prostate gland. Patients in the control group received saline solution and patients in the treated group received 200 U of botulinum toxin A. The outcome of each group was evaluated by comparing the symptom scores, serum prostate-specific antigen concentration, prostate volume, postvoid residual urine volume, and peak urinary flow rates. RESULTS: Thirty consecutive patients were enrolled. No local complications or systemic side effects were observed in any patient. After 2 months, 13 patients in the treated group and 3 in the control group had subjective symptomatic relief (P = 0.0007). In patients who received botulinum toxin, the symptom score was reduced by 65% compared with baseline values and the serum prostate-specific antigen concentration by 51% from baseline. In patients who received saline, the symptom score and serum prostate-specific antigen concentration were not significantly changed compared with the baseline values and 1-month values. Follow-up averaged 19.6 +/- 3.8 months. CONCLUSIONS: Botulinum toxin injected into the prostate seems to be a promising approach for the treatment of benign prostatic hyperplasia. It is safe, effective, and well-tolerated. Furthermore, it is not related to the patient’s willingness to complete treatment.

Parkinson’s disease (PD) is a progressive disturbances of movement that affects mainly the motor system. Prolonged pharmacological administration may result in insufficient control of symptoms and significant side effects. Deep brain stimulation (DBS), targeted at the STN, is a recent surgical procedure that, according to the symptoms response, allows modification of stimulation parameters; its effects are also reversible. In this paper management of surgical patients is reported. It includes patient selection, inclusion and exclusion criteria, postoperative clinical protocol. The evaluation rating scale such as UPDRS, Dyskinesias Rating Scale and Self-Reporting Questionnaire usually administrated on PD patients are analyzed. Surgical inclusion criteria are (1) idiopathic PD, (2) IV or V Hoehn-Yahr stage, (3) severe motor disability, and (4) no dementia or psychiatric abnormalities. Postoperative clinical protocol is analyzed and parameter of stimulation after surgery and at the follow up are reported. Generally DBS allows an improvement of rigidity and tremor; bradykinesia also improves with high frequency stimulation. Results obtained by continuous stimulation show a mean improvement of UPDRS of about 60% and a significant reduction in the drug intake.

The present paper reviews clinical studies on the use of dihydroergocriptine (DHEC), an ergot derivative with dopamine agonist activity, for the treatment of Parkinson’s disease. This compound is a hydrogenated ergot derivative structurally quite similar to bromocriptine, from which it differs because of the hydrogenation in C9 C10 and the lack of bromine in C2. DHEC has a potent D2-like receptor agonist and a partial D1-like receptor agonist activity; because of this biochemical profile, it has been suggested that DHEC may produce fewer side-effects and have clinical efficacy equal to that of a classical dopamine agonist. Several open-label and double-blind studies indicate that DHEC is an efficacious remedy for parkinsonian signs and symptoms. Further studies are necessary to compare DHEC to new dopamine agonists (pergolide, cabergoline, ropinirole, and pramipexole) which have been more recently marketed.

The so-called bradykinesia of Huntington’s disease (HD) seems not due to reduced movement speed alone but may also be task-dependent. We therefore investigated the influence of visual control on the ability of HD patients to perform a motor task. Ten HD patients, never treated with neuroleptic drugs and with mild functional impairment in activities of daily living, performed the task blindfolded and not blindfolded, as did 10 age- and education-matched healthy controls. The task was to use the dominant hand to trace out the contours of a 20 x 20 cm square in a clockwise direction, pausing at each corner. The square was marked on the table at which the subject sat. Accuracy was stressed rather than speed. A videocamerabased system recorded movement trajectories, from which kinematic and error parameters were derived. Patients and controls moved at comparable speeds but patients took longer to complete the task due to more curvilinear and hence longer trajectories. Patients spent more time in the deceleration phase of the movement, and in the blindfold condition had more variable movements as indicated by greater error variability scores. Correlation analysis showed that kinematic parameters in patients did not correlate with involuntary movement scores. These findings indicate that abnormalities of motor control are present in HD when movement accuracy (and not velocity) is required. HD patients are more dependent on visual control than normal subjects.

More than fifty years following the discovery that botulinum neurotoxins inhibit neuromuscular transmission, these powerful poisons have become drugs with many indications. First used to treat strabismus, local injections of botulinum neurotoxin are now considered a safe and efficacious treatment for neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum neurotoxin is a treatment for diseases of the gastrointestinal tract. Botulinum neurotoxin is not only potent in blocking skeletal neuromuscular transmission, but also block cholinergic nerve endings in the autonomic nervous system. The capability to inhibit contraction of smooth muscles of the gastrointestinal tract was first suggested based on in vitro observations and later demonstrated in vivo; it has also been shown that botulinum neurotoxin does not block non adrenergic non cholinergic responses mediated by nitric oxide. This has further promoted the interest to use botulinum neurotoxin as a treatment for overactive smooth muscles and sphincters, such as the lower esophageal sphincter to treat esophageal achalasia, or the internal anal sphincter to treat anal fissure. Information on the anatomical and functional organization of innervation of the gastrointestinal tract is a prerequisite to understand many features of botulinum neurotoxin action on the gut and the effects of injections placed into specific sphincters. This review presents current data on the use of botulinum neurotoxin to treat diseases of the gastrointestinal tract and summarizes recent knowledge on the pathogenesis of disorders of the gut due to a dysfunction of the enteric nervous system.

OBJECTIVE: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson’s disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. METHODS: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson’s disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. RESULTS: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. CONCLUSIONS: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic nucleus does not per se appear to impair cognitive performance in patients with Parkinson’s disease and may alleviate the postoperative decline in verbal fluency.

The diagnosis of Parkinson’s disease is not easy. Developments in basic research have indicated pathophysiological links among parkinsonian syndromes that are still classified as independent entities. On the other hand, genetic studies are dividing forms that fit into the clinical diagnosis of Parkinson’s disease. The diagnostic criteria used in current practice are by no means satisfactory, but cannot yet be replaced by new comprehensive criteria based on laboratory evidence.

AIM: High frequency stimulation of the subthalamic nucleus (STN) is gaining recognition as a new symptomatic treatment for Parkinson’s disease (PD). The first available long-term observations show the stability of the efficacy of this procedure in time. METHODS: Quadripolar leads were implanted bilaterally under stereotactic conditions in the STN of patients with advanced PD. High frequency stimulation was applied for 24 hours a day. Following implant, antiparkinsonian medication was reduced as much as possible and stimulation was gradually increased. The patients were evaluated in the practically defined “off” condition and in the “on” condition using the unified PD rating scale (UPDRS) and the Schwab & England scale. Neuropsychological testing was performed before and after the implant. Thirty-three patients were followed up for at least 3 months and 13 among them until 36 months. RESULTS: The patients had a mean age of 56.8+/-7.1 years and a mean disease duration of 13.8+/-5.5 years; they were followed-up for an average of 25.7+/-13.5 months. At the time of the last available visit, the stimulation amplitude was 2.47+/-0.40 V (the total energy delivered averaged 1.57+/-0.8 microW). The levodopa-equivalent daily dose was reduced by 56.2% (p<0.001). Parkinsonian features were improved in all patients, the greatest changes were seen for tremor, gait, bradykinesia and postural stability, then rigidity and limb akinesia. Compared with the pre-implant conditions, the UPDRS motor score in the “off” condition was improved by 51.6% at the time of the last visit (p<0.001), the UPDRS activities of daily living score was improved by 68.5% (p<0.001), the Schwab & England scale was improved by 196.8% (p<0.001). The neuropsychological data did not show significant changes. Night sleep improved in all patients, due to increased mobility at night. In almost all patients insomnia was resolved. All patients gained weight after surgery with an increase of 11.1% (p<0.001) compared to their pre-implant weight. The most common permanent side effects consisted in hypophonia and dysarthria, transient side effects were increased sexuality and mania, the most common side effects related to stimulation were ballic or choreic dyskinesias. The most common adverse event related to the surgical procedure was transient psychosis; unexplained switching-off of the stimulator was the most common device-related effect. CONCLUSION: This study extends our recently published 3-years FU series. It confirms again that symptomatic efficacy of STN stimulation is retained during the 2(nd) and 3(rd) years following the implant, without any obvious decay of efficacy or need for increase of energy delivered. Improvement of dyskinesias also persists and the procedure is well tolerated. Side effects and adverse events are sometimes severe, but can be managed in most cases. The improvement of daily living activities outweighs by far the motor benefit, indicating that the use of this procedure significantly improves the patients’ lifestyle.

OBJECTIVE: To study whether sensorimotor cortical areas are involved in Essential Tremor (ET) generation. BACKGROUND: It has been suggested that sensorimotor cortical areas can play a role in ET generation. Therefore, we studied median nerve somatosensory evoked potentials (SEPs) in 10 patients with definite ET. METHODS: To distinguish SEP changes due to hand movements from those specifically related to central mechanisms of tremor, SEPs were recorded at rest, during postural tremor and during active and passive movement of the hand. Moreover, we recorded SEPs from 5 volunteers who mimicked hand tremor. The traces were further submitted to dipolar source analysis. RESULTS: Mimicked tremor in controls as well as active and passive hand movements in ET patients caused a marked attenuation of all scalp SEP components. These SEP changes can be explained by the interference between movement and somatosensory input (‘gating’ phenomenon). By contrast, SEPs during postural tremor in ET patients showed a reduction of N20, P22, N24 and P24 cortical SEP components, whereas the fronto-central N30 wave remained unaffected. CONCLUSIONS: Our findings suggest that in ET patients the physiological interference between movement and somatosensory input to the cortex is not effective on the N30 response. This finding thus indicates that a dysfunction of the cortical generator of the N30 response may play a role in the pathogenesis of ET.

PARK6, a locus for early-onset recessive parkinsonism, has been causally implicated in nine unrelated families from four different countries. The gene is still unidentified and hence the importance of PARK6 as a cause of Parkinson’s disease is unknown. To date, no pathology or functional imaging studies are available on PARK6-linked parkinsonism. We have used (18)F-dopa positron emission tomography to study four patients who are homozygous and three asymptomatic relatives who are heterozygous for PARK6. The clinically affected PARK6 subjects had a similar 85% reduction in posterior dorsal putamen (18)F-dopa uptake to a group of idiopathic Parkinson’s disease patients matched for clinical disease severity and duration but showed significantly greater involvement of head of caudate and anterior putamen. The group of asymptomatic PARK6 carriers showed a significant mean 20 to 30% reduction in caudate and putamen (18)F-dopa uptake in comparison with controls, individual values falling toward the bottom of the normal range. Our results indicate that PARK6 pathology results in a more uniform loss of striatal dopamine terminal function than Parkinson’s disease. The subclinical loss of striatal dopamine storage capacity found in the PARK6 carriers implies that the unidentified gene on the short arm of chromosome 1 exhibits either haploinsufficency or a dominant negative effect.

We examined cognitive and psychiatric disturbances in patients with Huntington’s disease (HD) in comparison to at risk asymptomatic subjects. Cognitive and psychiatric scales and an HD motor scale were administered to 40 HD patients, 17 pre-symptomatic HD gene carriers (AR(+)) and 28 non gene carriers (AR(-)). HD patients did worse than AR(+) and AR(-) in all motor, cognitive and psychiatric measures, while AR(+) and ARsubjects did not differ between each other. HD patients had high scores for negative psychiatric symptoms, but there was no correlation between illness duration and psychiatric or cognitive performance. In HD, disease course and symptomatology are heterogeneous and negative psychiatric symptoms are common.

Among 30 Parkinson’s disease patients who received high frequency stimulation of the subthalamic nucleus, 5 developed remarkable disorders of mood or sexual behavior after the implant. We describe 2 men who developed mania and hypersexuality a few days after the implant that lasted for some months and then gradually disappeared spontaneously.

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant manner with reduced (30-40%) penetrance. The DYT1 gene on chromosome 9q34 is responsible for most cases of early limb-onset PTD. DYT1-PTD clinical spectrum is broad, as the disease may present with several degrees of body involvement and severity. We identified an Italian family with 4 members definitely affected by PTD, genetically diagnosed as carriers of the GAG mutation at DYT1 gene. Phenotype was homogeneous when considering the presentation at onset (limb involvement and early onset), the disease progression was variable; in the subjects of the last generation, the disease progressed to a severe, generalized PTD; in the remaining 2 subjects, dystonia presented with writer’s cramp or upper body segmental dystonia of mild severity. One family member, carrier of the GAG mutation on DYT1 gene and mother of the most severely affected individual, presented with a clinically established psychogenic movement disorder resembling dystonia initially diagnosed as a severe generalized PTD. Psychogenic movement disorders are among the most controversial and challenging diseases to diagnose, in particular when the affected individual belongs to a family with an inherited movement disorder.

Twenty-two patients with PD received bilateral implants for high frequency stimulation of the subthalamic nucleus. The patients were treated for more than 1 year (up to 36 months). At the last visit, the Unified Parkinson Disease Rating Scale (UPDRS) motor score without medication improved by 50.2% (p < 0.001) and the UPDRS activities of daily living score improved by 68.4% (p < 0.001). The most common long-lasting adverse events were hypophonia and dysarthria; transient events were increased sexuality and mania. The surgical procedure induced transient intraoperative psychosis in seven patients.

The Parkin gene on 6q25.2-27 is responsible for about 50% of autosomal recessive juvenile parkinsonism and less than 20% of sporadic early-onset cases. We recently mapped a novel locus for early-onset parkinsonism (PARK6) on chromosome 1p35-p36 in a large family from Sicily. We now confirm linkage to PARK6 in eight additional families with Parkin-negative autosomal recessive juvenile parkinsonism from four different European countries. The maximum cumulative pairwise LOD score was 5.39 for marker D1S478. Multipoint linkage analysis gave the highest cumulative LOD score of 6.29 for marker D1S478. Haplotype construction and determination of the smallest region of homozygosity in one consanguineous family has reduced the candidate interval to a 9cM region between markers D1S483 and D1S2674. No common haplotype could be detected, excluding a common founder effect. These families share some clinical features with the phenotype reported for European Parkin-positive cases, with a wide range of ages at onset (up to 68 yrs) and slow progression. However, features typical of autosomal recessive juvenile parkinsonism, including dystonia at onset and sleep benefit, were not observed in PARK6-linked families, thus making the clinical presentation of late-onset cases indistinguishable from idiopathic Parkinson’s disease. PARK6 appears to be an important locus for early-onset parkinsonism in European Parkin-negative patients.

BACKGROUND: Botulinum toxin induces healing in patients with idiopathic anal fissures. METHODS: One hundred-fifty patients with posterior anal fissures were treated with botulinum toxin injected in the internal anal sphincter on each side of the anterior midline. Subjects were randomized into 2 treatment groups based on the number of units of botulinum toxin injected. Patients in group I were treated with 20 units of botulinum toxin and, if the fissure persisted, were retreated with 30 units. Patients in group II were treated with 30 units and retreated with 50 units, if the fissure persisted. RESULTS: The 2 groups were comparable in age, gender distribution, duration of symptoms, resting pressure, and maximum voluntary pressure at anorectal manometry. One month after the injection, examinations revealed complete healing in 55 patients (73%) from group I and 65 patients (87%) from group II (P =.04). Five patients from group II reported a mild incontinence of flatus that lasted 2 weeks after the treatment and disappeared spontaneously. The values of the resting anal pressure (P=.3) and the maximum voluntary pressure (P =.2) did not differ between the 2 groups. At 2 months’ evaluation, a healing scar was found in 67 patients (89%) from group I and 72 patients (96%) from group II. A relapse of the fissure was observed in 6 patients (8%) from group I who had a healing scar at 1 month, and 2 other patients never healed. A persistent fissure was present in 3 patients from group II who had no other symptoms. CONCLUSIONS: Botulinum toxin injected into the internal anal sphincter is effective in managing anal fissures and avoiding permanent complications. All patients were treated with the active drug and healed after 1 or 2 successive treatments. The results also confirm that higher doses account for a higher success rate, with little increase in complications or side effects, which is probably related to the diffusion of the toxin to the external sphincter.

The clinical features of nine patients (three women and six men) affected by PARK6-linked parkinsonism, belonging to three unrelated Italian families, are reported. The occurrence of affected men and women within one generation suggested an autosomal recessive mode of inheritance in all three families. Mean age at disease onset was 36 +/- 4.6 years; all cases except one presented with asymmetrical signs, consisting of tremor and akinesia of one upper limb or unilateral short step gait. Affected individuals had a mean age of 57 +/- 8.5 years, and average disease duration was 21 +/- 7.8 years. Parkinsonian features included benign course, early onset of drug-induced dyskinesias, and a good and persistent response to levodopa. There were no other associated features (i.e., pyramidal or cerebellar signs, dysautonomia, or diurnal fluctuations unrelated to drug treatment). Cognition was unaffected. The clinical picture was remarkably similar in all patients; no relevant family-related differences were found. PARK6 disease is a new form of early-onset parkinsonism without other atypical clinical features.

BACKGROUND: Increased neuronal activity in the subthalamic nucleus and the pars interna of the globus pallidus is thought to account for motor dysfunction in patients with Parkinson’s disease. Although creating lesions in these structures improves motor function in monkeys with induced parkinsonism and patients with Parkinson’s disease, such lesions are associated with neurologic deficits, particularly when they are created bilaterally. Deep-brain stimulation simulates the effects of a lesion without destroying brain tissue. METHODS: We performed a prospective, double-blind, crossover study in patients with advanced Parkinson’s disease, in whom electrodes were implanted in the subthalamic nucleus or pars interna of the globus pallidus and who then underwent bilateral high-frequency deep-brain stimulation. We compared scores on the motor portion of the Unified Parkinson’s Disease Rating Scale when the stimulation was randomly assigned to be turned on or off. We performed unblinded evaluations of motor function preoperatively and one, three, and six months postoperatively. RESULTS: Electrodes were implanted bilaterally in 96 patients in the subthalamic-nucleus group and 38 patients in the globus-pallidus group. Three months after the procedures were performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score (as compared with no stimulation) of 49 percent, and stimulation of the pars interna of the globus pallidus with a median improvement of 37 percent (P<0.001 for both comparisons). Between the preoperative and six-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 percent to 74 percent (P<0.001) with subthalamic stimulation and from 28 percent to 64 percent (P<0.001) with pallidal stimulation. Adverse events included intracranial hemorrhage in seven patients and infection necessitating removal of the leads in two. CONCLUSIONS: Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus is associated with significant improvement in motor function in patients with Parkinson’s disease whose condition cannot be further improved with medical therapy.

The cause of Parkinson disease (PD) is still unknown, but genetic factors have recently been implicated in the etiology of the disease. So far, four loci responsible for autosomal dominant PD have been identified. Autosomal recessive juvenile parkinsonism (ARJP) is a clinically and genetically distinct entity; typical PD features are associated with early onset, sustained response to levodopa, and early occurrence of levodopa-induced dyskinesias, which are often severe. To date, only one ARJP gene, Parkin, has been identified, and multiple mutations have been detected both in families with autosomal recessive parkinsonism and in sporadic cases. The Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD. In > or = 50% of families with ARJP that have been analyzed, no mutations could be detected in the Parkin gene. We identified a large Sicilian family with four definitely affected members (the Marsala kindred). The phenotype was characterized by early-onset (range 32-48 years) parkinsonism, with slow progression and sustained response to levodopa. Linkage of the disease to the Parkin gene was excluded. A genomewide homozygosity screen was performed in the family. Linkage analysis and haplotype construction allowed identification of a single region of homozygosity shared by all the affected members, spanning 12.5 cM on the short arm of chromosome 1. This region contains a novel locus for autosomal recessive early-onset parkinsonism, PARK6. A maximum LOD score 4.01 at recombination fraction .00 was obtained for marker D1S199.

Background. Surgical repair of rectocele does not always alleviate symptoms related to difficulty in defecation, and some patients have impaired fecal continence after surgical treatment. To avoid complications of surgical repair, we investigated the efficacy of botulinum toxin in treating patients with symptomatic rectocele. Methods. Fourteen female patients with anterior rectocele were included in the study. The patients were studied by using anorectal manometry and defecography, and then treated with a total of 30 units of type A botulinum toxin, injected into 3 sites, 2 on either side of the puborectalis muscle and the third anteriorly in the external anal sphincter, under ultrasonographic guidance. Results. After 2 months, symptomatic improvement was noted in 9 patients (P =.0003). At the same time, rectocele depth (mean +/- SD) was reduced from 4.3 +/- 0.6 cm to 1.8 +/- 0.5 cm (P =.0000001) and rectocele area from 9.2 +/- 1.3 cm(2) to 2.8 +/- 1.6 cm(2) (P =.0000001). Anorectal manometry demonstrated decreased tone during straining from 70 +/- 28 mm Hg at baseline to 41 +/- 19 mm Hg at 1 month (P =.003) and to 41 +/- 22 mm Hg at 2 months (P =.005). No permanent complications were observed in any patient for a mean follow-up period of 18 +/- 4 months. At 1 year evaluation, incomplete or digitally assisted rectal voiding was not reported by any patient, and a rectocele was not found at physical examination. Four recurrent, asymptomatic rectoceles were noted at defecography. Conclusions. Botulinum toxin injections should be considered as a simple therapeutic approach in patients with anterior rectocele. The treatment is safe and less expensive than surgical repair. A more precise method of toxin injections under transrectal ultrasonography accounts for the high success rate. Repeated injections may be necessary to maintain the clinical improvement.

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion. Three PTD loci (DYT1, DYT6 and DYT7) have been identified to date. However, in several PTD families linkage to the known loci has been excluded. We identified an Italian PTD family with 11 definitely affected members. Phenotype was characterised by juvenile or early-adult onset, prominent cranial-cervical and upper limb involvement, mild course and occasional generalisation. A genome-wide search performed in the family identified a novel PTD locus (DYT13) within a 22-cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 (theta = 0) between the disease and marker D1S2667.

Although deep brain stimulation (DBS) is a clinically effective therapy for patients with advanced Parkinson’s disease (PD), its physiological effects on the brain and possible actions on non-motor functional systems remain largely unknown. This study evaluated the effects of DBS of the subthalamic nucleus (STN) on neurophysiological variables and on cardiovascular physiology. Nine patients affected by PD undergoing chronic DBS of the STN have been studied. We performed electroencephalography (EEG), somatosensory (SEPs) and visual evoked potentials (VEPs), exteroceptive masseteric silent period and sympathetic skin response (SSR) studies with DBS ON and OFF. To assess the effects of stimulation on the cardiovascular system the tilt test and plasma renin activity were studied. When we turned the DBS OFF, both SEP N20 and the VEP P100 component increased significantly in amplitude whereas the SSR decreased in amplitude and increased in latency. Although plasma renin activity tended to increase with DBS OFF, its modification induced by postural changes and blood pressure values did not significantly differ with DBS ON and OFF. We conclude that DBS of the STN in PD, besides inducing a clinical improvement, induces several non-motor effects.

Botulinum toxin is now widely used in neurology for the treatment of disorders involving muscle hyperactivity. Focal dystonia is the primary indication, and the key to effective treatment of dystonia is tailoring the treatment to the individual’s pattern of muscle involvement; even complex and generalized dystonias are treated as a collection of focal disorders. The dystonias known to respond to botulinum-toxin therapy include cervical dystonia, blepharospasm, laryngeal dystonia, writer’s cramp and anismus. Spasticity is another, growing, indication for the toxins. The treatment of these disorders with botulinum toxins is reviewed here.

Available evidence on the practice of acute pharmacological challenge tests in parkinsonian patients was reviewed by a committee of experts, which achieved a general consensus. The published data deal mainly with the acute administration of levodopa and apomorphine in Parkinson’s disease. Such challenge may serve different purposes, e.g., research, diagnosis, or tailoring of treatment. Unique protocols describing the clinical setting and practice parameters are not available. The present paper describes the scientific background and supplies practical guidelines, whenever possible, to perform and evaluate acute challenge tests in parkinsonian syndromes. With the appropriate indication and setting, acute challenge tests are useful in diagnosis and therapy of Parkinson’s disease and related disorders.

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion with reduced penetrance. The DYT1 gene on chromosome 9q34 is responsible for most cases of early limb-onset PTD. Two other PTD loci have been mapped to date. The DYT6 locus on chromosome 8 is associated with a mixed phenotype, whereas the DYT7 locus on chromosome 18p is associated with adult onset focal cervical dystonia Several families have been described in which linkage to the known PTD loci have been excluded. We identified a large Italian PTD family with 11 definitely affected members. Phenotype was characterized by prominent cranial-cervical and upper limb involvement and mild severity. A genome-wide search was performed in the family. Linkage analysis and haplotype construction allowed us to identify a novel PTD locus (DYT13) within a 22 cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 between the disease and marker D1S2667.

BACKGROUND: Botulinum toxin is a powerful, long-acting inhibitor of muscular contractions in both voluntary and smooth muscle. It acts by blocking the release of the neurotransmitter acetylcholine. In the stomach, propulsive contractions of the antrum are necessary for the gastric contents to pass into the duodenum. AIMS: To investigate whether intramuscular injections of botulinum toxin type A into the gastric antrum of rats would cause a reduction in food intake and hence body weight, by inhibition of gastric emptying. MATERIALS AND METHODS: This was a prospective, randomized, 3-way parallel group study in rats. The first group was anaesthetized, laparotomized and given 20 U of botulinum toxin type A by intramuscular injection into the gastric antrum (botulinum toxin type A group, n=14). The second group was anaesthetized, laparotomized and injected with saline (sham group, n=14) and the third group did not have any intervention (control group, n=5). Food intake was measured daily for 7 weeks and body weight was measured daily for 10 weeks. RESULTS: There was a significant difference in loss of body weight between the two treated groups (14.0 +/- 8.2% botulinum toxin type A group, 4.4 +/- 2.7% sham group; P < 0.001). Further, the time to reach the weight nadir was significantly longer in the botulinum toxin type A group (8.7 +/- 3.9 days) compared with the sham group (5.3 +/- 3.8 days; P < 0.04). There were no significant differences between the sham and control groups for any of the body weight parameters. The minimum dietary intake was significantly lower in the botulinum toxin type A group than in the sham group (37.8 +/- 21.8% of the basal value in the botulinum toxin type A group, vs. 65.5 +/- 32.0 in the sham group, P < 0.05). In addition, the time to reach the nadir was significantly prolonged (8.2 +/- 3.5 days, botulinum toxin type A group vs. 4.9 +/- 1.7 days, sham group, P < 0.001). CONCLUSIONS: The parallel reduction of body weight and food intake in botulinum toxin type A treated animals is consistent with a long lasting inhibition of the antral pump. This is probably due to slowed gastric emptying leading to early satiety. Patients with morbid obesity might benefit from endoscopic injections of botulinum toxin type A into the stomach wall.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) improves Parkinson’s disease and increases frontal blood flow. We assessed the effects of bilateral DBS on executive function in Parkinson’s disease patients, seven with electrodes implanted in the STN and six in the GPi. Patients were assessed off medication with stimulators off, on and off again. The groups showed differential change with stimulation on the Reitan Trail-Making test (TMT B) (STN more improved) and on some measures of random number generation and Wisconsin Card Sorting (STN improved, GPi worse with stimulation). Across the groups, stimulation speeded up responding (Stroop control trial, TMT A) and improved performance on paced serial addition and missing digit tests. Conversely, conditional associative learning became more errorful with stimulation across the two groups. In general, change in performance with stimulation was significant for the STN but not the GPi group. These results support two opposite predictions. In support of current models of Parkinson’s disease, ‘releasing the brake’ on frontal function with DBS improved aspects of executive function. Conversely, disruption of basal ganglia outflow during DBS impaired performance on tests requiring changing behaviour in novel contexts as predicted by Marsden and Obeso in 1994.

There have been few epidemiological studies of dystonia. Most previous studies have provided estimates based on few cases. A European prevalence study was undertaken to provide more precise rates of dystonia by pooling data from eight European countries. Diagnosed cases were ascertained by adult neurologists with specialist movement disorder (and botulinum toxin) clinics. The crude annual period prevalence rate (1996-1997) for primary dystonia was 152 per million (95% confidence interval 142-162), with focal dystonia having the highest rate of 117 per million (108-126). Prevalence rates for cervical dystonia, blepharospasm and writer’s cramp were as follows: 57 (95% confidence interval 51-63), 36 (31-41), and 14 (11-17). The age-adjusted relative rates were significantly higher in women than in men for segmental and focal dystonias with the exception of writer’s cramp. Comparing rates between centres demonstrated significant variations for cervical dystonia, blepharospasm and writer’s cramp, probably due to methodological differences. Our results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries. Due to under-ascertainment of cases, our rates should be seen as conservative and an under-estimate of the true prevalence of dystonia.

BACKGROUND: Botulinum toxin induces healing in patients with idiopathic anal fissure. METHODS: Fifty patients affected by posterior anal fissure were treated with 20 units of botulinum toxin, injection in the internal anal sphincter on each side of the posterior midline (group I) or on each side of the anterior midline (group II). RESULTS: At 2 months evaluation, a healing scar was observed in 15 patients of group I and in 22 patients of group II(P = 0.025). Resting anal pressure was significantly different from the baseline values at 1-month as well as at 2-month check-ups in both groups, but the values were significantly lower in patients of group II. CONCLUSIONS: The intersite comparison revealed that anterior injection of the internal anal sphincter resulted in improved lowering of resting anal pressure and produced an earlier healing scar.

PURPOSE: Puborectalis syndrome has been difficult to treat. We investigated the efficacy of botulinum toxin in treating patients with puborectalis syndrome who had previously failed to respond to electromyographic biofeedback sessions and who refused to use anal dilators. METHODS: Of a group of 50 patients with chronic outlet obstruction constipation, four patients with puborectalis syndrome were included in the study. The patients were studied using anorectal manometry, defecography, and electromyography and then treated with 30 units of Type A botulinum toxin, injected into two sites on either side of the puborectalis muscle, under ultrasonographic guidance. RESULTS: One patient was lost to follow-up. After treatment in other patients, the frequency of natural bowel movements increased from zero to six per week and laxatives were needed by only one patient. Anorectal manometry demonstrated decreased tone during straining from (mean +/- standard deviation) 96.2 +/- 12 mmHg to 42.5 +/- 13 mmHg at four weeks (P = 0.003) and 63.2 +/- 22 mmHg at eight weeks (P = 0.009). Defecography performed eight weeks after treatment showed improvement in the anorectal angle, which increased from 94 +/- 11 degrees to 114 +/- 13 degrees (P = 0.01), and evacuation of barium paste. Electromyography demonstrated mild paradoxical contraction. However, 16 weeks after treatment one of these three patients suffered symptomatic recurrence. This patient was re-treated with 50 units of toxin; eight months later he required a further 60 units. Seven months after the last injection he reported normal daily bowel movements without the use of laxatives. CONCLUSIONS: Botulinum toxin injection should be considered as a simple therapeutic approach in patients with puborectalis syndrome. The use of higher dosage and a more precise method of toxin injections under transrectal ultrasonography account for the long-term higher success rate. However, because the effects of the toxin wear off within three months of administration, repeated injections could be necessary to maintain the clinical improvement.

BACKGROUND: The diagnosis of different parkinsonian syndromes and the ability to predict long-term drug efficacy constitute important clinical issues. DESIGN: Motor responses to the acute administration of levodopa and apomorphine were analyzed in a series of 134 parkinsonian patients, including 83 patients with a clinical diagnosis of idiopathic Parkinson’s disease (PD), 28 patients with multiple-system atrophy (MSA), 6 with progressive supranuclear palsy, and 17 with an unclassified parkinsonian syndrome. METHODS: The patients received oral levodopa/carbidopa (250/25 mg) and subcutaneous apomorphine (1.5, 3 and 4.5 mg). Clinical variations of the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score were evaluated 1 h following levodopa administration or 20 min following apomorphine. The motor improvement produced by each acute challenge was matched with the clinical diagnosis and with the response to chronic levodopa treatment. The diagnosis was verified by repeated clinical assessments or by autopsy in 2 cases. A receiver operating characteristics curve was plotted comparing PD vs. non-PD, PD vs. MSA and chronic responders vs. nonresponders. Cutoff threshold improvement was defined as the value closest to the crossing point for 80% sensitivity and 80% specificity, corresponding to the best trade-off for a predictive evaluation. RESULTS: UPDRS motor score improvement was on average higher in PD than in non-PD patients (levodopa: 29.8 vs. 12.2%; apomorphine 1.5 mg: 27.1 vs. 10.5%; apomorphine 3 mg: 27.7 vs. 9.7%; apomorphine 4.5 mg: 28.8 vs. 11.8%; p < 0.01 with Student’s t test). When PD patients were compared to non-PD patients, levodopa challenge had the best diagnostic accuracy with a threshold improvement of 16%. Apomorphine had the best diagnostic accuracy with a threshold improvement of 13.5% for 1.5 mg, 13% for 3 mg, and 16% for 4.5 mg. This meant that patients improving at least 16% in all tests had the highest probability of having PD. When PD patients were compared to MSA patients, levodopa acute challenge had the best diagnostic accuracy with a threshold improvement of 17%. Apomorphine had the best diagnostic accuracy with an improvement of 13% for 1.5 mg, 15% for 3 mg, and 18% for 4.5 mg. This meant that patients improving at least 18% in all tests had the highest probability of having PD rather than MSA. When patients who responded to chronic levodopa treatment were compared to those who did not, acute challenge with levodopa had the best predictive accuracy with a threshold improvement of 14.5%. Apomorphine had the best predictive accuracy with an improvement of 13% for 1.5 mg, and 14% for 3 and 4.5 mg. This meant that patients improving at least 14.5% in all tests had the highest probability of responding to chronic treatment. CONCLUSION: A good agreement was found between acute challenges with levodopa/carbidopa and apomorphine, and the use of both improved the reliability of the test. Different threshold improvements after acute challenges would support a diagnosis of PD or the exclusion of MSA, and would have a predictive value for subsequent response to chronic levodopa therapy.

The revitalization of surgery for Parkinson’s disease (PD) has fueled discussion about the best methodology to define the target. Placement of electrodes for deep brain stimulation (DBS) requires the usual stereotactic technique but the argument is mainly centered on whether or not microrecording neuronal activity is necessary. We compared the accuracy of calculating the coordinates X (medio-lateral) and Y (rostro-caudal) considered by the classic stereotactic method, i.e., definition of the AC-PC intercomissural line by MRI and a digitized version of the Schaltenbrand’s atlas, with final electrode placement according with microrecording and microstimulation in 21 patients. For both the globus pallidum internum (GPi) (n = 21) and the subthalamic nucleus (STN) (n = 36) there was, respectively, a 43% and 45% mismatching of more than 3 mm between the theoretic coordinates and the final site of electrode location. This applies to both the X and Y planes. Accuracy was not improved in patients (n = 11) in whom the bilateral procedure was undertaken in a single day. We conclude that proper electrode positioning of the STN and GPi requires fine electrophysiologic assessment.

We studied 957 cases of primary (idiopathic) dystonia and found a significant excess of female patients for segmental and focal dystonia. A novel observation was a significantly earlier age at onset in males as opposed to females for primary segmental (mean age, 44.6 versus 53.3) and focal dystonia (43.8 versus 47.8). This trend was also apparent in cervical dystonia, blepharospasm, and laryngeal dystonia. For writer’s cramp and focal limb dystonia, this trend was reversed with an earlier age at onset in females. These results suggest that focal dystonia should not be treated as an homogenous group, and sex-linked factors may play a role.

Levodopa (in combination with a peripheral dopadecarboxylase inhibitor) substantially improves the quality of life of patients. However, physicians are not always comfortable prescribing it, and its administration is often delayed to retard the development of motor complications or is restricted to patients with relatively advanced disease, because there is a fear that the decreased response of parkinsonian symptoms may result from a self-limiting effect of the drug. Moreover, long-term treatment with levodopa is claimed by some to induce the degeneration of dopaminergic neurons, thereby accelerating disease progression. Whether long-term administration of levodopa in patients may result in the irreversible appearance of side effects or accelerate the neurodegenerative process is a crucial question, and it is therefore legitimate to ask whether one should delay the introduction or limit its use in patients.

Stereotaxtic surgery is an effective therapeutic maneuver in the management of advanced Parkinson’s disease (PD). Thalamotomy is an effective measure to control tremor but other PD symptoms are not changed. Bilateral operations are associated with a risk of severe speech impairment. Deep brain stimulation (DBS) of the thalamus is as effective as thalamotomy and is associated with fewer side effects. Pallidotomy is effective in reducing contralateral dyskinesias and the cardinal symptoms of PD. Bilateral pallidotomy often results in cognitive dysfunction. Deep brain stimulation of the pallidum replicates the positive effects of pallidotomy and appears to be safer than ablative lesions. Subthalamic DBS is currently under investigation. This procedure may control all PD symptoms, and the dose of levodopa can often be dramatically reduced. Neurotransplantation is a promising surgical approach to PD. However, further investigation is needed to optimize this approach.

Advances in the clinical use of botulinum neurotoxins continue. Of interest to the neurologist is the advanced practice in the treatment of focal dystonia and the new developments on other dyskinesias and on autonomic control of smooth muscle motility. New toxin serotypes are now being tested; their availability will improve clinical practice and will possibly lead to combined treatments. Indications in spasticity and in juvenile cerebral palsy are now under scrutiny. The combination of focal chemodenervation with specific rehabilitation procedures enables new development in this field.

BACKGROUND AND METHODS: Lateral internal sphincterotomy, the most common treatment for chronic anal fissure, may cause permanent injury to the anal sphincter, which can lead to fecal incontinence. We compared two nonsurgical treatments that avert the risk of fecal incontinence. We randomly assigned 50 adults with symptomatic chronic posterior anal fissures to receive treatment with either a total of 20 U of botulinum toxin injected into the internal anal sphincter on each side of the anterior midline or 0.2 percent nitroglycerin ointment applied twice daily for six weeks. RESULTS: After two months, the fissures were healed in 24 of the 25 patients (96 percent) in the botulinum-toxin group and in 15 of the 25 (60 percent) in the nitroglycerin group (P=0.005). No patient in either group had fecal incontinence. At some time during treatment, five patients in the nitroglycerin group had transient, moderate-to-severe headaches that were related to treatment. None of the patients in the botulinum-toxin group reported adverse effects. Ten patients who did not have a response to the assigned treatment – 1 in the botulinum-toxin group and 9 in the nitroglycerin group – crossed over to the other treatment; the fissures subsequently healed in all 10 patients. There were no relapses during an average of about 15 months of follow-up. CONCLUSIONS: Although treatment with either topical nitroglycerin or botulinum toxin is effective as an alternative to surgery for patients with chronic anal fissure, botulinum toxin is the more effective nonsurgical treatment.