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IRF2BPL is an intronless gene that was mapped to 14q24.3 chromosome in 2000 and codes for the interferon regulatory factor 2 binding like protein.To analyses the clinical characteristics of the patients reported in the literature and of an additional patient we observed in order to better delineate the phenomenological spectrum of the disease and provide indications to improve clinical recognition and facilitate diagnosis.We reported on 28 patients carrying the IRF2BPL mutation who were identified in 10 papers (n.27), using PUBMED as the search engine, and in our hospital (n. 1).All patients shared developmental delay/regression. Additional neurological symptoms were present in a large proportion of patients and reflected the involvement of five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances. Correlation analysis suggested a significant positive correlation between the number of affected neurological domains and the presence of MRI abnormalities (rho = 0.45, p = 0.02), while no significant correlation emerged between the number of affected clinical domains and age at disease onset (rho = 0.18, p = 0.35) or variant type (rho = 0.30, p = 0.12).Our analysis highlights that the IRF2BPL mutation syndrome is highly specific to the central nervous system. Diagnostic work-up should consider the clinical picture of the IRF2BPL mutation syndrome herein delineated and the existence of conditions that share developmental delay/regression and result from acquired/genetic or unidentifiable underlying etiology.

Background and purpose The clinical manifestation of dystonic spasms in blepharospasm (BSP) patients may be heterogeneous. Whether the varying phenomenology of eyelid spasms becomes manifest sequentially during the course of the disease or aggregates in separate clusters according to different disease courses is still unclear. For this purpose, the clinical features in BSP patients were evaluated longitudinally over a 5-year period and also the blink reflex recovery cycle was tested in a subgroup of BSP patients. Methods Sixty BSP patients were videotaped at time 0 and after approximately 5 years of follow-up. Two experts in movement disorders, who were blinded to the video order, reviewed the videotapes and scored the severity of BSP using the Blepharospasm Severity Rating Scale. Changes in the R2 recovery index were also evaluated in 18 patients twice, i.e. upon enrolment and at the follow-up. Results The severity of BSP worsened significantly over the 5-year follow-up period owing to the appearance or the increased duration and frequency of prolonged spasms. It was also found that the blink reflex recovery cycle worsened at follow-up in comparison with the baseline. Conclusions This study shows that the disease progression of BSP is characterized by the appearance or worsening of prolonged spasms. Prolonged spasms are accompanied by changes in the excitability of brainstem interneurons. Aging-related effects may exacerbate the pathophysiological mechanisms underlying spasms.

Background Idiopathic blepharospasm is a clinically heterogeneous condition. It is not known whether the various manifestations become manifest sequentially during the course of the disease or aggregate in separate clusters identifying subpopulations of patients. Methods Eighty-nine patients with idiopathic blepharospasm were assessed using k-means cluster analysis to identify relatively homogeneous groups on the basis of low-intragroup/high-intergroup differences across a set of selected variables. Results The results suggest that there may be three groups of patients. Group 1 included patients who had prolonged muscle spasms leading to complete rim closure associated with brief and/or prolonged spasms with incomplete rim closure, the most severe blepharospasm, and a greater tendency to spread to adjacent segments. Group 2 included patients characterized by prolonged spasms with partial rim closure, either alone or associated with brief spasms whereas Group 3 included patients with brief spasms with complete rim closure, the least severe blepharospasm, and the lowest tendency to spread. The severity of Group 2 blepharospasm was between that observed in Group 1 and Group 3, while the tendency to spread was similar to Group 3. The three groups did not differ for disease duration, age of onset, sex and other clinical features. The observation that inhibition of the R2 component of the blink reflex recovery cycle was more abnormal in Groups 1/2 2 than in Group 3 at least in part validates our classification. Conclusions The present study suggests that blepharospasm patients may be classified in different subtypes according to the type of spasms, severity of the condition and tendency to spread.

Background and purpose Action tremor may occur in patients with Parkinson's disease and cause misdiagnosis with other movement disorders such as essential tremor and dystonia. Data on the frequency of action tremor in Parkinson's disease and on the relationships with other motor and non-motor signs are limited. Methods A cross-sectional study of 237 patients with Parkinson's disease staging 1–2 on the Hoehn−Yahr scale was conducted. Data on action tremor and other motor and non-motor signs were collected using the Unified Parkinson's Disease Rating Scale part III and the Non-Motor Symptoms Scale. Results Action tremor was found in 46% of patients and was associated with both severity of rest tremor (adjusted odds ratio 3.0, P

Adult-onset dystonia (AOD) may manifest in focal forms (as blepharospasm, oromandibular dystonia, cervical dystonia, laryngeal dystonia, and hand dystonia) or in segmental forms. Time from onset of dystonia to diagnosis can be an indicator of the quality of care received during the diagnosis of AOD, likely reflecting factors associated with both the patient and their health system. Three previously reported single-center studies showed that diagnosis of AOD may be delayed for several years. Here, we examined the time lapse between onset and diagnosis in patients with different forms of AOD from an Italian movement disorder center. We found the time lapse between dystonia onset and diagnosis was very long for patients who developed AOD before 1980; and even in the most recent years reaching a correct diagnosis required more than year in almost half of cases. Our results suggest that the delay in diagnosis of adult-onset focal and segmental dystonia has improved over time, but remains unacceptable. The findings are a promising indicator of improvements in care of this uncommon disorder. However, education of patients and doctors is still needed.

Gilles de la Tourette syndrome (GTS) is characterized by motor and vocal tics and often associated with obsessive-compulsive disorder (OCD). Responses to intermittent/continuous theta-burst stimulation (iTBS/cTBS), which probe long-term potentiation (LTP)-/depression (LTD)-like plasticity in the primary motor cortex (M1), are reduced in GTS. ITBS-/cTBS-induced M1 plasticity can be affected by brain-derived neurotrophic factor (BDNF) polymorphism. We investigated whether the BDNF polymorphism influences iTBS-/cTBS-induced LTP-/LTD-like M1 plasticity in 50 GTS patients and in 50 age- and sex-matched healthy subjects. In GTS patients, motor and psychiatric (OCD) symptom severity was rated using the Yale Global Tic Severity Scale (YGTSS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). We compared M1 iTBS-/cTBS-induced plasticity in healthy subjects and in patients with GTS. We also compared responses to TBS according to BDNF polymorphism (Val/Val vs Met carriers) in patients and controls. Fourteen healthy subjects and 13 GTS patients were Met carriers. When considering the whole group of controls, as expected, iTBS increased whereas cTBS decreased MEPs. Differently, iTBS/cTBS failed to induce LTP-/LTD-like plasticity in patients with GTS. When comparing responses to TBS according to BDNF polymorphism, in healthy subjects, Met carriers showed reduced MEP changes compared with Val/Val individuals. Conversely, in patients with GTS, responses to iTBS/cTBS were comparable in Val/Val individuals and Met carriers. YGTSS and Y-BOCS scores were comparable in Met carriers and in Val/Val subjects. We conclude that iTBS and cTBS failed to induce LTP-/LTD-like plasticity in patients with GTS, and this was not affected by BDNF genotype.

Origins of replication are activated throughout the S phase of the cell cycle such that some origins fire early and others fire late to ensure that each chromosome is completely replicated in a timely fashion. However, in response to DNA damage or replication fork stalling, eukaryotic cells block activation of unfired origins. Human cells derived from patients with ataxia telangiectasia are deficient in this process due to the lack of a functional ataxia telangiectasia mutated (ATM) kinase and elicit radioresistant DNA synthesis after γ-irradiation(2). This effect is conserved in budding yeast, as yeast cells lacking the related kinase Mec1 (ATM and Rad3-related (ATR in humans)) also fail to inhibit DNA synthesis in the presence of DNA damage. This intra-S-phase checkpoint actively regulates DNA synthesis by inhibiting the firing of late replicating origins, and this inhibition requires both Mec1 and the downstream checkpoint kinase Rad53 (Chk2 in humans). However, the Rad53 substrate(s) whose phosphorylation is required to mediate this function has remained unknown. Here we show that the replication initiation protein Sld3 is phosphorylated by Rad53, and that this phosphorylation, along with phosphorylation of the Cdc7 kinase regulatory subunit Dbf4, blocks late origin firing in Saccharomyces cerevisiae. Upon exposure to DNA-damaging agents, cells expressing non-phosphorylatable alleles of SLD3 and DBF4 (SLD3-m25 and dbf4-m25, respectively) proceed through the S phase faster than wild-type cells by inappropriately firing late origins of replication. SLD3-m25 dbf4-m25 cells grow poorly in the presence of the replication inhibitor hydroxyurea and accumulate multiple Rad52 foci. Moreover, SLD3-m25 dbf4-m25 cells are delayed in recovering from transient blocks to replication and subsequently arrest at the DNA damage checkpoint. These data indicate that the intra-S-phase checkpoint functions to block late origin firing in adverse conditions to prevent genomic instability and maximize cell survival.

The number of existing cases of primary dystonia in the population is not precisely known, but the condition is probably much more frequent than reported. By minimum prevalence estimates, primary dystonia should be considered the third most frequent movement disorders after essential tremor and Parkinson's disease. The most likely etiologic scenario suggested by epidemiological data is that primary dystonias are products of a genetic background and an environmental insult. Current information on the causation of primary dystonia, late-onset dystonia in particular, is often unreliable because of methodological problems inherent to case-control investigation and to the heterogeneity of dystonia. To expand our knowledge on dystonia, we need to design population-based studies, to perform association studies taking into account the heterogeneity of dystonia, and to collect exhaustive clinical data in a standardized and reliable way.

Background: Sleep disturbances are common in patients with movement disorders. Evaluating quality of sleep is of primary importance because of the effect that nocturnal and daytime sleep abnormalities exert on general health status. However, quality of sleep has never been addressed in detail in patients with dystonia. The aim of this case–control study was to analyse quality of sleep in patients with the two most common forms of primary focal dystonia, blepharospasm (BSP) and cervical dystonia (CD). Methods: We evaluated quality of sleep (Pittsburgh Sleep Quality Index, PSQI) and excessive daytime sleepiness (Epworth Sleepiness Scale, ESS) in 98 patients with focal adult-onset dystonia (52 with BSP; 46 with CD) and in a group of 56 age-and gendermatched healthy subjects. The Beck Depression Inventory (BDI) was used for the evaluation of depressive symptomatology. Results: Quality of sleep was impaired (significantly higher PSQI scores) in both groups of patients. However, differences in PSQI scores between patients with CD and control subjects were partly confounded by BDI scores, whereas differences in PSQI scores between patients with BSP and control subjects were not influenced by BDI. Excessive daytime sleepiness was not significantly more frequent than in control subjects in either patients with BSP or patients with CD. Conclusions: This study suggests that the assessment and treatment of insomniarelated complaints should be considered in global management plans of patients with focal dystonia, particularly in those affected by BSP.

Background and purpose: Despite the growing number of reports describing adult-onset primary lower limb dystonia (LLD) this entity has never been systematically evaluated in the general population of patients with primary adult-onset dystonia. Methods: From outpatients with adult-onset primary dystonia attending nine Italian University centres for movement disorders we consecutively recruited 579 patients to undergo a standardized clinical evaluation. Results: Of the 579 patients assessed, 11 (1.9%) (8 women, 3 men) had LLD, either alone (n = 4, 0.7%) or as part of a segmental/multifocal dystonia (n = 7, 1.2%). The age at onset of LLD (47.9 ± 17 years) was significantly lower than the age at onset of cranial dystonias (57.9 ± 10.7 years for blepharospasm, and 58.9 ± 11.8 years for oromandibular dystonia) but similar to that of all the other adult-onset primary dystonias. The lower limb was either the site of dystonia onset (36.4%) or the site of dystonia spread (63.6%). In patients in whom LLD was a site of spread, dystonia seemed to spread following a somatotopic distribution. Only one patient reported a recent trauma involving the lower limb whereas 36.4% of the patients reported pain at the site of LLD. Only 64% of our patients needed treatment for LLD, and similarly to previously reported cases, the most frequently tried treatments was botulinum toxin and trihexyphenidyl. Conclusion: The lower limb is an uncommon but possible topographical site of dystonia in adulthood that should be kept in consideration during clinical evaluation.

Diffusion tensor imaging (DTI) analyses the movement of water molecules within the cerebral white matter thus providing information on ultrastructural brain changes. We studied 18 patients with cervical dystonia (CD), 16 with blepharospasm (BSP) and 35 years age-matched healthy controls. DTI data were obtained with a Philips 1.5 Tesla scanner and then processed to obtain maps of fractional anisotropy (FA) and mean diffusivity (MD). Twenty-three square regions of interest of uniform size were positioned on the FA maps and then automatically transferred to the MD maps. FA and MD values in the corpus callosum, left and right putamen, right caudate, left and right pre-frontal cortical area and left supplementary motor area in CD patients differed significantly from those in healthy controls. No significant regional differences were found between patients with BSP and healthy controls. In the CD group, age, duration and severity of dystonia did not correlate with regional FA/MD values, whereas the duration of botulinum toxin treatment correlated significantly with the MD value in the right-pre-frontal cortex. The abnormal DTI findings in patients with CD suggest the presence of brain ultrastructural changes in adult-onset primary CD.

Objective To assess whether cigarette smoking interferes with dopaminergic transmission in current- and never-smoking patients with Parkinson's disease. Materials and methods Striatal [123I]FP–CIT single photon emission computed tomography was performed in 67 patients with Parkinson's disease (35 women and 32 men aging 60.8 ± 10.1 years and staging 1.76 ± 0.5 on the Hoehn and Yahr scale). At study time, there were 13 current-smokers and 54 never-smokers. Results Current-smokers showed a significantly lower putamen/occipital [123I]FP–CIT ratio and a non-significant trend to a lower caudate/occipital [123I]FP–CIT ratio uptake. Current-smokers were also characterized by a lower off UPDRS-III motor score. A logistic regression analysis adjusted for age, sex, disease duration, Hoehn and Yahr staging, and medication indicated a significant lower [123I]FP–CIT uptake not only in the putamen (odds ratio, 0.1; 95% confidence interval, 0.01 to 0.65; P = 0.02) but also in the caudate (odds ratio, 0.2; 95% confidence interval, 0.04 to 0.71; P = 0.015) as well as a lower UPDRS-III motor score (odds ratio, 0.9; 95% confidence interval, 0.81 to 0.99; P = 0.04) in current-smokers. Conclusions The lower [123I]FP-CIT uptake together with the lower UPDRS-III motor score observed in our current-smokers patients with Parkinson's disease (even taking into account variables that are probably expression of dopaminergic neuron decline and treatment) would support an effect of smoking on dopaminergic synaptic mechanisms.

Background Tremor in dystonia has been described as a postural or kinetic abnormality. In recent series, however, patients with idiopathic adult-onset dystonia also displayed rest tremor. Methods The frequency and distribution of rest tremor were studied in a cohort of 173 consecutive Italian patients affected by various forms of idiopathic adult-onset dystonia attending our movement disorder clinic over 8 months. Results Examination revealed tremor in 59/173 patients (34%): 12 patients had head tremor, 34 patients had arm tremor, whilst 13 patients presented tremor in both sites. Head tremor was postural in all patients, whereas arm tremor was postural/kinetic in 28 patients, only at rest in one and both postural/kinetic and at rest in 18 patients. Patients with tremor were more likely to have segmental/multifocal dystonia. Patients who had rest tremor (either alone or associated with action tremor) had a higher age at dystonia onset and a greater frequency of dystonic arm involvement than patients with action tremor alone or without tremor. Conclusions Both action and rest tremor are part of the tremor spectrum of adult-onset dystonia and are more frequently encountered in segmental/multifocal dystonia. The higher age at dystonia onset and the greater frequency of arm dystonia in patients with rest tremor may have pathophysiological implications and may account, at least in part, for the previous lack of identification of rest tremor as one possible type of tremor present in dystonia.

Histone modifications, including H3 K56 acetylation, have been implicated in DNA damage tolerance. Here, we present evidence that Hst3 and Hst4, two paralogues of the histone deacetylase Sir2, target the cell cycle-regulated acetylation of H3 on K56 and are downregulated during DNA damage in a checkpoint-dependent manner. We show that Hst3 and Hst4 are themselves cell cycle regulated and that their misexpression affects H3 K56-Ac. Moreover, a histone H3 K56R mutation is epistatic to all phenotypes caused by HST3/4 deletion or HST3 overexpression, suggesting that H3K56-Ac is the major target of these histone deacetylases. On examining 18 members of the "Clb2 cluster" of cell cycle-regulated proteins to which Hst3 belongs, we find that two others, Ynl058c and Alk1, are significantly downregulated on DNA damage. Taken together, our data show that Hst3/Hst4 are negative regulators of H3 K56-Ac and that HST3 downregulation by a checkpoint-mediated transcriptional repression system is essential for surviving DNA damage.

To investigate the immune-mediated response in TS, and its relationship with streptococcal infection, we measured serum levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in patients with TS, compared to healthy and diseased controls. Soluble VCAM-1 and sE-selectin were significantly elevated in children and adults with TS, and sVCAM-1 was higher among anti-basal ganglia antibodies (ABGA)-positive adults with TS. No correlation of adhesion molecule levels to clinical severity or anti-streptococcal antibodies was observed. Children with Sydenham's chorea and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) showed an increased level of sICAM-1, but not sVCAM-1 and sE-selectin. These results provide initial evidence for a role of adhesion molecules and systemic inflammation in TS, and support the hypothesis of an ongoing immune-mediated process in this condition.

By means of light and electron microscopy we have studied the effect of interferon beta-1a (IFNbeta-1a) in the optic tecta of 20-day-old chick embryos under normal conditions and after exposure to lipopolysaccharide (LPS) which mimics the blood-brain barrier (BBB) disruption in meningoencephalitis. Optic tecta were examined for: (i) ultrastructure by means of transmission electron microscopy; (ii) the immunohistochemical localization of HT7 antigen, a specific marker of differentiation of the brain microvessels; (iii) the brain microvessel permeability, by means of horseradish peroxidase (HRP) tracer; (iv) the expression of microvessel glycoconjugates, by means of lectin histochemistry, using Ricinus communis agglutinin-I (RCA-I), specific for beta-D-galactosyl moieties and Wheat Germ agglutinin (WGA) specific for sialyl and N-acetylglucosaminyl moieties. A morphometric evaluation of brain microvessel permeability and of glycoconjugate expression was also performed. In control- and in IFNbeta-1a-treated embryos, HRP was confined to the vessel lumina which were sealed by the interendothelial tight junctions. RCA-I binding sites were recognizable both in the basal membranes and in the tight junctions, while WGA sites were present on the luminal side of the endothelial cells. HRP was blocked in the vessels lumina by the interendothelial tight junctions. After LPS treatment, HRP showed an extravascular localization and the labeling of microvessels by anti-HT7 antibodies disappeared. RCA-I binding was only found ultrastructurally and appeared as irregularly clustered gold particles, in the cleft of damaged tight junctions, but were no longer detectable in the endothelial basement membranes. After pretreatment of LPS-treated embryos with IFNbeta-1a, the vessel permeability to HRP strongly decreased and the vessels showed the normal pattern of HT7 protein and of the RCA-I binding sites. These results indicate that the changes induced by LPS in the endothelial cells are prevented by IFNbeta-1a.

We have studied the effect of interferon (IF) beta-1a on the basal and TNFalpha-induced intercellular adhesion molecule 1 (ICAM 1) expression and fluid phase endocytosis (FPE) of horseradish peroxidase in cultured rat brain microvascular endothelial cells. Neither basal ICAM 1 expression nor basal FPE were significantly affected by 24-72 h exposure to 1000 U/ml IFbeta-1a. ICAM 1 induction and FPE enhancement caused by 100 U/ml TNFalpha for 24 h was not influenced by simultaneous administration of 1000 U/ml IFbeta-1a. Treatment of cultures with IFbeta-1a for 48 h followed by 24-h coincubation with TNFalpha (100 U/ml) and IFbeta-1a (1000 U/ml) resulted in significant downregulation of TNFalpha-induced ICAM 1 expression and FPE. Downregulation of TNFalpha-induced ICAM 1 expression was not observed when combined treatment with TNFalpha (100 U/ml) and IFbeta-1a (1000 U/ml) for 24 h was followed by 48 h exposure to IFbeta-1a. We concluded that the blood-brain barrier endothelium may be a target of IFbeta-1a. Further, these in vitro findings may correlate with the results of recent clinical trials indicating that chronic treatment of relapsing remitting multiple sclerosis with IFbeta-1a prevents both clinical exacerbations and the appearance on Magnetic Resonance Imaging of new lesions enhanced by gadolinium which is taken up by increased transendothelial fluid phase vesicular transport.

The validity of serum sICAM-1 levels to assess Multiple Sclerosis (MS) activity was evaluated in 49 untreated definite relapsing-remitting (RR) patients. sICAM-1 levels were significantly (P = 0.0009) higher in the `clinically active' group (No 22) than in the `clinically inactive' (No 27), whereas no different values were found between patients with Gd-enhancing lesions at MRI (Gd-positive) (No 32) and patients without such lesions (Gd-negative) (No 17) independently of their clinical activity. Among the `clinically active' MS, the Gd-positive (No 16) subgroup showed significant (P50.05) lower sICAM-1 levels when compared to the Gd-negative (No 6) subgroup, but higher (P = 0.009) than those of the `clinically inactive Gd-positive' (No 16) patients. The sICAM-1 levels did not differ between the two `clinically inactive' subgroups Gd-positive (No 16) and Gd-negative (No 11). Finally the clinically active Gd-negative (No 6) showed sICAM-1 levels higher (P = 0.002) than the clinically inactive Gd-negative (No 11). The specificity of high serum sICAM-1 levels (above M+2 s.d. of control values) to assess the disease activity in MS resulted higher (100%) using clinical than Gd-MRI activity (76%) as gold standard. The changes induced by 1 year recombinant Interferon-b-1b (rIFNb-1b) treatment on sICAM- 1 serum levels were also longitudinally investigated in 36 of the 49 RR MS. sICAM-1 levels at baseline significantly increased in the first 2 months (baseline vs 1st month P50.0001 and 1st vs 2nd month P=0.02), persisted at high levels without any significant change after 3 months, showed a temporary decrease at 6 months, then significantly increased again at 9 and 12 months. Fourteen patients experienced relapses, with a total of 20 relapses, during the whole treatment duration. The mean relapse/rate and the frequency of patients with Gd-positive MRI scans resulted significantly higher in the first semester compared to the second semester of treatment. This study adds further insights into the validity of serum sICAM-1 to assess disease activity in MS and on the immunomodulatory properties of rIFNβ-1b.

Patients with writer's cramp present sensory and representational abnormalities relevant to motor control, such as impairment in the temporal discrimination between tactile stimuli and in pure motor imagery tasks, like the mental rotation of corporeal and inanimate objects. However, only limited information is available on the ability of patients with dystonia to process the time-dependent features (e.g. speed) of movement in real time. The processing of time-dependent features of movement has a crucial role in predicting whether the outcome of a complex motor sequence, such as handwriting or playing a musical passage, will be consistent with its ultimate goal, or results instead in an execution error. In this study, we sought to evaluate the implicit ability to perceive the temporal outcome of different movements in a group of patients with writer's cramp. Fourteen patients affected by writer's cramp in the right hand and 17 age- and gender-matched healthy subjects were recruited for the study. Subjects were asked to perform a temporal expectation task by predicting the end of visually perceived human body motion (handwriting, i.e. the action performed by the human body segment specifically affected by writer's cramp) or inanimate object motion (a moving circle reaching a spatial target). Videos representing movements were shown in full before experimental trials; the actual tasks consisted of watching the same videos, but interrupted after a variable interval ('pre-dark') from its onset by a dark interval of variable duration. During the 'dark' interval, subjects were asked to indicate when the movement represented in the video reached its end by clicking on the space bar of the keyboard. We also included a visual working memory task. Performance on the timing task was analysed measuring the absolute value of timing error, the coefficient of variability and the percentage of anticipation responses. Patients with writer's cramp exhibited greater absolute timing error compared with control subjects in the human body motion task (whereas no difference was observed in the inanimate object motion task). No effect of group was documented on the visual working memory tasks. Absolute timing error on the human body motion task did not significantly correlate with symptom severity, disease duration or writing speed. Our findings suggest an alteration of the writing movement representation at a central level and are consistent with the view that dystonia is not a purely motor disorder, but it also involves non-motor (sensory, cognitive) aspects related to movement processing and planning.

Objective: To study the reliability of the diagnosis of blepharospasm, oromandibular dystonia, cervical dystonia, and writer9s cramp among neurologists. Methods: 12 patients with adult onset focal segmental dystonia were videotaped in a standardised way. The tape was sent to six neurologists who are involved in clinical practice without a specific interest in movement disorders (general neurologists), and to four neurologists expert in movement disorders. The observers had to recognise whether the patients were affected by dystonia and to distinguish among blepharospasm, oromandibular dystonia, cervical dystonia, and writer9s cramp. Interobserver reliability was assessed by κ statistics, and the degree of agreement was classified according to the Landis classification. Results: The 10 neurologists reached slight to moderate agreement on the diagnosis of these four disorders. When the observers were subdivided according with their professional experience in the field, a moderate to perfect agreement on the diagnosis was achieved by specialists in movement disorders, and a fair to moderate agreement by the general neurologists. Conclusions: Neurologists may have different ability to recognise adult onset focal dystonia, depending on their experience and on the type of dystonia.

The reliability of a scale of 0 to 4 (where 0 is normal) in rating the severity of blepharospasm (BS) and oromandibular dystonia (OMD) was evaluated by the concordance among six neurologists from different neurological institutions. As expressed by k index, interobserver agreement was moderate either for BS or for OMD according to the Landis classification. Neurologists showed different rating attitude towards BS and OMD. In fact, the category analysis showed that raters were inclined to overestimate BS and to underestimate OMD. The familiarity with dystonia influenced reliability more than the length of professional experience in neurology. In fact, when examiners were subdivided into subgroups (each of three raters) according to the former criteria, the level of interobserver agreement increased significantly. Almost perfect agreement was obtained in intrarater comparisons. These results may be of value with regard to the conduct of multicenter epidemiologic and clinical studies on focal dystonias.

Despite the growing number of reports describing adult-onset primary lower limb dystonia (LLD) this entity has never been systematically evaluated in the general population of patients with primary adult-onset dystonia.From outpatients with adult-onset primary dystonia attending nine Italian University centres for movement disorders we consecutively recruited 579 patients to undergo a standardized clinical evaluation.Of the 579 patients assessed, 11 (1.9%) (8 women, 3 men) had LLD, either alone (n = 4, 0.7%) or as part of a segmental/multifocal dystonia (n = 7, 1.2%). The age at onset of LLD (47.9 +/- 17 years) was significantly lower than the age at onset of cranial dystonias (57.9 +/- 10.7 years for blepharospasm, and 58.9 +/- 11.8 years for oromandibular dystonia) but similar to that of all the other adult-onset primary dystonias. The lower limb was either the site of dystonia onset (36.4%) or the site of dystonia spread (63.6%). In patients in whom LLD was a site of spread, dystonia seemed to spread following a somatotopic distribution. Only one patient reported a recent trauma involving the lower limb whereas 36.4% of the patients reported pain at the site of LLD. Only 64% of our patients needed treatment for LLD, and similarly to previously reported cases, the most frequently tried treatments was botulinum toxin and trihexyphenidyl.The lower limb is an uncommon but possible topographical site of dystonia in adulthood that should be kept in consideration during clinical evaluation.

Sleep disturbances are common in patients with movement disorders. Evaluating quality of sleep is of primary importance because of the effect that nocturnal and daytime sleep abnormalities exert on general health status. However, quality of sleep has never been addressed in detail in patients with dystonia. The aim of this case-control study was to analyse quality of sleep in patients with the two most common forms of primary focal dystonia, blepharospasm (BSP) and cervical dystonia (CD).We evaluated quality of sleep (Pittsburgh Sleep Quality Index, PSQI) and excessive daytime sleepiness (Epworth Sleepiness Scale, ESS) in 98 patients with focal adult-onset dystonia (52 with BSP; 46 with CD) and in a group of 56 age-and gender-matched healthy subjects. The Beck Depression Inventory (BDI) was used for the evaluation of depressive symptomatology.Quality of sleep was impaired (significantly higher PSQI scores) in both groups of patients. However, differences in PSQI scores between patients with CD and control subjects were partly confounded by BDI scores, whereas differences in PSQI scores between patients with BSP and control subjects were not influenced by BDI. Excessive daytime sleepiness was not significantly more frequent than in control subjects in either patients with BSP or patients with CD.This study suggests that the assessment and treatment of insomnia-related complaints should be considered in global management plans of patients with focal dystonia, particularly in those affected by BSP.

Anti-basal ganglia antibodies (ABGAs) have been suggested to be a hallmark of autoimmunity in Gilles de la Tourette's syndrome (GTS), possibly related to prior exposure to streptococcal infection. In order to detect whether the presence of ABGAs was associated with subtle structural changes in GTS, whole-brain analysis using independent sets of T(1) and diffusion tensor imaging MRI-based methods were performed on 22 adults with GTS with (n = 9) and without (n = 13) detectable ABGAs in the serum. Voxel-based morphometry analysis failed to detect any significant difference in grey matter density between ABGA-positive and ABGA-negative groups in caudate nuclei, putamina, thalami and frontal lobes. These results suggest that ABGA synthesis is not related to structural changes in grey and white matter (detectable with these methods) within frontostriatal circuits.

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. 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

To study the association of pain with motor complications in 117 patients with Parkinson's disease.Patients were asked to refer any pain they experienced at the time of study and lasting since at least 2 months. Basic parkinsonian signs and motor complications (including motor fluctuations and dyskinesia) were assessed and Unified Parkinson's Disease Rating Scale (UPDRS) motor score part III (during on) and part IV were calculated. Information on age, sex, duration of disease, use of dopamine agonists and levodopa, years of levodopa treatment and current levodopa dosage, medical conditions possibly associated with pain, and depression were collected. Single and multiple explanatory variable logistic regression models were used to check the association of pain with the investigated variables.Pain was described by 47 patients (40%) and could be classified into dystonic (n.19) and non dystonic pain (n.16); in 12 patients both types coexisted. Multiple explanatory variable logistic regression models indicated a significant association of pain with motor complications (adjusted OR, 5.7; 95% CI, 2 to 16.5; p = 0.001). No association was found between pain, dystonic or non dystonic, and the other investigated variables including medical conditions known to be associated to pain in the general population. There was a significant correlation (r = 0.31, p0.05) between severity of pain (measured on a Visual Analogue Scale) and severity of motor complications (UPDRS part IV).Pain may be a representative feature of Parkinson's disease frequently associated with motor complications. The association is independent of a number of potentially relevant demographic and clinical variables.

Background: Previous family studies provided evidence that blepharospasm (BSP) can aggregate in families but did not give accurate and reliable information on the characteristics and degree of familial clustering. Aim: To evaluate the proportion of familial and non-familial BSP cases, the clinical expression of dystonia within families, the inheritance pattern, and the extent of penetrance. Methods: The study was based on the examination of the first degree relatives of 56 probands with primary BSP. Results: The 56 families produced a potential population of 436 first degree relatives of whom 296 were alive and 233 were examined. The proportion of index patients with at least one first degree relative affected by BSP, or adult onset dystonia other than BSP, was 27%. There was a remarkable degree of phenotypic variability of dystonia within families. Similar segregation ratios were calculated for probands’ siblings and children. Under the assumption of autosomal dominant transmission of adult onset dystonia, penetrance was about 20%. Conclusions: The findings of this family study are relevant for accurately counselling the families of patients with BSP and may help identify the most appropriate study design to explore genetic susceptibility in BSP.

Sydenham's chorea (SC) became a well defined nosological entity only during the second half of the nineteenth century. Such progress was promoted by the availability of large clinical series provided by newly founded paediatric hospitals. This paper analyses the demographic and clinical features of patients with chorea admitted to the first British paediatric hospital (the Hospital for Sick Children, Great Ormond Street, London) between 1852 and 1936. The seasonal and demographic characteristics of SC during this time appear strikingly similar to those observed today, and witness the introduction of modern "statistically averaging" techniques in the approach to complex paediatric syndromes. Great Ormond Street (GOS) hospital case notes provide detailed descriptions of the "typical cases" of SC, and show that British physicians working in the early age of paediatric hospitals succeeded in recognising the most distinctive clinical features of this fascinating condition.

We quantified Italian researchers' share of the scientific papers published in peer-reviewed medical Journals in the field of neurology in 2003 and 2004. The findings show that Italian researchers' gained an overall 7% share of peer-reviewed articles. This percentage places Italy in fourth place immediately after the United States, Great Britain and Germany.

Fatigue is a recognized problem in Parkinson’s disease and other clinical conditions. We characterized this symptom in 19 patients and 19 age- and sex-matched controls, using the Multidimensional Fatigue Inventory (MFI) and the Geriatric Depression Scale. Fatigue may be an independent symptom in Parkinson’s disease, frequently associated with depression. Our analysis showed the usefulness of the MFI in discriminating between different dimensions of fatigue for a better therapeutic approach.

Family history of definite/probable dystonia was studied in 36 probands with primary adult-onset cranial/cervical dystonia. Of the 157 relatives who were examined, 8 from 7 families and 11 from 10 families were diagnosed as having definite or probable dystonia, respectively. The frequency of familial occurrence of definite dystonia was 19.4%, 33% when considering both definite and probable dystonia. There was a tendency for relatives affected by either definite or probable dystonia to have the same type of dystonia as the index patient. Similar segregation ratios were found for parents, siblings, and children with either definite or probable dystonia. These observations raise the possibility that probable dystonia represents formes frustes/mild phenotypes of dystonia rather than another movement disorder.

To investigate the association between primary hemifacial spasm and arterial hypertension.114 patients with primary hemifacial spasm and 228 neurological controls, matched for age, sex, and referral centre, were recruited during an 18 month period from consecutive outpatients attending two neurological institutions.The association between exposure variables and case/control status was examined in conditional logistic regression models, adjusting simultaneously for disease duration and education level.Hypertension was more common among the patients with primary hemifacial spasm than among the controls. The association was independent of age, disease duration, years of schooling, and other diseases (adjusted odds ratio (OR) 2.76 (95% confidence interval (CI), 1.43 to 5.33); p = 0.002). Hypertension was associated with hemifacial spasm in both the left sided group (adjusted OR, 2.76 (1.18 to 6.44); p = 0.02) and the right sided group (adjusted OR, 3.02 (1.13 to 8.1); p = 0.03). The association of hypertension with hemifacial spasm was apparently greater in the age group60 years (adjusted OR, 4.2 (1.4 to 12); p = 0.008) than in the age group/= 60 years (adjusted OR, 2.5 (CI 1.3 to 4.6); p = 0.005), but the difference in the OR estimates between the two age groups was not significant. Among hypertensive patients, mean age at the diagnosis of hypertension was significantly lower than mean age at the onset of hemifacial spasm in the age group/= 60 years, but not significantly different in the age group60 years.The findings support the hypothesised association of primary hemifacial spasm with hypertension and raise the possibility that a different mechanism underlies the association in different age groups.

Single-voxel proton magnetic resonance spectroscopy (1H-MRS), localised to the basal ganglia, was used to determine changes in metabolite levels in idiopathic spasmodic torticollis (IST). We examined nine patients and 13 healthy subjects. The mean values (+/- SD) of peak area ratios were: IST: N-acetyl-aspartate (NAA)/choline-containing compounds (Cho) 1.79 +/- 0.39, NAA/creatine and phosphocreatine compounds (Cr) 1.61 +/- 0.38, Cho/Cr 0.91 +/- 0.19; controls: NAA/Cho 2.07 +/- 0.35, NAA/ Cr 1.82 +/- 0.31, Cho/Cr 0.89 +/- 0.12. Statistical analysis showed that NAA/Cho and NAA/Cr were significantly lower in patients than in controls (P = 0.0304 and 0.0431, respectively). These results indicate a reduction in NAA, and suggest striatal involvement in the pathogenesis IST.

DNA-dependent protein kinase (DNA-PK) is involved in joining DNA double-strand breaks induced by ionizing radiation or V(D)J recombination. The kinase is activated by DNA ends and composed of a DNA binding subunit, Ku, and a catalytic subunit, DNA-PK(CS). To define the DNA structure required for kinase activation, we synthesized a series of DNA molecules and tested their interactions with purified DNA-PK(CS). The addition of unpaired single strands to blunt DNA ends increased binding and activation of the kinase. When single-stranded loops were added to the DNA ends, binding was preserved, but kinase activation was severely reduced. Obstruction of DNA ends by streptavidin reduced both binding and activation of the kinase. Significantly, short single-stranded oligonucleotides of 3-10 bases were capable of activating DNA-PK(CS). Taken together, these data indicate that kinase activation involves a specific interaction with free single-stranded DNA ends. The structure of DNA-PK(CS) contains an open channel large enough for double-stranded DNA and an adjacent enclosed cavity with the dimensions of single-stranded DNA. The data presented here support a model in which duplex DNA binds to the open channel, and a single-stranded DNA end is inserted into the enclosed cavity to activate the kinase.

The validity of serum sICAM-I levels to assess Multiple Sclerosis (MS) activity was evaluated in 49 untreated definite relapsing-remitting (RR) patients. sICAM-I levels were significantly (P = 0.0009) higher in the 'clinically active' group (No 22) than in the 'clinically inactive' (No 27), whereas no different values were found between patients with Gd-enhancing lesions at MRI (Gd-positive) (No 32) and patients without such lesions (Gd-negative) (No 17) independently of their clinical activity. Among the 'clinically active' MS, the Gd-positive (No 16) subgroup showed significant (P0.05) lower sICAM-I levels when compared to the Gd-negative (No 6) subgroup, but higher (P = 0.009) than those of the 'clinically inactive Gd-positive' (No 16) patients. The sICAM-I levels did not differ between the two 'clinically inactive' subgroups Gd-positive (No 16) and Gd-negative (No 11). Finally the clinically active Gd-negative (No 6) showed sICAM-I levels higher (P = 0.002) than the clinically inactive Gd-negative (No 11). The specificity of high serum sICAM-I levels (above M +/- 2 s.d. of control values) to assess the disease activity in MS resulted higher (100%) using clinical than Gd-MRI activity (76%) as gold standard. The changes induced by 1 year recombinant Interferon-beta-Ib (rIFN beta-Ib) treatment on sICAM-I serum levels were also longitudinally investigated in 36 of the 49 RR MS. sICAM-I levels at baseline significantly increased in the first 2 months (baseline vs 1st month P0.0001 and 1st vs 2nd month P = 0.02), persisted at high levels without any significant change after 3 months, showed a temporary decrease at 6 months, then significantly increased again at 9 and 12 months. Fourteen patients experienced relapses, with a total of 20 relapses, during the whole treatment duration. The mean relapse/rate and the frequency of patients with Gd-positive MRI scans resulted significantly higher in the first semester compared to the second semester of treatment. This study adds further insights into the validity of serum sICAM-I to assess disease activity in MS and on the immunomodulatory properties of rIFN beta-Ib.

Single-volume proton magnetic resonance spectroscopy, localized to basal ganglia, was carried out in 10 patients with primary blepharospasm (PB) to assess the levels of N-acetyl aspartate (NAA), creatine-phosphocreatine, and choline-containing compounds. NAA was reduced significantly in patients compared with control subjects. This result suggests a striatal neuronal loss in PB.

Since its introduction in the early '80s the use of botulinum toxin has improved the quality of life of the patients affected by movement disorders. Toxin's neuromuscular blocking action allows a symptomatic treatment of those clinical conditions characterised by excessive muscular activity. Although the dosages used are safe and the side-effects are reversible, a correct use of botulinum toxin depends on the knowledge of its clinical pharmacology and of the anatomy of the body segments to be injected. In addition, the treatment of more complex conditions, i.e. laringeal dystonia, imposes an inter-disciplinary approach and specialised injection techniques. In this review, the Italian Study Group on Movement Disorders presents the consensus guidelines for the therapeutic use of botulinum toxin in movement disorders. The main toxin types, their use and administration modalities, and the training guidelines will be presented.

Botulinum-A toxin (botAtox) was used in the treatment of blepharospasm (BS), idiopathic hemifacial spasm (HFS), idiopathic spasmodic torticollis (ST) and apraxia of eyelid opening (AEO). The injection of 7.5–30 U botAtox per eye spread over 3 or 4 sites in the palpebral part of orbicularis palpebrae (OP) reduced palpebral spasm in 12/13 cases of BS and in 7/8 cases of HFS. The effect lasted for 14.5 weeks on average (range 4–30 weeks). Palpebral ptosis (lasting 1–3 weeks) was the most frequent side effect (16/107 eyes treated) but was not related to dose of botAtox or number of inoculation sites. Injection of 60–160 U botAtox into the sternocleidomastoid, trapezius and splenius capitis muscles reduced ST objectively in 1/4 patients for about 4 weeks. In the other patients the reduction or abolition of the hypertrophy of the previous hyperactive muscles was accompanied by persistence or rearrangement of the dystonia pattern, suggesting a change in the pattern of activity of the neck muscles after botAtox. 5 U botAtox per eye spread over 4 sites in the OP significantly reduced the frequency of the episodes of involuntary eyelid closure in 2 patients with AEO but not BS. The therapeutic effect lasted for 7 months after the first treatment and for 8 months after the second in a 46 year old woman with a 6 month history while the second patient (72 year old parkinsonian) has now completed her 3rd month of treatment.